POLICYFORUM

MEDICINE

Mitochondrial Replacement, Mitochondrial replacement therapy might bear

health risks, especially for males.

Evolution, and the Clinic

Klaus Reinhardt,1, 2* Damian K. Dowling,3 Edward H. Morrow 4

M
itochondrial diseases [often caused the United Kingdom, who suggested that available to couples at risk of having an
by mutations in mitochondrial MR will not affect characteristics normally affected child” (9). The results, published
DNA (mtDNA)] can manifest associated with individual identity (6). MR in March 2013, note general support within
in a range of severe symptoms, for which was compared with replacing the batteries the United Kingdom for permitting MR; if
there are currently no cures (1). The applied under strict regulation, such
diseases are passed from mothers to Health outcomes of intraspecies as case-by-case approval of licensed
offspring. Intense research efforts experimental mr in animals hospitals, ethical concerns about the
have recently focused on a germline implementation of MR were consid-
Studies using invasive techniques
therapeutic strategy to prevent the ered to be outweighed by arguments
inheritance of disease-causing mito- Human (Homo sapiens) in favor of MR (10). In June 2013,
Development to blastocyst stage

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chondria. However, although there has the British government announced
Normal gene expression and metabolic profile in cell lines
been increased government interest, they will produce draft regulations
Macaque (Macaca mulatta)
especially in the United Kingdom, for on therapeutic MR for further public
Normal embryo development and metabolic profile at juvenile age
using this approach to treat patients, consultation, to be debated in parlia-
Mouse (Mus musculus)
there are reasons to believe that it is ment in 2014 (11).
Altered respiration and growth in mouse hybrid cell line
premature to move this technology Much of the scientific debate
into the clinic at this stage. has focused on genetic factors that
Studies using genetic crossing techniques
Early experiments in mice pro- are well known to affect mitochon-
duced disease-free oocytes by means Mouse (Mus musculus) drial disease, which typically devel-
Normal survival to adulthood
of mitochondrial replacement (MR): Reduced growth, exercise ability, learning in adult
ops only if the relative amount of
the fertilized nucleus from an oocyte mutated, relative to healthy, mtDNA
Fruit fly (Drosophila melanogaster)
laden with mitochondria carry- in any given tissue surpasses a criti-
Altered juvenile viability
ing mtDNA mutations was injected Altered nuclear gene expression in adult cal threshold (1, 10). These frequen-
into the cytoplasm of an enucleated Altered, aging mostly in adult cies can shift rapidly at embryogen-
donor oocyte that carried mutation- Altered, often reduced, fertility in adult esis. If any mutant mtDNA remains
free mitochondria (2). A break- Seed beetle (Callosobruchus maculatus) in an enucleated oocyte after MR, the
through in primates came when four Altered development time and metabolic rate children might be at risk of develop-
macaque babies were born after Altered fertility in adult ing the disease or passing the patho-
MR-assisted in vitro fertilization Altered survival in adult genic mutation on to their offspring.
(IVF) (3) and when human embryos Copepod (Tigriopus californicus) As a result, the HFEA considered
survived intact after MR to the blas- Reduced juvenile viability whether only male embryos should
tocyst stage (4). Consequently, the Reduced mitochondrial function and ATP production in adults be allowed to develop post-MR, to
British government commissioned ensure that no mutations are inadver-
the Human Fertilisation and Embry- Health outcomes of intraspecies experimental MR in animals. tently transmitted after the treatment.
ology Authority (HFEA) to col- Studies either invasively removed the nucleus by placing it into the This body of research was carefully
lect evidence as to the suitability of enucleated donor oocyte (blue shading) or replaced mitochondria by considered by the HFEA, and we do
MR as a therapeutic approach. The repeatedly crossing foreign mitochondrial genotypes into nuclear back- not review it here (10).
HFEA urged further experiments grounds (green shading) (see table S1 for details). All species share the Rather, we draw attention to the-
same 37 mitochondrial encoded genes. Studies of health effects of MR on
before clinical use of MR (5). The vertebrates that have reached reproductive ages are lacking. ory and experimental findings that
U.K. Nuffield Council on Bioeth- appear to have been overlooked in the
ics initiated an ethical review of MR and of a camera (6), an analogy picked up by the scientific and public forums of this debate.
concluded it was ethically acceptable (6). popular press. Studies on model organisms, ranging from
This view was supported by the Medical Subsequently, the four macaques born mice to fruit flies, indicate that MR can pro-
Research Council and Wellcome Trust of after MR were shown to be healthy at 3 years foundly change the expression profiles of
of age (7), and technical difficulties have nuclear genes and affect a range of impor-
1
Animal Evolutionary Ecology, University of Tuebingen, been reduced in human blastocysts (7, 8). tant traits such as individual development,
72076 Tuebingen, Germany. 2Department of Animal and These results were used to urge the U.S. Food cognitive behavior, and key health parame-
Plant Sciences, University of Sheffield, Sheffield S10 2TN,
3
UK. School of Biological Sciences, Monash University, 3800 and Drug Administration to review its fund- ters. These studies also suggest that males of
Victoria, Australia. 4Evolution, Behaviour, and Environment ing policy on gene therapy (7). reproductive age are particularly sensitive to
Group, School of Life Sciences, University of Sussex Brighton The HFEA then was asked to initiate MR-induced effects.
BN1 9QG, UK.
a public consultation into the question of Natural genetic differences in the mtDNA
*Corresponding author. [email protected] whether MR-assisted IVF “should be made sequence exist from one individual to another,

www.sciencemag.org SCIENCE VOL 341 20 SEPTEMBER 2013 1345

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 POLICYFORUM

broadly denoted as mtDNA haplotypes. Puta- effects were naturally occurring, putatively In conclusion, recent technical advances
tively healthy mitochondrial haplotypes dif- healthy variants. Hundreds of mitochondrial- suggest that MR-assisted gene therapy could
fer in their effect on the expression of key sensitive nuclear genes identified in that study soon be available to help female sufferers of
health and performance parameters. In par- had a core role in male fertility. For example, mitochondrial diseases have healthy chil-
ticular, energy production critically hinges on one of the five combinations in which mito- dren, and this is clearly an exciting pros-
extensive cross-talk between genes dispersed chondrial-nucleus interactions were disrupted pect. Changing legislation that would facili-
across the nucleus and the mitochondria (12). by mismatching was completely male-ster- tate this technique will require a debate over
Because phenotypes with less-than-ideal ile but female-fertile (14). In other fly stud- the extent to which the results and principles
cross-talk are disfavored by natural selection, ies, MR resulted in male-biased modifica- outlined here are ethically and clinically rele-
coordinated mitochondrial-nuclear interac- tions to components of aging and affected vant to MR in humans. MtDNA diseases vary
tions become highly specific over evolution- the outcomes of in vivo male fertility (see from mild symptoms and learning disabilities
ary time. If MR disrupts such specific, highly the table). Together, these results suggest that to severe disabilities and premature death.
coordinated mito-nuclear allelic interactions, core components of male health depend on Assessing the costs and benefits of MR treat-
adverse health outcomes might occur. fine-tuned coordination between mitochon- ment requires that prospective patients are
This prediction is supported by experi- drial and nuclear gene complexes, and thus as fully informed as possible. The difference
mental studies reporting the expression of the HFEA conclusion that “there is no evi- across patients in the severity of expected off-
disease phenotypes when genetic backcross- dence for any mismatch between the nucleus spring symptoms in the event that MR treat-
ing was used to replace mitochondria and and any mtDNA haplogroup, at least within ment is not taken will shape the decision of
to create intergenomic mismatches in mice. a species” [(10), 6.17 on p. 17] is incomplete choosing the treatment versus waiting for the

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Altered respiratory metabolism and reduced and unsubstantiated. outcomes of further research. Some families
performance, learning, and exploratory Two points may deserve careful consid- who are predicted to be, or who have previ-
capacity in males were reported when mito- eration prior to any change in legislation. ously conceived offspring that were, severely
chondrial-nuclear genomic interactions were First, studies in humans have only tracked afflicted by mtDNA diseases are more likely
experimentally mismatched (see the table and health through to the blastocyst stage and in to be prepared to take the risk. Others whose
table S1). Females were not tested in those macaques to 3 years of age (see the table). The children are expected to suffer less detrimen-
studies. The health effects were observed results from mice and invertebrates suggest tal symptoms, cognition problems or infer-
after mismatches between mitochondrial that many deleterious effects of MR would not tility, may wish to wait for further empirical
and nuclear genomes in mice of different be revealed until adulthood. Without preclini- clarification of the risks involved.
inbred strains of the same species. Further- cal trials that take a longer-term approach, the
References and Notes
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16770 (2005).
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5. N. Haites, R. Lovell-Badge, “Scientific review of the
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and supplementary materials (SM) for addi- tility and health outcomes through to sexual disease through assisted conception” (HFEA, London,
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dria_review_-_final_report.PDF.
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alongside a novel set of maternal and pater- seems a relatively low-cost endeavor. Equiva- Council on Bioethics, London, 2012), www.nuffieldbio-
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9. HFEA, HFEA launches public consultation, Medical Fron-
offspring’s mitochondrial DNA is invariably would help to further quantify the potential tiers: Debating mitochondria replacement; www.hfea.gov.
inherited together with and exposed to a hap- costs and benefits of MR therapy. uk/7517.html.
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gov.uk/6896.html.
inheritance of mitochondria means natural may be improved by matching mtDNA hap- 11. U.K. government, www.gov.uk/government/news/
selection can only shape mitochondrial gene lotypes of donor and recipient (10) warrants innovative-genetic-treatment-to-prevent-mitochondrial-
evolution directly through females. This facil- experimental attention. The proof-of-principle disease.
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Acknowledgments: We thank J. Abbott and a reviewer for
disease, or forms of impaired fertility, might els of mitochondrial-nuclear mismatch, prob- helpful discussion. K.R. was funded by the VolkswagenStiftung,
be clinical manifestations of this evolutionary ably to a degree that makes it unrepresentative D.K.D. by the Australian Research Council through fellowship
hypothesis. This specific prediction has exper- for prospective donors and recipients from the and grants and by Monash University, and E.H.M. by a Royal
Society University Research Fellowship and the European
imental backing: MR in fruit flies had little targeted general human population. Compar- Research Council (grant 280632).
effect on nuclear gene expression in females ing the genetic relatedness between recipients
Supplementary Materials
but changed the expression of roughly 10% of and donors for both successful and failed MR www.sciencemag.org/cgi/content/full/341/6152/1345/DC1
genes in adult males (14). The mitochondrial outcomes in the studies of macaques (3, 7)
haplotypes responsible for these male-specific should be relatively simple. 10.1126/science.1237146

1346 20 SEPTEMBER 2013 VOL 341 SCIENCE www.sciencemag.org

Published by AAAS
Mitochondrial Replacement, Evolution, and the Clinic
Klaus Reinhardt, Damian K. Dowling and Edward H. Morrow

Science 341 (6152), 1345-1346.

DOI: 10.1126/science.1237146

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