New Herbert lab Nature paper reinforces mitochondrial replacement Achilles heel

Today a new Nature paper from Dr. Mary Herbert’s group in the UK has found a key problem with mitochondrial replacement therapy that fits with data from others.

The goal of preventing mitochondrial disease using various kinds of genome transfer technologies is a noble one, but mitochondrial replacement therapy has faced a number of technological challenges including perhaps most prominently the carryover and subsequent amplification of diseased mitochondria.

This mitochondrial replacement carryover issue was clearly defined in an excellent recent Cell Stem Cell paper from Dieter Egli’s lab, which demonstrated some cases of pronounced carryover and/or amplification of certain mitochondrial types following nuclear transfer. For more on my perspectives on the Egli paper see here.Herbert mitochondria Nature paper

In the data from the Herbert group paper, the same kind of problem is evident despite the use of a somewhat different adaptation of this technology in which pronuclei are transferred instead of nuclei or spindles from the mom-to-be. In the new paper, Hyslop, et al., the data point toward mitochondrial carryover as a significant problem still to overcome. Some scientists and politicians in the UK successfully pushed for governmental approval there to proceed with mitochondrial replacement therapy in humans last year, but I argued that this technology was not ready for prime time yet due to a number of gaps in our knowledge of both mitochondria themselves in germ cells and also what happens in actual human embryos post-genome transfer.

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UK should freeze mitochondrial replacement as Egli paper ID’s serious problem

An important new Cell Stem Cell paper from Dieter Egli’s lab points to an inherent, serious problem with so-called 3-person IVF or mitochondrial replacement technology that warrants putting an immediate hold on all efforts to use it in humans. I have pasted the graphical abstract from the paper below.

Egli genetic drift paper

Graphical Abstract, Cell Stem Cell

For years a few of us scientists and policy groups have argued strongly that this experimental technology is far too risky to try in humans for reproductive efforts in the near future. There were simply not enough data to support the reasonable expectation that the technique would be safe and effective to use to create new children. I felt so strongly I wrote an open letter to the UK Parliament suggesting that they not proceed and this led to a bit of a kerfuffle.

The UK leadership approved the clinical use of 3-person IVF, which was a bold, but highly risky decision.  I believe the UK is now going to have to step back and authorities there should now freeze all clinical efforts at 3-person IVF/mitochondrial transfer for the time being because of seriousness of this new paper’s findings.

What concerns me specifically?

One of the big potential issues about 3-person IVF raised by those of us who earlier argued for more time and more data before pulling that regulatory approval trigger to proceed with use in humans is that the nuclear transfer from the mom-to-be’s egg into the donor’s enucleated egg would bring some diseased mitochondria with it and those faulty mitochondria could amplify. The new paper from Egli’s lab proves that this kind of thing can happen. It suggests that in some cases this troublesome phenomenon is likely to occur after 3-person IVF and in my view this is likely to lead to health consequences for the future offspring.

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NAS proposes prudent US policy on 3-person IVF

3-parent babyA new report from the National Academies of Sciences, Engineering, and Medicine here in the US recommends a policy significantly more cautious on first read for 3-person IVF than that in place now in the UK.

My initial take on this new 164-page report is that it is very well thought out and the recommendations are both appropriate and prudent. I’m still reading the report so it is possible I may feel differently at the end or that others may point out concerns that I missed, but so far my impression is positive.

Keep in mind that 3-person IVF also goes by the monikers mitochondrial transfer, 3-parent IVF, and mitochondrial replacement therapy (MRT, the term used by the Academy).

Alta Charo Mito TransferNotably, the Academy committee explicitly stated that MRT is a form of human genetic modification and human germline therapy. Some proponents of MRT in the UK and even in the US had mysteriously claimed otherwise.

While the Academy committee wrote in the report that 3-person IVF is ethically permissible in theory, in practice the depth of their concern about the risks of this technology was reflected in the array of conditions that they detailed must be met first.

These conditions include, but are not limited to the following as taken in some cases verbatim from the report or the Academy press release:

  • initial MRT clinical investigations should be limited to women who are at risk of transmitting a severe mitochondrial genetic disease that could lead to a child’s early death or substantial impairment.
  • Only male embryos should be permitted to be used for pregnancy. This would avoid transmission of the donor mitochondria should something go wrong.
  • initial safety is established and risks to all parties directly involved in the proposed clinical investigations are minimized, although minimizing risk to future children should be of highest priority; (note, my interpretation of this is that more preclinical data are needed)
  • the likelihood of efficacy is established by preclinical research using in vitro modeling, animal testing, and testing on human embryos as necessary;
  • if the intended mother at risk of transmitting mitochondrial disease also desires to carry the pregnancy, it is determined by professional opinion that she is able to complete a pregnancy without significant risk of serious adverse consequences to her health or the health of the fetus;
  • clinical investigations are limited to investigators and centers with demonstrated expertise in and skill with the relevant techniques; and
  • FDA has reviewed the science surrounding matching the mitochondrial DNA subtype of the egg provider with that of the intended mother and if compelling, has considered such matching as a means of mitigating the possible risk of incompatibility that could arise from combining the egg provider’s mitochondrial DNA with the nuclear DNA of the intended mother.

I’m largely in agreement with the Academy on this policy recommendation. It seems wise and frankly more appropriately cautious based on the science than what is now allowed in the UK.

The policy recommendations were summed up by the committee Chair in this way:

“In examining the ethical, social, and policy issues associated with mitochondrial replacement techniques, we concluded that the most germane issues could be avoided if the use of these techniques were restricted by certain conditions, rather than prohibiting them altogether,” said Jeffrey Kahn, chair of the committee and the Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy at The Johns Hopkins Berman Institute of Bioethics in Baltimore.  “Although MRT would not treat a person with a mitochondrial disease, its pursuit could satisfy prospective parents’ desire to bear genetically related offspring with a significantly reduced risk of passing on mitochondrial disease.  The limitations on MRT that we propose focus on protecting the health and well-being of children born as a result of the techniques.”

Now it will be interesting to see how and to what extent the FDA implements these policy recommendations as well as the response in the scientific community. I would predict that some proponents of MRT may view this policy as too restrictive. Perhaps some might interpret it as a green light, but so far in my reading I don’t see it that way.

The other fascinating thing is to compare this report on 3-person IVF to the organizer’s closing statement from the NAS Meeting on Human Gene Editing from December. Some of the issues raised in the new report on 3-person IVF seem to directly apply to human gene editing as well.

I appreciate that the committee was cognizant of larger issues such as transparency, access, and public discourse.

Here is the committee roster.

Jeffrey Kahn, Ph.D., M.P.H. (chair)

Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy Berman Institute of Bioethics

Johns Hopkins University

Baltimore, M.D.

Jeffrey R. Botkin, M.D., M.P.H.

Chief

Division of Medical Ethics and Humanities, and

Professor of Pediatrics

University of Utah School of Medicine

Salt Lake City, U.T.

David Chan, M.D., Ph.D.

Professor of Biology

California Institute of Technology

Pasadena, C.A.

R. Alta Charo, J.D.1

Warren P. Knowles Professor of Law and Bioethics

School of Law and Department of Medicine and Public Health

University of Wisconsin at Madison

Madison, W.I.

James F. Childress, Ph.D.1

University Professor and John Allen Hollingsworth Professor of Ethics

Department of Religious Studies

University of Virginia

Charlottesville, V.A.

Alan H. DeCherney, M.D.1

Associate Clinical Director and Branch Chief

Intramural Program in Reproductive Endocrinology and Gynecology

Eunice Kennedy Shriver National Institute of Child Health and Human Development

National Institutes of Health

Bethesda, M.D.

Marni Falk, M.D.

Assistant Professor of Pediatrics

Division of Human Genetics

Children’s Hospital of Pennsylvania

University of Pennsylvania Perelman School of Medicine

Philadelphia, P.A.

 

Jonathan Kimmelman, Ph.D.

Associate Professor in Biomedical Ethics

Biomedical Ethics Unit

McGill University

Montreal, Canada

Anna C. Mastroianni, J.D., M.P.H.

Professor

University of Washington School of Law

Seattle, W.A.

Vamsi K. Mootha, M.D.2

Investigator

Howard Hughes Medical Institute, and

Professor of Systems Biology and Medicine

Harvard Medical School

Boston, M.A.

Laurie Strongin

Founder and Executive Director

Hope for Henry Foundation

Washington, D.C.

Keith Wailoo, Ph.D.1

Townsend Martin Professor of History and Public Affairs

Department of History

Woodrow Wilson School of Public and International Affairs

Princeton University

Princeton, N.J.

STAFF

 

Anne B. Claiborne J.D., M.P.H.

Responsible Staff Officer

Rebecca English, M.P.H.

Program Officer

Morgan Stathem, M.S.

Associate Program Officer

Michael Berrios

Senior Program Assistant

_________________

1Member, National Academy of Medicine

2Member, National Academy of Sciences

Stem cell predictions top 20 list for 2016

Stem Cell PredictionsWhat will the new year have in store for stem cells?

2016 promises to have many striking stem cell developments. Below are my top 20 stem cell predictions for what is to come this year in no particular order. Share your stem cell tea leaves in the comments please.

  1. Another stem cell biotech acquisition by pharma (recall Ocata (almost now finally sold) & CDI in 2015).
  2. Charging patients for clinical trial participation, particularly in Japan due to the new policy and here in the US related to predatory clinics, remains a hot topic
  3. Stem cell clinics and doping in sports flares up more
  4. Organoids continue to excite
  5. Bioheart and some other small stem cell companies struggle
  6. Stem cell stocks overall have a bad year
  7. Stem cell clinics ever more aggressively use celeb clients for PR and marketing Why? It is powerful, effective, and essentially free advertising
  8. More news on human-animal chimeras
  9. FDA continues its slow-go approach to action on stem cell clinics/unapproved stem cell products
  10. Pressure from industry and some academics on FDA to not regulate adipose products as drugs and/or to not enforce some other draft guidances including at the upcoming public hearing on the draft guidances
  11. FDA receives increasing public criticism for “slowness” on approving new stem cell therapies including from beyond the stem cell clinic industry
  12. One or more lawsuits against a stem cell clinic
  13. A new stem cell scandal pops up related to publication issues
  14. Some hiccups on mitochondrial transfer/3-person IVF in the UK or China
  15. The trend last year of increasingly blurred lines between legit research entities such as universities and dubious stem cell enterprises continues. This is worrisome.
  16. Stem cell-derived human germ cells stay in the headlines. This has exciting potential for providing new windows into human development and tackling infertility, but also raises thorny issues such as human genetic modification
  17. ViaCyte has some big news
  18. High-profile developments on veterinary use of stem cells
  19. Animal cloning, particularly in China, continues to proliferate
  20. More rumblings on possible human reproductive cloning attempts

Disclaimer: This post is not meant as financial advice. Consult an expert before making financial decisions.

Nature mixed signals on 3-person IVF: deep risks, but forge ahead

3-parent babyNature recently published a very thorough, insightful piece on the major risks that would come with the use of so-called 3-person IVF (aka mitochondrial transfer or 3-parent baby method).

In the UK 3-person IVF has, as of earlier this year, the government’s blessing to proceed despite the many serious unresolved risks that Nature‘s own piece so nicely outlines. Some scientists including myself have spoken out publicly about these risks, which include potentially disastrous developmental problems for the children produced via this method. However, others including a panel formed by HFEA, think the risks are small. The Nature piece on risk quoted the HFEA panel this way, “most respondents presenting evidence to the panel viewed these issues as “at best minor or non-existent”. Still, this particular Nature piece is quite convincing on there really being major, unresolved risks. It also highlights how much the field doesn’t know about mitochondria.

On the same day as this Nature piece on the risks, the journal also oddly enough published a cheery editorial that didn’t even mention risk and instead slapped HFEA and the UK on the back for forging ahead with this human experimentation. The editorial concluded:

“The United Kingdom has made an advisable step forward that serves as a useful invitation for all to follow.”

So what are we to think, Nature? Are there many serious risks to 3-person IVF? Or not so much?