When genome editing meets the germline…

Hello movers, shakers, and policy-makers!

What's up Barack!? It's Sam.
What’s up Barack!?

Today’s post is inspired by a pair of editorials in Nature and Science calling for a worldwide moratorium on genome editing in the human germline. I highly recommend reading both pieces; the authors each contributed to developing the TALEN zinc-finger nuclease and CRISPR/Cas9 technology for use in genetically modifying human cells. Both TALENs and CRISPRs are systems that may be engineered to cut DNA in a specific spot, the cut can then be used to introduce a change in the genome by hijacking a cell’s own repair capabilities (see my previous post on Genome Editing, or this excellent review by Jennifer Doudna for a more detailed explanation). These technologies are not exactly new, in fact the field has an established track record of successfully producing viable transgenic primates and edited human cell lines with both techniques, why are scientists suddenly calling for a stop to this type of research?

The first transgenic primates produced with CRISPR (source, Niu et al. Cell, 2014)
The first transgenic primates produced with CRISPR (source, Niu et al. Cell, 2014)

The authors are not calling for a blanket ban on genome-editing itself; the technology shows considerable promise for treating incurable genetic diseases. Last year Yin et al. successfully used CRISPR to correct hereditary tyrosinemia (a blood disease) in adult mice. Another group used TALEN to remove a gene in human T-cell lines, which effectively rendered the cells immune to HIV. The biotech industry is paying attention to these academic successes: Novartis recently acquired the small CRISPR-focused start-up Intella biosciences, with the express purpose of developing genome-edited stem-cell therapies for cancer. Editas, a boston based firm, aims to apply CRISPR-mediated genome editing to correcting Sickle-Cell Anemia. The F.D.A. has strict regulatory guidelines in place to oversee the thousands of gene-therapy clinical trials currently underway in the United States.

The future IS now.
The future IS now.

The key distinction between the amazing advances described above and the research that is currently making genome-editors in general very nervous is the type of tissue targeted for tinkering. All of the efforts to correct blood diseases or cure HIV introduce changes into the genomes of somatic cells in specific adult tissues. Any alterations in somatic cells are not passed on to the next generation. However, advances in genome editing, combined with expertise in in vitro fertilization could allow researchers to change the DNA in embryos before implantation. Any resulting edited offspring would carry the alteration in every single cell in their entire body, including the germline, so any changes would then be passed on to their progeny.

Don't edit me...
Don’t edit me…

The idea of genome-edited embryos and designer babies seems like a scene from a science fiction story. However, biotech firms such as OvaScience are working to improve the efficiency of successful IVF by modifying a mother’s eggs. The U.K. recently approved embryonic mitochondrial transfers (a.k.a three-parent children) to treat incurable genetic disorders of the cell’s energy factories. Neither of these advances are examples of targeted embryo-editing, however, a provocative piece from MIT’s Technology Review cites unnamed sources purporting that “such [germline editing] experiments had already been carried out in China and that results describing edited embryos were pending publication.”

Communist mutants!
Communist mutants!

Adding to the general unease, a recent publication in Science combined CRISPRs with gene-drive technology to generate a heritable mutation in fruit-flies that spread rapidly through the population in subsequent generations. In other words, we know how to make make genetic changes that are heritable, and highly transmissible. Scientists see a potential Pandora’s Box opening up all over our chromosomes, if this research is allowed to continue unchecked.

What could possibly go wrong?
What could possibly go wrong?

This isn’t the first time scientists have convened to consider something new and scary; in 1975 the Asilomar Conference issued common-sense guidelines for research using Recombinant DNA Molecules. We’re approaching the 40 year anniversary of this seminal meeting, recombinant research is alive and well, and despite the doomsday predictions, we haven’t inadvertently created a manmade Andromeda Strain.

Although we did produce a Kardashian...which might be just as bad
Although we did produce a Kardashian…which might be just as bad

I’m skeptical that Chinese scientists are on the cusp of publishing about modified mutants. I HIGHLY doubt that any reputable journal would agree to publish such blatantly unethical research. No institutional review board at a major academic institution would EVER approve a such a study. If a rogue scientist, working in isolation DID somehow successfully bring a CRISPR-modified embryo to term tomorrow they SHOULD be exiled from academia, and the details of the findings SHOULD be buried away from public consumption. The world isn’t ready for germline genome editing…yet.

We're BARELY ready for somatic cell editing...but that ship has sailed.
We’re BARELY ready for somatic cell editing…but that ship has sailed.

I applaud the exhortations for more careful consideration. I agree that scientists, ethicists, and policy-makers need to carefully consider exactly what is acceptable and what are the best practices governing genome-editing research. I’m encouraged that meetings devoted to this very topic are happening worldwide. I also don’t believe that the technology ought to be rejected outright. If a parent knows that they carry a genetic allele that will cause their children to develop cystic fibrosis or aggressive breast cancer, correcting the problem before birth through embryonic editing could decrease the societal burden of incurable diseases. Although pop-science pieces fan the flames of false controversy by imagining “designer babies” or “eliminating the gay gene (er…gay-8-megabase region on the X-chromosome),” the realistic applications of the technology could substantially improve peoples’ lives.

No WAY are we getting rid of the gay gene...but we might be able to eliminate HIV
No WAY are we getting rid of the gay gene…but we might be able to eliminate HIV

However, ethical concerns remain, even if this technique is only ever applied in the service of promoting human health. One of my main questions is: who will benefit from this technology? DNA sequencing and in vitro fertilization are EXPENSIVE. If embryonic genome editing does become widely available, are we setting ourselves up for a future where the burden of genetic disorders falls disproportionately upon the poor? What types of diseases are candidates for treatment by genome editing? Certainly disorders that would otherwise be lethal, such as Huntington’s Disease seem like prime candidates; what about severe developmental disabilities such as autism? What about congenital blindness? Is it ethical to “correct” mutations that don’t necessarily kill afflicted individuals, but do carry a societal cost?

Help us out, Abe, we need some guidance.
Help us out, Abe, we need some guidance.

I’m excited to see high-profile scientists engaging the ethical questions. I think genome-editing has enormous potential, but like any technology, it needs to be considered in terms of its applications. I don’t think a blanket ban or all-purpose endorsement is appropriate; this research SHOULD proceed…with immense caution. I think that the concluding paragraph of the Asilomar Meeting‘s report is as applicable today as it was in 1975:

“the standards of protection should be greater at the beginning and modified as improvements in the method-ology occur and assessments of the risks change”…”future research and experience may show that many of the potential biohazards are less serious and/or less probable than we now suspect.”




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