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The Future of In-Vitro Fertilization and Gene Editing

A "The Eminents" interview with Stephen Hsu.

Courtesy, Stephen Hsu
Source: Courtesy, Stephen Hsu

Stephen Hsu is Vice President for Research and Professor of Theoretical Physics at Michigan State University. He is also a researcher in computational genomics and founder of several Silicon Valley startups, ranging from information security to biotech. Educated at Caltech and Berkeley, he was a Harvard Junior Fellow and held faculty positions at Yale and the University of Oregon before joining MSU. He is a founder of Genomic Prediction, a company that provides advanced genetic testing to IVF laboratories and clinics.

Because this is Psychology Today, I asked Steve about IQ, a measure of reasoning and problem-solving skill, commonly termed "intelligence", that is highly correlated with school and life success. But in light of the two gene-edited baby girls in China, I started there, regarding both the ethics and the science.

Marty Nemko: The news of two gene edited baby girls in China has shocked the world. What are your thoughts on what this means for the future?

Steve Hsu: What He Jiankui did -- gene-editing using CRISPR -- was not a technical breakthrough -- it has been possible for some time. What is new is that someone had the audacity to push it to completion with human embryos. Some researchers who attended his talk a few months ago at Cold Spring Harbor (the talk covered methodology but with no hint that real babies would be produced) found it sound but unremarkable.

In the near term, most applications of CRISPR in IVF can already be accomplished simply by screening (genetic testing) for the undesirable genetic variant. No need to edit; just select one of the embryos without the variant.

With CRISPR, one can edit in new genetic variants that neither parent has. This is in effect what He may have done if he was successful with his edit to protect against HIV. Such enhancement is much more controversial among ethicists. However, it can only be done with simple single-gene conditions.

Eventually, we may have the technology to do multiple (hundreds?) of edits at a time, which will allow modification of polygenic traits. (Most traits are highly polygenic.) But this requires us to first identify actual causal variants as opposed to variants used in a predictor that merely correlate strongly with the causal ones. This is a difficult scientific problem that may take a decade or more to solve. Predicting a complex trait is much easier than modifying it—hence selection will dominate editing in utility for some time.

The possibility of gene editing could lead the public to view embryo selection as a less aggressive course of action.

MN: Would you explain polygenic complex traits embryo selection in more detail?

SH: Most human traits (e.g., height or cognitive ability) and most disease risks (e.g., for diabetes or heart disease) are polygenic—they depend on many different genetic loci. For the first time, thanks to very large datasets and advances in AI/machine learning, we have genomic predictors for these traits. Our height predictor is accurate to a few centimeters! Individuals who are outliers for risk—for example, have 5 or 10 times the probability of heart disease than the typical person—can now be identified using inexpensive genotyping.

Many although not all parents using IVF are confronted by an “embryo choice” problem: They have more viable embryos than they intend to use. For these parents, it is useful to have additional information about each embryo, such as whether it is at high risk for certain health conditions. Each year, a million embryos are genetically screened. Most of the time, this is just a screen for chromosomal normality (e.g., against Down’s Syndrome), but with better technology, we can screen against many mutations and complex disease risks.

MN: What ethical safeguards need to be in place before this kind of technology is put to use?

SH: The birth of the gene-edited baby girls has brought this issue to the forefront. While bioethicists and researchers have already thought through many of the ethical questions (the obvious criteria are safety, effectiveness, and benefit to the child, as well as implementation that would ensure net benefit to society, for example, the procedure’s cost being covered by health insurance provided to the poor), the average person has not. It seems important that there be a high level of public understanding of and consensus about these new technologies before widespread use.

However, It is probably too much to ask that each country come to the same conclusions as to what is permissible or best. Hence I think we will see a patchwork of legal and regulatory practices.

MN: Since this is Psychology Today I want to ask about cognitive ability and personality traits. Can we predict these from genotype? How will this be used in IVF?

SH: From genotype, we can predict cognitive ability (i.e., IQ) with correlation 0.3 to 0.4, which is as well as standardized tests like SAT or ACT predict college performance. That's nowhere near the accuracy of, for example, height prediction. However, despite the SAT's only moderate accuracy, it is easy to understand why colleges are reluctant to admit students with low (say, bottom 10%) scores, and generally very enthusiastic about students with high scores. It’s similar with the current genomic predictors. We can identify embryos that have unusually high risk of intellectual disability but we can’t reliably rank-order embryos that are in the normal range.

At the moment, the situation is even worse for predicting Big-5 personality traits, such as conscientiousness or extraversion, even though we know those traits are fairly heritable. I expect the situation for all psychological traits to improve dramatically in the near future as more data become available.

At present, we can apply genomic prediction to cognitive traits in the same way we apply it to disease risk—to warn parents about embryos that are outliers in risk. In the future, we may be able to rank-order embryos, although this would raise further important ethical issues that need to be explored. By comparison, we’ve found in our testing that we correctly predict height ordering between two same-sex siblings 80 to 90 percent of the time. I don’t see any reason we won’t get to that point with IQ but it may take some years.

MN: Tell me something about yourself that people might find surprising.

SH: I’m a huge fan of Mixed Martial Arts (MMA) and jiujitsu. I learned judo growing up and got into Brazilian jiujitsu and MMA in the early 1990s when the UFC first started. I trained pretty seriously in the US and Japan, including with some professional fighters. Jiujitsu is like chess with the human body -- move and countermove, dominate position, then force a submission.

Perhaps the most beautiful thing about jiujitsu is that one can submit the opponent without either getting hurt. It would be great if intellectual and scientific disagreements worked the same way :-)

NOTE: I conducted a "The Eminents" interview with another luminary in this field, Harvard's George Church.