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)


Rationale treatment strats combating mito oxidative phosphorylation (OXPHOROS) disorders


charac genes and proeins involves in formation and reg


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: 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


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


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!?


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


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


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


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


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


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


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


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


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


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.

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