FDA to Hold Public Meeting about a Form of Human Germline Modification

Posted by Jessica Cussins September 12, 2013
Biopolitical Times
man working with DNA

On October 22-23, an advisory committee of the Food and Drug Administration (FDA) will hold a public meeting on "oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility."

That description – which is the sum total of the information the FDA has so far released about the meeting – is a mouthful. What it apparently means is that the agency will, for the first time in over a decade, be considering a technique that would constitute a form of human inheritable genetic modification. It is the first time that the FDA has ever held a public meeting to discuss such a technique. That the agency is providing a forum for public comment seems like a good sign; the FDA surely realizes there are broad issues and profound societal consequences to consider.

The term the FDA has adopted – “oocyte modification” – is a new and somewhat strange framing. Though there is no way to be sure, oocyte modification for “treatment of infertility” may refer to a new in vitro fertilization technique being developed by a Boston-based company called Ovascience.  The technique involves combining the egg of an older woman with mitochondria from egg precursor cells taken from her body. Ovascience had started enrolling women in a clinical trial, but this week the FDA sent the company a letter asserting its oversight and telling Ovascience it could not proceed without approval.  

The FDA public meeting will almost certainly consider another technique – far more biologically extreme and socially consequential – known as mitochondrial replacement that is being developed by Shoukhrat Mitalipov and his research team at Oregon Health and Science University (OHSU). Unlike the Ovascience technique, mitochondrial replacement is a form of inheritable genetic modification. It is intended to allow a small number of women with a rare kind of severe mitochondrial disease to attempt to have a healthy and mostly genetically related child, but raises profound safety and societal risks.

The Mitalipov team’s version of mitochondrial replacement, called maternal spindle transfer (MST), works by inserting the nucleus of an affected woman into an enucleated egg – with healthy mitochondria – from another woman. This constructed egg is then fertilized with sperm from the father. Hypothetically, the resulting embryo could be transferred into the mother to create a healthy child, genetically related to his or her parents but not affected by the mother’s mitochondrial disease. Because the child would also carry genes from another woman, the media often refers to mitochondrial replacement as "three-parent in vitro fertilization" or as creating "three-parent babies."

The OHSU researchers believe their technique will work because they used it in rhesus macaques to produce four live offspring who after three years appear to be healthy and developing normally. Last year they were also able to generate embryonic stem cells from human blastocysts created with MST, which they view as a demonstration that the technique could produce a viable human embryo and child.

However, there are reasons to be dubious. A worrying difference was noted between the study of MST on the rhesus macaques and the trials so far on human zygotes: More than half the human MST zygotes had abnormalities that were not observed in the monkeys, leading the researchers to conclude that human oocytes are more sensitive to spindle manipulations than monkey oocytes.

MST can also introduce other kinds of errors. Genetic material can be lost during transfer; small amounts of mitochondrial DNA (mtDNA) from the unhealthy egg can be transferred; a mismatch between foreign mtDNA and nuclear DNA can occur; and the segregation of mutated mtDNA to specific tissues may lead to a significant accumulation of the mutant load. Negative effects caused by any of these would not be reversible, either in the child born as a result of the procedures or in any subsequent generations (if the child is female, since mitochondria are inherited only from mothers).

A number of scientists have voiced concern.

  • Joanna Poulton, Nuffield Department of Obstetrics, University of Oxford and others wrote a paper discussing nuclear transfer and noted that “huge problems need to be overcome.”
  • Stuart A. Newman, Professor of Cell Biology and Anatomy at New York Medical College, voiced strong doubt about the safety and efficacy of this technique in an article earlier this year, pointing out that it is extremely unlikely that billions of years of evolutionary complexity could be tweaked with any predictable outcome.
  • David King of Human Genetics Alert wrote a report on the dangers of epigenetic harm caused by the “crude excision process” of nuclear transfer. He noted that limited safety implications can be drawn from studies on human blastocysts because “only the most crude effects upon embryo viability are reflected in embryo death, and embryos can survive to the blastocyst stage with metabolic and gene expression abnormalities that will have profound effects later in prenatal development or postnatal life.”
  • Paul Knoepfler, Associate Professor of Cell Biology and Human Anatomy at the University of California, Davis School of Medicine, reiterated this point in an article that said, “Moving one oocyte nucleus into the enucleated oocyte of another person could trigger all kinds of devastating problems (most likely through epigenetic changes) that might not manifest until you try to make a human being out of it. Then it’s too late.”

The desire of the few women with mitochondrial disease who would be candidates for this technique to have a genetically related, healthy child is certainly understandable. But given that there is already a safe, available alternative way to accomplish this, why would anyone choose to subject a child to a highly risky experiment?

Back in 2002, the FDA stopped a number of fertility clinics from using a similar technique called “ooplasmic transfer” that was intended to help older women overcome infertility. The FDA’s communications at the time cited concerns about the genetic abnormalities (including Turner’s syndrome and Pervasive Developmental Disorder) found in several of the small number of resulting children, the lack of oversight, the paucity of safety data, and the resulting permanent changes to the human genome. As was noted by observers at the time, procedures that alter the human germline would violate the widely observed international consensus against inheritable genetic modification.

The same is true today. If the FDA gives the OHSU researchers a green light to move towards human clinical trials, it will be the first instance of regulatory approval for human germline modification ever, anywhere in the world.

Given the current regulatory void in the United States and the paucity of safety data, allowing scientists to experiment with creating permanent changes to the human genome is a genie that must be kept in the bottle.

The FDA is currently accepting public comments. Written submissions must be made before October 15; oral presentations must be confirmed before October 7. See here for more information, and spread the word.

Previously on Biopolitical Times: