Viewing entries in
Bioethics

Understanding transhumanism

Understanding transhumanism

Last weekend, I featured in an article by Robin McKie on transhumanism, following Wellcome awarding their annual book prize to Mark O'Connell for his 'To be a machine'. It's a really great article, but I've a few things to add based on some of the responses I've seen online and will make a podcast about it over the next couple of weeks. In the meantime, here's the article. 

Also, if you want a deep dive into this, check out something I wrote a few years ago, which draws together some related ideas on posthumanism and cyborgs.

 

GATTACA 20 years later

GATTACA 20 years later

Here's the final edit of the event, created by Luke....

 

Last week, I took part in a debate hosted by Luke Robert Mason of Virtual Futures, which focused on the legacy and impact of GATTACA. We covered everything from CRISPR Cas9 to film theory and the challenge of speculative ethics. 

It was fantastic to have put this together with Luke, as the film is such a remarkable examination of a potential future, where the prospect of genetic perfection is taken seriously. Having worked in bioethics for nearly 20 years now, it feels still like a really pressing subject, which we haven't quite figured out still.

 

Digital Health

Digital Health

Last week, I was in Bath for an ESRC seminar about Digital Health and the Older Generation, set up by Cassie Phoenix. Within my closing talk for the day, I was able to get into the many ways that healthcare is being transformed through digital systems, mobile culture, artificial intelligence, and ingestible sensors. The latest article I wrote on this was published in Health Sociology Review and is with my colleague Dr Emma Rich, with whom we presently have a Wellcome Trust grant to explore how young people use digital environments to make sense of health.

NanoEthics

NanoEthics

This year, I am delighted to be joining the Editorial Board of NanoEthics, edited by Christopher Coenen. It has a fantastic back catalogue of really provocative articles on cutting edge issues in ethics and I look forward to reading submissions in the future! Here's an overview of what it does:

Nanoscale technologies are surrounded by both hype and fear. Optimists suggest they are desperately needed to solve problems of terrorism, global warming, clean water, land degradation and public health. Pessimists fear the loss of privacy and autonomy, "grey goo" and weapons of mass destruction, and unforeseen environmental and health risks. Concern over fair distribution of the costs and benefits of nanotechnology is also rising.
Introduced in 2007, NanoEthics: Ethics for Technologies that Converge at the Nanoscale provides a needed forum for informed discussion of ethical and social concerns related to nanotechnology, and a counterbalance to fragmented popular discussion.
While the central focus of the journal is on ethical issues, discussion extends to the physical, biological and social sciences and the law. NanoEthics provides a philosophically and scientifically rigorous examination of ethical and societal considerations and policy concerns raised by nanotechnology. 

How artificial intelligence could provide some respite for the NHS

How artificial intelligence could provide some respite for the NHS

How artificial intelligence could provide some respite for the NHS

Emma Rich, University of Bath and Andy Miah, University of Salford

The NHS recently announced plans to trial an artificially intelligent mobile health app to a million people in London. The aim is to help diagnose and treat patients by engaging them in a real time text message conversation which will complement the NHS 111 phone based service (which was criticised by the Care Quality Commission watchdog). The app’s designers, Babylon Healthcare Ltd, use algorithms to make initial diagnoses which are then followed up with human consultations. It has already received a glowing CQC evaluation.

The app is likely to provoke a mixed response, with enthusiastic technophiles up against those concerned that more technology means a less human healthcare service. Yet, with the NHS being described as suffering from a humanitarian crisis, and with a growing healthcare burden and limited resources, some smart solutions are needed. It is hard to deny that problems of limited funding are enduring features of this unique public service. Perhaps AI has the answer.

In fact, providing effective healthcare is always a combination of systematised technological efficiency combined with patient centred human care. Polarised views on technology are often not helpful. It’s also necessary to recognise how this approach to healthcare is part of a wider technical revolution in which connected objects in the Internet of Things will change everything from healthcare to traffic maintenance.

The NHS app is really simple to use and has been likened to using the social messaging service WhatsApp – but with one crucial difference: you are chatting with a computer, not a person. Once the app is downloaded, you log your basic health information, and then start explaining your symptoms. The robotic “responder” will say things like: “I just need a few details from you before we get started,” and “nearly there” to keep the conversation going. After a more detailed exchange, it might come to a conclusion along these lines:

Ok so your symptoms don’t sound urgent, but I think they require further investigation. Make sure you arrange a consultation with a GP within the next two weeks. If left, symptoms like yours can become more serious, so book now while you remember and I’ll remind you closer to the time. If things change in the meantime and you become more unwell, speak to a doctor as soon as you can.

This digital diagnosis service intends to provide an additional communication tool between the NHS and patients. It it part of a broader ecosystem of digital health services which include online health tracking. Also, the app takes advantage of the fact that some people these days are likely to be more comfortable chatting by text than they are with talking on the phone.

This digital phenomenon is driven by the promise of a wider technological fix to social problems. Applications within healthcare could bring about big wins for society, where the functionality of the device is made all the more efficient by the aggregation of “big data” that it generates. Tech firm Babylon is joined by other big players seeking to do similar things, such as Google’s Deep Mind, which wants to mine NHS data to to enable earlier diagnoses for example, or to achieve more effective monitoring of treatments.

At the world’s largest tech expo in Las Vegas at the start of 2017, home AI systems have been one of the biggest hits. So perhaps the NHS has found an intelligent solution at just the right time. People may now be far more willing to have a “relationship” with an attentive machine than a call centre drone.

Digital doctor

Driving these developments is the assumption that, within a digital knowledge economy, these forms of communication can offer more neutral and accurate responses, circumventing human error. Yet, scholars within the emerging field of critical digital health studies suggest that algorithms must be understood as part of a complex network of interconnections between human and non-human actors. A recent study comparing physician and computer diagnostic accuracy revealed that doctors “vastly outperformed” algorithms

So we need to ask some key questions about the assimilation of AI into healthcare. How do people make sense of the list of possible diagnoses they receive from the machine? Will people follow the advice, or trust it? How will AI need to be tailored to accommodate human variation, by geography, capacity, or cultural identity. Another important aspect of this trial will be the consideration given to the backgrounds of the users. Given enduring concerns about inequalities of digital access and digital literacy, trials for future digital health tech need to be conducted amongst those populations with limited resources, experiences, and technological infrastructure.

Perhaps the biggest question we face in a world where ever more of our data is locked up in the mobile app environment, is over the proprietary and privacy of our data. How can we ensure that we have the freedom to move our health data around, over time, and ensure that it is safe and secure? We may need a new Bill of Health Data Rights to underpin and limit their exploitation of our data, and work on this must start now.

The Conversation

Emma Rich, Reader, Department for Health, University of Bath and Andy Miah, Chair in Science Communication & Future Media, University of Salford

This article was originally published on The Conversation. Read the original article.

Media, Ethics, & Dementia

Media, Ethics, & Dementia

This week, I took part in a dinner debate about media, ethics, and dementia. The conversation was run by the Dementia Festival of ideas, a year-long programme of events designed to interrogate key issues in dementia studies and research, along with an exploration of how to create novel forms of public engagement and public responsibility around the subjects. The debate took place with a range of experts fom different areas of interest, from journalism to medical ethics and was a really far reaching discussion. What struck me is how much has yet to be done, to ensure that care is adequate, and that social stigma around dementia is challenged.

Some possible interventions will follow from this event, including finding a way to empower families of suffers to take more decisive action to influence best practice and care within hospitals, along with developing a university alliance that can take strategic action in influencing policy, agenda setting, and generating research funds.

 

How to make your own superhero

How to make your own superhero

Screen-Shot-2014-05-09-at-11.00.51-PM.png

It is a rare thing for me to be invited to speak at a Science Fiction convention, but this year I was asked to present my research within the George Hay memorial lecture slot within this Easter science fiction convention. It was a real delight to be present at this meeting and I had such a great time. I hope I get asked again some time soon! My talk was titled 'How to make your own superhero: Science, Morality and the Politics of Human Enhancement,' and it was especially nice because the event took place in Glasgow.  

Justifying Human Enhancement: The Case for Posthumanity

Justifying Human Enhancement: The Case for Posthumanity

Screen-Shot-2013-07-08-at-10.36.04-AM.png

Presentation given for the 'Imagining the (Post-) Human Future: Meaning, Critique, and Consequences.

Along with the manuscript...

This paper argues on behalf of a posthuman future that is intimately tied to the use of human enhancement technology. It presents three principal justifications for enhancement, which focus on functionality, creative expression, and the ritual of re-making the self through biological modification. Collectively, these aspirations articulate the values surrounding posthuman life and the pursuit of biocultural capital. 

When Christopher told me I would have the opening slot for the conference, I thought there was some merit in trying to deliver a polemic that would set the tone for our subsequent discussions. In part, this is why I decided to consider arguing on behalf of a posthuman existence, as it seems to me to be the most crucial dimension of what we need to consider, in order for this debate to have any merit. After all, if we are not prepared to embrace a posthuman life, then we may as well go home. That’s not to say we all need to embrace own inner posthuman for the project of posthumanism to have merit. Rather, if we conclude that posthumanism is a topic of no political or social urgency, then its currency as a contemporary debate is lost. Indeed, within some applied context, this is catastrophic, as it is a way for the professions to dismiss or ignore the long term implications of their work.

I want to present the case for thinking of ourselves as already posthuman and consider that the pursuit of human enhancements are a definingfeature of that life. One of the rather awkward questions one faces upon making such a statement is ‘when exactly did we become posthuman’, either that or, scholars conclude we have always been posthuman, or – even worse – we have never been human.

Other moral philosophers critique the idea of humanness at all as a defining characteristic of our species, utilizing the concept of ‘personhood’ as a non-speciesist, richer interpretation of the sentient condition, even affording similar moral status to animals, when they exhibit such intellectual capacities. Alternatively, some scholars appeal to such ideas as ‘dignity’ or capacities to experience certain second order psychological states, such as shame or embarrassment, as indicative of our uniqueness.

Moral philosophers have each employed these ideas to argue about a number of beginning and end of life issues, such as infanticide or assisted suicide. Indeed, bioethics has broadly been a place where this debate has found considerable traction, as many authors find themselves debating the merits of life and the conditions that give it value.

You might conclude already that, then, the debate about posthumanism need not be about human enhancements at all. Indeed, the literature outlines a much more complex set of relationship and behaviors that interpret the posthuman condition as intimately tied to discussions about our place within the ecosystem, rather than our identity as technological agents. Posthumanism may also be about the way in which human communities recognize the moral status of certain kinds of lives or lifestyles. For example, I think Chris Hables Gray’s appeal to ‘Cyborg Citizenship’ is crucially about the way that societies fail to give legitimacy to certain forms of sexual identity. We live in a world where still society is reticent to acknowledge the value of certain lifestyles and so posthumanism may be seen as a rejection of certain prejudices and be a project principally about the promotion of freedom of lifestyle. Indeed, I had a conversation last week about whether the contraceptive pill was a human enhancement or not. I think it is and we can debate why later, if you like.

I anticipate that many of the papers we hear over the next two days will explain just how much more complex is our relationship with posthumanism than we first imagined. When I think of this relationship, I draw on what Jacques Ellul refers to as la technique – that complex arrangement of technics, techniques and technologies through our humanness is made and remade. In this sense, being posthuman is to operatewithinthis complexity and to navigate through it, for better or worse.

Nevertheless, there seems something crucial to me about the human enhancement debate, as a defining characteristic of posthumanism and I don’t think I’m alone in making this case. Even authors who reject posthumanism as a worthy direction for humanity, recognize that this mau be the long term goal of Western science – Steve Fuller may talk to us more about that later (but that doesn’t mean I consider Steve as someone rejects his inner posthuman. Steve’s on Twitter for goodness sake.).

Recognising the human species as a ‘work in progress’ is inextricable from this project. However, it’s crucial that we understand the many ways in which human enhancement takes place and the broad social and cultural fascinations we may have with it. In this respect, I think we can identify at least three crucial trends that explain the pursuit of HE.

First, we can talk about the functional benefit that arises from human enhancement. Good examples of this are laser eye surgery, cognitive enhancers and gene transfer.

Second, we can discuss enhancements as a form of creative expression, as a way of exploring new aesthetic experiences. For example, we might look to make up as an early form of this, then to cosmetic surgery as a more radical and permanent change.

Third, we can talk about enhancements as rituals, as ways of marking out ourselves from others or as part of a community. Scarification, tattoo, and body piercing may be like this. More recent examples may ‘bagel heads’ in Japan.

There are examples that fit across these three types in different ways. For example, the use of LSD or other lifestyle drugs like ecstasy may be ways of trying to access new kinds of physical or mental experiences that could be seen as engaging all three of these parameters. If you take ecstasy when going to a nightclub, you might be seeking to enhance your capacity to dance all night.

Of course, many of these examples seem quite close to the present day. There is nothing controversial about laser eye surgery or body piercing.

Collectively, I want to talk about these values as indicative of how people pursue the accumulation of biocultural capital throughout their lives. Drawing on Bourdieu, it is apparent that we seek to enrich our lives today by modifying ourselves. We may have done this in the past by education or leisure. Each similarly reconfigures our mental and physical capacities, hopefully improving our lives by providing greater health or making us feel more capable.

Of course, there is no guarantee that they will, but we shouldn’t be too worried this. Those who argue against human enhancement, like Michael Hauskellar, seem to require us to have certainty over whether our choices will lead to an improvement in our circumstances. I can’t guarantee that. I can’t guarantee that your being able to run faster by genetically increasing your proportion of fast twitch muscle fibre count will mean that your life will be better off over all. Similarly, I can’t guarantee that having television, motor cars, or the telephone makes the world a better place or being human any richer. But we shouldn’t place too much stock in the critique from certainty. Most of what we do in life is a risk. We exercise judgment as to whether something will improve our lives in some way, or not and we for it. Sometimes it works out, other times it doesn’t. If you have a tattoo, there’s no guarantee that you won’t regret it when you are 60 years old.

So, why do I think the pursuit of HE is crucial to the case for posthumanity? Going back to the start of my talk, I wanted us to begin this inquiry by asking into the merit of a posthuman life. If we seek to live as posthumans, what ought that entail? How will we justify employing that term, rather than simply conclude that humans have always been on this trajectory – that what defines our species is this endless pursuit of pushing back the limits of biology and nature?

We have always done that, but if you look at the industries that guard against these posthumanist aspirations, they stillendeavor to stay at the top of the slippery slope, claiming that there are such things as biostatistical norms that explain why medicine should be used only for repair or therapy. They don’t.

Furthermore , we live in a world where such things as dwarf corn exist and where 66% of all cotton is genetically modified. Next year, the first commercial space flights will take place, while the ‘bottom billion’ people are still trying to get above the poverty line.

There is no selfless justification for pursuing longer, healthier lives, while millions of people barely have the resources to promote a healthy-ish lifestyle, or any reasonable expectation of living a long life. There is credible no system of justice that can reasonably argue that a broad social system that fails to protect fundamental needs is justified in trying to raise the upper level of human functioning. Indeed, the biggest collective human enhancement would arise from engaging more people in the democratic process, or in society generally. Providing greater chances to perform as citizens in a world where less than 20% of an electoral register turn up to vote would be a major enhancement for society ,the value of which is beyond measure.

But neither should we assume that these systems of human enhancement would be jeopardized or frustrated by their biotechnological counterparts, or vice versa. We should be vigilient over how such systems are used mosrly because of their efficiency, which may lead to us medicalizing certain problems or prioritizing a quick fix, rather than the best fix.

Yet, societies are moving targets. We edge closer to 9 billion people. James Lovelock – of Gaia theory – thought the planet should be able to sustain just 1 billion. So, we can’t look at the increase in people suffering as an explanation for the world having been made worse.

Neither can we assume that enhancements would benefit only the privileged few, as is commonly assumed. Some research that indicates that the larger benefits to enhancing IQ, for instance, are for those at the lower end of the income scale. Quite simply, being smarter improves your life.

But there are no guarantees that human enhancement will bring us happier lives as individuals. Being an ‘unhappy Socrates’ may be the consequence of our pursuit of betterment.

We ought not get too carried away with the idea that human enhancement is a project that seeks to pursue perfection or control. It is more likely to bring us more opportunities to screw up our lives, than greater certainty about it being better! But, I would rather have that opportunity, than to leave things to chance.

We do have to wise up. Last week, I had a conversation with a nutritional scientist and a dedicated body builder. The body builder asked the scientist which supplements he should be using to bulk up. He went through a list of the ones he had tried and, after each one, the scientists said ‘waste of time’ or ‘does nothing at all’.

So, it’s important we are not ignorant about what actually does what it says on the tin. We need to understand the limits of science and technology and the way that enhancement technologies operate within an unregulated commercial system that and may promise things it cannot deliver, yet. Genetic tests for performance genes claim to identify whether you are more likely to be good at one kind of sport over another, but presently they have no predictive value. Laser eye surgery promises High Definition vision, but only if you are lucky. Modafinil may boost your cognitive alertness, but only in certain situations and not necessarily in situations of high demand. In this sense, it may enhance your humanness, but may not be an enhancement of the human species as a whole.

I’m conscious of having just spent 20 minutes explaining the value of HE, but the last 5 telling you that nothing actually works and it may not be worth the bother! That’s not really how it is, but my main point is that we should not conclude that you can just download a mobile app for enhancement. (Although already people with prosthetic limbs are controlling them with mobile apps.)

Rather, any form of body modification operates within a complex system of experiences thatdetermine the value we attribute to it and derive from it. Moreover, we can’t expect enhancements to be universally sought, unless they are broadly pure biological dimensions, such as the pursuit of making our gums and teeth healthier by using fluoride in our tap water. When HE is like this, then it can be justified on the basis of promoting public health – and many examples may eventually be like this. After all, the WHO talks less about health and illness as a distinguishing factor in health care rationing decisions and much more about ‘well being’. Furthermore, doctors and scientists talk now of ageing as a disease. These shifts in belief systems are intimately tied to the human enhancement project. Recognising that life cannot be just about the alleviation of suffering is a crucial part of this.

So, the language of our posthuman future is already embedded into the professions, which previously just made us well, rather than ‘better than well’ as Peter Kramer’s patient put it when describing her state of health when using Prozac. The project of modern medicine has always led us towards human enhancement because of our desire to stave off death and promote freedom throughout life. Freedom from ill health or the debilitating limits of our bodies is, therefore, the principal justification for human enhancement and the most important argument on behalf of posthumanity. The expansion of this commitment to the eradication of all sufferingis a logical step, but we ought not presume to achieve this, or that life would be better if we could remove all of it. I’m not convinced that a life without suffering would be well lived. However, I do think we can shift the kind of suffering we experience away from that associated with biological illness and disease. Unlike Martha Nussbaum, I don’t believe in the goodness of our fragility.

In due course, the twenty first century may be likened to the swinging sixties, not for its sexual liberation, but for its anthropomorphic liberation. However, it’s important to remember, that the conventional explanation for the sexual revolution misleads us. For while many have tied it to the birth of the contraceptive pill, others point out it was the discovery of penicillin bringing about greater freedom from disease that was more crucial.

For the present day, it may not be the radical transhumanist technologies that usher in a posthuman present, not the botox parties, the cosmetic surgery, or the life extension. In other words, it may not be the pursuit of immortality that allows us to live forever

Instead, it might be the least technological innovations, like DNA biobanks for stem cell harvesting, or selecting out disabilities through PGD. It might be granting certain civil rights that gives birth to a posthuman generation, a generation less worried about the ‘yuck factor’ of biotechnological change; more willing to donate their organs to those in need; more likely to give blood.

This is my kind of posthuman future and throughout all of it, there is no loss of humanity one can presume. If anything, we will become more morally conscious agents.

Thank you very much.

Justifying Human Enhancement: The Accumulation of Biocultural Capital (2013)

Justifying Human Enhancement: The Accumulation of Biocultural Capital (2013)

Kraftwerk.png
Miah, A. (2013) Justifying Human Enhancement: The Accumulation of Biocultural Capital, in More, M. & Vita-More, N. The Transhumanist Reader: Classical and Contemporary Essays on the Science, Technology, and Philosophy of the Human Future, Wiley-Blackwell. MORE INFO

Here are the editors talking about the book...

Extract of my Chapter

The argument on behalf of biocultural capital claims that the pursuit of human enhancements is consistent with other ways in which people modify their lifestyles and is analogous in principle to buying a new mobile phone, learning a language, or exercising. It is a process of acquiring ideas, goods, assets, and experiences that distinguish one person from another, either as an individual or as a member of a community. While one might – and should - scrutinize the merits of such individual choices, we should recognize the limits of this task. Furthermore, the argument for biocultural capital considers that it is unreasonable for enhancement choices to be imposed upon individuals by the state. The normative transhumanist concept of morphological freedom emphasizes this prohibition. (More, 1993; Sandberg 2001) While general consensus on enhancements might have legal force, they will not necessarily have universal persuasive value – not everybody would wish to be tall, stronger, or whatever it may be - since enhancements only confer positive value within particular cultural contexts. As such, the precise value attached to any particular enhancement cannot be assumed to be a shared, universal good, particularly where choices of enhancements involve a trade-off.

The argument from biocultural capital explains that the designation of a biological modification as a human enhancement does not correspond with some prescribed or abstract value claim. There is no necessary “good” that, in itself, can be objectively identified to justify (or reject) enhancements. For instance, if I were to enhance the efficiency of my digestive system to allow me to assimilate foods that are generally shown to be unhealthy, it is difficult to argue that this is a tangible enhancement, other than through its allowing me to satisfy the desire of always wanting to eat foods that I find tasty but which would, otherwise, be unhealthy. While such a modification would be beneficial to me, it is unlikely to withstand the scrutiny of those who have no such desire. Such a choice also faces the criticism that one’s taste cannot develop in a positive sense if one closes off the potential to find value in experiencing other tastes. So, if I were a twelve year old and really like McDonald’s food, I might enjoy enhancing my metabolism to assimilate such food, rather than to treat it like junk food. In doing so, by failing to choose alternative foods, I also restrict the possibility of developing tastes for other foods.[7] Yet, again, it seems premature to panic too much about such a prospect. Rather, it may emerge that one’s taste develops alongside such new alternatives to consumption and that moderation will thus emerge.

Importantly, and as enshrined in the idea of morphological freedom, this argument on behalf of human enhancements does not extend to the freedom to modify others – for example, through genetically engineering embryos. Rather, this argument presents an initial position as to why certain obstacles towards human enhancement may be overcome by acknowledging the limits of concerns over rationalizing medical resources and avoiding a slippery slope towards undesirable circumstances, I have endeavored to explain the value of pursuing self-regarding, biological enhancements and, as such, to suggest why such freedom of choice should not be withheld.

In conclusion, asking why we should enhance ourselves limits the discussion prematurely. It prescribes a particular kind of moral justification, which would explain a choice that makes sense only in the particular case. However, treating such actions as micro-ethical processes, contrasts with the macro-ethical task of regulating the commercial and non-medical use of such interventions. In short, via this argument, one cannot offer a good reason for why all people should enhance themselves in a specific way, since each reason would require embedding the clause within a particular context that another individual might not deem to be valuable at all. So, understanding the value of improving attention span or enhancing sexual function would require understanding the specific context that give rise to such an interest. Instead, one may give reasons for why a motorcyclist might value an enhancement to protect the durability of her head, or why a ballerina might welcome enhanced strength in specific parts of her body, or why a mathematician or a chess player should value cognitive enhancements. These are all sensible human enhancements for particular kinds of people, but are not generally good enhancements for all kinds of people.

The rise of a privately funded human enhancement market and the possibility of commodifying life are each relevant moral concerns that should concern the governance of such industries.  While a publicly-funded system for human enhancements may be preferable to a privately-funded one, areas of human desire are always likely to outweigh the limited funds available to accommodate such desires on a nationally funded system, even if one can aspire to a certain level of social care throughout a population. As such, it is sensible to presume that a transhuman future will be brought about within a commercial structure, though as argued earlier there are reasons to presume that some forms of enhancement will eventually ease the burden on a national health care system, by ensuring more people are less vulnerable to common illnesses.

Can technology set you free?

Can technology set you free?

DSC_0721e.jpg

What: roundtable discussion, Battle of Ideas satellite eventWhen: 22 Nov, 2012 Where: Royal Academy of Engineering Who: Dr Mo Ibrahim of TIME's 100 most influential, Dr Aleks Krotoski of BBC Radio 4 tech fame and Chair David Bowden.

Institute for Ethics and Emerging Technologies (2006, May, Stanford Law School)

Stanford Law School Ron Bailey, Reason Magazine

Designer babies PGD Sex selection

Consent of unborn concern -    but nobody has consent over birth

‘much against my will’

ME: Is action done against those who cannot exercise will, an affront to it.

X-men enhanced vs naturals

People oft say what will happen to equality -    Bill McKibben: declaration of independence cant withstand equality -    Fukuyama:

Are people equal? -    nothing self-evident about this.

Political equality idea arise from enlightenment that nobody has truth

Political equality has never rested on playing to human biology

George Annas: ‘the new species or Posthuman will likely view the…. As …. The normals on the other hand may view the posthumans as….potential for genocide….makes weapons of mass desutrction’

Remind Annas that enlightenment people of tolerance.

Political liberalism is already answer

David DeGrazia -    are any X inviolable

no reason

expanding healthy human life spans

Erik Davis Author of ‘Techgnosis’

Not going to talk about normative concerns. Not interested in debate about enhancement

Interested to draw a space where all will be engaged in a way that is difficult, confusing, enlightening, etc.

‘the Posthuman condition’

attempt to explain an existential view of human acxtion, etc.

‘being unto death’ Heidegger. -    maybe we can change this now

whether or not I accept Ron’s arguments, I have to live in possibility that death as I imagine it is not going to work out that way

another aspect of human condition that doesn’t change: choice -    will still be faced with decisions

transhuman or poshuman?

I use post to invoke postmodern

One element of postmodern that has resonance: loss of grand narratives

Posthuman condition

The Matrix ‘red’ or ‘blue’ pill - choices

Why does morpheus offer a ‘pill’

Pharmacology offers way of grappling with Posthuman condition

Funl mistake that proenhanement make sometimes – confusing ends and means -    richness of means -    ie. End is more happiness, learn to live with my anxiety. I can take a pill or try something more tedius, like yoga, etc.

technologies that enhance abiliy to inquiry about Posthuman.

Hope we never lose process of inquiry when pursue more psychology good

Disenchantment of self and reimagining it

William Hurlbut New paradigm in medicine Gaylin: physician as nature’s assistant – old  paradigm Now freedom from natural life processes

If enhancement an increase then need guidance

Within frame of natural limitations, desire serve as purposeful passions

Gordon Lightfoot: think its  sin when I think I’m winning when I’m losing again.

Without considerable caution, might think we’re winning when we’re losing.

Conclusion: all enhancement might more rightly be recognised as diminishments. Might not mean that not useful

Need some sense of relationship between biotech and natural world – this relates to human good

Need ustdg and wisdom/character

Need to enhance capacity for wisdom and character

ME: my prob is that I don’t like the tone of any of these speakers

‘rising tide of freedom and peril’

need to step back into something rooted more in scientific evidence reflect on where we’ve come from be realistic about scientific meaning and reaslism of what we’re saying doubt much of what’s been referenced already is going to be scientifically feasible

matter, mechanism and meaning

fragile flexibility = life

marvel of life forms – specifically human

balance of body and being

‘embodied intelligent freedom’

reflect on this before seeking posthumans

we might be the ultimate formatio

plato: animals as degraded humans with specific functions

body is not equipment

are there no uses of enhancements? No. surely there are

surgeon using betablocker to steady hand. But you do these with a recognition that a higher good has been served.

Enhancement is a specialisation that XXXX with the world, but occassionalyl undergo alterations

What is a serious purpose?

Not too specific things. Not pleasure. Not competition.

If pleasure, then reduce to free-play – aesthetics of self. Using biologically driven resources to just enjoy. Nothing wrong with that, but deracinated is a great danger. And is trivialising, Nietzsche…

Competitive advantage seeking. Used for selfish ambition. Disrupts our deepest meaning.

We are creatures of the earth

Human word derives from earth

Humility also same root.

Be humble.

Questions and Answers

John Schlender, Arizona State Uni

John: are you asking whether I would give…..

John S: any therepy that can cure age related diseases and extend life span.

John: do I favour radical interventions in human life to increase life span? Very cautious, since level of operation would be disruptive to other purposes of human life. Rennard Hayflick says the reason we age is because we have complex biological systems which ultimately canot repair. Can we make magic bullet interventions. I don’t think so. We already are a specieis with an enhanced life span.rhesus macats already selected for longevity. Not convinced it will be easy. If there is a way consistent with human agency that enhances, then great. Not at cost of other phases of life.

Carl Jacksy, Uni of Washington: funl conservatism that all panels express. ‘adapt to the world’ ‘understanding’. If really about ethics and morality,not posthumanism, but postcapitalism. Never once has discussion fo changing political system. Issue of ludism – social structures need to change. Ultimatel ethical desirada is ecosystem that is 100% symbiotic and 0% parasidic. Marcuse: potential of human race not to dominate nature but transcend struggle for survival. People talk about life extneions as xXX, but majority of species on earth are physically immortal.

Erik: I was not calling for radical political transformation, buit invioking drugs as model, was to raise issue of consumerism, capital, etc. people here have a good sense of how decisions in pharma are driven by capital as well as ethics. But I don’t call for things, nor believe they are around the corner. But invoke impossibility of escaping these questions.

Ron: put in a good word for capitalism. Only social system that allows people to get above natural tate of poverty.

Jean Pierre de XX, Paris and Stanford Uni: respond to Erik Davis – vantage point of history of philosophy. If I heard correct, human condition defined by limitations of human possibilities. I think exactly contrary. Human condition when limits of human life strated to be seen not as lack, but as source of meaning. Kant. Heideggerian notion of being unto death. Recall Satre rejoinder to Heidegger: even if became immoral would remain finite, since condemned to be XXXX, to be free is to choose. The more open possibilities, the more finite – chnoice implies renouncing openness. Equation between choice and possiblitiy to overcome finiteness is dubious. If following satre, of course.

ME: if I’m hnst, I should even be speaking

Nick Bostrom: what are the costs of the surgeon using beta blockers.

Bill: when using a drug, effecting range of responses in body. either body accommodate, or provoke imbalance. Foundation of experience – don’t do interventions unless you need to do them. Not convinced that enhancements will effect desired ends or even reasonably feasible. What is evidence that Posthuman are better? There are obviously conditions that need counterbalancing, but what is the goal?

Ron: who is the we? Societal ‘we’ is very totalitarian. You doubt feasibility, so let us try. Don’t stop now. Humanity is terrible at foresight. Never been good at it.\

Wyre Sententia: choice and freedom. I know ron holds to idea of political liberalism. Potential of Erik’s discussion of grand and small narratives. Who will constrain? For what purpose? Douglas Ruskkoff, echoing Satre: defined more by technologies we choose not to use, rather than those that we do.

Erik: I know an electronic musician. I play acoustic guitar and is quite limited machine in formal characteristics. But if electronic musician today can spend limited mony and have range of capacities.

Bill: I do think there are some things we should tell our citizens that there are some things they can’t do. Germ-line intevention is a very bad idea.

Ron: but probably not in 50 years? Eugenics whether allow or restrict. Enhanced lives are not goalless. Eduardo Kac from Brasil, biotech artist – art gene put into e coli, then art gene in a dish and people could.

Claude XXX, Palo Alto: are you somewhat concerned that all these new powers could lead to a nightmare scenario, dictatorship wher government make decisions for people.

Ron: It has to be a concern. Surveillance technologies.

Erik: proximity to catastrophe is relevant. So many nightmare scenarios though.

XXX: what benefits would acrrue form enhancements. Previously, I evaluated ed programmes for disadvantaged. Yet after spending millions, effects not good. If I were parent of a kid, seems sad to me that many kids that have 2 strikes against them because they’ve lost in genetic lottery. How wonderful if could afford choice to do something about that. This is a good application of microeugenic choice.

Bill: what did you have in mind? Predesigning child to be smarter?

XXX: parent in annual wellness exam, might mention will have a child, and physician says we can evaluate eggs to see if there are eggs or sperm that are normal with regard to intelligence and we can allow you to select.

Bill: so, PGD

XXX: yes, but not just morphological, but actually inspection of genome.

Bill: what about improving genome in progress?

XXX: not sure.

Bill: so, selecting, rather than enhancing?

XXX: yes, first, not sure second.

Bill: so what is intelligence? We have standardised talent recognition. Many people who cant read well are more likely to be in jail than others. People on death row, many are dyslexics. So select out dyslexia? Well maybe, but maybe physiological – tendency to ear ache in early life. Trouble with this is that even if goal acceptable, what goes into intelligence is complex. Hundreds of gene. Multitrait loci. No one gene has 1-2% contribution of a given trait like intelligence. To improve must select complex number to select – eg 1,200 embryos. What’s the goal? So they can all go to Stanford!?

Ron: what you’re hoping for will be achiceved by neuropharmacology before embryo selection. People in memory field .

Bill: would these be drugs they take all the time?

Ron: XXX

Bill ??: how draw line between therapy and enhancement. Stronger immune systems. Bill, in your talk you spoke of Lennard Hayflick of ageing as breakdown of repair. How draw line? If you don’t draw the line, are you into enhancement?

Bill: I’m not a bioconservative. I’m from California. But conservation is a good word, when there is something worth conserving. Medicine is conservative. First principle ‘do no harm’. But first principle should be ‘stay away from docctors’, one in 6 is iatrogenic ‘caused by doc’. If non-invasive that doesn’t harm, I wouldn’t be against, but sceptical. Immune system is a balance – cant work out how to enhance it. We know of deficiencies. But with regard to gene thing, we should make it clear that genetic germline enhancements- genes are not legos. Every system we care about – beauty, intelligence- complex interactions of genes. If really try to bring about scenario, will need cloned human embryos and alter one at a time. Otherwise, natural selection could not predict. Multi body problem raised to nothing degree. This will all amount to experiments on human beings and don’t think we have entitlement to do that.

Ron: with regard to germline, they wont work now. Bioinformatics might produce enough info to simulate genome, interactions of proteins, etc.

Bill: let me correct that. Concordance of identical twins only 18% higher than fraternal. Misimpression that genes are determinate. The bioinformatics prob is so complex that cant do without known genome – so need cloned humans.we have false impressions about how genes work based on genetic diseae. But these are usually missing links in chain, but not just one trait, we just don’t analyse it that way in popular level. Polygenic inheritance means one gene affects many traits. I doubt bioinformatics will solve.

James, Sanfransciso: gentlemen from Washintgon answer question about where this is going – symbiotic rather than parasitic. Ref back to Matrix, agent compared human beings to a virus, uising up resources. Best estimates that lifeblood of oil runs out in a couple of decades. So, question: since 40years since outlaw of psychedelics, so what hindsight of that decision.

Ron: affront of human freedom. Stop drug war and help people who go too far.

YXXXX, Stanford student: ‘we humans might be highest form of physical form’. Something Nick Bostrom wrote on ‘reversal test’. Unlikelt in grand scheme that we are at a local optimum in this point in history. How respond to reversal test.

Bill: human beings are a marvel of balanced capacities. Hands as tool of tools. We could do better. Owls see better at night. But enhancing one thing upsets balance. I think about danger of being torn between arrogance and anxious striving. When ask what really makes people better? My thoughts aren’t something technological. But who is happiest? St Francis: recognised of natural value. Became weak to become strong. French theologian: man can recover true life…certain voluntary poverty is the condition for possessing the world in a way that will not reduce it to ashes.

Erik: I’m a melancholic Posthuman. I recog validity of human ways. Media.

ME: the charge of responsibility and its bearing on enhancement decisions.

Ron: we do have grand narratives: ending of poverty, suffering, etc.

Saturday

Enhancement and Human Rights Session

Why Human Rights are a problem for enhancement Patrick Hopkins

Right almost gives no carte blanche to harm others. Not absolute Alleged right to enhancement in appeal to autonomy no greater appeal than appeal to damgage oneself.

Extreme specificity of contemporary autonomy claims weaken it. Previously, autonomy meant something broader. In deontology, rights recognised some moral laws Autonomy in consequentialist meant that when authorities decided for us, they often got it wrong In none of these views was autonomy content free Autonomy required rationality. So, irrational choices had no validity. Autonomy = self lawed, not no lawed

How is enhancement reasonably way of pursuing interests.

Pro-enhancement crowd must ask what they want from enhancement. If power, gratification, etc, then less than human, not more.

To defend as a right, must be worthwhile, dignified and noble.

Chris Gray Cyborg technology had horrible possibility of taking what rights we have. Must make sure we don’t lose rights we currently enjoy. V good to have a philosophical understanding – or epistemological – but what’s really imp is how you have power in the world. Fact that we have rights now is that many people struggled for them.

Political systems are systems of discourse. Discourse of rights is a metarule Imp we mobiles this to keep freedom

Steve Mann –‘Digital Futures..’

Kevin Warwick says he’s a cyborg, but he isn’t.

Before right to enhance, right as normal citizen.

Epistemological – any imp question need this – how do you know what you know?

In this case, assumes what you need

Manfred Clynes

Goedl – showed mathematics was incomplete and/or imperfect

Church-turing thesis - incompetent

Understand human culture as a discourse. -    change discourse

smartest thing in the world is a community, much smarter than any individual

dialetic – thesis, antithesis, new synthesis

Nigel Cameron Associate Dean, Chicago College of Law

Author of ‘The NewMedicine’ And ‘Human Dignity in the Biotech Century’

(From Edinburgh in Scotland)

caveats of answers

identity complex questions

putative enhancement: proportionality enhancement

recog prob of drawing lines –eg between therapy and enhancement

nobody claims it is easy to draw such lines

role of policy inthis debate is complex naïve freedom of science argument

IRBs make life difficilt

Science constrained by social norms

A defining discussion about human future not easy to resolve.

Enhancement debates are surrogate to discussions about value of human – what is the good life?

This will be the dominating theme of the 21st century.

Questions and Answers

Positive and negative right distinc? David Calvery, Arizona State:

Wesley Smith, Weekly Standard: for Dr Gray:

GraY: proliferation of transhumans. May have its own problems.

Question: are human limits a threshold or a fn of technology and culture?

Gray: universal machine faces same problem. Infiinitte computer cannot understand world.

Carl chansky: human race has been involved in enhancement since time immemorial. Two phases: enhancement of muscular abilities. Now this is closed. We have infinitised our musculature.

Nigel: Much less concerned about steroids

Kirsten Rabe Smolensky

Assume intervention before birth Assume 2: germline not somatic Assume3: safe enough Assume4: intervention before born, resulting in outcome that they dislike and want to sue parents.

Eg. Superior athletic ability given and wanted superior musical ability.

Current state of tort law makes v unlikely that child could bring such a case

Tort Wrongful birth/death

Two potential claims

Wrongful life/birth: Least likely, but worth mention Current law:

Claim: you didn’t screen me when in womb and I have this condition because of that.

Generally not recognised in court, since would require court to accept better off dead than with condition.

Court disagrees.

Alternative: negligence claim.

Ot bring: Need duty of care. Breach of duty Breach must be proximate cause

Question of whether we owe foetus duty of care?

If someone hits pregnant woman and injures child, then potential negligence.

if pregnant woman in car and both damage, also independently liable to foetus

in some jursifactions parent can claim child cant sue.

Hewitt vs Jordan 1981, Mississippi – committed child. When got out sued parent. Disupts family harmony

ME: what is length of term a child would have to make such a claim? In uk, it’s 3 years after realisation or after 18.

Alternative: Negligence Claim

Is duty owed to foetus?

About 6 cases o prenatal harm -    where held: Groto v Grotom 1980, mother tetracycl…, discoloured teeth. -    In Michigan, willallow prenatal harm claims -    Bonti vs Bonti, 1992, New Hampshire: woman cross streetnegligently, hit by vehicle, foetus born, brought suit against mother. Court said mother was negligent. -    Vs. Norton trust bank, 2002, court of appeals, automobile, mother negligent driver, brorn, sued, only upto limits of mothers insurnance – suggests ok if someone else paying, but if from parents’ pocket, then no. -    In all cases, 3rd party tort. If allow 3rd party to be liable, then parents also. -    Also in places where parental tort almost abolished.

If genetically enhance child inappropriately, could be similarly negigleb as if had harmed

3 other cases

car accident case, cocaine using mother and car accident -    when courts focus on duty, say mother doesn’t have duty. If we control mother, then limiting her autonomy -    if recog duty to foetus, then limiting her capacities

genetic enhancement a  little dim -    at preimplantation stage, not changes by parent altering lifestyle. But actually choices of child before hand, which don’t necessarily affect mothers determiniation -    thus, potential court liability more likely

ME: in the case where an award was made, what was it for ‘diminished life’, harm?

ME: defensive medicine a consequence of this prospect? Ie. Genetic counsellor advising about risk. Is counsellor liable? Not so much parent’s being sued, but subsequently – they will act under the advice of health care professionals. Can the child sue the genetic engineer for ineffectiveness. Ie. I was supposed to get 2m legs, and they’re only 30cm, or something.

Defensive medicine concen – spinabifida, alters advice if prospect of being sued.

ME: eg of child who’s born with athletic genes but wants musical genes. Isn’t this too specific an articulation. Ie. No right to all enhancements. A better example might be muscle fibre type selection. Selecting a child with greater fasttwitch fibre types and they want to be a marathon runner, because this an ‘either/or’ decision. My having of fast limits my slow.

Genetic Engineering and the Consent of future generations Martin Gunderson

sceptical of deontological conservatism and consequential utopianism

doctrine of informed consent – not subhect to experiment/treatment without informed consent

Kantian notion of autonomy

Consent can change normative relations

Questions and Answers

Anita: consent issue. Issue is permitting parents to choose for their children. What are standards for surrogate consent.

James: concept of substituted judgmeent is time constraint and cultural constraint of knowl: standard of care.does concept of substituted judgement…at the time what parents were allowed to do.

Kirsten:

George: parent consent illusion. Gattaca, selecting genes. Over interiew, doctor is guiding them. Is this medical liability?

Kirsten: if child bring suit, probably also malpractice suit from parents on informed issue. Another issue is diff notions of informed consent.

ME: you mentioned tht child sues parent and gets money from insurance company. Is this a way of gaining additional support for people with disabilities? Ie. Is there an incentive for parent to take out insurance that would allow them to claim…

James: cant have consent without knowledge of informed consent.

Anders: difference between treatments outside … blur of zone.

Everybody is already different.

Standard body not only non-existent, but also atemporal.

The Right Not to be Normal as the Essence of Freedom Anita Silvers

Prosthetic used by cyclist

Whether lack of flesh enhances

Making better athlete

Equality of opp requires participation in social practices

Over last century commitment to equality of opp in USA has embraced diversity.

Some critics worry that enhancing lead to social inequality

Boil gifts.

Advantageous in some contexts, not others.

Don’t make people stronger, otherwise disabled will be even weaker, assumes what constitutes strength and weakness

Natural vs artificial – you cant go that way.

Whether boil differences are unfair

Assumption that we are naturally competitive.

Mistaken to assume this.

A lot of evolutionary biology that suggest this to be false

Just as likely to be naturally cooperative

So, if working in a group, don’t you want your colleagues to have strengths that you might not have?

Transhumanist continue to buy in to competitive theory

Enhance our ability to cooperate

Transhumanism and the O(/o)Ther Shannon Ramdin

Politics of technological empowerment

Are transhumanists colonial subject or object?

Haraway’s manifesto

James Hughes – WTA alls under liberal democratic transhumanism. Doesn’t mean not affiliated with radical.

Cyborgs and cytberspace connection.

Web not a new world, but reflection of non-virtual world.

Ever widening digtal divide.

Identity not invisible.

Transhuman technologies -    genome

inequalities exist in society

even when technology starts off

ME: why should we expect the Internet to be equally available?

Suffering bodily tolerances and enhancement discourse Jessica Cadwalladar Doctoral candidate critical cultural studies

suffering more than bodily pain

cast as most unquestionable, most natural

poststructuralist claim … to be natural has a number of effects -    places thing outside culture -    Haraway’s Primate Visions – natural as human and thus cultural description -    Patriarchy as natural state of being fed into studies of gorillas

Suffering is a politicised cultural space

Carl Elliott, Better than well Human growth hormone, used to treat shortness almost exclusively in boys Early years, debates about how to use. Some suggested that any boy in shortest 1% should be treated. Short men were observed to suffer following disadvantages – less good jobs, less long term relationships. But parents of boys who grow up to be short men didn’t care about reason, just wanted child not to suffer.

Suffering as trump card.

Yet, suffering not neutral either.

Occurs in relation to deviation from cultural norm.

Those who suffer because of a range of things, don’t suffer because it is natural for them to do so, but because cant fully achieve cultural norms

Taken on by subject.

Merleu ponty

Normal not natural, but conceptions

Pathological deviation from natural functioning

Deviance when not adhering to Norm Fost

Disability already marked as pathological, even in absence of disease.

Any kind fo corporeal difference is taken as diseae

Questions and Answers

ME: competitive with a small c and big C. is competitiveness necessarily a lack of care for one’s competitiveness. One can be competitive without having competitive anxiety.

Anita: what would it mean to engage the public?

Question: you all mentoned respecting difference. What is common ground on which we respect difference?  What is our common humanity?

Jessica: Dewey: there is a human nature, but it is built  by us.

Anita: where does the burden of proof lie? Why on those who accept difference who don’t even notice it. Example of student who probably had asbergers didn’t know this difference. Are we hardwired to attach certain kinds of difference? Lone wolves. Blind wolves are often lone wolves, because they attach the pack.

Jessica: I have major questions about individual liberty. I have a more inter-subjective view on how subjects come to be. People want to conform.

Of genes, bemes and conscious things: from transhuman enhancements to transbeman rights Martine Rothblartt Martine4@gmail.com

Problem/opptunity/solution

Bemes, like memes but cultural.

Beme mightier than gene

How do DNA and BNA matter? -    dna genes -    bna translated via neurochemistry or software

Our Right to Life: Life extension, human rights, and the rational refiniement of repugnance Aubrey de Grey

Structure of talk

Leon kass – credit where due

My flavour of non-cognitivism

Evidence from past precedent

Relevance to the (un)desirability of aging

Non-cog – no one true morality

Will aging become repugnant?

ME: it is already isn’t t?

Launch of James Martin Institute, Oxford University (2006, March)

Oxford forumOxford forum    1 Wednesday    2 Tom Kirkwood    2 Rally curing aging: the other sociological obstacle    4 Aubry DNJ de Grey    4 Jay Olshansky    5 How would you assess current aging research, and the prospects for significant breakthroughs in any of its major branches    5 Extending Life Span: Scientific prospects and political obstacles    7 Richard Miller    7 Discussant    9 Paul Hodge    9 Sarah Harper and Kenneth Howse    11 Is more life always a good thing?    11 Stronger?    14 Ellen Heber-Katz    15 Stem cell research and its ethical considerations in china    16 Pei Xuetao, Beijing institute of transfusion medicine, stem cell research center    16 Thursday    19 Cognitive Enhancement    19 Nick    19 Happier    21 Susan Greenfield    21 Professor Lord Richard Layard    23 nick baylis    23 Donald bruce    23 Fairer?    25 Enhancement and Fairness,    25 Julian Savulescu    25 When /if Longer, faster strong, smarter life is happier: reflectins on slower, sustainable and more inclusive life experiences    28 Anil Gupta    28 Gregor Wolbring    29 Enhancement, Justice and rights: immortality    29 John Harris    29 Utility pets    31 Elio caccavale    31 Governable?    31 Baroness Sally Greengross    31 Suzi Leather    32 Creativity and Governance    32 Christopher Newfield    32

Wednesday

845-1030

Tom Kirkwood Oeppen and Vaupel, Science, 2002 – shows continuing  increasee in life expectancy

Idea that ageing is genetically programmed is fundamentally wrong -    illustrated in 1950-s – david lack – zoology in oxford: wild animals never show any intrinsic sign of ageing, because they die young – do not have a chance to become old

thus, no potential…

peter medawa and george Williams

selection shadow – animals die young because environment is dangerous – don’t need to grow old

disposable soma theory – Kirkwood, nature 1977 -    animals invest only what they see to be necessary to remain competitive

how much should animals bother in maintaining and repair

shouldn’t talk about natural selection in these terms

geens make choices

dawkins – imperative on genes

regardless of thesis, realities exist

how much invest in reproducing or repairing

there is no genetic programme for ageing. We age because in evol past…

ageing process model

age related frailty, disability, and disease – accumulation of cellular defects, caused by random molecular damage

build bridges between biomedical and social sciences -    because we know influ of environment

we know that healthy lifestyle and food can affect this

malleiability of the ageing process -    by decreasing exposure to damage (nutrition, lifestyle, environment) -    enhance natural mechanisms for protection and repairt ( nutrition, novel drugs, stem cell)

traditional view of ageing -    is biololgically determined with inbuilt limit -    progressive, irreversible capacity -    ageing distinct phase of life style -    disases of ageing distinct from intrinsic underlying processes of healthy ageing

dismiss the first -    we are programmed for survival not death -    ageing intrinsically malleable -    youth and age are continuum -    intrinsic ageing and many age related diseases share common underlying

successes and limitations – managing expectations -    current success o    good ustdg, but more to learn o    beginnings of ustdg of underlying mechanisms of ageing and age relationship disease o    can modify longevity in some animal models – fruit fly, etc – but in nearly every case is uncertain -    Current limitations o    V little evidence for effecicaly of drug/nutraceutical effects o    Cannot yet perform successful gene therapy for well-defined targets such as cystic fibrosis o    Cannot yet perform successful stem cell therapy for well defined targets o    Potential future discussions largely speculative and unacceptable in other biomedical spheres

Meeting

Education and public engagement- education and professional training -    expand research capacity in ageing science -    inc professions and industry

Public engagement- government

Public engagement – Citizens -    challenge and change negative atts to ageing

Ageing: scientific Aspects – select committee publication from last year

Rally curing aging: the other sociological obstacle Aubry DNJ de Grey

Strategies for engineered Negligle Senescene (SENS)

Jbs haldane, 1963

Four stages of acceptance i)    worthless nonsense…

Arthur c Clarke

New ideas pas through three periods Tom Kirkwood

The rejuvenation dividend: the precepts -    stretching frailty is v hard, luckilty -    the faster we delay frailty without stretching it, the fewer people wil be frail o    rate, not extent, of progress is key -    partial repair gives more delay than partial prevention o    how achieve? – eg. Someone aged a lot, only so much we can do – concept of reserve: amount of additional damage your body can afford to accumulate before things go wrong.  How help: start sooner – be healthy earlier; -    when a plausible rate of medical progress is presumed o    even better repair is possible!

Promising progress or arrogant nonsense

Embo reports 2005 nov 6,(11) 1006-=1008 -    None of us believes tht plans to ‘engineer’ the body to prevent ageing indefinitely or to turn old people young again have the remotest chance to success’

Reasons given for dismissing SENS -    is unscientific: ‘ easily recognized as a pretence by those -    ‘nnoneof pthe sens] -    T

Technology and science differe in how they best evaluate evidence -    goal: powered flight. Solutions? o    Engineer vs scientist

Scientists way of analyzing evidence is misapplied in context of technological goal

‘if an expet cant explain something in his field to an educated laymen…’

the sens challenge with MIT Technology review – www.technologyreview.com -    offered $20,000 to discredit de Grey – open to any molecular -    editor of technology review thought high profile panel -    panel is: craig venter, rod brooks, Nathan myrvhold, vikram kumar, anita goel -    two entries submitted, another threatened

sens is following Gandhi -    firs tthey ignore you -    then they laugh ay ou -    then they oopose you -    then they say they were with you all along

de grey, adnj, embro Reports 2005; 6(11): 1000 -    offer no apology for using media interest in llife extn to make the biologiyt of ageing an exception to planck’s observation that science advances funeral by funaeral, lives lots of them, are at stake

life extension not just science, a biomedical prob too

causes considerable suffering

spoke

himsworht and goldacre, 1999, bmj, 319: 1138-1339 -    the older you are, the healthier you’ve been (Perls)

Jay Olshansky How would you assess current aging research, and the prospects for significant breakthroughs in any of its major branches

(background in sociology, but leading biodemographers) now at Uni of Illinois

was at US President’s council in 2002 on ageing

in answer to that, prefer question

can we justify theattempts to slow ageing and how?

answerL yes:

March ‘The Scientist’ -    co author with Daniel perry, Richard a miller, Robert n. butler

if can extend healthy life, it would pay longevity dividends, far in excess of anything we could imagine, for indivs and nations

ME: how nations?

Brendon Mayer – editor support for scientist publication

Rationale for pursuing the ‘longevity dividend’ is already in place -    current medical model will not work in long run

current medical model -    biological limit to life

pharmaceutical industry

surgical procedures

early detection of disease

already commited ourselves emotionally, financially to extending lifelonglearning

the value of life at every age -    we value it at every age

by  slowing aging we willl do what no drug, surgical procedure, or behaviour modification can ever do – extend your years of youthful vigor and simiulatenously postpone all t costly, disably, and legal conditions expressed at later ages

‘in pursuit of the longeviry dividend’ – TITLe

operative word is: DELAY

not searching for fountain of youth

not proposing transformation of older people to younger

not stopping or reversing aging process

the words, ‘stopping’ and ‘reversing’ should not be in vocabulary

not dramatic extension of duration of lifelonglearning

‘pursuing health extension’ -    improvement in public health -    extension of period of youthful health and vigor -    reductions in frailyy and disability at all ages

if we succeed in delaying aging, bonuses will likely be extn of life and dramatic….

Target -    7 year delay in boil process of ageing

why 7? -    it tooko 100 yrs for the total mortality risk of a 74… -    Olshanksy, carnes and grahn, 1998 – confronting t boundaries… -    Brody, 1983, prospects for an ageing population, nature -    The7 is associated with great impact to reduce everything associatd with ageing by half

Longevity dividend -    calling on congres to invest 3 biillion dollars annually o    dividends •    compression of mortality and morbidity •    reduction in age-specific risk of all diseases •    reduction health care costs •    inc indiv and national wealth •    benefits will occur for lifespan and across generations •    health and economic benefits will exceed elimination of cancer or hearth disease

if we don’t do this?

For those pushing immortality – this is how you would start doing it

Don’t want people making it too old age extremely frail

Extending Life Span: Scientific prospects and political obstacles Richard Miller

ME: first says should not talk about radical etension,

Traditional approach to medical research – one disease at a time

But conquering one cancer, for eg, would have limited yield

Antiaging interventions. Solid facts -    seer caloric restriction increases mean and maximal life span in mice -    with ex they get old later

now 10 gene mutations that can accomplish same effect

other mutants with lover igf-1 levels also live longer than controls -    dogs too: low igf-1 and long life span

treat later life diseases as a group

ageing can be delayed by two diets and by each of > 9 genes, in laboratory animals that repsont o many of the same drugs and hormones that we do

ME: comments that those making biggest claims about extension get headlines

Longevity projectopn: the reality Based ™ approach -    calorific rstriction: 30-40% -    small dogs: 40% -    methionine..

thesis: the obstacles to finding a ‘cure’ for aging are 85% political and 15% scientific

research on the ageing process -    for every $100 us congress spends on medical, 6cents goes to ageing

why haven’t we cured aging yet? (ie learned how to slow) -    most ‘public’ gerontologist are crackpots and who wants to hang out with that sort of person?

We don’t want to be associated – gi

Eg. Deepak Chopra DHEA Growth Hormne Mealtonin Miracle

This is clearly a scheme for making money

Why haven’t we cured ageing yet?- -= is viewed (incoorectly) as incurable

voters relatives died of some diseas, os diseassa have lobbies, so congress spends money on diseases

aging research lobby v small

drugs that actually slow aging cannot be tested in time to show a profit within the ceo’s lifetime

drugs purported to slow aging are highly profitable even though they don’t work

a poiticaian who wants to conquer cancer or conquer aids is a hero

a politician who wants to slow aging is a nut case

people don’t unstd that quickest way to help diseas

socioo of science

scientists follow money

young scientist follow high tech and need papers NOW, alas key biogerontology expts are often low tech and take a few years

to be honest, it’s not that easy to cure..

gerontologiphobia n: a syndrome charac by a fea of what antiaging might do to soc

‘how far could we go. Too far is one possible answer…like drunks with drink, enough is…

the ‘lynch’ position -    ‘stop research on aging because we don’t want t world to fill up with old people’ -    ethical

if presented to people 200 yrs ago – would people say we don’t want insulin, etc

ethically when:

a)    me only b)    well ok, you too c)    but not them. We don’t want the world to fill up with old people, now do we.

Discussant Paul Hodge

Thanks peter healey

Baby boomers Nothing done after this

2005 whitehouse conference dec 14, was asked to testify on policy issues and mentioned baby boomers, but first point was longevity

Questions and Answers

Question from Scot: key issues is delay, but if can do repair, that is better. Why isn’t repair possible?

Jaye: similar concept to Aubrey

Aubrey: difference are to do with feasibility of approaches.

Alex Kalasha from WHO: was at whitehouse conf and disappointing that such advanced nation presented such a poor public debate around science. How optimistic are you with the $3billion?

Jaye: agree with Bob Butler’s conclusion that we need to be ambitious. Buit relative to amount of money on medicaare - $300billion, going ater one disease at a time, is miniscule. This is just the beginning of full court press to go after aging in a much more aggressive way thant we have gone after diseases previously

Tom: must be more connectivity between science and political/social agenda. I don’t think we are saying same thing. I think Aubrey is trying to generate enthusiasm that sidesteps practical problems facing problem. We all want the science to come through, but it doesn’t serve any usefl purpose to extrapolate beyond immediate. No great exptn about extn but might change profile of health.trying to find better way to age, and if that leads to life extension, that’s great.

Jay: aging research should appeal to people. Same goes for why should talk about delay rather than sudden immortaility

Aubrey: cross agency cooperation. In my own work, many exptl scientists not gerontologisty, many working on repair and regeneration technology. Not simply lines on graphs but collaborations. On political side, emphasise that actually it’s perfectly ok to have signif life extn as side benefit to addressing frailty and decline.

Chaotics, Philidelphiaa.: historical  fallacy, several speakers say we are in a special age. Food, etc. no reason to believe we are in any special time or place. In time of Copernicus, Einstein, etc, every time is special. Advances occurring no diff. Aubrey pointed out max planck’s progress thesis, but he might have chosen Voltaire: I have only made but one prayer…please render my enemies ridiculous, and

Donald Bruce: some speakers mentioned the ‘sales pitch’. What is real in this debate? Question of Shakespeare 7 ages of sans…. All the idea of whatever it is you will do, must have so many things right all at once. Getting one or two bits right not enough. Seems a matter of belief rather than evidence.

Tom: how do you know you wont mke things worse? The rate of progress on research on aging is quite slow. Need to know aims and objectives and priorities. You might say it’s a terrible thing to die of heart disease, but it is quick and if solve, then will leave vulnerable to other degenerative diseases, such as alzheimers etc. it is an imp q.

XX: imp but not answerable in rational way 20 years ago, but middle part of talk was about that. What is evidence. By delaying, one does create animals which postpone, together, these diseases.tf, hypothetical worries about creating people that might have other probs is imp, but are ways that we can begin this.

Jay: what happens if we don’t intervene.

11-1200

Lecture Theatre 5 Sarah Harper and Kenneth Howse Is more life always a good thing?

Sarah: I am an anthropologist by training, interested in demographic and social. Kenneth has a philosophy background.

Discuss both extending max life span, but also extending normal active healthy life span for everyone in world.

IT is better for everyone to live slightly longer than a few much longer.

Now have 4 or 5 generations alive at same time.

Kenneth

2 scenarios -    on one side, Jay, Richard and Tom: best prospect of reducing burden of ill health is to go straight for biology of aging -    everyone endorsed that and concerned to get across to you that this was a good thing, otherwise stick with what current medicine can offer, which is not so useful. -    They suggested that nobody would argue against this -    Next to this, is Aubrey’s ideas:

Must consider continuities and discontinuities of these 2 projects.

Not just a feasibility debate. Must confront gerontophobia

I will lay out the case on behalf of gerontophobia

The question Richard miller flagged up is one that a lot of people have taken very seriously

For eg. Jay mentioned US President’s Council Beyond Therapy, they said ‘let’s suppose we can double life expectancy’ would it be a good thing? General conclusions of that report were mainly sceptical. Commissions report did not come down on one side.

ME: should it have? I don’t think this was its remit. Would we have wanted it to? Public debate. Ethical engagement.

Does Jay’s commitment lead to Aubrey’s vision.

ME: we continually refer to Aubrey’s view in a same way to how we refer to Huxley’s

David Sarfadi, Chaotics: husband of working scientist, when they go into lab, don’t have goal to double lifespan of mouse, for instance. You are altering genes that have effects. Don’t choose which route, it’s what the science renders. If scientist thought was bad idea, would have to kill mouse and tell nobody. Never happens, usually scientist runs to NYT. Society will deal with those choices. Always be confronted with maximal of possibility.

Kenneth: but policy makers decide how much we pay.

David: capital will demonstrate: private funders will begin.

Kenneth: in Europe, worry of inequalities

Bill Baingridge, national science foundation: certainly rtrue that long term goals do shape funding. Rhetoric is that start up companies is on short term goals rather than longer term ones.

XX: do not find 2 approaches mutually exclusive. They will feed each other.

Evelyne Bull, ox student.

Kenneth: if I say yes to Jay, am I committed to Aubrey?

Sarah: public privte us Europe divide.

Raphael Ramirez, oxford: advising on patenting. If life becomes a bnusiness, acceptability of that differes. Nobel prize winner in ox who said whoever igns TRIPS agreement, signed death warrant of tens of thousands of Africans. Human rights vs property rights. Even today can patent mouse in USA. Who owns the findingsa. Is it a good thing? What criteria and ‘for whom’. Who frames this? Not good for some poor somalian.

Kenneth: choice as indiv and collectively.

Rachel Hurst, disability and human rights: assumnption that health is absence of disease and disability. I don’t agree. Whichever side we go down, we need to recog that is humans that we are talking about and are they going to be contained. Whatever way you choose, does it matter, if retaining ethical premise that are dealing with human beings.

Sue (Oxford): assumption that longer means happier.

Anil Gupter: is strongter, etc a better life. Health not absense of sickness, it is well-being.  What is a good thing? When communities.  Society not appreciated handicaps of those who do not see those of others.

ME: allocation of resources as assertion about what is happiness.

Robin Hanson, Economist: often float into abstractions. Prospect of doubling. We have already doubled our lifespan.

ME: is is thte same kind of doubling. Is doubling the issue?

Question: disting ‘whether’ from ‘what if’. Policy has tendency to react to convergent of diff hells. What are hells and heavens in traking this forward.

Donald Bruce: anthropology: what is our ustdg of the human.  Premise is based on functional part of us.  Diminished view of human. I was once on a sci fi programme – ‘what would it be like to live forever’ what do you do after 2000 years. Ok, stupid scenario. Fact that prince charles not king at his age, phenomenon exponential in this situation.

Sarah: finality, goals, - must keep that within human condition. Mustn’t negate that side.

ME: a ritual death?

Question: reproductive span should go to 80-90 yrs old.

Wolfgang Luca: don’t think will hit 9billion level of population, because birthrate decline. Glad that reproduction has been added to reproduction. Why gerontophobia is with diffciculty of imagining.  If assume 3-4 yrs inc per decade, then in west Europe, third of entire population above 80. Prob for legal pension. V little poss for change. Life expectancy goes beyond state increase in retirement age.

Jerry Rav, JMI: is there a culture where is accepted for people to dcide when to go. People in good health.

Gupter: in border of west Bengal and Bangladesh, is custom that go to forest and death by tiger eating you is most devine death.

Sarah: aboriginal – indivs do decide that burden they place on society means they should die. But these are problematic discussions.

James (JMI): by what criteria do we measure a good life. Having discussion about people as indivs planning to life extend as long as poss. Not sure psychologically a good idea. People make choices that involve a whole range of issues. One of obvious techniques of life extension is constrained calorifgic intake – opposite side of prob with obesity. Raises prob. People make choices in that context – taking too much, which makes you live less. These are issues of preventative medicine and public health. People don’t choose to make choices. Am I reasding this issue of calorific intake right. Biggest medical issue at moment is absolute opposite of that.  Food and life choices and risk taking in a social context.

Kenneth: fair amount of disagreement

James: healthcare funding so stilted towards treatement rather than preventionl

??: if we’re right about fertility decline in developing countries, major prob not aging but reproduction.

Srah: various myths about aging. By 2050 2 billion people in developing nations over 50.. not just a developed world problem.

Bill SharpE:  continuity/discontinuity thesis.  Systemic prob. Community in formation here. Contention over goals. None of them know degree of continuity between 2 goals. They are self admitting that we cant tell. Is it worth it? Clearly yes. I have had pleasure watching parents move into 90s. every year has been worth it for them. Only issue is when problems become insurmountable. Tigers as good as some alternatives. Living and learning has indefinite pleasure and learning. Gandhi: live as if you die tomorrow and learn as if you will live forever.

Kahn, oxford:  main issue arising for devle countries. What would be the healthy life expectancy, not expectancy at all.

Michael Morrison, Uni of Nottingham: medical and social ideas of health. Strong strteam of technological determinism.

1300-1500

Stronger? Chair: Zhanfeng Cui

Ellen Heber-Katz

Regrowth of tissue

Tissue remodelling during regeneration

DL Stocum

Transfer cells across scar tissue

If can identify cell might be able tccccccccccccccccc

Kevin Warwick

I, Robot with Will Smith

Last implant was chip into nervous system. 100 electrodes fired into medial nerve in left arm – 10,000 nerve fibres, receive sensory signals.

Not as reported in guardian that fits into top pocket, but it was fired into nervous system. Each pin is 1.5mm long. Nerve fibres are 3.5-4mm in diameter.

What could we do with it.

Link with computer

Human senses 5% of world around them – stats from CERN.

ME: how is this different from extra sensory experience through drug use?

Ultra sonic and infrared

What is difference between tv having it and you having it, ethically?

Future of research

With wife, did direct telegraphic nervous system link – brain to brain

Remaining humans will be sub-set.

Stem cell research and its ethical considerations in china Pei Xuetao, Beijing institute of transfusion medicine, stem cell research center

Selfrenewal (Extensive or unlimited) Clonal Multilineage differentation Plasticity Engraftment and repopulation

Stem cells can undergo self-renewal

Stem cells – foundation of regenerative medicine

Big problem with aging in china

Number of stem cell and regen med research projects funded by NSFC annually from 199-2005

Two projects for stem cell research and another two projects for tissue engi neering supported by t Chinese national key project of basic research

Ethical considerations of human embryonic stem cells big issue now

Basic principles of life ethics -    respect, non-mal, beneficience, justice

use of stem cell technology -    replaceable tissues/organs -    repair defective cell types -    gene therapy -    chemotherapy -    drug discover -    tumour therapy

ethical debate – i: derivation of ESCs -    harvesting es cells destroys t blastocyst -    ‘this is murder’ -    how to think about embryo, t dispute tht if embryo is a living life has become focus question on each side of dispute

human life, hnumanbeing or human person

definition of personhood - conscio0usly performing personal acts elmi

worldwide cloning research legislation

illegal in china

ethical debate III -    any kinds of

etihical debate in chona -    gov: against reprod cloning, support therapeutic -    scientist: balance sci freedom with erthical constraint public: hESC should not be banned Confucian: human embryo not a person Buddhistic: reincarnation occurs at birth

Ethical Guidelines and regulations for Human ES cell research in china Promiulagated by the ministroy of sc I and technology

Principled stance of china gov -    support biotech -    acknowl and observe international basic principle -    banning human clopning

image of person standing by wal with shadow projecting. At top of wall is apple. Person is reaching for it.

Human Assistance/Function Augmentation/Capability Enahncement by Robotic Advanced Technologies Nagoya University Toshio FUKUDA

Safety, security health -    environment, daily life, war and terrorism, product, health, ITS, communication, plant

Transition of work area -    manufacturing industry -    sensing, recognition, adaptation, learning, security -    service industry o    medical robot o    care robot o    transfer system o    security o    competition (RoboCup, Sport)

Humanoid Robot Vs

Rehabilitation Robot

Society in 21st century

Comfortable space using Robot Technology and Information Technology - in home or

human support technology 1.    physical support, sensory/actuation augmentation 2.    skill support; dexterity/experience, language 3.    intelligence support, information, communication, knowledge, augmentation, enhancement, decision making

human machine symbiosis 1.    cell level 2.    human and unit level (arm leg) 3.    multi human and indiv level (multirobot) 4.    organic device level (stomach, heart) 5.    human and indiv level (one to one) 6.    network level (multi robot and multihuman through network)

Robots: WE4, SAYA, KISMET, CRF1

CRF3 -    quiz, Questions and Answers -    email retrieval -    reaction of touch sensor

communication with CRF multi-scale bio-operations

engineering, bio, medical

Summary: stronger? -    human friendly robnotic technology to be advanced ofr aged society -    physical/skill/intelligence supports realizable in near future -    domains for applications: experts in medical and others. Daily life support for disabled and aged -    usage: depends on human decision back to society

natika XXX: amazement and alarm; only available to only those who can afford it

Donald bruce:

Norton, uni of dankstedt: interested in japan and robotics. What do you think about Kevin warwick. You want to make robots work for us, he wants to be one. Who is better off?

Response:

The Nature of Human Natures?

Chair: James Tansey James Hughes, James J.

Lee Silver

Thursday

845-1030

Smarter?

Cognitive Enhancement Nick

Forms of enhancing intelligence

Stimulants (Lee and Ma, 1995) Nutrients and hormones (Martinez and Kesner 1991) Cholinergic agonists (McGaugh and Petrinoc 1995, Levin 1992, Buccafusco, et al 1995) Piracetam famly Ampakines Consolidation enhancers

Learning enhancement for unlearning phobias and addictions (Pittman 2002; hall 2003)

Animal models

Genetic enhancement of memory

Pre- and perinatal enhancement -    giving choline supp to pregnant rats improves performance of pups (Meck, Smith and Williams 1987; Mellott et al 2004)

external software and hardware enhancements

multielectrode recordings from more than 300 electrodes (Nicolelis et al 2003, Carmena et al 2003, Shenoy et al 2003) Kennedy and Makay 1998 Alteheld et al 2004, von Wild et al 2002

Uploading Neuromorphic engineering Classical AI

Psychopharmacology of cognitive enhancement Dr Danielle Turner, Uni of Cambridge

An espresso at three in the morning is just so last year, article form Stephen Phillips (THES, last week)

Most people engage with some form of enhancement almost every day

Effective cognitive enhancement for patients -    quality of life -    benefits to patient, family, society

drugs as tools to investigate how the normal brain works

to improve cognitio0n in healthy indivs for eg -    military

one-touch tower of London planning task

modafinil

Questions and Answers

Daniel Reynolds

Jennifer Swift

Lucy Kimble, SAID: will robots be smart enough to bring up children

James Tansey – ‘dyfunctional’ people often are most high performing Joel: why would an athlete want to use modafinil?

Danielle: when Kelly white took, was not a specifically banned substance. Not sure if would enhance. Perhaps makes less impulsive.

Question

Danielle: first time take Ritalin, performance improves. Only helps in novel situation. When familiar, it drops.

Chris, nanotech, Santa Barbera: cognitive effects of hockey stick (graph curve)

David Wood (Scottish, mobile phone industry)

Alfred nordmann – nordmann@phil.tu-darmstadt.de

Happier

Susan Greenfield

Healthier and longer lives Increased leisure Expectation of happiness

The thin line…between therapy and lifestyle

Drugs work by -    increasing chemical messewnger (speed) -    slow down removal (cocaine) -    empty stores (ecstacy) -    block it acting (trancquiliers) -    act as imposter (heroin) -    making trarget more /less sensitive (addiction)

cure for life experiences -    flu -    feeling blue -    about to pig-out -    moody -    shy -    need energy? -    Too much energy -    Stupid

Taking a drug might not make you better

Efficacy of smart drug determined by baseline – ie more XX your attention more effective they willl be

So called transhumanist idea probc

Difference between well-being and happiness

Depression -    if medicate, not making them ecstatically happy -    outside world remote -    colourless -    emptionally numb -    little movement -    anhedonia

opposite of this ‘active happiness’

screen induced as well as drug induced – plays some computer game footage.

Are we going to live in this cyberworld which will not giove us the kind of happiness that we really want

Total abandonment

Susan Greenfield – Tomorrow’s People

Alleviation of suffering Active abandonment Fulfilment

Options -    Techno-ism: no indiv, no fulfilment -    Fundamentalism: fulfilment, no individual -    Consumerism: indiv, no fulfilment -    ..or we could use to development new technology o    eureka moment! Basis for happiness.

Professor Lord Richard Layard LSE, Economics, Centre for Economic Performance – Programme on Well-being Welfare to work; chaired UN Universities Economic ; Happiness: lessons from  - published march now translated into 11 languages

Happiness is simpler. A single dimension of various emotions.

David Nutt

Already there? -    happy pills o    pejorative term by both right and left wing media with antipathy to t drug treatment of depression o    refer usually to antidep especially new ones, aprtic SSRIs (Prozac, Seroxat, Lustral) o    previously benzodiazepines (Valium, Ativan) o    but none of these make people happy

potential routes for inc happi -    decrease stress o    amines – 5HT (noradrenaline) etc o    peptides – especially hpa axis -    active ‘happiness’ circuits o    opiates, alcohol-like, ecstacy-like, drugs o    intracranial stimulation (deep brain stimulation)

nick baylis

not happiness, but improvement – in life. Invest in healthy relationships

Donald bruce

Broken shower story

Nuclear energy industry

Computers

What can go wrong….

Athletics -    would have known that he cheated if he had used a pill to beat dave Bedford

would we see drug induced athlete as epitome of human ability or something else.

Are there rules about human race? If we step outside, are we less human?

1530

Stem Cell research

Current Policy in Europe

China, loose standards of ethical review.

Problems.

Human genome project progress through huge global collaboration

Not poss with stem cell because some countries ban it

One of probs is

English researchers want to collab with china or India, but heldback because funding bodies concerned about how the research is carried out in development world -    woo sung wong controversty (korea) – were supposed to come to the conference

Jerry Shatens

Flexible regulation with respect to research

Australia initially rejected cloning research and is now revisiting that

Has had a lot of attention in the media

‘funding bodies must take adequate steps to satisfy themselves that those they fund intend to carry out their research ethically and in accordance with relevant national regulations and appropriate international guidance as it emerges’.

Questions and Answers

Question: if woman consented to organ donation, would it be ethical to remove her eggs.

Julian: healthy young eggs better for research than older eggs. Science would like eggs from young healthy women, but many people’s intuition. Risks of donation eggs, small but real. Superobviation drugs associated with rare but lethal conditions

What risks can healthy individuals undergo for research? I say ‘quite significant’, but others say much less.

John harris and savulescu: like a horse race. What matters is which horse crosses the lline first, but cannot and should not back just one horse – must be collaborative.

1630

Fairer? Enhancement and Fairness, Julian Savulescu

George Annas ‘improved, posthumans would inevitably come to view the ‘naturals’ as inferor, as  subspecies….

Francis Fukuyama -    ‘the first victim of transhumanism might be equality…underlying this idea…

Bill McKibben -    these would be mere consumer decisions – but aht also means that they would benefit the rich far more than the poor’

nothing new about enhancement -    rich buy better o    education o    health care o    technology

these can alter biology direct biological intervention raises no new ethical issues -    just a question of which theory of justice goven socity

4 concepts - 1. Fairness or justice 2. enhancement 3. natural distribution of capabilities and disabilities 4. 1. fairness/justice - util egal: strict equality; rawls maximnl prioritarian

john Mackie ‘rights, utility, and universalisation’ -    right to fair go

maximising version of giving peoplpe a ‘fair go’ -    give as many people as poss a decent (reasonable) chance of decent (good) life

enhancement- -    makes our lives better -    increases t chance of us having a good life – instrumental goods (health, wealth)

biological – mor beautiful, stronger psychology – better person social, incliuding socially determined environment – cleaner air, better osiac secuiorty controversial – biological or internal technological enhacenemtns – focus on these

enhamcement, disability, and capability

well-being: how well a life goes (goodness); difficult to distribute well-being capability: state of person that inc probab of achieving a good life disability: state of person…

what is a disability?

Typically, deafness etc

But is context dependent

Atopic tendency -    asthma in developed world -    potection against worm infestation in devl world

need to fix or predict social or other environment circums

biology/psychology as capability/disability -    biological or psychology state can be predicted as ether -    biologica contributes to health but how well life goes -    we are all disabled

eg self control -    in 1960s Walter Mischel conducted impulse control, 4 year old children with marshmellow, request resist, but if not give two. Followed up and the ‘delay gratification’ more likely to succeed – impulse control

other categories capacity to work hard or be lazy – gene therapy in monkeys

Buchanan, Brock, Daniels and Wikler (‘all purpose goods’ -    intelligence, memory, self-discipline, foresight….

Autonomy enhancing traits Social Moral character

Genes, not men, may hold the key to femal pleasure’- genes accounted for 31% of the chance of having an orgasm during intercourse and 51% during masturbation

3. distribution of capabilities and disabilities

not distrib equally

eg. Intelligence. – normal distribution

example performance enhancement in sport: EPO -    natural hormone produced by kidney which stim red blood celss prod -    Eero Maentyranta: 3 medals, had 40-50% more red blood cells

Correcting natural inequality -    increase red blood cell level o    natural

capability we could efficiently set red blood cell level -    safety -    performance

sport -    test of natural biology? -    We want to reward naturally best

In sport, only one winner

No reason why there has to be a person who comes last in life

If unit not red cells, but units of the good life -    is it really just that there is a natural distrib in how well life goes

social not biological enhancement -    good reasons to prefer social rather than biological o    if safer, more likely to be successful, if justice requires it, etc o    but vice versa – sometimes cheaper, easier, and fairere to alter biology

responses to bioconservatives -    nature alots advantage and disadv with no mind to fairness -    enhancement improves peoples lives -    how well t lives of those who are disav go depends on

conclusion -    fairness requires enhancement -    failing to enahcnce may result in signif injustice (supervaccine) -    conservatives guilty of social detemrinism

When /if Longer, faster strong, smarter life is happier: reflectins on slower, sustainable and more inclusive life experiences Anil Gupta anilg@sristi.org

disabled or differently abled?

When live longer do we exp more?

What is purpose of more meaningful lifelonglearning -    accommodates community happiness -    sensitivey towards children

what is human capital? -    depth of social networks fo which one is a aprt -    how do we enhance this depth -    are we afraid of being in company of other normal impulsive, intuitive and inspirational people

ways of knowing -    knowing, feeling and doing

who is smarter, stronger and stable? -    smartness lies in sharing opps

Towards a Fairer Distribution of Technology… Zhao Yangdong

Inequality and immunisatin

Gregor Wolbring

Enhancement would be doping

Link enhancement products to health

2 chjoices

WHO definition – complete social well-being not just absence of disease -    social well-being still part of health

more common now is well-being above and health is a determinant of it

for today, health is seen as just medical health

transhjumanist model of health -    no matter how conventionally medically healthy, body is defined as limited and in need of modification

‘everyone is impaired’ -    Rachel also said this, but with diff connotation

Amatyra sen

David nutt -    pharma not going into happier drugs – cannot sell in medical framework so too many probs

transhumanisation of medicalisation

1830

Enhancement, Justice and rights: immortality John Harris

Art Panel

Teresa.dilon@polarproduce.org

Theatre/psychology

Polar produce, mixed media experiences Ma, music within therapeutic context

What kinds of knowledge do art/design practitioners have?

Why – it’s I the mix, baby’ Interdisciplinarity Slippage Languages and knowledges Lens and frames Fun

Difference between artist and scientist

Approach, language, tools, privileging certain types of knowledge, methods, outcomes, reception, interpretations

Comparisons -    cyclic creative processes, question finding, depth and explorationh, knowledge generation, outputs/outcomes, transformations

ME: artists believe they are the only ones who are marginal

Blurring the traditional ‘audience-spectator’ relationships – where the audience becomes part of the performance – and the performer becomes a member of the audience

Tina Gonsalves UCL Cognitive Sci, AHRC, ACE fellowship

She had read some pieces

Mobile phone project with University of Toronto

Rama gheerawo Research fellow and programme leader Designing the future through working with users The Helen hamlyn research centre Royal College of Art]

Inclusive design Disability discrimination act 2004

Video ethnography

Utility pets Elio caccavale

GM pets that do not give you the allergy

Translator for dog

Cloning pets

Genetic saving and clone, inc

Transgenic, ornamental fish, taikong corp

Utility pet memento form -    request part of animal to be preserved

www.eliocaccavale.com

social fiction scenario

1100-1230

Governable?

Baroness Sally Greengross

Can we make it fair What is role of state (government bodies) Poss to do it without them?

Wolfgang Lutz Vienna Institute of Demography Austrian Academy of Sciences

Suzi Leather

Spain, compensation of €900 for egg donation – how consistent with altruism?

Last year, euro parliament raised profile on Romanian clinic – led to government intervention

Concern about people trafficking

If we could only enhance one charac or trait, which one would we choose if we wanted to enhance the greatest benefit for humanity as a whole?

Creativity and Governance Christopher Newfield

Uni of California, santa barbera Cultural theorist and anti-dualist Centre for nanotechnolo

Disjunction between economic thought and cultural thought

The Innovator’s Dilemma -    clayton m christenen

open science model

minimum proprietary, peer review, open pub: 1.    tell the people 2.    listen to the people

better model

governance is governmentality, not just regulation (Foucault) -    care for all t elements of a system in their relations

flourishing -    Coleridge: intventions are ‘proofs of original genius only as far as they are modified by a predominant passion, or…when a human and intellectual life is transffered to them from the poet’s own spirit’

The creative process -    mihaly csikszentmihalyi (+CN) o    preparation o    incubation o    insight o    evaluation o    elaboration

governance (governmentality) must support this for community members

governing collaborations -    Simonton, rhotgen, 2003, seibold, henwfield

Maximising innovation is to set up a social system

Better model 1.    governance is governmentality, not just regulation 2.    better modelled as collaborative creativity than as markets, regulation or top-down management (but includes these) 3.    collaborative creativity works much better with equality in relations , in labs (valued ‘bridges’) 4.    analogy among nations: innovation cannot be separated from justice 5.    governance via global institutions promoting egalitarian communication among the diverse knowledge of all stakeholders

better model -    from ‘the lexus or the olive tree’

to innovation via justice

Questions and Answers

Question: egg donation is uncomfortable and not without risk, if no compensation, why would a woman do this?

Suzi: sheer altruism is one, but v few people. All donors extensively counselled. Physical and emotional risks. In uk, we do allow egg sharing – in exchnge for reduce cost. Ie woman using ivf to give away some of eggs to 1 or 2 other women and recompensed in kind with reduced cost for treatment. If open system of donation, poss that fewer people will come through, but might deal with by targeting donor. Earlier, sperm donation was 18-24, now are 35-40 yr olds.

James Hughes:

Suzi: challenge your view that regulation restricts. In uk, not true. Clear benefit. What does restrict is that this is not available on NHS and this is by far most imp issue. Most generous country is Israel. – all about state funding. Perhaps with ageing popultion this will improve elsewhere.

Anders: if free innovation is needed in governmentality, if have more bridges, prob is that transdisciplinarity, but gov structure wil have prob getting solutions, restfucture government? Complementary institutions?

Chris Newfield: practical construction  effort

Donald Bruce: is there distinction between enhancement and medical? HFEA has embodied that on sex selection for family balancing. Council of Europe has embodied on convention on human rights and biomedicine – sex selection only for serious gender related genetic disease. What is rationale for the distinction? It is one I support, but is it valid as result of distinction?

Suzi: evidence is that public does think can draw clear distinction between selection for family balancing and disease, for instance. Do I think this will hold? No I don’t. I thjink it will be increasingly difficult to do that. One of the reasons is because any kind of disadvantage that can be conceived of as a disability, parents will say ‘I must have this’. I must be able to have a child that doesn’t suffer from x, y or z.

Shefield institute for biotech:

Dave Wood: which charac should we enhance? If spread too far, get nowhere. becom

World Anti-Doping Agency Gene Doping Symposium (2005)

WADA gene doping Symposium4-5 Dec, 2005, Karolinska Institutet

Welcome

improve people's health. misuse of medical tes

Richard Pound

banbury conference

wada

OM contributions shared by NOCs - but..

gene doping research $3m

gene doping panel in WADA, help with detection

new results - WADC, mar 2003 -

ME: who are stakeholders of gene doping?

Olympic charter amended stating that only countries signed to  WADC can participate in Olympics

UNESCO convention Oct 19 2005 120 supporting states, observed by all 191 states

gov actions - now wider gov support

gov can do sth sports cannot sports cannot address trafficking, seizing, regulation of med professionals

trying to widen network of stakeholders recently, an athlete committee athlete outreach committee

gene doping inevitable

athletes believe they are immune to risk and their entourage seem not to care

New Trends in Anti-Doping Arne Ljungqvist

need to be ahead of the game first time in history

purpose - describe recent developments

some key years 1960 olympic games in rome - danish cyclist died in 100km road race. ioc took action, as first televised Olympics. athlete dying in front of ioc 1961 ioc mc 1964-72 testing for stimulants 1972 munich first serious case, us athlete ephedrine, controversial, still claims medal 1974 testing for AAS - tentative for 76 games in montreal 1983 IOC labs 1988 seoul -arne gave press  conference in rel to  johnson's positive. huge press. death of sport question. response was that this should be stopped. led to unified global effort. iron curtain drop changed this. 1999 ioc code, wada - changed med code into antidoping code 2004 wada code 2005 unesco convention

arne was olympian in1952 and nothing then,

doping code explanation

doping is definedas...

violation new 4. inadequate whereabouts information 8. administration, assisting, encouraging

prohibited list - wada publish each year

criteria - enhance, health risk, spirit of sport

(two of three)

doping need not be cheating to be banned

could say that any substance could be on list, and this is a legal prob

need common sense

substances w similar structures likewise banned, but legal difficulty to try

prohib method enhancement of oxygene trtansfer

distrib of substances 2004 - 36% anabolic 0.1% oxygen transfer enhancement

TUE

anti-doping strategy - info, educatioo, doping control,research

wada allocates 25-30% of budget to research vasst improvement since 2000

ioc never took this responsibility

strategy of doping controls - in comp - unanncounced out of comp - random - targeting (intelligence)

ME: what is current status of intelligence on gene doping?

need to improve intell

ME: how?

recent negative envts

- salt lake city experience, tendency  to make use of most recent advancements. 3 cross country skiers on aranesp - The Sweeney Experience' 2002: first reported that athletes had been contacting him to see how they could benefit; - The BALCO affair 2003; shows illegal production jsut for doping - The Athens experience 2004; first olympics at whch people banned for non-analytic positive; greek athletes; were using artif device for urine - Further designer drugs 2005; don catlin found further egs

The maked Machine false urine

REcent positive evens

SLC2002 -showed that we are close to athletes; these were subsrtances that had been on market for some months - Athens - pursued cheats successfully - WADA Code - UNESCO convention - Research fund - Proactive initiatives

whycontinue fight? - in ethics session. must be unbiased ME: this is too far. to pose all or nth is mistaken.

funl facts must be mentioned 1. no support for such an idea in t sports communioty - there was a debate. but it no longer exists. everyone agrees 2. wada andunesco convention, political estab has reinforced support 3. athletes themselves dont want it. athletes commisions are strongest

ME: when asking athletes about their feelings, hat do you think they are rejecting?

President of K: what are legal conseqs for med professionals?

AL: any person assisting may be banned. will not receive accreditation to be Olympic doctors. but we have limited legal action in civ law. at World Championships some years ago, some finnish professionals weree encouraging, investigation into law. found that action could not be taken. no legal ground .this changed the law.

The Irrefutable Success of Gene Transfer for Therapy of Human Disease) Concepts and techniques of gene therapy - applicationsv to doping in spoprt Ted Friedmann

give overview of underlying baasis of justif for potential of gene doping

rationale is direct outgrowth of gene therapy itself a controversial and difficult field

now a real area of cliincal research basis to think that direct attack can be and has been therapeutic

gene based doping - realstic poss imminent threat to sport - same pressure  that sustain drug doping  will lead to gene doping - based on advances in gene therapy

Evol and current state of gene therapy -controversial history - tools and concepts still immature - clinical reality, effective treatment, poss  cure -- serious risks, tolerable in context of therapy -- still subject to oversight and regulation

gene therapy for human genetic disease science, 1972, mar 3, 172, n 4205 friedman and robin

Proposal for human gene theerapy - needed - technically diffi -use disabled viruses as gene transfer vectors - many ethical and policy problems - reqs local and nationaal oversight - likely to be used for non-therapeuticapplics (enhnacmenet)

dark side broader than gene doping - enhancement of human traits in a eugenic sense.

LeRoy Walters, Kennedy Institute, Georgetown - somatic cell - germ cell

two major technical advances

recombinant DNA -cohen and boyer, 1973 - first efficient transfer tools (engineered viruses), 1981-1982; retrovirus vectors - Temin, Weinberg, Scolnick

retrovirus 1981-2 random integratioon, insertional mutagenesis adenovirus adeno-associate virus liposomes naked dna

ref: j biological chemistry; 1984, 25 12, 7842-9 - restored gene function and reversed phenotype

optimisms - beginnings of human clinical studies - 1989-90 - high expectations - exaggerated promises

gene transfer trials by year crash in 2000

ME: why? at the time of HGP completion

photo of jesse gellsinger

gene directly injected into liver

3 or 4 days later after injection, died react to vector not gene

Uni of Pennsylvania OTC study - a patient death -1999 - adenovirus vector to transfer ornithine transcarbamylase gene (OTTC) directly to liver - patient (JG) developed explosive

visible depression in Society of Gene Therapy

yet, heard of a diff technique

Paris study, Fischer, Great Ormond St LondonX- SCID

photo of Bubble Boy syndrome child - protect from inections

X-linked SCID,sevcombined immunodef dise - mutations in..

ex vivo study

introduiced to bone marrow cells

REF: NEJM article ,Fischer, Alain, lead Hacein-Bey-Abina, S -sustained correction of X-linked severe combined immuno

complete recovery - complete immunecorection 14 patients - some >6 yrs

but at high cost - 3 cases of T-cell leukemia -direct result of treatment - responsive to chemotherapy but reqd eventual one marrow transplantation - one death 2004

other two aree still alive and no evidence of residual disease. but diff to ustd

three cases of leukemia during effective treatment of x-scid deficiency

LMO2 oncogene has been disrupted - this is why we have leukemia

Why is this result imp? - proof - can be therapeutic - all previous studies ,potential or marginal benefits ,theoretical risks - no risk/benefit -X-SCID -quantifiable beenfits - gene transferrresearch becomes gene therapy - opens new era for med

legitmately therapy not just gene transfer

current successful therapies - X-SCID - q14 patients ,3 leuk, 1 death - ADA-SCID - 4 patients - prolonged - chronic grnaulomatous disease -2 patients

addl imminent and probable successes - cancer vaccines - introdcue genes (GM-CSF, CD40) to cancer cells to enhnace immune response (melanoma, CML, others) - restore tumour suppressor fn (p.53) - some photoreceptor degeneration andblindness -restored sight in blind dogs by gene transfer into retina - coronary artery disease

intra-tumoral...

CNS prophylaxis, new chemo agents

additional info into genome, which maintains mutant gene

now, te to fix defect - to change to wildtype gene from mutant

emerging tes - siRNA for gene modulation -especially for dominant diseasee - vector targeting -gene deliv - targetd gene modifi -zinc finger delivery of transcription factors ,transgenes

so, darker side -therapy is poss, what about enhnacement?

socially and ethically 'acceptable' enhnacement -we already do pharma, so why not gene - reelvant genes are becoming identified - tf, applic of gene tools to non-disease traits seem inevitable -

extension to sport - one of most imminent - unlikely to conform to standards of human clinical research -safety, informed voluntary consent

ME: why is informed vol consent unlikely?

sport or bioengineering? is it still sport?

ME: yes ,good photo, the q might be whether he would have been ahigh jumper if he had info about his genes

germ cell -therapy or enhance?

eugenics - old eugenics of late19th and early  20th C - new eugenics based on genetics - new potential for restrictive ,discrimintory

conclusions - all human gene transfer  -immature ,exptl clinical research, not standard of care -but if i had a child with X-SCID, i would opt for genetic approach - proven concept ,truly therapeutic - many dangers, known and unknown,reqs oversight

risks tolerable in light of disease ,but for healthypeople?

conclusion -sport may lead the way - opp to define social atts and responses

in US, not entertaining proposals for enhancement

discussion

how is read out monitored ?/ dosage? how follow efficacy of therapy? if so, might be poss to detect.

ME: what lev of cooperation is expected from biotech industry?

change position but

Goldspink Kathy Howe, killing off cells. factor 9 expt study shelved becuse of immune response to vector

holy grail is sequence correction

goldspink:

tom: surprised by one thing, which  was your optimism. I sat on FDA committe which looked at gene transfer when French study began.  what is your assessment of the science. is it  likely that LMO2 will not be repeated.

Ted: it hasnt in

Olivier: you refereed to over 700 studies, by RAC. do we have idea of success rate? are we aware of  some genes, neverr been poss to transfer. some genes more capable of expression than others. how long to go from animal model to human.

Ted: not all of 700 studies led to clinical. need to learn much more about how to turn genes on and off.

Olivier: side effects?

Ted: dont see them until you see effect.

Olivier: procedure itself not harmful?

Ted: in Gelsinger it did. will not see ath going wrong until see sth happening

Q: state for muscular.

Q: leukemia. single gene as key factor .also v shiort period - 3-4 years. usually cancer 10yrs. sth peculiar of case , it is activation of agene. are ways to avoid activation.

Ted: but not activitation, but disruption

Q: 3rd case special since dif

Odile: transgene role is enormous. cannot claim thatt there are no te that could counteract potential activations.

Chair: what is view on detection of gene transfer? willl this stop? or need legislation on other level?

Ted: no, wont be enough ,but will be strong deterrent.

Coffee

Effects on organ systems/tissues

Heart -    bigger, greater stroke vol -    inc maximal cardiac output

Blood vessel (heart and trained skel musc) -    more capillaries -    improved dilatory capacity

Blood -    ic total amount of red blood cells -    evevn larger expansion of plsma vol, reduced blood count in a blood sample

Adipose tissue -    reduced amount

Connective tissue/bone cartilage -    inc amount/strengthened

efects on organs systs

endocrine system -    insulin sensitivity -    catecholamine and gH response to ex

skin

imune systt

lungs

nervous system/brain -    inc capillaries more utilised

what factors influe performance

bouchard, C. et al 2005 -    gene map -    summarise what has happened in last year -    prediction of health or fitness -    no agreement yet on ‘key genes’ using popn genetics -    difficult to validate – separate population studies reqd

how study human muscle ‘phenotype’? -    skeletal muscle. -    How dna, to mRNA to protein -    Strength and endurance mapped to samples

Considerations -    species -    type/duration/intensity of intervention o    aerobic, resistance, inactivityy -    acute or repeated -    sampling site and time(s) -    amount needed -    mRNA and/or protein -    localisation -    housekeeping genes/normalization procedures o    complicates, regulation -    method – broad or narrow?

ReF: fluck et al 2005,

REF: Mahoney FASEBJ 2005 -    after acute ex, more genes activated in sets -    limited by number of biopsies you can take. Scientists would ilke one every hour -    but used 3h and 48hr

Generating a human endurance ‘transcriptome’ -    24 sedentar subjects -    240 musc biopsies -    24hr post ex -    measured phenotypic by important

500 genes ‘activated’ by ex in humans - COL3A1, FABP4, IGF-1, TGFBR2

what prdicts for improved cycle performance following 6 weeks training?

What genes regulate -    better oxy deliv

Timmons et al FASEB K, 2005

Gene ontology analysis

PGC-1 inc by training in following hours

Ameln et al FASEBJ 2005 -    HIF-1 drives expresion of epo. -    And VEGF -    At protein levvel, was regulated by acute ex, bound more to Dna, drives target genes,

Does epo play role in muscle? -    perhaps, protective or androgenic -    thus, epo might have systemic and local eeffects beneficial for performance

receptors of VEGF go up – inc to manipulate receptor side

5wks of training, VEGF goes up

to develop gene therapy fully, must understand cocktail of things that are going on

in gene therapy, CV side things are going on, but must know more to grow complex structues such as vessels

Targets of interest at geen level -    transcription factors, angiogenic, mit biogenesis, hypertrophyt

cell doping -    naked cells -    encapsulated – put into tissue, then remove. – safe for cheater, since no trace. Can be done with epo and inserted anywhere. -    sooner than one might expect. As many cell trials. And move towards gene modified cells. -    Yesterday, venture capitalist in san diego, using fibroblaysts, for parkinsons

Questions and Answers

Question: focused on up regulation, but what was freq v down reg

A: usually more up regulated, but perhaps a quarter, 3-4times more up than down

Question: how do trained, elite athletes differ?

A: some surprising, some expected. Not easy to predict.

Question: can distinguish

A: no of subjects needed to study polymorphisms v high, often differe considerably. W n24, impossible

Question: important?

A: extremely. But every thousand base is … bypassed polymorphy by looking at integrated response

Question: study in male, not female? Same for female? Each react differently to training

A: what would you expect?

REsponse:

Response: total of 16mins, can dramatically inc endurance performance, no gender related differences. Might depend on ex mode.

Olivier: concern of cell therpay, problem earlier than gene doping. Today, company proposing use of tendon cells to strengthen repair of horses. So is coming at commercial level soon. One key element in detection is time window we have. You have observed some transformation at mRNA level. What is order of magnitude of change?  Concern that signature will be lost.

A: presume that gene copying intensively is more stable and chronic than when you train. I would guess there is an elevation of gene doping product.

Olivier: what level should we detect?

A: problem is legal. Ban people that have strange pattern? Cell therapy been around for long while. Blood transfusion for over 100yrs. Bone marrow transplant since 70s, skin transplant, etc. cell therpay not new, but gene modified cells is novel and cells that are hidden.

Olivier: cells that grown and reinjected

A: yes, like cell

Andren Sandberg is rapporteur

Lunch

Session 2

Chair: Odile Cohen-Hagenauer

Vectors and Delivery Methods C. I Edvard Smith, Karolinska

Gene therapy -    gene could be 10,000 base pairs -    virus contains maybe 3,000 base pairs -    human genome, thousand books with thousand pages

today, cannot fix gene, but put in an extra one

concept oif a gene

if cell goes through many divisions and gene is in episome, will be lost. So if need to put in cells that divide many times must go for integration. Only way to ascertaint hat will be in cell.

Problem with going from outside of cell to nucleus

Local and systemic gene therapy

Gene transfer techniques -    non-biol methods (plamids, oligonueclotides) o    liposomes and polycations (lipofections) o    electroporation o    in situ naked dna injection o    gene gun (biolistics) -    biol methods o    transduction (virus-mediated transfer, most efficient)

drawbacks to viruses

DNA complexes – plasmids or oligonucleotides -    insert size no limit (can use long stretch of DNA, makes possible sequences, marker of normal) -    episomal – normally this; outside chromosome -    short-term expression -    broad host range -    unstable in vivo

is possible to remove all foreign elements. Ie design genes that do not carry any foreign elements, so  harder to trace

Virus as a vector for therapeutic genes, eg hiv

How use a virus?

Concept: the packaging cell line

IMAGE

Empty particles – allow introduction

Packing cell line 2nd generation

There are a number of viruses that can be used -    ecah has benefits and drawbacks

Concept: RNAi – how does it work?

IMAGE

Recent phenomenon, a decade, first observed in plants. If introduce double stranded rna has different features

In mammalian cells, if, instead of long dsRNA sequence, use short siRNA molecule, can have same effect. Si = short interferring

Regulates gene expression

Can achieve stable expression – deliver shRNA

Vectors contain unique sequences that can be trace Provided you know where and how to look Apart from t vectors there are their products

Questions and Answers

A: when expresss siRNA, is v short.

Question: if do cell culture, get up to 10,000 fold interference.

Question: will day come when can do entirely in vitro?

A: yes, should be. But viruses also have problems. They rely on cellular machinary, so good but also limitations – must use normal process of making proteins. If do invitro can avoid regulatory problems.

Vectors and delivery methods – vector and transgene vector detection H. Haisma

www.rug.nl/farmacie/tgm

in non-viral vectors, mostly have much chemical stuff added to them to allow entry to cell

adenovirus

shedding data, gene therapy stdies

shedding

excreta – semen, stool, saliva, urine, blood germ line – sperm, ovum

environmnent – next of kin

if people treated with gene therapy, can find vectors in almost any of tissues

do not find anything in germ line - ie no transfer to next generation

Gene doping detection

IMAGE OF TABLE

Dna – muscle – no shedding - months For adenovirus, shed in serum, saliva and urine, but only last days AAV – muscle – serum saliva urine – weeks Retrovirus – iv blood – semen (probably through prostate) – weeks

Vector: -    protein – no, requires biopsy -    dna, rna – yes, blood, urine -    chemicals – no, requires biopsy -    antibody response – yes, blood

clearance of free dna IMAGE OF GRAPHS

Even if inject into muscle and leaks into circulation, no way of finding. -    goes to liver and is broken down – perhaps find 10% of it in blood, after 30mins

dna detection?

Baterial is immunogenic

CpG dna: -    unmethylated CpG motifs are abundant in bacterial DNA -    the frequency of t CpG motif is supporess and highly methylated in mammalian DNA

detection?

Transgene -    protein o    human original, yes, elevated blood, urine o    new modified, yes if in blood, urine o    human modified, yes if in blood urine -    effect – yes, if in blood, urine

use effect as most promising

specific detection?

IMAGE

Isoelectric patterns of epo

REF: Lasne F et al Mol Ther 2004, 10:409-10 -    can see difference in number of glucose; same gene, same protein looks different from muscle or kidney -    possible fror detection

detection?

Specific – every potential drug needsa  specific sampling and analysis method – also detect other doping General – profiling allows t determination of (major) changes in gene expresion pattens by: gene array or proteomics

Genetic interventions IMAGE

Serum Protein Pattern diagnostics IMAGE

DETECT MAJOR CHANGE

Proteomics IMAGE

Establshes normalised picture of sports people on proteomic level, then look for major changes

Detection by proteomics

May be indication of gene doping – ME: WHAT else might it be

Post translation modifs

Mann and Jensen, Nature Biotech, 21, 255 (2005)

Gene expression profiles

IMAGE

Alreay used for cancer patients -    sample from tumour, isolate its rna, then matched on a chip, comparative analysis from arrays -    in sport, chip would convey change, 25,000 patterns on chip

Gene Array

IMAGE OF CHIP

Discussion -    gene doping vectors will be undetectable -    proteomics and gene expression profiling are powerful generally applicable methods and will be part of diagnosis and therapy in t future -    requires fresh tissue, urine or blood sample of good (RNA or protein) quality -    logistic (handlig, storage) -    global change in sampling handling is needed

Questions and Answers

A: once gene is active, no way of shutting it down.

Chair: Problem, because need 100% proof to commit someone

A review of current gene transfger models relevant to athletic performance

Haematological system and red cells in particular O. Cohen-Hagenauer

Launched European Society of Gene Therapy

Mainly deal with EPO

What matters, detection of EPO or that carry more level of EPO than rules permit? -    v costful

do you want to detect exogenous and transgeneand rEPO, or have world athlete not go beyond a certain threshold

Epo gene transfer -    can easily be monitored in vivo (hematocrit) – as hematocrit will just increase -    not supposed to induce an immune reaction -    therapeutic indications: epo sensitive anemias, eg chronic renal failure

epo gene transfer 1.    state of t art of vector systems 2.    regulatable expression – pharmacological control 3.    adverse effects – alluded to by haisma 4.    detection of abuse and gene doping

state of art of vector stys

state of art of vector systs 1.    dna electroctransfer of plasmid dna in rate muscle- just need needle, introduce gene in muscle, then electric field and dna will stay in. 2.    polymer encapsulation of xenogrenic or allogenicc fibroblasts or myoblsasts engineered to secrete epo 3.    sub-cutaneous implantation of microdermis biopump 4.    IM injection of epo-recombinnt AAV

IMAGES

AAV-mediated epo gene transfer 1.    long term expression (over 6 yrs) 2.    fatal polycythemia (excessive levels) 3.    regulatory system reqd – pharmacological control by an orally administered drug 4.    adverse event: auto-immune anemia 5.    detection of abuse and gene-doping

regulatable expressoin (3)

companies now investing into this sector

Questions and Answers

Coffee

Gene doping and the regulation of skeletal muscle hypertrophy Lee Sweeney

Skeletal muscle

Gene delivery into muscle -    primary targets are post-mitotic (non-dividing) nuclei of mature muscle fibers -    gene delivery vectors o    naked (plasmid) o    virus •    aav serotypes 6 and 8 are most efficient •    capsule modified lentiviruses o    non-viral dna conjugates o    adult stem cells •    muscle and bone marrow derived

adeno-assoviated virus mediateed gene transfer -    readily infects skel musc -    accommodates <4.7kb synthetic gene -    delayed onset of expression (Biut self compleent and high titrs decreates) -    no viral gene expressio -    no immune response in mice /capsid immune response in larger animals -    no integration (?) into post-mitotic nuclei – better for FDA safety -    long duration of xpression (likel years to decades) – but depends on usage, since only hitting postmitotic. Eg. Normal sedentary mouse loses no expression, but if hypertrophy, then lose in matter of months o    in monkeys that are not exercising, expression remains

efficiency of aav gene transfer -    50-95% of fibers show expression of reporter gene (LacZ) delivered by AAV1 -    transduction of -200% of all muscle in mouse possible w high levels -    looks possible for dogs now.

So, enhancement?....

potential appliocs for sskel musc -    primary musc diseases, duchenne beckeer, muscl dyst -    loss of muscle function during aging -    secration of therpaeutic proteins into t blood (factor 9 for haemophilia)

loss of muscle function during aging (sarcopenia) -    progressive loss of muscle mass and force beginning in fourth decade of life -    slowed, but not prevented by exerccise -    negatively impats health and quality of life -    occurs in all mammals -    may be due to progressive failure of skel musc to repair damage (decline in regenerative capacity) o    prob with ageing when satellite cell fusion doesn’t occur as well

Muscle Growth and regeneration. -    Various growth factors, HGF (hamatocrit) -    IGF-1 one of key factors – imp property (most inhibit maturation of muscle cells, so if over express, would inhibit muscile) but igf-1 drives proliferation, then XXXX

IGF-1 -    drieves protein synth -    reduces protein degred -    stimulates sat cell different

GH-IGF-1 axis - local synthesis decreases with ageing

Will inc IGFF-1 expression im muscl promote growth and refgernation pathways?

IGF-1 expression targetd to muscle -    utilize aav to achieve efficient skel musc delivery -    utilize musc specific promoter (MLC1/3) to limit expression to skel -    igf-1 over exzpresiosn should promote growh -    injected legs did not have age related loss -    also stopped loss of power

hyp -    igf1 overexpres should promote musc growth ad repair leading to t following outcomes

IGF-1

Conclusions – -    igf1 ocer express prevents age-relationship atrophy and loss of skel musc function -    skel musc regen i\

20% or more depending

prevented fibrosis due to severe injury

would it lead to enhanceemnt for athletes? If combined w trainig?

IMAGES

Igf-1 effect local- -    avoids harmful side effects, since blood levels of igf-1 not eleveanted -    decteion difi or impossible without biopsy, unless surrogate markers. -    But difficult to seee surrogate

Could systematic delivery of any ageny provide a similar effect to that achieved w local prodn of igf-1?

-    a TF-beta family membner, myostain antagonise igf-1 action, limiting skeltal musc growht. With igf-1 trying to create a balance. So knock down myostat to create effect on igf-1 -    possible cardiac toxicity -    relatively speciic to skeletal musc -    decreases fat -    loss or inhjib or myostat inc musc mass -    wyeth is in phase 2 clin trials w anti-myosttin antibodies for multiple types of muscle dystrophy – scarey note: all have dlated cardiomyopathy – could exacerbate cardiac condition, but speculative at this stage. Beginning to see effects. In obse patient, marked decrease in fat

Muscle growth and regen -    would inhibit prolif of sat cells, igf inrceases

myostatin inhib could allow systemic delivery -    antimyostat antibody injections into t blood of mice result in muscle hypertrophy -    viral delivery to liver or peripheral skel musc could generate screaion of anti-myostatin inhib in blood o    could look in blood for trace -    should result in inc growth and repair -    not clear if harmful side effects. Not clear would prov all benefits of igf-1 especially during senesence

gene doping could be detected by screening

myostatin KO Mouse -    wild type v myostatin null -    in any athlete, would not want total knock out

belgian bull

young child -    parents, mother is competitive athlete

conclusion -    gene transfer could be used for skel musc

nuber of properties could be changed -    strength, but repair, better muscle mass, strength and speed, maintainence of mass and strangth during disue, inc endurance

is genetic enhancement going to be a reality? -    inevitable -    banned on safety and fairness o    but safety sufficient -    if used in widespread for preventing aging, then harder to ban in athletic population. Especially when earlier better for intervention. -    Genetic profiling of athletes ‘ raise issues of genetic ‘fairness’ -  If someone has genetically decreawed myostatin, then is also unfair

Where are we now? -    can do this today o    naked dna o    direct injection o    vasula injection o    regulated gene expression

acknowledgement -    elizaeth barton, linda morris, rosenthal, farrar

Questions and Answers

Question: these are small animals. But how many injections for thigh muscle of human?

A: we are moving away from injection, rather vascular delivery. But problem is immune response in vector

Geoff Goldspink

Animal gene transfer model Interested in musc regulation

Looking at XXX, derived from IGF-1

IMAGES

Biol actions of gh/igf1

Mgf seems to cause sat cells to inc in no –then goes away

Igf1 also involved, but later in process

Damage

Real outcome is muscle force

With knockout myostatin not strong – lacking in functionality

35% inc in mujscle strength within 3 weeks

already company on internet creating mgf – Phoenix pharmaceuticals

ME: how did you find this?

Splicing can be induced by siRNA

Prediction

IMAGE

Put

Detection -    rapid screen mas spec

confirmatory tests -    antibody methods and o -    cell signalling using differeential gene expression

Questions and Answers

Tom: difference of view about what happens to myostatin knockout. Does it give strenght or not?

A: JHU argue that 17% increase in Arnold Schwarzenegger mice. Not a good balance in extra weight.

Lee: agree, if knockout altogether then not much strength .

Odile: but mujst increase other body parts

Lee: bones do compensate, do get larger. But not looked at tendons. But would assume they would hypertrophy as well

Geoff: myostatin KO; if keep putting into req state, can activtate w mgf, but if keep knocking out myostatin, energy pool diminishes over time. Athletes might use on short term, .

Lee: child born with KO liely to have problems, but mother doesn’t.

Question: shown that athletes using steroids get inc in sat cells, so can detect by muscle biopsy.

Geoff: butler brown in paris when taking biopsy from steroid using athletes, telelle length – life of sat cells – diminished – whereaas we might live to 180 efore run out of sat cells, athletes and exessive exercise might run out

Mitochondrian power plants: target for performance enhancing gene therapy Doug Wallace

Mit genome -    1500 chromosomes, 37mtdna genes -    all key energy genes

african

expressed through oocyte

males do not contribute

life = structure + energy

Schriner s et al 2006, science, 308, 5730, 11… -    increased lifespan by 20%, assoc w marked decrease in mtDNA

mtDNA, since maternally inherited, can only change over long period of time -    difference between everyone in room influences level

women started in africa about 200,000 years ago move to asian then to northern and then to americas

highly correlated w geographic origin – specifically latitude – because of temperature

mtDNA have specific point mutations that change coupling from ATP to decreasing work efficiency, hbut increaseing heat efficiency

changing of coupling efficiency

excess calories burned as heat

A nieme and k majamaa, 2005 Euro j hum gen 13 965-969 - mt dna genotypes correlates w finnish elite endurance versus sprinter athletes - functional difference between type one or two nucleotides

can radically change performance

possible that might be strand invasion of nucleiotide -    if switch from tightly to loosely coupled, would introduce muation, change 1 polymorphic base, inrcease performance 5-10%

Questions and Answers

Question: what is importance of mt ….?

A:

PPAR and the creation of the Marathon Mouse Ronald M. Evans, Salk Institute

What are they? -    peroxisome proliferator-activator receptors, comprise set of three related nuclear hormone receptors, that control broad aspects of lipid metabolism -    expresed in different tissues and are naturally activated

Fat storage and burning -    determined by relative levels of ppars,

revving up metabolism -    synthetic ligand GW1516

created marathon mouse (ppar)

transgenic mouse -    now expresses ppar-delta

muscling in on endurance -    will also treat wildtype (ie. Normal) littermates w orally active PPARd specific rdug

red muscle increased transgenic mice -    pink – glycolytpic fast twitch type ii -    - suggest switch to type 1 myosin rich fibres (slow twitch) -    from carbo burning to fat burning

A – better B – worse C – same

?

treadmill challenge

improved exercise performance in transgenic mice -    80% more time and distance capacity what about ppard null mice? -    Total running time only 20min, compared to wildtype of over 1hr and transgenic of more than 2hrs

Under study – does GW1516 enhance performance in mice?

Future – magic pill?

Clinical -    muscle wasting -    weight loss mec related to inc oxidative meabolism

opp for abuse -    inquiries from athletes, coaches, a horse trainer

conclusions -    ppar-delta directed metabolic changes produces a mouse w a long distance running phenotype -    possible to alter single component of compplex system –ie muscle fiber en burning ) to enttrain t rest of physiologic network -    genetically produced ‘delta’ muscle fibers confer high performance even in absence of exercise (training) -    exercise physiology can be predictively manipulated -    ppar-delter receptor

lead by Yongxu Wang – now running own lab at U Mass.

Gene Doping -  possible orthopedic applications Chris Evans, Harvard Medical School, Boston, MA, USA

Inflammation/arthiritis – phase I

And repair of: Bone Cartilage Ligament and tendon

Arthiritis is chronic, requiring long term gene expression, the other 3 are not – repair, then stop

Gene tansfer to the synovial fluid of joint

ex vivo and in vivo

Some success with ex-vivo

ex-vivo preclinical -    safe feasible in rabbits, rats, dogs, mice horses -    levels of expresion sufficient to inhiit animal models of RA

use retrovirus

phase 1 study in knuckle joint w rhumatoid arthiritis

put into joints that were due for removal

PAHSE I RA STUDY conclusion  (N=2) -    gene transfer to human joints is safe and feaible -    intra-articular gene expresion occurs -    patients accept procedure well -    reported relief, but not fully documented -    phase II studies merited    , BUT which vector

not progressed due to lack of funding. Big pharma wont touch it, small biotech don’t have enough money, millions just to treat small number f patients, but made progress by going around with it.

REF: Evans et al PNAS 102 8698-8706,2005

Targetted genetics company in seattle study.

Also in dusseldorf on modifications to determine clinical response. First year patients respnonded dramatically.

Horses Colorado state uni collab Experimental study in horse wrist joint, experimental model. Remove cartilage and inntroduce chip, measure effects of XX.

Induced disease at day 0, introduced vector after 2 weeks, disease under way, therapeutc not prophlyactivc, at end of experiment untreated joint shows erosion of articular cartilage

Absent from horse who recent therapy

Now bone

Direct injection of adenovirus – BMP-2

V responsive to gene transfer

Do this by making hole in animal’s bone and intro virus (BMP-2)

Rate undergo surgery, where femur exposed and external XX attached 5mm defect in femur would not heal if now use adenovirus and inject 40micro ltirs

after 8 weeks,good healing

Wolf’s law – how bone responds to load

After pins removed normal mineral content returns

Effectively repairing bone that would otherwise not occur

Concluding that we can do this

Cartilage

No intrinsic ability to heal

If partial injury to articular cartilage will not repair

If goes through to bone bone marrow defect

Trying to take adv of fact

Use with rabbit

ligament and tendon -    healing initiated by forming of blood clot -    gene transfer to healing ligament

see if enhance healing

gel-mediated gene transfer -    ad GFP placed into migration model gel -    1 week -    after 3 seeks more cells transduced

Presnet status

Indication – status – relevance to doping Inflam/arthiritus – phase1 clinical – high Bone – advanced preclin - ? Cartilage – preclin - ? Tendon/ligament – experimental – high tendon-muscle

If uses it when injured, then goes back to track, is horse doping?

Overlap between legit medical use – do have arthiritis – but overlaps with doping, since reason for arthiritis is due to over-traiing, so we increae their ability to train

Questions and Answers

Arne: Different between doping and treatment is already in use as TUE. Sports peple should be able to benefit. Problem is when it may go beyond.

Monday

Chair: Friedmann Standard in medical doping involves looking for assays

Don’t worry about looking for epo if you are interested in finding it

Look for local effects Systemic Homeostatic

Need un-biased global assays Changes in gene expression patterns in distal non-target tissues

WADA Perspectives on Gene Doping in Sport Olivier Rabin

Anti-doping analyses started in 60s based on detection of drugs in urine (stimulants and anabolic steroids) Progressive incorporation of -    immunassays: hcG (1987); LH (1997); hGh (2004) -    electrophoresis/focusing: EPO (2000); HBOCs (2004) – human blood oxygen carriers -    flow cytometry: blood transfusions in 2004 trend evolving from pure chemical analysis to incorporate more biochemistry and biology

evolution of rules -    from imperative need to detect and characterize t doping substance(s) in athlete’s biol specimen -    to -    possibiilty to use markers of abuse of substances to report doping -    as long as scientifically validated (concept and method)

markers approach already in final development phase for hGh detection: -    IGF-1 (liver) -    P-III-P (bone) Abnormal markers variation are used to qualify doping Hwr, almost 10 yrs of research and more than $4m

Fundamental concept

Abuse: substance – extra gene -    non physiological modification (imbalance) – change in homeostasis -    detection: where to look? o    Genomic o    Transcriptomic o    Proteomic o    Meabonomic

What to look for? -    signatures of changes unique to doping classes of substances

cannot say one substance equals one specific signature, but can make claims about relationships

limits in -    interpretation of gene modifications -    protein and peptide knowledge -    interpretation of metabolic changes

some gene regulations not fully understood

where to look? -    accessible cells or biol fluids w minimal invasiveness (urine? Blood cell lines, buccal cells; ) -    imaging (changes, markers, radiolabeled tracers)

challenges faced -    identification of right target: where, what how, interpret? -    Accessibility to measurable modifications (invasiveness, time window, ethical methods) -    Eliminate other explanations than doping (gender, age, diseases, enviro, ethnicity) -    Development of specific tools for anti-doping -    Extremely sophisticated constructs w fine modulation already in animal models -    Approaches may well work for gene doping or some substances, but what about cell therapy, in partic autoloous cell transplants – eg. Tendon strengthening in horses – extremely difficult to monitor. Looking for same cells in same organ. Already in application -    Costs. o    Money we can invest has limits. o    Also limit of cost we can ask for analysis. -    Layman accessible! – particularly lawyers.

Hope -    epo study in monkey showed genetically transferred epo still detectable o    not endog -    microarrays and SAGE appear to reveal target genes or mRNA. Proteins are promising. Metabonomics will grow. -    Combination of discriminant factors o    Projects ongoing on physiological markers that can be followed by biochem o    Have longitudinal XXX of athletes and detect unusual variations o    Doubt in future that can test every athlete for gene doping. Must start

Pragmatism -    science is likely to deeliver the antidote. When and how? -    Resources can be v demanding on anti-doping and beyond capability. Need to partner. -    Anti-doping market is limited. -    Partner with academic or private org -    Hope for some large scope methods, not too narrow in application -    Even if gene doping applied, limited chance of success, delay in significance impact in sport, though success will come…

DHEA is an anabolic steroid like testosterone and THG: Global gene expression analysis F Labrie

Use of microarrays applied to DHEA (hormone mutant)

Thg includes a genomic signature typical of a potent anabolic steroid J of Endocrinology 2005, 184, 427-33 Labrie, …. Claude Labrie

What is DHEA? -    precursor of all androgens -    from adrenal or food supplement (will argue against food supp) -    dhydroepiandrosterone (DHEA) -    leads to DHT dihydrotestosterone

The anabolic steroid control Act of 2004 has amended the US controlled substant act to include androstenedione, but it excluded DHEA.

‘ther term anabolic steroid means any drug or hormonal substance chem or pharm relationship to testost (other than estrogenes, progestins, cortico…’

JAMA 280, 1565-1566, 1998 -    qual control of DHEA dietary supplement products

HFL Jane Roberts

Difficulties, always new pharma drugs

Current methods cannot detect gene therapy

But if devevlop, perhaps could apply to other things, proteins/peptides, etc

Gene therapy to gene doping -    non-therapeutic use of genes, genet elements, and/or cells that have capacity to enhance -    muscular, anaemia, pain relief

alternative testing strategy -    surrogate marker approach (biomarker)

cell tissue, organ, organism -    complete ensable of biomolecules -    reflects influecnes of t enviro introduce exogenous substance

biomarkers -    transcripts -    proteins -    metabolites

transcriptomics vs proteomics

transcrcipts (mRNA) -    cellular material o    white blood cells o    urine epithelial cells -    differential gene expression -    complementary to proteomics

proteins -    serum/plasma -    secreted proteins -    includes PTM -    simpler assay -    sample stability?

Surrogate marker approach

Screening approaches

1.    pattern recog (uncharac markers) a.    transcriptomics i.    microarrays ii.    PCA, PC-DA b.    Proteomics i.    Gels, mass spectra ii.    ANNs (WADA Grant) – artif neural networks

2.    biomarkers assays (charac markers) a.    transcriptomics, proteomics b.    characterise proteins c.    development panel assays (multiplexing)

1.    pattern recog

sample prep is key- proteins in serum

Questions and Answers

Question: 4% cvould make world performance difference. Can array technology detect sorts of changes to give improvements of performance. Also legal issues – if athlete tested with array, about 36% of affeymetrix, not confident.

A: at proof of principle stage. Relies on probability

Proteomics J Yates, The Scripps Research Institute

Used for biol discovery

Ideas have been to apply technology to understand how proteins come together

Achieve total protein charcaterisation

Driven by mass spec

Single protein vs shotgun proteomics

Quantification

Global method: Would not stand up in court of law

Questions and Answers

Question: mentioned 20-30% SD, how about if shipped around world?

A: 20-30 is within sample.

Question: what preventive measures to keep stable.

Question; had possible to look at disease or treatment?

A: if biomarker, than one that shows dramatic. PSA doesn’t show much variation across sick and normal.

Question: Haima – not easy to detect in mass spec because some proetins don’t fly very well

A: at peptide level are problems

Proteomics as a tool to tdetect gene doping: intro to protein profiling C C King, San Diego, UoCalif, dept of pediatrics

How can embryonic SCs be used for …

Proteome complete set of proteins in a defined cell type, their relative quantitiates…

Outline -    2D electrophoresis: analysis and pitfalls -    establishing positional databases of proteins for analywsis -    frcaction -    applics for wada

2D gel electrophoresis -    few do this, since pattern recog alone does not give much diagnostic information -    but does offer possible to analyse specific proteins

coffee

Research Report on studies Geoff Goldspink

Exercise -    knee extensor weightlifting exercise -    3 sessions per week

using muscle biopsy

with elderley people

if give growth hormone and then exercise, leads to substantial inc in MGF -    related to inc in cross-sectional area of muscle fibres -    these old people are hormone deficient (drop by 2/3 from teenage to 70+)

relationship between MGF and muscle

studied young people next -    n16 -    give growth hormone, then 4 week washout, then placebo -    take biopsies before and at wk2 and wk8 with blood samples -    untrained indviduals

repeated with trained athletes -    blood levs went up considerably

been taking muscle cells in culture and putting serum on them

use muscle cells in culture

IGF-1 gene transfer

3 Different types of IGF-1 in muscle tissue

actually 6 types (2 classes of 3)

with placebo, inc in class 2 with Gh wen down

with MGF of Class 2,

can now purchase human muscle cells

with GH, get inc in Class II with MGF, mainly class 2

Class II MGF trascripts in cells treated w Human Serum Samples -    clear distinction

Present project with NHFL Newmarket and Nott Trent Uni -    human and murine serium samples for o    biosensor o    other markers o    proteomics – mass spec/neural network

Study 2 Trained Subjects Experimental protocol -    n15 -    from uni exercise science dept -    in training -    randomised o    GH + training o    or Placebo + training,

concern that they might be disqualified from sport

Currently collab

1.    mice receiveing hgh delivered using a mini osmotic pump

mass spec can distinguish

detection -    rapid screening using mass spec -    confirmatroy w o    antibody o    cell signalling using differential gene expression

present and future challenges in detecting enhacneing substances -    synthetic/recombinant analogues -    generic sbstances -    new methods of admin -    gene doping

providing we have good methods, it’s almost immaterial whether gene doping or not

Transcriptional and proteomic effects of IGF-1 Ted Friedmann

Does igf-1 casue sig molecular changes useful for detecion? -    changes? Basis for detection?

Model systems – in vitro and in vivo -    initial studies in in-bred mice – avoid problem of indivd variability, polymorphisms -    cultured murine and human muscle cells o    C2C12 o    Primary human muscle cell -    In vivo, IGF-treated mice o    Muscle, blood, urine, saliva, other organs

Exptl design – short term

I. transcriptional response to IGF-1 - microarray, affymetrix

candidate of genes that can be used to detct

approach to screening for IGF-1 -    identify genes most markedly regulated by IGF-1

Application of microarray technology for the detection of changes in gene expression after doping w recombinant human growth hormone Rene Stempfer…. Christa Nohammer

Goal: development of target dna microarray to identify specific change sin blood cell gene expression related to t admin of hgh

Present project -    feasibility study o    in vitro – different blood cells o    in vitro -  peripheral blood mononuclear cells

microarray procedure

Application of cellular chemistry and proetomic approaches to t detection of gene doping Jane roberts

Objectives -    identify and validate protein expression patterns (fingerprints) o    GH IGF-1 protein gene construct o    Mouse model o    Applic to humans y2-3

Yr1 -    show that genetic manipulation results in change in genetic fingerprint -    can detect w pattern recog

Doping analysis relevant for potential application to gene doping detection James Segura, Biomedical Research Park, PRBB, Barcelona

Oxymoron -    a thetorical figure in which an epigrammatic effect is created by t conjunction of incongrous or contradictory terms -    eg. Not-for-profit drugs; research and physician

detection of doping substacnes -    problem w substances identical to t endogenous ones (endogenous-like substances) is it possible to detect non-natural traits in natural substances?

Gene doping makes this problem harder

Peptide hormones

Indirect markers -    physiological effects -    popn studies: probability

direct markers -    subtle chemical difference between t admin drug and t natural hhormne produced by t b -    difficult to find direct markers

indirect dtection of GH

liver metabolism -    igf-1, igfbp-2 and 3, als

bone metab -    osteocalcine, p-III-p ; picp; ictp

gene expression of gh isoforms

need further verificaiton that change derives from gene therapy and not something else -    use non invasive imaging that shows expression in an unexpected tissue o    IMAGENE

A long way to go before detection

Potential for non-invasive imaging in anti-doping efforts Kurt Zinn

Outline -    background -    imaging -    potential -    points for consideratoin

potential imaging targets -    direct o    transferred genee o    products from gene -    indirect o    change in metab due to chronic exposure to transferred gene products o    changes in anatomy due to chronic exposure to transferredgene products o    inflamm arising from gene transfer or expresed gene product o    reporters of pathway activation

imaging modalities -    radioactive-based -    gamma-ray imaging -    posittron empission tomography -    xray computer tomography -    magnetic resonance imagine -    light-based imaging -    ultrasonography

imaging that maybe immediately applicable to gene doping

Roussel et al, Fig1, J app physio, 94, 1145-1152, 2003

Richardson et al Biochem Soc Trans, 30, 2002 232-237

Potential methods -    direct o    imaging gene transfer agent o    imaging protein gene product o    eg

meausrement of firefly gene for light if mouse produces light, then gene is being expressed

Imaging tc-99m-ad-luciferase

Particle goes to liver

Shows light ommision from liver of mouse

Questions and Answers

Lunch

Session 4

Tom murray

Screening a worry

Matt

T culture of sport Natural talent and effort Natural variation of talent is intrinsic to sport – if your body doesn’t fit, then do something else

New types of sport have developed that appreciate natural talents – where certain body types suit

Equal opportunities -    not part of culture of sport

cannot complain that

does not imply that sport activity is result of genetic lottery -    there is no genetic lottery, but evolution of natural talent combined with effort

fair chance – if different heights where height is relevant, then is unfair – so we divide in groups -    age differences, sex

limits of accessibility on fair innings argument

need sufficient number of competitors to make it worthwhile

natural variation –s mostly self-regulation

people w extreme gene mutations not become elite athletes

limits of genetic screening

gene doping for improvement talent and level of effort -    opening for fair innings – set up games where GM athletes complete, but should we?

The phenotype routlette -    natural phenotype is t result of a delicate balance in order to master o    genetic program o    epigenetic instabilities o    biological chance o    environmental challenges

for safety reasons -    major reason against -    keepin athletes healthy is difficult enough at such extremes of performance. With gene doping more complicated -    delivery, expression and safety -    protect athletes from their own winner instincts -    protect next generation from manipulating their health -    health expenss for sports moveement will likely sky rocket

if we assume safety? -    natural mutations have many advantages appreciated and accepted -    some can be screened for -    hwe, where draw line, w gene doping, one has to screeen for many genetic variants in order to meet t same requirement

snowballing inflation -

rules of fair play -    sport activities presume a pre-competition agreement about rules -    winning is essnetial but so is also fair play

fairness as equal opp not part of sport

as fair share of innings – part of sport with rough measures

as fair play – intrinsic

protecting privacy -    can we protect, with testing -    it can, if understand what privacy is all about -    often willing to give up privacy in certain conditions o    enjoying sport activities is one of those conditions

gene testing – includeed in rules of fair play -    accepted part of different practices -    research, medical treatment, sport activities -    need to regulate. How reliable? Who has access? How handle safely

yes to gene technology -    no to gene doping is consistent w a yes to medical treamtnet

aging of muscles problem – fear that cannot set limits -    distinc between gene transfer in care of patient, always balancing – benefits v risk -    patients are closely mointored to correct for unforeseen -    v different thing to do this on healthy people, where not monitoring closely

these questions not new, many drugs that used on old people that we would not use on younger

eg. Morphine good for people at end state, does not mean that give to anyone in pain

ethics and t challenge of t potential use of genetic technology in sport. Angela Schneider

Summary of effort, talent and fair play -    sport is rule governed -    action against rule is cheating -    should thre be a rule against – yes -    hwr, important practical and ethical problems

Winning the genetic lottery -    is it fair to compensate for those who have lost t genetic lottery from a sport perspective but still wish to compete in elite sport by enhazncing -    Hannson ‘why not allow gene doping’

Need to answer some important concepts

Contested distinctions -    natural and unnatural (artif) -    point of sport is to measure difference o    we have allow naturally differences to affect outcomes o    hwe, we wil not allow t potentially fairere gnetic equalization that would occur through enhancement. Do we have good grounds?

Ethical foundation -    preventing avoidable harm -    paternalism -    performance enhancement -    vision of sport and how gene doping fits within this context -    sport for humans not humans fro sport -    contested

do not design humans for sport

ME: but we do

Sport exhibits values -    leadership must choose which values -    eg. Equity of access; implications of genet therapy for those who currently live with disease or disability; specific sport oriented issues

Laser eye surgery -    language is intructive – if describe as removing normal variation, status as enhancement clear. But if removing abnormalities, more like correction

LASIK -    used in some sports. Should it be? -    Enhances

Comparison w rules against doping -    one point of rules is to limit risk -    risk of laser eye, 5-10%, possible risk -    how much risk is too much? -    Not clear why sport should accept any degre of risk for beyond performance – ie enhancement -    Most relevant value is definition of health

Consistency and credibility of rules In anti-doping have analogous substances

Principle at stake

Distinction between enhancement and repair -    restorative and addtive distinction (fost)

repair is unprobc

incidental improvement -    Tommy John elbow injjury – generalyl accepted

Surgery in absense of defect is enhancement

But Tiger Woods – laser eye

Laser correction public use now

Not like cheating in way that steroid use is

Practice doesn’t cause sufficient harm But this sets bar high

Things that are acceptable elsewhere, not aceptable elsewhere

What do with grey zones? -    arbitrary, but

with strict liability

privacy issues and access to genetic information -    genetic information especially private -    indicative of identities in special way -    puzzle – genetic make up not indicative

social question -    maintaining privacy of personal genetic information  vs potential role of sport community becoming wedge used to derive greater geneal

wituhout moral support, sport will not be able to preserve humanizing influecnce s if sport recognises and re

genetic modification and improving humans -    enhancement

sport conflronst problems

if sport faces problems

who decides?

Sport is leading by saying we will regulate

Ethics, enhancement and sport Tom Murray

Meaning of soprt as a human activity: why the world loves the olympic games

Excellence in sport as expression of -    natural talents -    virtuous perfection of those talents

Aristotle – eudamonia -    full good natual ilfe

there are unvirtuous ways of getting these

objections to doping control in sport -    claim of incoherency -    line drawing problem -    resistance Is futile -    appeal to individual liberty -    romantic/promethean view

ME: but this ignores game theory. It’s not about the rules. It’s about the intended test.

incoherency claim -    no cnpcetual ethical or practical distinction among different means of enhancement sport performance o    the marathoner’s shoes

response -    hypothetical

Line Drawing problem -    all possible lines are arbitary -    aribtrariness is fatal flaw

conflates two meaning of arbitrary -    as unprincipled, indefensible -    as reasonable response when o    drawing SOME line is defensible o    placing line IN THIS PLACE likewise

athletic virtues – fast.

Why 5 players Why not 50 players, look like rugby -    ME: not really. Dimensions of playing field,

But this would not have any of the characteristics of bball

Why draw in this place? -    why not 6 in team? Or 4? No 1 on 1

would not have a game of bball

ME: tom is not distinguishing different kinds of rules – he is talking about constitute rules, not regulative rules

Resistance is Futile -    not a first-order ethical claim -    primarily two empirical predictions o    control will be impossible o    bad conseques ensue -    control is never perfect -    depends upon o    public consensus o    effetive enforcement

ME: he is now switching to regulative rules

ME: breaking some rules is not bad in intelf

there are silly rules – prohibition in us

So must have a public consensus in support of rules

In sport, if ban certain things but do not enfocre

Argument from Individual Liberty

Presumption in favour of liberty Paternalism difficult to defend w adult athletes Hasting Center project -    coercive impact of drugs in sport: the unlevel field

doping control done well provides level playing field

argument from liberty fails to

romantic/promethean view -    humans as self-creators -    understand cultural and philosophical context and implications -    valorizes unfettered will and self-manipulation -    relation to human flourishing? -    Case of anorexia o    ‘anorexia is t cultivation of a specific image as an image – it is purely artficial rceation and that is why it is so admired. Will alone produces it and maintains against considerable odds’ noelle casky, 2003, 129

Triump of Performance Principle -    max performance by any means at any cost -    power lifting: drug free and? -    Unavoidable conseq of refusing to set limits o    Greatly increased risk    rules governing a practice not equal indefensible parternalism -    Threat to spirit of sport

No longer throw people to lions

ME: so the level of risk in sports is just right?

Ethics of enhancement in context -    non-trembling neurosurgeon -    point of practice: spirit of sport -    not t means per se, rather their relationship to t goals of t practice, values and human flourishing

imagine drug with no side effect

imagine drug diminishes hand tremour and neurosurgeons see benefit

let’s also assume that mperson you love most in world needs operation

2 surgeons, one says biomedical enhancement always ethically wrong, never use tremour reducing, and second says, I use it all the time

you would choose one w best results

first surgeon missed practice of surgery

point of sport is natural excellence

point of surgery is to make well

different kinds of human activity calls for different kinds of rules -    partic to circum of relevance

not bad to prevent muscle wasting , but still suspect as use in sport

because of goals and values of practice

challenge of genetic enhancement in sport

what do we value in sport? -    natural talents -    virtuous perfection of talents

what do we disvlaue -    distortion of relationship between natural talent, virtue

what makes a talent natural?

Complex phenotypes -    genome as ecosyst o    genes interact complexly w each other genes, w external environment -    genetic difference in general not rigidly determinative for human behaviour o    see behavioural genetics report at hastings center website

child who has been engineered prenatally, natural?

ME: ecosyst argument – just a complexity argument?

Differences in natural talents? -    as vicious inequalities to be redressed? 1.    Vonnegut’s ‘handicapper general’ •    Disable smart -    As expression of human of human variaton to be celebrated? -    Olympic movement opts for t latter? 1.    Alternative romantic/promtehan, triumph of performance principle

ME

Final session

Jacque Rogge

Test to check for drugs for neurosurgeon

Need clear rules for world of sport

Fairness – but is life fair?

Sport is arbitrary in some ways

Can this be accepted?

Is it fair that kenyan athlete born at 2000m of altitutde has special diet, runs 10km twice a day? Fair to compare with swedish athlete

Laser eye surgery, but would any physician accept to do that? Any ethical physician would refuse operation without pathology

Look at high-jumpers

Achilles tendon most fragile for fosbury

If in 10-15yrs, cell therapy to heal tendon and grow by 10% more and allow better training, forbid? – yes it should, but I need advice.

Paternalism -    we cannot have been told to decide for -    gov put strong warnings on sale of tobacco. But athletes do not know what is dangerous for their health.

Basis of beliefs

850million people practcising sport, 750million recreational

every recreational is competing with self

only 150million in sports contest

we believe that this pyramid provides great educational tool, for body and mind

sport taches social sskills- achieve more in a team, than alone

respct sport, respect society

sport integrates

sport brings health

sport shapes identity

we know life and soc is unfair, but social value of hierarchy – doping destroys ranking system

we believe that protect health, even if paternalism

believe in one example – that fight against doping is important for keeping explemar of sport

different between nature and nurture -    virtuous perfection is essence of sport -    everyone wants to reach limits – leaves sense of accomplishment -    important anser against existential fear that everyone has – who am i?

recruitment -    social aspect -    champion is admired -    not everyone born with talents, but way athlete behaves and lead life is important to protect. Genetic doping would destroy

doping rules are imperect

compensation theory -    compensate up to normal level, but then are cheating, but allowing less effort athlete to be compensated, then penalising the champion

my plea is please give us clear rules – must be crystal clear

enhancement not be allowed

where draw line must be done with ethicists and scientists

Stockholm Declaration Arne Ljungqvist

Composed of olivier, ted, and arne

Today, several human genetic diseaes can be succesffuly reated by gene transfer Gene transfer is still a very immature and it is still an exptl field of human medicine

Challenge?

Change serveal to  ‘a few’

Extensive and rigorous regulatory mechanisms need to ensure safety of research subjects and patients

Gene transfer procedures must -    follow code and principles of human exptn and clinical research -    be performed strictly in accord w local and national rules and regulations for gene transfer in clinical research

Comment: these are more general reseacrh

Tom: human beings?

Lee: clinical trials

Tom: clinical research aimed at dealing with human disease, but some of this will not be about disease. ‘Follow codes and principals governing research to human subjects’

Matt: follows nuremberg, etc

Tom: these are minimal conditions, we can elaborate

Lack of compliane w standards an rules of gene trasnfer procedures must be considered as medical malpractice and/or professional mis-conduct

Development appropriate sanction mechanism for illegal application of gene transfer in sport

Gary: who will develop?

Comment: since no legal, ma

Maybe unethical or illicit

Illegal implies court of law

Unethical and/or illegal

Promote public discussion issues on THE PROSPECT OF gene based enhancement and develop education progrms

Be developed

Comment: this implies it exists

Olivier: can argue this in animal models

Odiele: reservations, since education can be spreading

scientficic progress made through resarch projects supported by WADA and others suggest that new detecion and screening methods are likely to emerge in t near future, which will help to keep sport untainted by gene based doping methods

Cell doping? It is covered if we move entirely towards gene.

Delete ‘near’?

Lee: must emphasise need for research

Support research programs instituted by WADA and other anti-doping organizations

Comment: ‘should be supported’ at end remove support

academic and private research organizations to dedicate resources to further progress in gene doping research should be encouraged

Larry: deter, not just detect – progress to ‘deter’ gene doping

Gary:  government?

Academic, government and private research

Genetic and denomic charcaterisation of athletes to determine genetic traits is contrary to the principles of sport

Rogge: contradiction with screening

Odiele: when speak of genetic trait, must speak of interited trait

Dave: might be reasons to screen for genetic traits in medicine

Tom: say something about unwise nature, but not sure contrary to principles of sport. Not because against principle of sport, but because of potential harm

Lee: must specify athletic traits, not genetic

Ted: not determination of trait, but use of it to exclude. Ie. To determine eligibility

Peter Fricker: this research has been done. Issue here is about discrimination. Need to look at genes and risk of illness.

Tom: use of genetic information about putative athletic ability to discriminate against athlete, should be strongly discouraged.

Add to ‘select’ or discriminate

Peter: must allow ethical reseearch must proceed to validate role of genetic information

Enhance awareness of potentiall illicit use of gene transfer techniques in sport

Promote knowledge on medical and physical dangers associated with gene doping

Odiele: woiuld we like to put forward idea that there are dangers?

Olivier: dangers alone?

Odiele: why not ‘misuse of gene transfer’

Olivier: risks or dangers?

How about potential risks?

Olivier Rabin

ME: why not inter-governmental rules and regulations? As well as local and national

Mitochondrial Disease Research: Social and Ethical Considerations (2005)

Mitochondrial Disease Research:Social and Ethical Considerations

Workshop at Lancaster University, October 28-29, 2005 sponsored by The Wellcome Trust

Friday 28th October 2005

1p.m. to 2 p.m.  Lunch: Conference Centre

2 p.m.  Welcome by Ruth Chadwick, Lancaster University, Director of the Centre for Economic and Social Aspects of Genomics (CESAGen)

Eumitocombat

Rationale treatment strats combating mito oxidative phosphorylation (OXPHOROS) disorders

www.eumitocombat.org

obj

charac genes and proeins involves in formation and reg

SEAC

Carlos, Ruth, Bert, Henk, Ysbrand Poortman, Urban Wiesing

Another euro project separate from this (more reprod than disease)

First Session:  Chair:  Carlos Alonso Bedate,  Madrid

2.15 p.m.  Peter Whittaker, CESAGen, Lancaster University. Mitochondria: structure, function and assembly.

Mito have a critical function in all cells T mechs for carrying out this function are extremely  complex T process for assembling mitochondria is also v complex There are many things that might go wrong If something goes wrong, t effects seen in all organs and systs

What are Mito

Organelees found in cells (other than bacteria) whose primary role is t formation of ATP (adenosine triphosphate)

Mito use t energy madde availale in t breakdown of foodstuffs to make ATP – oxidative phosophorylation (OSphos)

Importance of ATP energy of cell movement synthesis of complex molecules transport of material into and out of cells and within cells

What else do mito do? help regulate cytoplasmic calcium levels – important for control sev cellular activities important role in apoptosis

how do mito make atop?

- 2 stages

Protoon motive force -    drive atp synthesis

synth of atp -    proton motive force now provs t en for t enzyme complex ATP synthase to bring about t synth of ATP

2.4 – dinitrophenol (DNP)

in us was used as a drug for slimming, which led to eye problems too

re-appared in 1990s as slimming divice for body builders

Sean Zhang, 24, of Bloomington

If look for this on internet, still offered for sale in body building sites

Division of mitochondria (assembly)

(mito are scaled down bacteria)

mitochondrial dna looks v much like bacterial dna

they have ribosomes, different from regular, protein making ones – more like bac

mitochondrial rna and protein synth -    mito make rna copies of t genes on t mito dna and these are translated to give proteins on special mitol ribosomes. Most of these are delivered to t inner membrane as parts of t OxPhos syst

a lot can go wrong in the functioning and assembly of mito

Muscle mito from mitol disease patient

Question&A

Question: neurological dysfunction?

Turnbull: not clear.

Blue: but the debilitating effects are precursor to psych cond

Mark: does it spread

Turnbull:  some segregation;

Donald: function of energy production main or only function?

Peter: main, but not only critical function

Donald: diotriphenol, where originate?

Peter: synthetic. Tried as possible uncoupler, use of slimming aid was before observation of coupling.

Donald: not naturally occurring product in body

Doug: are now natural uncoupling proteins in the body, linked to energy metabolism, eg, in brown fat, requires uncoupling

Donald: these are nuclear?

Doug: yes, and protein specific

Donald: mito performance radically affected by hings going on around

Doug: 2,00 proteins in mito, only 30 by XXX;

Bert: agreed upon classif of mito diseases? If so, basis? Genetic defect or clnical?

Doug: no, because of complic of new diseases and complexity of mito genome. There are consensus genome classifs.

3.00 p.m.  Doug Turnbull, Mitochondrial Research Group, Newcastle University Reproductive options for women with mitochondrial DNA disease

Clinical features and reproductive options for mitochondrial dna disease

Defects of mito genome -    need to be clear on perspective -    majority of adult patients with mito disease seem to have primary mutations in genome, rather than nuclear genetic mutations

problem majority of mito diseases due to nuclear genetic mutations -    one or two nuclear are v common among certain populations

nuclear mutations might affect mito dna or can affect nuceucide metab

nuclear make up bulk of resp chain individual components mito replic and repair

nucleus dominates mito

no evidence that mito feedbacks to nucleus- perhaps switches on transcription factors

NOT TALK ABOUT NUCLEAR

Focus on mito disorder

Mito dna is tiny piece, 16,500 basis (32 rows on sequence); not a big task to sequence

Human mtDNA -    located ONLY in mitol matrix -    circular genoome w short non-coding region (Dloop) -    multiple copies in single cells approx 700 in fibroblasts to >200,000 in mammalian oocytes -    maternally inherited o    important in charting evol of species. Eve of Africa based on mito dna patterns; o    until 1988 when first diseases found, already used for evol studs -    genetics of populatins -    no redundancy of dna (introns) in mito genome. Very compact full of genes -    unusual piece of dna

as clinicians/scientists, need to think differently from other diseases, such as huntingtons, duchennes,etc

Human mtDNA -    >50 different mt DNA point muitations -    100 different deletions -    are some common mutations, but mostly irregular – throughout genome

Mito genetics different nucl gen

Homoplasmic wild-type HETEROPLASMIC – most patients w mt dna mut have normal mix Homoplasmic mutant – in some w mt dna mutations, all copies abnormal

Heteroplasmy -    link between mutation patient -    wild-type phenotype o    scientists name for normal -    mutant phenotype o    symptoms occur only when large amount of mutant dna o    many people can be perfectly fine w low level •    mother could have low, child could have high

influ of mt dna

if mutation in genome, affects respiratory chain produces all kinds of disease

Non-neuro -    resp failure -    cardiomy -    liv failure -    shortstature, marrow failure -    diabetes -    thyroid

Neuro (any bit of neurosystem affected) -    optic atrophy, -    CVA, eixure -    Deafness -    Peripheral neuro

CLiniacal mito disease “may affect patients of any age and any tissue of t body”

Adult mito disease Neurol – migraine, strokes, epilepsy, dementia, myopathy, perio, neuro, dip

Acute medicine - seizures and stroke - increasing coma

Cardiology - quite a few myopathies - heart gets big, or abnormal beats - common problem

Gastroen - smooth muscle of gut affected

neurol - drooping of eyelid - not turning eyes properly - involuntary movement (posture) affects all muscles

how patients felt about it - when made diagnosis, was not only affected familymember - investigated family members - in family, aunt has diabetes and eafness, other aunt has cognitive impairment, nephew at 9yrs old first stroke like episode – remarkable variation in family - can we understand anything by looking at family?

Can we understand anything about nature of sisters - each have different conditions or none - look at lev of mutant acquired from mother, does it correlate w clinical symptoms? -  normal – nearly no - second sister 30-40% - most affected sister 80%

important to know when advising on reproductive options….

Patients with high levels of mutations have most disease

Mt DNA disorders

Clinically affected 9.18 (141) – 1 in 10,000 affected At risk 16.49 (335) Total: 25.67 (476) – 25 per 100,000 affected

Newcastle - not much movement of popn within Newcastle)

Looked at all patients that have been referred to us

Common for a genetic disease

Reproductive options fro women w mtDNA mutations

How do we treat patients with mtDNA mut?

We are a long way from this. No drugs in double blind clin trials that

Patrick Chinery

V little drug trial info - part due to clinical heterogeneity

if inherit, how likely to find agent that would help?

While cant cure, we can do a lot to help - Eg. Treat cardiac, diabetes, etc

women were requesting info on reprod options

MtDNA disease

Approx 4.5 per 100,000 clinically affected females (Caucasian popn in uk) Approx 8 per 100,000 at risk females (adult females due to cohort) Counselling and options for 13 per 100,000 females or 6500 females in uk (not neces’y that thes people are wanting children)

Mito DNA Diease -    mt DNA diease is maternally inheritated o    a margin of dount. One single case that questions. •    ME: more info -    MtDNA mutations may be homoplasmic or hetero -    Htero -    Bottleck important for hetero mtdna disorders

Egs

Homoplasmic mutations C1624T in mt-trnavl

Genome sequencing Mt tRNAVal

All children of Sharon have same mt mutation

Why Sharon is unaffected, we do not know.

Heteroplasmic 3243A>G -    commonest mt mutatin in uk -    woman 2 children

bottleneck -    suppose mother had 50% mt molecules -    what happens in development of primary oocyte -    molecules go down to tiny number (bottleneck) -    then expands again -    bottleneck seems reasonable hypothesis for why, if go down to small, then when expands can lead to more affected

it happens in real terms mother 36% son 95% daughter 0% undetectable

13513 G>A ND5

45% 13513G>A mother, normal, 3 pregnancies, still birth, child dying shortly after birth 85% 13513 G>A (third child) since then, child has died

mother has been incredibly unlucky, or perhaps in some mutations it is forcing to mutant form. We don’t know why all 3 affected given mothers stats

What can be done? -    counselling – limited knowledge -    oocyte donation – limited availability, not own o    sensible options, since would be normal mito o    few taken up ption, due to limited availability, need non-maternal friend; also, mothers want to have their own children; for some, mothers reluctant, -    oocyte sampling -    chorionic villus sampling and amniocentesis – termination o    potentially harmful -    PGD o    Major possibility

Stages of oocyte maturation

No of mt genomes – 1milion

No effective mt replication during embryogenesis

Becoming diluted from 1million

Can look at embryo and transfer back to mother with less mutated mt dna

Current genetic techniques, relatively straight forward to do this rather than

Not much point in PGD for Sharon (homoplasmic)

So what else could we do?

Prevent transmission of t disease

Roberts RM (Prevention of n AM J Medicine Genetic 1997 -    technique will not work because no nucleus, no nucleus membraine -    not a practical soln, would have to stain chromosomes and would be worried about transferring chromes

sensible thing to do is at GV egg stage -    people have done GV transfers

there are ethical issues perhaps, but no legal

why don’t we do that? Because GV egg is v immature To get from GV to fertilised is different Chances of genetic transfer to fertilisation, v difficult, no successful examples

If cant do it at different stages, why not at the Fertilised Oocte stage

Laurance Smith – in mice -    taken two strains of mice (inbred mice have v little mt difference) -    take out pronuclei and swap them over

transfer pronuclei

will it carry any mt?

yes, about 16%

when mice developed had between 10-37% in tissue

threshold for diease is over 50%

so in mouse expt, shown technique is feasible, can have live births of mice

Lawrence Smith – taken to 20 generations and no defect

Potentially valuable technique to stop transmission

No point in further animal work, since inherent difference between human and mouse oocytes and embryos

Press coverage Ethics of tabloid news!?

MTDNA

Applying for research license

Approx 2% of all uk ivf pregnancies are abnormal – 2 or 3 pronuclei - oocytes are not used

Tripronucleate zygotes

Take abnormally fertilised

Take out all pronuclei Transfer back 2 pronuclei into oocyye with different mt Make best use by doing reciprocal transfers

Then culturefor a couple of days, then embryo biopsy to conduct mito

Look at proportion of embryos developing to blastocyst

Look at cytogenetic, epigenetic, and mito dna analysis to see how much carried over

One of reasions for difficulty in obtaining license MT dna disorders

MTDNA

LREC (Local research ethics comm.) applic april 2005 HFEA applic license committee april – turned down HFEA appeal – rejected on same grounds HFEA authority itself sept 2005 -    employed barrister and solicitor to represent -    people writing letters to support -    5 members of authority listening to arguments vs legal expert from licensing -    challenged in high court by prolife -    act is being reviewed – asking for views on act -    gov guidelines are supportive

prob

HFEA - embryo is an egg undergoing fertilisation - “a licence under this paragraph cannot authorise alteration t genetic structure of any cell while it forms part of an embryo” (HFEA Act)

members of Committee - sharmila nebrajani -hossam abdalla - prof iain Cameron - rt rev Richard harries - Jennifer

Question&A

Doug: Warnock – act talks about genetic composition, and discuss genetic structure in relation to designer babies – this was their concern. Was not to stop research in this area. No actual prohibition about changing genetic omposition. Genetic structure not a defined . in 1989, were trying to stop characteristics of people, so that true designer babies. Warnock always in favour preventing dieases.

Peter: can you extrapolate from this to genetic modif on nucleus to prevent disease

Doug: we were not altering genetic structure – ie. Not cutting dna backbone when trying to correct nuclear gene, would have to cut backbone and insert dna . we are not doing that. Were trying to prevent disease, not changing characteristics of self. Like changing batteries in the radio.

Donald: making a value judgement.

Doug: we can transfer less mt

4.00 p.m.  Tea/Coffee

4.30 p.m  Jo Poulton, Nuffield Dept Obstetrics and Gynaecology, University of Oxford Does Genetic Counselling Help Families with mtDNA Disease?

Disagree with doug that nuclear mutation is going to be common

Clinician Started in field in 1986

What can a geneticist offer? Predict transmission risks based -    published cass -    pre-conception oocyte sampling prenatal diagnosis -    ? CVS- technical difficulties – might not be getting representative dose, or what a level of mutant is going to mean to a patient (thresholds) -    ? Pre-implantation diagnosis (trying to develop) Nuclear transplant on single cell embryos -    lots of biological questions The A3243G mutant load in blood declines over t time period between t 2 samples -    if sample heteroplasmic in blood at two different ties, level of mutant in blood can fall to 15% over 18 yrs -    counselling difficult, Chinnery Brain (1998) 121, 1889-1894 -    suppose woman 30% mutant, if met 18yrs later, would have halfed to 15%, so 25% recurrence risk -    difficult to counsel on basis of samples

why study germline segregation?

To help - need clear threshold - need criteria to ensure tha  sample would be representative

load of 9176 mutant mtDNA increases w severity - lev of mutant correlates w severity - lev in blood and other tissues similar - no sequential data to know – ie start with low to high

NOW NORMAL 3 YEAR OLD.

Refined genetic risk by samplinyg oocytes

No one in uk that have license to do it for patients

A3252G - Rory

what can we offer? - recurrance estimates? - not much info - Oocyte sampling? – possibly - oocyte donation? Availability?? Need donor. But all sisters could have been carrying variant - PGD - availability? - concordance testing > 2 blastomees (NOT JUST ONE) - low pregnancy rate: Mother 40y (do not take on over 35), D banked sperm - CVS - problem lack of info on threshold - No intervention

need to know what lev of mutant is below which might not have problems

nightmare to do CVS and having no idea about likelihood

PGD then CVS

Offered oocyte sampling, pgd, then cvs

Couple chose no intervention

Have we helped or hindered this family?

Mrs O: My opinion is that you must absolutely give people the choice

Nuclear transplant -    we must be allowed to research t interactions between mtDNA and t embryonic nucelus -    essential for understanding how mtDNA diseases o    are transmitted, cause disease -    mito abnorm likely to play role in infertility (male and female) and development anomalies -    too early toknow wether will be useable as therapy for patients with mtDNA

Sun, YH, Chen SP, Wang, YP .. Biol Reprod 2005; 72, 510-515 -    carp and goldfish -    cloned fish looked like carp -    nucleus not determining vertebrae -    in fish fertilised egg, enough cytoplasmic of rna to deterine

Question&A

Jo: batteries? Well, cytoplasm contains more

Doug: we want to transfer as little cytoplasm as possible. Mouse: Laurance Smith has done hemotyping of mice. Are they batteries?  Yes. Evidence that they are not batteries is flimsy.

Carlos: but if interacting with dna of nucleus, no evidence

Jo: mt dna must interact with…

?: question of donation. If do nuclear transplant, who?

Doug: presently, using 10%of IVF have abnormal embryos; using  these; many ivfs don’t put back normal embryos; would a mother be prepared to donate one of healthy embryos for treatment? No idea. Once people have gone through ivf, there are many that are not transferred.

Donald: not many.

?: can we freeze them?

Jo: stem cells – unfertilised egg, donor nuclei; stem cells for treat disease, could use to put into mt; expts on this could tell us a lot about early development and help focus what expts we do;

?: big demand on these embryos

Doug: consent procedure – funded by MRC – Alison Murdoch. Question is availability of oocytes.

5.00 – 6.00 p.m.  General Discussion.  Chair: Bert Gordijn, Nijmegen

Bert: study is complex; interactions are numerous. Many things can go wrong. Clinical manifestations highly varied. Disease classifications still being discussed. Treatment possibilities are v limited. Social ethical issues needs classification.

Trichotomy -    in-vitro -    animal research -    clinical trials -    clinical practice

state of the art of these different contexts

in-vitro -    can take from patients and look at cells -    take cells from patients and grow cells and look at effects on cells -    or make cells cybrids -    now looking at pluripotent cells -    ethical question: o    best way is using SL lines. o    Currently using embtyonic carconoma, but not as pluripotent as other cells o    Issues is not around these expts but using human ES cells -    In-vitro do not draw out unique ethical issues

Mark: issues with how HFEA – problem of foreseeability – science canot tell us what is trying to do

Peter: problems with taking biopsies from patients who are somewhat handicapped already?

Doug: Koreans are setting up centres around the world to do this, for motor neuron, or other

Carlos: problem is that cells do not have the disease. May analyse and find biochemical alterations, but this says nothing about phenotype. Phenotypic. This is why need to do expt in humans. Animal models are not going to help.

Doug: this is what we normally do: we have clinical trials.

Animal Research

Jo: people are trying to make mouse models of mito disease, but v difficult. Some given up. Where nuclear gene mutation, mutate mouse then clone out offspring. Japanese have mouse model.

Doug: model never been shared outside of Japan. No pathogenic that have been passed through germline.

Jo: if we can get decent animal models that is very good.

Doug: animal models would be helpful.

Kevin: other animals

Doug: mouse useful for trying treatments, but not for understanding how it would work in humans. Are free radicals ,…..

Clinical Trials

Doug: recent review of published clin trials on mt disease. There is a Cockran collaboration – visual way of assessing clinical trials. Despite fact that diseases wellknown, limited number that are accepted by Cockran. Still only a few number of patients.  For most of diseases, have around 40 people. Not large scale. How assess benefit of any agent. Is benefit because of treatment? Need clinical end points. No good rating scale for mt disease.

Special ethical trials?

Peter: maybe go back to animal trials. Do we need to return?

Doug: people are looking at effects of antioxidants on animal models. If one of antoxidents proves to be good, we still need to trial in humans.

Dog: Exercise might change mt genotype

Ruth: how?

Doug: when you exercise, you increase no. of mt. if looking at muscle when exercising, does it change proportion of wild-type to mutant? Might be able to change mt genotype by ex? Strength training – destroy muscle fibre, and stem cell grows in.  stem cells have low levels of mutation. Change in mt genotype. If we can think of an agent to bring about controlled destruction, might be able to do something.

How high a proportion of

ME: does this alter on trained or untrained?

Doug: if controse muscles in controlled way and let stem cells grow in, could be a treatment.

Jo: stem cell therapy overhyped.

Doug: more sensible to use exogenous stem cells.

Mark: similarity between mt dna

?: patient organisation

Doug: difficult problem in mtl disease. Big part is caring and sharing exp. Duchenne has similar course in many of children affected. For mtDNA, totally varied. Makes it harder to generate community. Limited develop of patient organisations. To do this properly, requires great amount of …. Problem of giving wrong information. If people just don’t understand that this varies so much, then can misinform. In US, is United MT Organisation – for parents.  Has been putting money into research. Mt disease is oft misdiagnosed, so many people go to meeting who do not have the condition. In US, has been big expansion of mt research w little clinical imput. Europe is stronger due to org of health care syst.  Not been a development of good parent patient org.

ME: because of nature of this condition, does this mean that counselling is more important.  If so, how does this inform the counselling process?

Doug: if you go on internet to find mt disease

Doug: considerable under diagnosis

ME: does this radically transform the estimated

Ubiquinone

Little evidence that you get super mitochondria -    endurance athletes – needs more studies

ME: are some batteries better than others?

Genetically influencing by using third source?

Influencing disease likelihood

7.30 p.m. Dinner in Lancaster House Hotel.

Saturday 29th October 2005

Second Session: Chair: Doug Turnbull, Newcastle

9.15 a.m.  Carlos Alonso Bedate, Universidad Autónoma de Madrid, Spain. Handling of complex diseases. An ethical and social viewpoint.

What does it mean to be complex?

If concept not well defined, can be abused. This is partic true of complexity, a concept that has penetrated a range of intelligence fields from physicas, biomed to linguistics Complexity has become a popular word that in many cases is ambiguous Complex is not similar to complicated or multiple A syst if called complex when emerges from the interaction of multiple factors and it can only be explained by that interaction (The bigger picture, tamas vicsek, july 2002)

analysis of t simple or complex - who can tell from studying single or sev neurons what laws describe intricate flow patterns of electrical activ produced by brain? Reason is that randomness and determinism are both relevant to t systs overall behjav Identical systs may exhibit almost regular behav (determ) but because they exist on edge of chaos, can also change dramatically as a result of small changes in conds

Because of Epigenesis: impossible to predict which alternative pathway will be used in a partic case but by analysis of syst possible to determine potential for adaptive change under precisely defined intial conditions It would be possible to alter

Complex systsm in physics, - knowledge of elementary particles for interpreting behav on larger scales because each new lev or scale is charac by new, emergent laws that govern it - t behav of t complex cannot be explained by t sum of t behaviour of each element taking indep - t complex phenotype is nothing more than t sum of t elements of t path but something else (health or disease)

In a new context - disease or health understood as a complex system that emerges from t interaction of simple elements that disrupt t homeostasis of t whole (disease) or maintains homeostatis (health) - in some way then t resulting phenomenon (disease or health) is an epiphenomenon

In many cases treatment (Symptomatic treat) of epiphenomena (disease ) is not going to restore t homeostasis unless we remove t insult BEFORE disruption of homeostatis or by altering some elements of the path - even in that case: the organism wil be able to heal himself only is t insult is limited and no pathogenesis occurred

the crucial thing is to understand t rules and to know t simple elements hat disrupt homeostasis - nin this view early diagosis and treatment critical

at present biomed sci are based mostly on genetic paradigm commited to idea that major diseases will be diagnosed and treated through genee technology because t disease results from genetic changes in thje key ‘rate-controlling enczyme or signal

this approach is, in theorty, applicable to true monogenic diseases only about 1.5% of total disease load

we are told to enter a new golden period of medical discovery

but since a change in evniro may alter t final phenotype it is becoming clear that geneticc analysis in itself will not serve to predict diagnos or treat disease like polygeneic cancer , or hypertension or other complex human complex multifactorial disease

medical research todat dominated by genome-centred view. Clnical discovery and patient-oriented research less common

Jonathan Res

The assumptions of tradl molecular medicine summarised as follows

Assumption has been a paradtim in

- medical genetics - molecular boil - development boil

Brenner and Wilkins, the uniqueness assumption of genetic determ

Unique genes – unique effects

Is undermined by an emerging body of evidence showing functional informational redundancy in cell regulation

1. more than one gene may specify any given function

2. single gene may specify more than one function

Drosophilia (Pumilio) bind to hunchback – induce patterning bind to Ciclin B – remain pole cells

identical genes have opposite effects on germ cell survival when expressed in t germline and soma

it is proposed that germ cell survival is controlled through comp between somatic and germ cell cWunens for an extracellular lipid phosphate

Renault et al. science, 2004, sept 24; 305 (5692): 1963-6 Epub, 2004, Aug 26

Disease

4 modes of activity that are operative 1. monogenic 2. polygenic 3. epigenetic 4. epigenesic –

conclusion -    genetic pathways specify organismal fns only in rare casese (monogenic diseases) where mutation produces dysfunction in a protein of crucial importance. In these rare cases t cell

identical genotpes may produce different phenotypes different genotypes may result in identical phenotypes

Hsp70, 83 and 90 proteins are crucial to maintain homeostasis ion perturbed conditions even in t presence of gene muitations that induce abnormal phenotypes

When t conditions are severly peru drosophilia -    stress to flies leads to different phenotypes among population -    this transferred to subsequent generations

Importance for clnical assays

1.    different genotypes bay be hidden in an homogenous popn: genotypic variation does not neces’y lead to phenogypic varation 2.    t enviro may modulate t effect of a therapy

t mapping of genotypes into phenotypes in one enviro is often completely unpredictable from their mapping in another enviro (Lewontin and Goss, 2004)

The results of a therapy in one enviro could not correlate w its effect in another

what we thought was homogenous popn was NOT

ME: does this bring into question other medical developments we currently accept

medicine research has grown as never before:

we have solved t easy problems we need new post-genomic stratic procedures to solve ‘complex disease’ can these strats be based on DNA or proteomic analysis ? – no

are these thoughts relevant for mt Diseases? -    yes o    no lineal relationship between disorder and phenotype o    no lineal inheritance -    2. Mt disease are rare

1.25% of all genetic disorders may derive from t mtl genome

-    BUT THIS IS A LOW estimate

My proposal

1.    careful mt control analysis 2.    carry out controlled transnational clinical trials used commonly used pharmaceuticals in a.    Patients w clinical mt diseases b.    In defined genetically diagnosd asymptomatic patients

All proposals raise ethical issues

Harmonization requires -    common guideline at international level for transfer of data and boil materials, sharing of biological samples, unified conditions for sample preparation and management; sharing of personal and clnical data -    open and transparent comm. Between researchers and clinicians regarding clinical and research data and their publication; start from simple and go to complex -    estabb unified protocols for transnaitional trials -    estab criteria for quality assessment and consistency -    estab scientific and ethical review boards -    admin, political and ethical consensus

ME: what bodies would you see as bringing about this consensus?

Adequate and fair human subjects selection

Prior decisions

Registration of boil materials to be used -    who is going to register t material to be used? -    Is there going to be a centralised site? A biobank? -    Unified procedures? -    Use of human biological material o    By partners only? o    Other labs outside of program? o    Who is going to control mamangement of material and exchange of this material? o    How? -    Data management – will data be open? -    Anonymous linked or/and unliked from beginnings (Pros and cons) -    Data anonymous to lab doing analysis (pros and cons) -    Each lab maintain code of their own data? (pros cons) -    Who is going to control exchange of material and how? -    Who wil correlate t data obtained w patient -    Favourable risk-benefit ratio

Questions and Answers

Carlos: 40% of genes do not have function- redundancy. PKU. Function of gene supplied by another gene.

Donald: not looking at specific effect

Carlos: yes, no specific effect. But not completely true, since with knockout mice, if infect mice, will get tremendous infection – even though not clear phenotype, not

Beard: Richard Strobeman, common conditions such as asthma, where issues about enviro factors where are then larger scale issues on public health. Where focus limited resources to control incidents of conditions.

Carlos: disease found in the phenome. Most of common diseases enviro.

Celia: what is environment?

Carlos: v grey area. Concentrate on internal factors, such as stress for metabolism. If have cells from PKU. If culture cells at 37% different from at 25%. At 37% will produce HSP, 90, 70, etc which creates correct enzyme.

Peter: need individualised medicine, ie for privileged?

Carlos: perhaps not. Perhaps common elements.

Doug: much of what you have proposed is sensible. Over last 4 yrs, EU has successfully funded two aspects of work you discuss – EUMITOCOMBAT – develop database.  Funding of clinical trials is incredibly expensive. And if most tend to be either MRC funded or EU, or many are drug companies – many of organisations are out of license. Need mechanism to fund activity, which is v expensive.

Carlos: if we don’t do this, forget about treating mt disease.

Doug: yes, but we need political will to allow us to do it.

Carlos: from Chinnery ‘ a deep understanding of t pathological….’

Doug: political side needs considerable financial input

10.00 a.m.  Ruth Chadwick, CESAGen, Lancaster University. Mitochondrial exceptionalism?

Genetic exceptionalism -    Genetic info demands special protection (cambon Thomsen et al) -    T ethical issues in genetics are different explained in relation to features of the differences) o    Nature of t info o    Predictive o    Time-indep o    Shared w blood relatives -    These critier have been advanced to support idea that is special -    But has been criticised – these features not specific to genetics -    Another version – weaker – is that has been perceived as different -    If we look at these criteria in relationship to mt, is complicated o    No time independence – relevant info can change w time o    Extent to which is predictive is v complicated o    Shared with blood relatives is v complicated

Genomic exceptionalism (look at extent to which featrures of susceptibility testing are different from genetic testing as conventionally understood) -    dhuman genome project and after o    SNPS o    Susceptibility testing o    Pharmacogenetics and nutrigenetis o    Pharmaacogenetic exceptionalism •    Allan Rose claims is much less sensitive than other genetic, because to tell someone ‘you should not take that drug’ is different from saying ‘you have a predisposition to…’

In mt genome, not a big discussion about that as there was for HGP, exception for HGDP.

In context of medicine, not same discussion about exceptionalism as there has been about gneomic and genetic

What are we looking for? -    potential conflicts of interests o    hallmark of ethical issue is conflict of interest, but ethics not reduced to this -    could be competing interests of different indivs or troups;; or different interests of t same indivs or groups o    each competing for same resource o    or different interests and cant both be satisfied, eg conflict between interest in getting some  benefit and not being harmed, cant have one without the other, need tradeoff -    vulnerabilities -    …and possible resolutions/processes of resolution

another way in which issues might be exceptional might not just be different conflicts of interest, but that require new ways of looking at problem or processes to deal with.

Prevailing individualism of tradl biomedical ethics not been adequate to deal with sorts of conflicts of interest coming up in genetics, partyl because of genetic exceptionalism because interests of people connected in specific ways. Need ethical frames that take into account these connections

In context of mt disease, ways in which interests of different family members are connected is particularly interesting, because even people with same mutation are affected differently

How are interests identified? -    Empirically o    Social science research identifying what people perceive as their interests -    Legally o    Eg. Hfea on what interests are to be protected as matter of law -    Conceptually o    What kind of being can be bearer of interest? o    Embryo, but also ‘interests’ of children as opposed to adults. L o    Logical questions of activity involve partic interests

Generic issues -    consent -    benefit sharing -    resources

Mitochondrial genome -    possible areas of exceptionalism o    nature of diseases o    research – process and implics o    diagnosis and treatment issues o    nuclear transplantation o    databases o    identity and difference o    ‘blaming it on the mother’ (gender issues)

Diseases -    OXPHOS disorders -    Assoc w diverse array of multisystem diseases – problem of variable expression – conceptual issues about how classify -    Rare – or not? -    mtDNA versus nuclear DNA involvement o    mutations in nuclear dna seems potential for massive confusion in terms of thinking about and understand the field

ME: what theory of normal underpins this classif?

Treatment strategies It is exceptional the treatment of mt disease, potential for cutting edge treatmetnts -    genetic strategies -    pharmaceutical strategies -    transplantation strategies -    germline gene therapy -    potential for novel therapies

what are t interests involved? -    what counts as success? -    Indicators – how determined?

Database issues -    different kinds of database involved: eg to facilitate associations (as in Mitokor database) o    PPP – Public Population Project in genomics. How facilitiate datasharing between biobanks in different countries. Includes debates about social/ethical o    Question for us is whether anything exceptional about mt database -    info databasese, publicly accessible o    purpose of database? To inform ,for consult?

Nuclear transplantation - HUGH Ethics Committee recognised mt diseae as an exception in 1999 - ‘given appropriate technology t avoidance of disease by…nuclear transfer may be supported provided that it is certain that a disease is caused by an error in the mt (non-nuclear) DNA’ - interesting to hear about problem of ‘where is the nuclear’. Although jo was talking about nuclear

this year, another statement on stem cells, currently considering amendment to that to deal with mt disease, but no work done on it yet.

Identity and difference -    role of mt dna in identity o    human diversity o    ancestry tracing -    what makes me me or a child one’s own? -    Difference o    Identical twins vs reproductive cloning

Yesterday, interest that Doug said about what makes children your own insofar as related to genes is nuclear dna that is important, rather than mt -    is important since mt dna inherited only from mother -    interesting to research people’s perceptions of that issue -    this is eg of exceptional mt dna has played important role in reproductive cloning debate because in somatic cell transfer (dolly) wasn’t exact copy of donor, because she had different mt dna -    important different between reproductive twins and reprod twins, commonly ignored. People oft say ‘its’ only same as identical twins’, but it isn’t

Gender -    mtl inheritance -    blame it on mother -    mother blaming self in terms of inheritance -    potential for confusions, since many diseases are nuclear rather than mt dna origin -    gender issues particularly interesting in this field -    whether people feel differently about them in relationship to other gen diseases would be interesting

Summary

What is Exceptional? -    complexity -    severity -    strategies -    symbolic importance o    identity and gender – meaning ascribed to mt dna, its role in either evol etc

Questions and Answers

Donald: why frame question as ‘exceptionalism’? can be a means of obscuring or dismissing. GM was seen as selective breeding early on. If GM crop product seemed to have no detectable difference, they were substantially equivalent. Only question is ‘is it different?’, but this obscures other issues. Why ‘excpeiotnalism’ rather than just ‘what issues does it raise’. Eg. Nanotechnology issues similar to other things, but let’s look at them anyway. Why start with exceptional case.

Ruth: I accept what you say. I don’t think identifying what is special about an area excludes looking at other aspects. At practical level, if want to research issues, need to estab what needs to be done.

Donald: question is research funding generated – show ‘we need to do this, because it’s different’

Ruth: would not have got funding if was nothing different about it. Approach includes presenting ‘what is special’ and ‘what is different’.

Doug: gender issue. I seee what happens to mothers who have children who die. Do they feel different from mothers of children who die from other genetic disease? I don’t know. A lot of mothers who feel tremendous guilt. Is it more, less, different?

Carlos: two cases in spain, tremendous depression because they know they have transmitted disease to children.

Doug: but is it different?

Celia: been talking to people going through PGD. True in general that women feel more guilt about children dying. Women take more responsibility. Patients make distinct between children they knew had genetic disease and future children. People that end up in pgd are people who would find prospect of same situation worrying

Doug: any difference between relative consequences of different genetic disease (autosomal or x linked)  for mothers

Celia:

Peter: mt might not be an exception

Celia: might make men feel different

Beard: comparative point. Charles Rosenberg – in 19th c, inheritance environment debate placyed completely different fashion – inheritance as a given – nothing for which you took responsibility. Samuel Smiles self help was focus of responsibility. Attachments of responsibility completely opposite

Doug: but now we have more control over genetic factors. Debae over whether should do pgd for mt disease. I feel v strongly that we should. Guilt of leaving it to chance.

Celia: guilt is produced by chance.

Doug: but making diagnosis produces the guilt.

ME: but guilt is only one condition that can make people feel bad. Fate. From Chance to Choice, or From Fate to Guilt. How do patiens reconcile the inexplicable? (as fatalistic, bad luck)

Ruth: informed consent functions in different ways.

Doug: what interest of animal has

Carlos: since many of mt are late onset, but can be diagnosed genetically, we have case where can predict, this makes special case. By modulating biochemical phenotype, could prevent onset. This is particular in mt. no other diseases, where person genetically diagnosed can be homogenised as well.

Doug: but for huntingtons,e tc, basis of therapy is to treat early.  Treat asymptomatic

Carlos: but maybe Huntington will be mt.

Glasses: how move towards harmonisation?

10.45 a.m.  Tea/Coffee

11.15 a.m.  Donald Bruce, Society, Religion and Technology Project, Edinburgh "Have you been talking to one of your mothers again?” – Mitochondrial Nuclear Transfer, Identity and Ethics.

Quote is taken from a song ‘the reluctant cannibal’ ‘(flanders and sawnn, circa 1956) -    expresses media fears -    child with three mothers -    makes a very good headline -    ignites ethical flashmpoint

Donald Bruce -    Society, Religion and Technology Project -    Set up in 1970, Church of Scotland, working ecumenically -    Full time scientific director -    Exploring ethical issues in current and future technology -    Engaging technologists w ethical/social implications -    Informed and independent assessment to policy makers -    Stimulating balanced public debate -    Discussion and policy making within the churches

Dolly: an icon for biotech -    promise and threat of biotech o    potential of what we could do o    fears about what we might do -    Roslin focus: cloning as tool for animal GM -    Media focus: human reproductive cloning o    Associations from scifi – good story lines -    Scientists insisted – not what cloning was for o    Vocal in protecting any ‘therapeutic’ uses (Winston, BMJ, 1997) o    Especially treating mt diseasee

MTl transfer: a daunting ethical cocktail? -    exptn on embryos -    nuclear transfer: cf reprod cloning -    multiple genetic identities in reprod -    genetic modification of human germline -    risk of nuclear transfer -    who/what drives research – need or technique? -    Accountability – should HFEA have consulted public or parliament before licensing?

Basic ethical questions raised -    when does human life begin? -    Limits to reprod intervention? -    What is nature of a human being and identity? o    Eg genetic or holistic -    Should we change human genome or untouchable -    To what ends? -    Social ethics, justice, drivers, powers, winners, individual/social

Mitochondrial tansfer: expt on embryo -    embryo status is critical issue -    if fertilised egg has moral status of person, then procedure completely unacceptable -    if embryo has ‘special statu’s research is not ‘anything goes’ but ‘no, unless…’ – cannot research, except for… -    two embryos to produce one baby o    putting an embryo to a different use than reproduction o    sacrificing t potential of one – non-trivial -    beware reducing human embryonic life to a status less than lab mice

mitochondrial transfer: nuclear transfer -    nuclear transfer but not reproductive cloning o    manipulation of eggs already fertilised o    not asexual reproduction of existing person o    Dawson report – not the same thing as cloning -    More like IVF w modification than ‘cloning’ o    Swapping cytoplasm and nuclei o    Still radical -    Confusion identity -    Significant risks -    Confused perceptions also?

ME: do confused perceptions warrant prohibition?

Mitochondrial transfer: multiple identities in reproduction -    embryo w genetic material from three people o    compared w sperm or egg donation? o    3rd party intervention in genetic bond or parents (chutch Scotland worried about osing bond) -    how much do mt constitute identity? o    Are these 37 genes common to all o    are we merely changing batteries o    matter of degree or absolutes? ME: I still struggle with the idea that my batteries are not my identity

-    how much do genes constitute identity? o    Reductionist or holistic accounts or identity

Not as big an issues

-    identity more than genes, but where draw line?

Mitochondrial transfer: human germline GM -    germline therapy highly controversial in bioethics -    1992 Clothier Report: UK says ‘no’ for time being -    nuclear transfer cloning provides new route o    Polly (July, 1997) – nuclear transfer + GM in sheep o    Target GM and gene knockout possible (sheep, pig) -    Human germline by nuclear transfer? o    Feb 2004: Ian Wilmut speculates future use of reproductive cloning for germline gene therapy o    Mitochondrial transfer as potential applic (1996)

Mitochondrial transfer: germline therapy ethical problems -    permanent inheritable genetic change o    informed consent impossible; inter-generational issue o    no right to force genetic change on all future offspring o    deep concerns about non-medical human GM o    does extreme genetic disease make an exception? •    Would future person say ‘why didn’t you’, rather than ‘how dare you’? -    High risks involved o    Micro-injecting human embryo; germline DNA intervention -    Clothier (ethical’ committee judges solely on risk, not  ethics -    Expt to solve t risk would be unethical o    Would need to make future humans research subjects

Is mitochondrial transfer a germline change? -    yes, it changes inheritable dna -    it is not nuclear dna – does that make a difference? o    If mt not tied to identity, does it matter? o    ‘relatively modest’ change to human genome (Donaldson) -    What is t ethical issue? o    Making permanent change? o    Degree of change o    Type of change?

Mt transfer: is it just changing batteries? -    reductionist claim o    makes a (hidden) value judgement o    changes t discourse from inherent to functional o    is CF gene therapy ‘just changing chemical signals in t lung’? o    is athletic enhancement just functional? -    Is it ‘just’ batteries – if mt do moer than make ATP? -    Beware of so focusing on t medical/technical objective that close mind to wider issues  cf. GM – saw what gm was for and neglect wider issues -    Case for mitochondrial germline change not yet proven

Mitochondrial transfer: other issues -    risks of nuclear transfer o    IF mt are box of genes o    Is it safer/riskier to change complete gene set than 1 gene? o    Risk of nuclear transfer procedure – serious issue o    Do you know t quality of donor egg? o    Unpredictiability of effect? o    Is it possible to anser risks without running them? -    Who/What drives research – need or technique? o    If for people withj condito, is it best way to address need? o    Or is it technique driven? -    Animal research issues -    Acccountability o    Should HFEA have consulted public or Parliament before licensing? o    Cf sex selection.

Questions and Answers

Carlos: in conversation with Wilmut, Dolly not perfect copy, since variation occurs. Dolly was not at all  a copy – nuclear genes were not the same. So, careful with nuclear transfer – which cell is used? Because mutations can be tremendous, compared with mutations in early embryo. If take from fibreblast, thousands of mutations which do not influ function of fibreblast, but not embryo.

Kevin: any position on the ethics of mt?

Donald: not yet. Question of identity

ME: what do you think would have happened? Question about public consultation? What should be the criteria/mechanism for establishing whether public consultation is required and what structure should establish that? Ok, perhaps the HFEA, but if they all agree?

Is the division of opinion within the HFEA the justification for public consultation, or is it questioning the foundation of the HFEA legal authority to make this decision? If the latter, then what form should public consultation take?

Doug: encourage to engage with public consultation predominantly through the media. Pressure for patients to tell story to the media.

Doug: doesn’t have to be germline gene therapy. Could stop this by just allowing male births. With sex selection being allowed.

Glasses: may not happen in uk, but will be done elsewhere. If perfected elsewhere where lower ethical standards, then this is going to become used in Europe.

Donald: is this a thought expt? Will germline be so thoroughly explored.

Glasses: if look at importance of biotech in south east asia, then likely that will.

Donald: from UNESCOs point of view, is degree of international pressure. If some country presents it

Doug: some techniques are being developed in other countries.

12.00 to 1.00 p.m.  Discussion. Planning for the future.  Chair: Ruth Chadwick.

Promised scoping paper on social and ethical issues.

EU project (EUMITOCOMBAT). Will report back to coordinator on proceedings of the seminar.

www.eumitocombat.org

potential for doing something else. Setting up a project, for which we might seek further funding.

Develop cesagen project linked to European project and other interested parties

Scoping paper -    have made progress on the issues -    New Jersey version of the therapy (cytoplasm) o    Doug: Jack Cohen – improve fertility of oocytes of women. Injected cytoplasm, children born with lower amount of affected. But evidence base and ethical base lacking. Banned by FDA. Don’t think this would work, since would not be able to transfer enough cytoplasm o

Mark: can mt dysfunction be desirable

Doug: some evidence that allows us to adapt to cold.

Workshop will prove to have been useful.

European project

Ruth: are there particular issues with European. Eg. Euroean database.

Doug: what information should go on the website? Eg. Information for patients, families, access, etc. language? Basis of information?

Celia: dipex website – putting online social scientific interviews with patients, video and audio files.  For patients and social researchers.

Donald: engaging w media – can do nothing with tabloids,

Beard: but cannot assume that is such a big deal

Doug: relate to Carlos and clinical research. Needs to be continued. Are centres that specialise in …..  until understand more about disease and patients, cannot understand. Need to continue EU funded projects where we have…

Mark: jurisdiction shopping in science. Need review of ethical frameworks and regulation of this area of science across nations.

Ruth: for mt disease?

Mark: question of regulation and transfer.

Ruth: HUGO ethics committee wants to do some work on nuclear transfer. From Doug Wallace.

Carlos: CoE approved popn biobanks exchange last week. Minister still have to approve, but big consensus. Disagreement regarding scope of recommendation. Some delegations wanted to include biological materials for embryo and foetus.

GlasseS: will there be a European wide regulatory body

Carlos: v difficult. Even in spain difficult. Next week, in London meeting of represn of national ethics committee.

Donald: unesco docs from ibc may have covered some of these questions

Donald: my presentation was on the assumption on therapy, rather than research towards therapy – important to make distinction.

Specific recommendations - patient information - regulative - distinction between research and therapy - gender/identity issues -

Doug: big push now is to find nuclear dna mitochondrial mutations. We focused too much on mt dna. Patrick searching for nuclear/mito interactions. Mt genetics is very different. Need cohorts of patients regardless whether nuclear mt or mt dna.

Bert: orphan disease and justice.

1.00 p.m. to 2.00 p.m.  Lunch

Ethics and Philosophy of Future Medical Technologies (2005, Barcelona)

Ethics and Philosophy of Future Medical Technologies, Aug 2005, BCN. Thursday 2pm

Life Extension Session

What does the community think? An Empirical base for philosophical and ethical debates about life extension Lucy Carter, Jayne Lucke, Bree Ryan & Wayne Hall (Australia)

T science - successful life extension in model organisms - suggestion of human applications within 10-20 - possible of pharma therapies to extend life span (strong life extension) - biomedical advances to treat disease and maintain health (weak life extn)

caloric constriction – reduce calories by 30-50% extn life by up to 30% in mice -    if we promote thi, not good for adolescents -

maximum life expectancy has not advanced at all

Policy implics -    global, popn and fertility control, work and employment, superannuation and pensions, health and life insurance, regulation of antiageing industry, health and social (disability) services, end of life issues

Public Opinion

Assumptions -    people are repulsed by the prospect -    huge demand for life extn

no empirical data available despite t importance of public opinion in policy development

this study -    examined public ustdgs of life extn -    aiomed to provide empirical data to controbitute..

Questions

How do members of t public understand t possible for inc life expecracny How likely is gen publ likely to take up What are the mpotivations that influence intentions

Method

Structured indiv interviews

Sample -    31 men and women, research registrer for over 50s -    11male, 20 female -    18 aged 50-65, 13 over 65; -    14 had tertiary ed

Do you think that new technology will be successful in extending life span? -    ‘Yes’ this has already occurred o    sources: •    biomedical devevlops eg spare body parts •    research eg. Genetics, applic of model org findings •    lifestyle improvements, eg diet and activity

Limit to life extn? ‘ as a mortal being you are programmed to die at a certain time. Despite what technology might b able to do wof you to make you healthier, there comes a cetain point where that’s it”

Concern about cost “ I would be concerned abgout being a drain on t economy of t country – living on handouts – and this is t b

influ of family and friends ‘ I would like to extend my life because I married late and I’m not going to see my grandchildren;…

If you were offred some technology that made you live longer, would you use it -    95% declined

ME: what comparative qs and studies could be used here?

Comments from older pop seemed more concerned about quality, younger still concerned about the way they looked

Qual of Life -    health is paramount

looks not a high priority -

findings show 1.    people are concerd about issues to do w life extension and eager to talk 2.    range of opinions, but QoL paramamount 3.    intervention that did not enhance health less popular 4.    looks not important

Limitations -    small sample, characs of sample, exploratory qualitative study -    confirmation reqd in larger study

Who wants to live forever? 3 args against interventions in biological ageing Carlo Leget nd Martien Pijenburg Radboud University Medical Centre, Nijmegen, NL

Distinctions

Chronological ageing – calendar time Biological ageing – process of decline

Goals 1.    prolonging natural life span 2.    combating defects and disease that re intrinsically connected  w biological ageing

Args so far

1.    risks/dangers 2.    financial burden 3.    social injustice 4.    risks of overpopulation 5.    societal side-effects (medicalisation, pressure, evasion, genetics)

observations

never positive args, only rebuttal of negative args treat of args is separate ‘more of the same’

this paper: coherent alternative viewpoint – 3 args against

1.    dimension of time 2.    social nature of human 3.    value of global justice

1.    the time dimensions

time is seen as an object – more one has, happier one is

but time is not an object

we do not exp time, merely ourselves and the world around us

ME: no, it is brought into being – revealed – through systems of measurement. We do have these systems

Paradox: more life is expd as meaningful, more one’s perception of time vanishes – when completely absorbed, time flies

We don’t seek more time, only more meaningful experiences

ME: who needs to many os?

Spiritual

Decentrered self

Meaaningufl life as eternal

Decentred = no interest

2.    the social nature of human

life = living w others meaning of ‘with’? -    indep, stand-alone indivs (liberalism) -    members of a community (communitarianism)

liberal -    negative freedom ‘absence of barriers’ -    self-interest -    negotiations -    instrumental value of t other / t community -    goof life FOR ME

communitarian -    positive freedom: possibilities to act -    common good -    social context as precondition for a human life -    t good for me includes for us

ethical justif -    liberal: autonomous choice -    communitarian o    social network as condition sine qua non for human life o    morally good life includes living in communities and meaningful relations

quality v quantity

- life-extending e only valuable if it benefits all – our – networks - unrealistic perspective since networks exist in diversity and worldwide

‘People do not want to bury their children, so should be  open to all!!’ -    ME: this statement draws from a well known popular view and completely takes it out of context so as to be meaningfless

3.    ethical dimension: global justice

expectancy

Canada: 80; Malawi: 40 -ME : yes, but Malawians have sex a lot more! Under-five mortality Norway: 4/1000; sierra leone: 316/1000 75% HIV infected in Africa (more than 27 milions) 12 million orphans

What moral obligations follow from justice?

“If immortality or increased life is a good it is doubtful ethics…. Harris, 2004)

Objections -    immortality only a good as a life in meaningful time and relations -    life extending technology is not an available benefit yet -    question is whether we should choose to develop it

Global justice -    including equitable access for all and promotion of the common good -    broadinig t moral agenda towards justice of institutions

life expectancy as a moral challenge

discussion

1.    to improve t life expectancy of millions that die at 40 outweights by far t relevance of expanding t life o 80yrs old people 2.    how balance between broading and limiting t agenda of bioethics

Conclusions -    3 args against, stressing social nature of humans -    args against interventions in biological aging -    also relevant for other medical technologies

Living LongeR: Ethical aspects of age retardation

Elisabreth Hildt

Intro Age-retard ethics Age retard and autonomy -    informed consent -    self-creation -    determ of course of ones life conclusion

Intro Age-retard ethics -    risk benefit ratio, beneficience snd non-mal -    autonomy and freedom from time constraints -    biological life cycle -    atts towards ageing, death and morality -    chang in family rels -    aging of soc -    justice

Age retard and autonomy -    informed consent o    info transfer; freedom of choice o    adult and competent persons -    self-creation o    transformation of the self o    personality traits and personal identity o    authenticity -    determ of course of ones life o    creation of a full and active life o    some drawbacks •    sense of time •    extended period of old age •    implics of widespread use o    family structure •    growing up and role of family •    formative influ of older generations •    role of trads •    independence o    structure of soc •    concentration of power and authority •    flexibility to change •

Age retard and autonomy -    autonomy does not solve question, might even be arg against techniques -

Controlling Human Ageing: Alternative Rationales and Impications Robert Binstock, Jennifer Fishman, Eric Jeungst

Grant from NIH on implics of anti-ageing interventions

The Politics of Presentation -    how one presents what one is upto in antiageing science can shape regulation/funding/priority

The Fountain of Youth: A Perennial -    today: o    anti-aging entrepreneurs and longevity practitioners (medicine) o    biogerontologists (science)

why is antiage med flourishing? -    Post WWIII baby boom -    Only light regulation on anti-aging prods and services -    Internet sites for marketing -    Dozens of antiaing how to -    Market 64bilion in 2007

Youngevity.com -    the anti-aging -    Patenting Antiaging miracle minerals are called -    ‘The Vlicabamba mineral essence’

American Academicy of Anti-Ageing Medicine (A4M) -    provides board certif. for practitioners of longevity med -    13000 members -    70 international and national conferences -    2million hits per month on website -    net asserts from $65k to $3.5m

RRonald M Klatz ‘Ten Weks to a Younger You’

Biogerontologists -    40% extn In av life expect and mx life in dietary caloric restrictuions (CR) expts -    development of CR mimetics -    genetic interventions

scientific legitimacy of biogerontologists is shakey -    little better than charlatans -    gerovital, anna aslant and nikita kruschev -    in US, National Instititue on Ageing (NIA) in mid-1970s path to legitimacy, but still fragile

War by gerontologists on Anti-Aging Medicine -‘No truth to the fountain of youth’ - published online (CHECK!) - SILVER FLEECE AWARDS TO A4M – for misleading public - continuing publications and media appearances - boundary work to disting themselves from t illegitimate antiaging med movement ‘Those who have legitimate…. R. Miller’

Similarly A4M seeks legit -    denigrates ‘gerontologist estab’ -    files lawsuits against specific …

Ideal models of aging seniors

Imagery beyond boundary work -    the politics of presentation has important social implics -    3 rhetorial strates for defining aims of anti-aging prods, etc o    1. Med tratement o    2. Enhancement o    3. Prevention

1.    med treatment

eg. A4m: reating maldadeies of aging -    moral authority and prof autonomy of med prof

renews debate over whether aging pathological or risk factor

2.    enhancements

‘stay young’ restore mental and phys capacities that decline w age politically, this rhetoric takes enterprise out of biomed realm -    outside of med prof and gov reg

provokes criticism from bioethicists’not natural’ and tf unethical

beyond therapy (2004)

3.    prevention

forestall chronic health probs, associated w aging for as long as possible strategy avoids criticisms of unethical enahcnement skirts debate over whether aging is a disease

embraced by gerontologists

want to be seen as ‘the good buys who favor…..R.Miller essential for maintaining and enhancing funding for further research

internecine warfare against propoent of enhamcenent – Aubrey de Grey, ‘virtual immortality’ is achievable – claims possible to only die from apoptosis - European Journal of ‘Resistance to debate on how to postpone ageing’

‘We are gradually, much too gradually ….’

The Politics of Presentation: Issues for Empirical Research

Tretment -    will treatment rhetoric by anti-aging entrepreneur and clinicians lead to control by org med? -    Or, will org med engage in boundary work, as t biogeront

Enhancement -    will enhance rhetoric lead to political movement to curtail interventions?

Prevention - does prev rhet succeed in strengthening scientific status of bioger

Friday 26 Aug

Therapy & Enhancement Ruth Chadwick

Disagree with Bayliss definition of enhancement, must disting between improvement

Inevitability thesis is incomplete

Moral argument fails to account for context

Instead, improvement should be focus, but wheth enhancement is improvement depends on context

Eugenics revisited

Negative v positive

Enhancement just eugenics repackaged

Disting between germline and non

Eubionics: the pursuit of bodily perfection – negative and positive -    McNally

Negative eubionics – elimination of body Positivev – pursuit of bodily perfections

Case by case?

Beyond therapy US Pres council -    argue for case by case

enhancements 4 approaches -    beyond therapy -    additionality view -    improvement view o    if qualitative, but if enhance to such an extent that X (human) no longer exists as a category -    umbrella view – enhancement just convenient label for number of interventions

limitations of enhancement/therapy distinct -    enhancements likely to arise from therapeutic med -    this will be difficult o    ME: why?  Drug regulation

Beyond therapy probc definition -    Therapeutic intentions? -    Therapeutic effects -    Evidence based therapy -    Proper scope of medicine -    Indiv vs species issue

Norman Daniels: eliminating shyness relies on understanding cause, which is complex

Why should we be more concerned w cause of condition than suffering

Enhnancement and the self

Baylis and Robert -    ‘the resulting alterations may be conservative (ie used to normalise the self), liberal (i.e used to liberate the self) or radical (used to fashion a self that effectively challenges others’ conception of oneself)’

what would count as a preventive therapeutic intervention? -    preventive mastectomy for woman with strong family history -    since we don’t know whether it would arise, can argument is therapeutic, but also as reassurance -    main aim is to reduce risk status -    counterintuitive to speak of mastectomy as enhancement -    need more to concept of enhancement that just beyond therapy

Norman Daniels, Species typical functionign

While enhancement is always characteristic specific, whether something is improved or not requires a judgement -    good eg. Is height -    depends on what we are trying to achieve – context

improvement should not be included in any definition of enhancement

the inevitability thesis

baylis and roberts -    contemporary Western democracies have no experience with permanently halting the development and use of any enhancement technology on ethical grounds.

What doesit mean that it is inevitable -    if simply that someone will try it, not interesting -    ‘despite the likely failure of particular genetic enhancements, there are some among us who will inevitably attempt to engineer the human genome8 for the purpose of improving Homo sapiens.’ Bayliss and Robert

rape and murder doesn’t stop but doesn’t mean not worth trying

they distance themselves from empirical slippery slope argument -    not clear that views will become more liberal

Ithe future is ours for the shaping, tf genetic enhancement inevitable -    an ‘avant garde’ portayal of human nature o    ME: what not merely health improvement?

Perfectibility different from enhancement

Moral Arguments -    boutique model (individual) -    species approach (collective)

boutique model -    Abdul Adah

Central question is whether medicine resources should be used here

Spectrum of positions -    wrong in itself -    injustice arises -    not a priority -    morally required

Habermasian concern not mentioned

My view is that enhancement permissible in certain conditions

From an impartial position, if can improve, we should make it -    but judgement about what is improvement not easy

no gains without compensating losses

consider context

sport

Aristotle -    if ten pounds are too much for a particular person to eat and two too little, it does not ffollow that t trainer will order six pounds; for this is perhaps too much for the person who is to take it, or too little too little – too little for Milo, too much for the beginner in athletic exercises

whether improvement first depends on context of sport, then internal good of sport

with human ‘improvement’ overall

3 areas in need of consideation

1.    enhancements which undermine t possible of moral agency are not morally permissible

but does either the fact of design or the nature of a given enhancement have this effect?

2.    wht si the relationship between moral permissibility and improvement

is improvement a necessary and/or sufficient condition -    if enhancement did not improve, but did not worsen, might also be permissible -    not sufficient, since issues about distrib

3.    priority should be given to enhancements which reduce existing inequalities

morally required?

Important issue not disting between therapy and enhancement, but whether is improvement -    depends on context and purposes

does thinking about whether it is an improvement overall contradict the context specific position?

There has been a huge trend towards public engagement about ethics -    ME: what does she mean by this?

Nordenfelt, L Honorary Session

Nordenfelt

Health goal as medicine

Edmund Pellegrino and David Thomasma in their book Philosophy as t basis of medicine 14, p.26 -    medicine is an activity whose essence lies in t clinical event, which demands that scientific and other knowl be particularised in t lived reality of a particular human for t purpose of attaining health or curing illness through the direct manipulation of t body and in a value-laden decision matrix

other goals exist – saving lives and QoL, health is central goal

task of interpreting health remains

contemporary philosophy of health determ from scientific point of view -    some argue they are value free and descriptive

Christopher Boorse and Thomas Schramme

BST -    ‘a disease is a type of internal state which is eitheran impairment of normal functional ability, eie a reduction of one or more functional abilities below typical efficiency, or a limitation on functional ability caused by environmental agents’ Health is identical w t absense of disease (Boorse, 1997). -    Ill if probability of survival lowered, or…..

‘health is a state in which we neither suffer from any evil nor are prevented from t functions of daily life’ (galen Ars Medica 193AD)

main rivals – in positive tersms

boorse health bst -    A is completely health, iff , all organs of A function normally, ie if they, given a statistically normal enviro, make at least their statistically normal conttrb to t surviaal of a -    A has a disese, iff, there is at least one organ o As which fns subnormally, given a statistically normal enviro

Holistic theory -    A is completely health, iff, a has t ability given standard cicrcums, to reach all his or her vital goals -    Notion of a vital goal is crucial -    Standard circumstance = different from statistical o    related to a cultural norm -    ‘A has a disease, iff, A has at least one organ which is involved in such a state or process as tends to reduce t health of A. t disease is identical w t state or process itself.’ -    Tends to reduce t health of A – sleected since not all diseases compromise health in relationship to vital goals -    Some maladies can be aborted before they have influenced the bearer

How reconcile these defns?

2 stories

genuses of probable health by considering illness and disting between illness and disease -    percevived problem

in the beginning…

illness recognitionand illness communication the illness language illness experts – doctors did not rely on stories from people who were ill, but looked for causes doctors found regular connections between states and symptoms and fourmed hypotheses designates causes as diseases

disease recognition

a quasi-historical sketch

concept of illness primary to disease

problem to be solved

causes assumed to exist within b or m

illness need not entail threat to reproduction

often concerns pain, suffering or disability subject often believes internal cause thus, human disease relationship to suffering and disability, not inc probability of death

3.    standard medical encounter today

john, pain stomach, sees doctor, presumes illness, pain  indicates this, and observes he is prevented from working

doctor examines, when convinced of nature, will find cause in organic function – organic disease, but not for own seek, not any old malady, needs cause of problem, then treats it in relationship to contemporary art, when successful john is healthy – no longer feels pain and can work as usual

thus: health concept used is variant of holistic – -    estab of fact that he is ill does not rely on diagnosis, john can establish through his own exp of illness -    ME: is he not doing what the doctor does? -    In favour of hgh

Endorse idea of reverse theory of disease XXXX - Josh Congilen? 1943 – Wilford 1989

illness recognition essential, but to avoid misunderstanding, illness need not have occurred in individual case, but disease not discovered unless someone in history who had similar case

Disease (holistic) = bod or ment process which is such rthat it tends to cause an illness (understood as a state of suffering or disability expd by the subject)

ME: presumes sincerity on behalf of subject

Gaylin and Resnik – illness caused by suffering or disability

Ability/disability relevant concepts than well-being/suffering -    pluralist notion of health? -    Do not deny relevance of well-being or suffering, but philosophical technique requires that Ockham’s razor (simple and as universal as possible), ability and disability most potent

Differences

In bst, health is entirely internal In holistic (hth) – goals and other abilities (not just intentional), but ability to perceive, feel, etc

In bst

In hth – extr

In bst – health identical w absence of disease, hth health is compatiable w t presence of disease. T concept of disease is, however, logically related to t concept of ill health (or illness) and also according to t hth. A malady is defined as a state or process which tends to reduce its bearer’s health

Hth – whether person as whole, whether can achieve goals -    goals differ: survival, QoL,

Thomas Schamme

2 theories of health of importance to philosophy of medicine, nordenfelt and boorse

defence of naturalist is critical discussion of nordenfelt

nordenfelt includes too many phenomena in definition of ill health

conclusion: analytical framework of naturalistic view should obtain conceptual priority

nordenfelt focus on concept of health, instead of its contraries – illness, etc

starts with health, which is unusual since typically easier to agree on disease, whereas health more contested

Fullfort focuses on illness, Nordenfelt on health

Cannot identify illnesss unless have view of positive health (nordenfelt)

Critique of N, say something of conceptual priority, but Fulford’s argument is non-starter

Fact that we usually observe illness before seeking explanation has no bearing, merely epistemological effect, -    priority in this case not about temporarlityu

dubious to ground medicine on particular goal (individual health) without idea bout what that signifies

must disting between fullfulling positive health

we might mean positive or direct definition of health – not a lack of something

eg. Boorse says absence of disease, but also positive definition of health

or give more than minimum

other examples, such as freedom – different between positive or negative -    state an ideal, not just minimum -    or ideal/true freedom

if apply this to health, WHO definition states both positive definition and positive conception

nothing depends on wherther we give a positive definition of term -    eg. WHO definition as negative, does not lose positive ideal definition o    ie. Health is merely t absence of disease and infirmity, disease and infirmity are states when complete phys and mental .. is lacking’

common mistake to want to talk about positive health, but then people talk about ideal health, which is different

is N ideal or positive?

N might open way to positive, because includes criterion of individual goals, but he adds a restriction by clarification – ‘vital goals whose aspiriation for minimum happiness…so to count as healthy…good health does not imply ability to become completely happy’ – is less extensive than WHO

But still too wide since coveres disabilities that are not ill health

Paradigmatic eg. – -    Lily, an athlete who struggles to becom accomplished high jumper, but does not succced, wants to jump over 2m, not to succeed means not minimally happy, but even sad, though N says minimal happiness not sufficient, but disability is crucial. Lily is unable to realise at least one vital goal. Still, we would not call her unhealthy or in state of ill health, since not a disease, which would be indep of ambitions.

3 possible responses from N - 2 ambitious goals are ruled out by theory. If goal is unreasonable, cannot count as necessary. N opts for objective accounts, but discusess counter productive and trivial goals. - ME: doesit change if Lily wants to be a doctor? - 2. Must lack a second order ability,ie. We could help her by training or education. - 3. Let’s accept she is not unhealthy. But must not discuss as counter intuitive, because is a welfare theory. Nothing left to argue about. Nothing wrong with this definition, but state reluctance to accept. Welfare theory not approp since health is a medical term – end up with medicalisation of all problems

cannot refer to all people who are unhappy just because cannot fulfil goals as ill

must rely on medical normality

we need distinc between 2 interprets of health 1.    taking account medical science (boorse) 2.    grasping eval of medical conditions (normativism)

since normative is logically prior for N, cannot understand why healthXX

from perspective of medicine science people w same condition are both unhealthy

N proposes ideal which leads to medicalisation

We need scientific perspective to restrict

Defence of naturalism qualified by restriction of particular perspective of science -    naturalism must be supplemented by normative, but cannot be removed

G Khushf

Situate health concepts debate in slightly different state

Beginw observation of the debate which is puzzling -    urge to return to Boorse -    Boorse’s work seems to be situated in theoretical biology, but in theoretical biology, nobody cites boorse -    Why does Boorse play such a role in this debate

Need to see how health concepts have been a lens for models in medicine science

Use debate as a lens and look at background context, to suggest that we have real traction.

It is now moving forward

N has made t contribution that enables us to go forward

Rather than argue with Boorse, argue w N.

Science depends on social conditions, but these conds remain implicit

Division of labour between administrators and practitioners of science

Sustain myth of fact/value divide -    colour all features of scientific landscape

medicine not immune to this divide -    in hyperform

consider division between clinical practitoeners and adminitstrators of health care

inc role of administrators

implied that scientifically based practitioners determine what is medically indicated, then negotiate treatment in accord w patients values – this is essential

contrast, admin provide economic circums – estab the conditions

but they are not supposed to influence

these are manifest in ethical deliberations

eg. How are patient’s views Integrated in medical decision making

patient autonomy does not mean equality with physician’s view

physicians are masters of means

eg. Medical futility – approp and inapprop domains of patient autonomy

thus, fact value divide in 2 features of modern medicine -    admin (value)/physician (fact) -    patient autonomy (value)/clinical interaction (fact)

health and disease

appreciate importance of boorse

examine core features of boorse account -    value free and scientific -    broad social and individual patient values are second strand influencing treatment -    socio-economic factors should not play rolein determining disease o    historically problematic: eg masturbation, etc

if focus on these rubricks, we find his position compelling

Nordenfelt -    appreciated predicament fasced by critics of Boorse -    shows why disease canot be value free, but understand sympathy for Boorsian project -    not coincidental that Boorse has taken the BST term from N and uses it to characterise his own theory

focus on deep resonance between Boorse and N and suggest they are much closer

N view of medical science - health concepts tied to human ends, not survival and reproduction - both he and boorse share fundamental assumptions - both think we can tease out the factual and evaluative and applied science involves reasoning and guard against values - N argues health conceptsa re PARTLY evaluative so must speific where they end - onec we do this, can use as basis for empirical eval - does not question purely empirical investigation what marks of end of the domain -    once end is given can apply to realise that end

can understand why health concept is primary -    allows clarification of the end, which is necessary tyo estabg proper role of medicine

health concepts functional analogue of medicine -    mark of legit from illegit

N’s wants based notion of happiness -    focus on: ends integral to medicine are individually relative -    approp values are thus this or that patient, not patients in general -    ends of clinical encounter specified by patient/physician interaction – allows specification approp treatment -    health concept specifies role of…. -    N upholds core features of Boorse, but sustain value ladenness of Health and disease

Nordenfelt should be seen as biomedical ideal

1.    contrast classes for situating the debate

in one of Boorses early aarticles, presents naturalist, weak naturalist, and strong normativist (pure constructivists) -    these are linked to Boorses health concept -    wanted to disting legit (weak) from illegit (storng

but this clouds the debate hard to find anyone that does not have no descriptive -    everyone is a weak normativist

core difference between N and B

new definition of weak and strong -    weak: can disting between fact and eval components (medical v non-medical), while see values as integral, share w naturalist role of descriptive -    strong: not possible to disentangle fact and value in this way. Seek to show how diverse values configure health concepts

Conclusion: new context

In current context, see shift in whatmakes debate important Until now, has been disconnected from trends in medical practice Health concepts incl’y important

Changes in medicine

Eg. Manage care and total quality review

Now being incorporated into standards of care Overlap between admin and pract

Some see as distortion of medicine – economic

Challenge to classical jurisfictions of medical practitioners

Debate also reframed -    is it possible to disting sociopoliticaland economic from microethic of clinical encounter?

Strong normativist is best? (ME: did he say this?)

Cannot sustain neat fact/value distinc in classical form

How to appropriately address in management strategies?

Nordenfelt Reply

Reply to Schramme -    priority of health -    S says order is solely epistemological not logical priority, so fact that we observe before diagnosis says little. Hwr, purpose was not about logical priority, it is health that is logically prior. The observation temporal priority that Bill fulford has argued, not just epistemology, also bearing on conceptual substance. In doctor patient case, we have paradigm case of HC. Tells us what is at stake in the encounter  - patient’s disaibity and suffering. Fact that we label that as disease, tells us something about concept of disease. -    2 arguments: o    1. Ought to be able to explain why someone canbe medically abnormal, without being badly off •    answer: do not claim that all diseases produce suffering. Consider various stages of disease. But for it to be called a disease in the first place, must in some if not most, result in some suffering. o    2. Must be able ot explain why someone is ill and not simply sufferinf from other impairments, such as loneliness, etc. idfs that we include too much. Someone hwo is sad or unhappy will be labelled ill. EG. Lily the athlete, who cannot jump 2ms. She is obviously healthy, says Schramme, so theory inadequate •    answer: talks about health and illness in contradictory, but also in complete. He also says it is a dimension. So when lily does not achieve and when this is a vital goal, it is not automatically that she is ill. It is merely that her complete health is reduced. She can realise her basic vital goals.  Though S would not admit that her health is somewhat reduced, he would maintain that she is completely healthy. Her is an unrealistic goal. If she should be helped, cure is not to turn to orthopaedics, but in ‘goal care’. We should try to convince lilly about the unrealistic nature of her goal. She can set a utopian goal, but be emotionally prepared for its failure. She has a hidh degree of health. Do not enter into people’s lives when they do not call for it. Unrealistic goal setting.

S accuses of including too much, I say he includes too little

Response to George

Constructivist strong normativism

Present concrete eg to test

Need there be a profound shift in concept of health or that we will constantly reconstruction

Distinc between reconstruction and operationalisation

Eg. If clinic accepts ground of someone as unhealthy because cannot go to work – this is operational

What could be reconstructions of health concept

Eg. Measuring health and divising instruments for such measurements. E. sickness impact profile, euroqual, Nottingham health profile -    all contain critieria for measuring health -    they indicate concepts of health -    perhaps the instrument makers construct different concepts of health -    these are postmodern measures of health -    we might have 1000 withiin a decade -    a good state of affairs? I doubt it, descriptively and normatively -    descriptive: o    instrument makers might claim they are merely trying to describe an aspect of health, eg. Mental or dental, or to measure technologies, so not all aspects are accounted for – practical purpose. o    Evaluative: doubt hey would be happy that theya re constructing new concepts of health. They want to measure ordinary understanding – just a partic way of measuring o    May be 150 defns, but from this does not follow that there are 150 good or adequate concepts. Few have derived from careful conceptual analysis o    Thus, maqy find dubious claims within them. Eg Nottingham health profile ‘I lie awake for most of the night’ – explanation? Not just ill health o    We have some intuitive understanding of health and make good judgements. But this does not mean we or they are constructing new concepts of health o    But is there only one concept of health? •    No. like all abstract concepts, health vague. Borders fuzzy. From conceptual analysis only, cannot define sharply.  Must stipulate minimal. But is, at least, a conceptual torso that is given in conceptual language which tells us what dimensions are relevant to health. •    Cconsider Aristotle or gaylen.

Debate

ME: If I cannot work, I am ill. If I cannot be the best worker, I am not ill.

4.2 Future of Medicine

The moral significance of future ‘persons’ G. Papagounous

Question: role of personhood in ethics in relationship to specific entities, namely human beings

In ethics, should not evaluate natural phenomena -    eg. Earthquake, tsunami are neither good nor bad, but consequences can be described in such terms

what is the different between a pilot and a volcano?

Person

Personhood delimintes 2 things

1.    limits of the act. 2.    Allocatrion of the possibility of an act

Warnock – personhood – consciousness, reasoning, self-motivated, communication, self-awareness

Not complete -    if replace ‘raven’ with 2 yr old child, stil theft of ring? – fits personhood as Warnock

must modify personhood

ME: not harm to future persons – they are not harmed. Rather, environmental actions are worsening the conditions within which future persons will exist

Is transferred parental responsibility legitimately enforceable. Matti Hayry matti.hayry@manchester.ac.uk

Premises -    You have (or want to have ) children -    I do not -    You have not been coerced into having (or wanting to have) children by force, threats, deception, or lack or competence or info -    Your children can have children of their own, and so can your possible grandchildren, and so on

Questions

Are you responsible forr t wellbeing of your progeny, including t future generations in your direct family line Are you resposnib for t ewellbeing of other members of t future gen Ami i Are you entitled to coerce me into securing t wellbeing of t future gens?

Are you respon sible for your own? -    box of surprises o    inherited sealed box, cannot open, may contain valuable material or explosive, but smaller chance for latter. Choice: never open box, or give to stranger as give. If give it away, can open it, but no knowledge of contents. Should you give box to stranger

are you responsible for your own?

Conditions for giving t box -    if ou can you can ask t potential recipient. Free informed consent might provide justif -    if not, consider her current sitn. Abject povery might be a factor -    you should be prepared to assume responsib for t conseqs if they are adverse.

Are you responsible for your own? -    the gift of life o    when consider having children, you consider creating indivdwho does not exist yet and giving her a box of surprises o    you  have metaphorically inheretned t gift of life as an heirloom, and you are thinking of

received cannot but open box life might be good or bad

are you responsib for your own conditions for passing on gift -    cannot seek consent of receiver, can only assume -    cannot argue for t situation of t receiver – can only assume life’s value -    must recog your responsib for wellbeing of the (non-voluntary) receiptients -    you must try to guarantee that t lives of your children etc are as good as they can be

are oyu responsib for your own -    answer to first question o    you are responsib for wellbeing of progency, because commitment to this responsib is moralc ond of having kids

are you responsib for others?

How t parental contract comessa bout -    as a prarent you must ask yourself: o    ‘who will take care of my children and my children’s children if I cannot? o    And the natural answer is o    ‘parents of other children. We make a deal. They take care of my progeny if I cannot and I take control of theirs -    how t parental contract is binding o    because by reproducing you have taken on duty to guarantee wellbeing of offspring o    your mutuial contract is not morally binding to anyone else (nonparents) -    answer to this question: o    ou are responsib to other members o t future generations beasides yourown

am I responsib for your children? -    why would I be? o    Because I have made a parental commitment? NO o    Parental contract? No o    Because a need exists, and I should respond to it? •    3 layers •    immediate need in an emergency sitn: your existing child drawoning in a pond? Only I can help. Should i?-yes •    longer term, non-emergency needs: your children need an education, should I contribuite? – probably (prudential), but you first: ME: WHY? SO, REJECT A NATIONAL EDUCATION SYSTEM? •    the needs of your non-existing progeny: why would I sacrifice my worthwhile goals to promote your reproductive aspirations? •    INVOLUNTARY PRODUCED OFFPSRING: should I respond to needs of future children whose existence is due to force, devception or lack or competence or info, of course, but you should join me in preventing such reproduction •    Saving resources to future generations: 5 generations down t line you have burdened t natural enviro 5 units against my one. Could I have double portions, please? •    ME: is he setting up an us and them that is false? •    Answer to 3rd question o    I am not responsib for wellbeing of your distant progeny, or for t wellbeing of other voluntarily produced members of the future gens because I am in no way responsible for their existence

Can you justifiably coerce me? -    possible grounds o    do I have moral duty that you re entitled to make me dispense by coercion or force? No o    have I made a commitment that you are entitle to hold b to by coercion orfoce? No o    have I entered a contract that you are entitled ot make me honour, by coercion or force? No

possible grounds for coercion? -    doyou represent a dominant protective agency which is entitled to coerce me? NO -    if everyone acted like me humanitiy would cease to exist. NO CHANCE. (and voluntarily, what’s the problem) -    if many peoplea cted like me there would be too few tax payers (MOST UNLIKELY) (revise immigration policies)

answer? -    not entitled to coerce me because no valid moral, social or political grounds for such an entitlememnt (I may chip in from time to time voluntarily)

Soren response -    everyone might trace their roots to involuntary creation -    contractarianism: why no contract between procreator and non-procreator to take care of latter

reply -    yes, some involuntariness, but my first duty as non-reproducer is to change world where every reprod choice is voluntary -    wider contract issue with society? Yes, perhaps, but I acknowledged that immediate needs will be met.

Question: the discourse is liberal, but narrow concept of responsibility -    alternative: necessity of action in face of evil.thus responsible for future generations, because the evil exists. Eveil is beginning of responsibility

Question: if you don’t want responsibility, you don’t have responsib for others and if you have your own, you have sole responsibility. But this is not true. Even if you

ME: parental responsibility does not convey, in its entirety, responsiibilty towards children. Parents do not have sole responsibility over their children.

Responsibility for future generations F. Turoldo (Italy) university of Venice.

Why is t term responsibility not t common term in ancient and modern philosophy? -    why contemporary?

Rotation of meaning of responsibility

Initially a juridicial concept – a consequent way – I am responsible for an action and its consequences

2 conditions 1. individuality (I am responsible) 2. consequent (towards past actions)

respondre – to answer for

moral concept of responsibility -    inner judge

T problem of allocating health care resources considering future generations M Igoumenidis

Is it fair to spend mony on moon trips and cloning sheep when could use money to save present people’s lives?

6