Embryo Screening for Polygenic Disease Risk: Recent Advances and Ethical Considerations (Genes 2021 Special Issue)

It is a great honor to co-author a paper with Simon Fishel, the last surviving member of the team that produced the first IVF baby (Louise Brown) in 1978. His mentors and collaborators were Robert Edwards (Nobel Prize 2010) and Patrick Steptoe (passed before 2010). In the photo above, of the very first scientific conference on In Vitro Fertilization (1981), Fishel (far right), Steptoe, and Edwards are in the first row. More on Simon and his experiences as a medical pioneer below. 

This article appears in a Special Issue: Application of Genomic Technology in Disease Outcome Prediction.

Embryo Screening for Polygenic Disease Risk: Recent Advances and Ethical Considerations 

L. Tellier, J. Eccles, L. Lello, N. Treff, S. Fishel, S. Hsu 

Genes 2021, 12(8), 1105 

https://doi.org/10.3390/genes12081105 

Machine learning methods applied to large genomic datasets (such as those used in GWAS) have led to the creation of polygenic risk scores (PRSs) that can be used identify individuals who are at highly elevated risk for important disease conditions, such as coronary artery disease (CAD), diabetes, hypertension, breast cancer, and many more. PRSs have been validated in large population groups across multiple continents and are under evaluation for widespread clinical use in adult health. It has been shown that PRSs can be used to identify which of two individuals is at a lower disease risk, even when these two individuals are siblings from a shared family environment. The relative risk reduction (RRR) from choosing an embryo with a lower PRS (with respect to one chosen at random) can be quantified by using these sibling results. New technology for precise embryo genotyping allows more sophisticated preimplantation ranking with better results than the current method of selection that is based on morphology. We review the advances described above and discuss related ethical considerations.

I excerpt from the paper below. 

Some related links: 

First Baby Born from a Polygenically Screened Embryo (video panel) 

Polygenic Embryo Screening: comments on Carmi et al. and Visscher et al.

Dalton Conley (Princeton) and collaborators find that 68% of surveyed Americans had positive attitudes concerning polygenic screening of embryos.

Introduction:

Over a million babies are born each year via IVF [1,2]. It is not uncommon for IVF parents to have more than one viable embryo from which to choose, as typical IVF cycles can produce four or five. The embryo that is transferred may become their child, while the others might not be used at all. We refer to this selection problem as the “embryo choice problem”. In the past, selections were made based on criteria such as morphology (i.e., rate of development, symmetry, general appearance) and chromosomal normality as determined by aneuploidy testing. 

Recently, large datasets of human genomes together with health and disease histories have become available to researchers in computational genomics [3]. Statistical methods from machine learning have allowed researchers to build risk predictors (e.g., for specific disease conditions or related quantitative traits, such as height or longevity) that use the genotype alone as input information. Combined with the precision genotyping of embryos, these advances provide significantly more information that can be used for embryo selection to IVF parents. 

In this brief article, we provide an overview of the advances in genotyping and computational genomics that have been applied to embryo selection. We also discuss related ethical issues, although a full discussion of these would require a much longer paper. ...

 Ethical considerations:

For further clarification, we explore a specific scenario involving breast cancer. It is well known that monogenic BRCA1 and BRCA2 variants predispose women to breast cancer, but this population is small—perhaps a few per thousand in the general population. The subset of women who do not carry a BRCA1 or BRCA2 risk variant but are at high polygenic risk is about ten times as large as the BRCA1/2 group. Thus, the majority of breast cancer can be traced to polygenic causes in comparison with commonly tested monogenic variants. 

For BRCA carrier families, preimplantation screening against BRCA is a standard (and largely uncontroversial) recommendation [39]. The new technologies discussed here allow a similar course of action for the much larger set of families with breast cancer history who are not carriers of BRCA1 or BRCA2. They can screen their embryos in favor of a daughter whose breast cancer PRS is in the normal range, avoiding a potentially much higher absolute risk of the condition. 

The main difference between monogenic BRCA screening and the new PRS screening against breast cancer is that the latter technology can help an order of magnitude more families. From an ethical perspective, it would be unconscionable to deny PRS screening to BRCA1/2-negative families with a history of breast cancer. ...

 

On Simon Fishel's experiences as an IVF pioneer (see here):

Today millions of babies are produced through IVF. In most developed countries roughly 3-5 percent of all births are through IVF, and in Denmark the fraction is about 10 percent! But when the technology was first introduced with the birth of Louise Brown in 1978, the pioneering scientists had to overcome significant resistance. There may be an alternate universe in which IVF was not allowed to develop, and those millions of children were never born. 

Wikipedia: ...During these controversial early years of IVF, Fishel and his colleagues received extensive opposition from critics both outside of and within the medical and scientific communities, including a civil writ for murder.[16] Fishel has since stated that "the whole establishment was outraged" by their early work and that people thought that he was "potentially a mad scientist".[17] 

I predict that within 5 years the use of polygenic risk scores will become common in some health systems (i.e., for adults) and in IVF. Reasonable people will wonder why the technology was ever controversial at all, just as in the case of IVF.

Figure below from our paper. EHS = Embryo Health Score. 

COVID-19: False Positive Rates for Serological Tests

It looks like very few of the tests have false positive rates in the percent range. Since most populations (with the exception of NYC and some other highly impacted places) do not have infection rates higher than a few percent, there is a danger of overestimating total infection rates and underestimating IFR using these tests. (See, e.g., the recent Stanford-USC papers.)

Sure Biotech seems to be an HK company, while Wondfo is in Guangzhou.

NYTimes: ... Each test was evaluated with the same set of blood samples: from 80 people known to be infected with the coronavirus, at different points after infection; 108 samples donated before the pandemic; and 52 samples from people who were positive for other viral infections but had tested negative for SARS-CoV-2.

Tests made by Sure Biotech and Wondfo Biotech, along with an in-house Elisa test, produced the fewest false positives.

A test made by Bioperfectus detected antibodies in 100 percent of the infected samples, but only after three weeks of infection. None of the tests did better than 80 percent until that time period, which was longer than expected, Dr. Hsu said.

The lesson is that the tests are less likely to produce false negatives the longer ago the initial infection occurred, he said.

The tests were particularly variable when looking for a transient antibody that comes up soon after infection, called IgM, and more consistent in identifying a subsequent antibody, called IgG, that may signal longer-term immunity.

“You can see that antibody levels rise at different points for every patient,” Dr. Hsu said. The tests performed best when the researchers assessed both types of antibodies together. None of the tests could say whether the presence of these antibodies means a person is protected from reinfection, however.

The results overall are promising, Dr. Marson added. “There are multiple tests that have specificities greater than 95 percent.”

Preprint: Test performance evaluation of SARS-CoV-2 serological assays

From Table 2 in the paper:

Dr. Patrick Hsu -- quoted in the Times article above, and a co-author of the paper -- is no relation, although we know each other. He has appeared in this blog before for his CRISPR work.

CRISPR patent fight

Earlier CRISPR posts. MSU symposium with video. Patrick Hsu, one of the speakers (no relation), is from the Zhang lab.

Technology Review: Discovery of the Century?

There’s a bitter fight over the patents for CRISPR, a breakthrough new form of DNA editing.

... In April of this year, Zhang and the Broad won the first of several sweeping patents that cover using CRISPR in eukaryotes—or any species whose cells contain a nucleus (see “Broad Institute Gets Patent on Revolutionary Gene-Editing Method”). That meant that they’d won the rights to use CRISPR in mice, pigs, cattle, humans—in essence, in every creature other than bacteria.

The patent came as a shock to some. That was because Broad had paid extra to get it reviewed very quickly, in less than six months, and few knew it was coming. Along with the patent came more than 1,000 pages of documents. According to Zhang, Doudna’s predictions in her own earlier patent application that her discovery would work in humans was “mere conjecture” and that, instead, he was the first to show it, in a separate and “surprising” act of invention.

The patent documents have caused consternation. The scientific literature shows that several scientists managed to get CRISPR to work in human cells. In fact, its easy reproducibility in different organisms is the technology’s most exciting hallmark. That would suggest that, in patent terms, it was “obvious” that CRISPR would work in human cells, and that Zhang’s invention might not be worthy of its own patent.

What’s more, there’s scientific credit at stake. In order to show he was “first to invent” the use of CRISPR-Cas in human cells, Zhang supplied snapshots of lab notebooks that he says show he had the system up and running in early 2012, even before Doudna and Charpentier published their results or filed their own patent application. That timeline would mean he hit on the CRISPR-Cas editing system independently. In an interview, Zhang affirmed he’d made the discoveries on his own. Asked what he’d learned from Doudna and Charpentier’s paper, he said “not much.”

Not everyone is convinced. “All I can say is that we did it in my lab with Jennifer Doudna,” says Charpentier, now a professor at the Helmholtz Centre for Infection Research and Hannover Medical School in Germany. “Everything here is very exaggerated because this is one of those unique cases of a technology that people can really pick up easily, and it’s changing researchers’ lives. Things are happening fast, maybe a bit too fast.”

CRISPR symposium at MSU

CRISPR Symposium, Saturday April 5, 8:30-4:00, Snyder Theater, C20 Snyder Hall.

Sponsored by the Office of the Vice-President for Research.

Speaker Information:

Dan Bauer is a lecturer in Pediatrics at Harvard Medical School. He is first author on the October 2013 Science paper “An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level”. He received his MD and PhD from the University of Pennsylvania and his BS from Brown University.

Patrick Hsu is a graduate student in Feng Zhang’s lab at the Broad Institute at MIT and Harvard and the McGovern Institute for brain research at MIT. In the past year he has contributed to 8 papers from the Zhang lab on CRISPR and genome engineering. He received his BS from Berkeley in Cellular and Molecular Biology.

Ophir Shalem is a postdoctoral research fellow in Feng Zhang’s lab at the Broad Institute of MIT and Harvard and the McGovern Institute for brain research at MIT. He is the first author on the January 2014 Science paper “Genome-scale CRISPR-Cas9 knockout screening in human cells” from the Zhang lab. He received his PhD from the Weizmann institute of Science in Biology and Computer Science and his BS from Ben Gurion University in Bioinformatics and Computer Science.

Jian-Kang Zhu is Distinguished Professor in the Departments of Biochemistry and Horticulture and Landscape Architecture at Purdue University. Recent work in his lab, which includes publications in Nature, PLOS Genetics and PNAS, has focused on RNA binding, genome engineering and DNA methylation. He received his BS from Beijing Agricultural University and his PhD from Purdue. He was a post-doctoral researcher at Rockefeller University.

Here's some recent CRIPSR coverage, focused on a method for measuring editing accuracy:

Recently a powerful new technology has emerged (called CRISPR) that allows researchers to make small, precise and permanent changes in the DNA of animal and human cells. It builds on the concept of genome editing that is key to generating cells, cell lines or even whole animals such as laboratory mice, containing specific genetic changes for study. With CRISPR, however, researchers can generate in days or weeks experimental models that usually take months or years. As a result, they can quickly assess the effect of a particular gene by deleting it entirely, or experiment with repeated, tiny changes to its DNA sequence.

According to a recent New York Times article, scientists roundly agree that CRISPR is revolutionary. At least three companies have been launched in the mere 18 months since the first results were reported by researchers at the University of California, Berkeley and Umea University in Sweden, and more than 100 research papers based on the technique have been published. But, although it’s highly specific, it’s (sadly) not perfect. According to the New York Times piece:

Quick is not always accurate, however. While Crispr is generally precise, it can have off-target effects, cutting DNA at places where the sequence is similar but not identical to that of the guide RNA.

Obviously it’s important to know when (and how frequently) this happens. Unfortunately, that’s been difficult to assess.

Enter researchers in the laboratory of pediatric cancer biologist Matthew Porteus, MD, PhD. Porteus’s lab is interested in (among other things) learning how to a particular type of genome editing called homologous recombination to treat diseases like sickle cell anemia, thalassemia, hemophilia and HIV. They’ve devised a way to monitor the efficiency of genome editing by CRISPR (as well as other more-traditional genome editing technologies) that could be widely helpful to researchers worldwide. Their technique was published today in Cell Reports. As postdoctoral researcher Ayal Hendel, PhD, told me:

We have developed a novel method for quantifying individual genome editing outcomes at any site of interest using single-molecule real-time (also known as SMRT) DNA sequencing. This approach works regardless of the editing technique used, and in any type of cell from any species.

See also here:

MIT scientists report the use of a CRISPR methodology to cure mice of a rare liver disorder caused by a single genetic mutation. They say their study (“Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype”), published in Nature Biotechnology, offers the first evidence that this gene-editing technique can reverse disease symptoms in living animals. CRISPR, which provides a way to snip out mutated DNA and replace it with the correct sequence, holds potential for treating many genetic disorders, according to the research team.

CRISPR

This looks like a huge development. Video. See also here, and this talk (audio) by Harvard graduate student Patrick Hsu (no relation; recent paper in Cell; genome-engineering.org).

Independent (UK): Scientists are calling for a wider public debate on a new development in genetics that could allow the simple and accurate manipulation of the human genome, as revealed yesterday by The Independent.

The technique, known as CRISPR, could revolutionise human gene therapy and genetic engineering because it allows scientists for the first time to make the finest changes to the DNA of the chromosomes with relative ease.

One Nobel scientist, Craig Mello of the University of Massachusetts, said that the “jaw dropping” technique has the potential to transform the study and manipulation of genes and “lowers the barrier” to genetic engineering of human IVF embryos – something he would oppose.

Professor George Church of Harvard University, who was the first scientist to get the process working in human cells and mouse embryos, said that it was important to air the social and ethical implications of the technique to the wider public.

“Talking about the future is better than letting it sneak up on us. We need to do more of this or we will be left with very limited vocabulary in the space between positive and negative hype,” Professor Church said. ...

The CRISPR technique has developed rapidly since last year when Jennifer Doudna and her colleagues at the University of California, Berkeley, first demonstrated how it can be used in genetic engineering.

Scientists have since shown that it works well on human cells and mouse embryos and are talking about the possibility of refining it for gene therapy trials on patients with HIV and inherited disorders such as sickle-cell anaemia and Huntington’s disease.

Professor Dagan Wells, an IVF researcher at Oxford University, said that although there is still a long way to go before CRISPR could even be considered for use on IVF embryos, the technique could overcome many of the objections to permanently altering the germline of families affected by inherited disorders

“If the new method is as precise as has been suggested then concerns about inducing inadvertent, detrimental changes to the genome might start to subside. In that case, permanently fixing a lethal genetic defect might not seem so controversial,” Professor Wells said.

“However, I'm sure there will be some concern about the possibility that the technology could be used for 'enhancement' rather than repair, veering from medicine towards eugenics,” he warned. ...