A safety concern with gene editing

Hat-tip to Dr. Joe Kelley for bring this to my attention…

As readers of this blog will recall, there is keen interest in exploiting recent discoveries in genetic engineering to “edit” disease-causing gene mutations and develop treatments for various diseases.  Initially, such treatments would likely use a patient’s own cells—removed from the body, edited to change the cells’ genes in a potentially therapeutic way, then return the altered cells to the patient’s bloodstream to find their way to the appropriate place and work to treat the disease.  How that would work could differ—make the cells do something they wouldn’t normally do, or make them do something better than they otherwise do (as in altering immune cells to treat cancer); or maybe make them work normally so that the normal function would replace the patient’s diseased function (as in altering blood cells for people with sickle cell anemia so that the altered cells make normal hemoglobin to replace the person’s diseased hemoglobin).

Or maybe we could even edit out a gene that causes disease (sickle cell anemia, Huntington’s disease) or increases the risk of disease (e.g., BRCA and cancer) so that future generations wouldn’t inherit it.  Or maybe we could edit genes to enhance certain health-promoting or other desirable qualities.

The recent scientific enthusiasm for gene editing is fueled by the discovery of the relatively slick and easy-to-use (if you’re a scientist, anyway) CRISPR-Cas9 system, which is a sort of immune system for bacteria but can be used to edit/alter genes in a lot of different kinds of cells.

It turns out that cells’ normal system to repair gene damage can and does thwart this, reducing the efficiency of the process.  The key component to this is something called p53, a critical protein that, if abnormal, may not do its repair job so well.  When that happens, the risk of cancer increases, often dramatically.  In cancer research, abnormal p53 is high on the list of culprits to look out for.

Two groups of scientists, one from the drug company Novartis and one from the Karolinska Institute in Sweden, have published on this.  P53’s thwarting of gene editing is particularly active in pluripotent stem cells, that are some, but not the only, candidate cells to be edited to create treatments.  These cells are also constituent cells of human embryos.  If the CRISPR-Cas9 process is used on these cells, p53 usually kills them off—unless it’s lacking or deficient, in which case it doesn’t, but also in which case it means that the altered cells could themselves become cancers, later on.

This is something that has to be monitored carefully in developing cells as medicines, so to speak, with genetic editing.  One does not want the patient to appear to be healed, only to develop a cancer, or a new cancer, later on.  One certainly would want to know the risk of that before editing an embryo—an unborn human, a future baby if placed in the right environment—to create a gene-edited human being.

Yet, as I’ve written here in the past, it appears that experimentation in heritable gene editing is pressing on.  I’ve argued, and continue to argue, that heritable human gene editing is a line that must not be crossed, that would place too much trust in the providence of the scientists/technologists who are the “actors” exerting power over fellow humans who become “subjects” in a deep sense of the term; that the risks to the subjects are undefinable; that it would enable perception of humans as “engineering projects”; that the gift of life would tend to be replaced by seeking to limit birth to “the people we want”; that the people acted upon are unable to provide consent or know what risks have been chosen for them by others, even before birth.  Rather than press ahead, we in the human race should exercise a “presumption to forbear.”

A counter argument is that, in limited cases where the genetic defect is limited and known, the disease is terrible, treatment alternatives are few or none, that the risks are worth it.  The recent papers seem to expose that line as a bit too facile.  How many embryos created (and destroyed) to develop the technique before “taking it live?”  Could we work things out in animals—monkeys, maybe?  How many generations to alter, create, and follow to be sure that a late risk—such as cancer—does not emerge?  Or maybe our animal rights sensibilities stop us from putting monkeys at such risk—maybe mice will do?

The new papers are dense science.  Frankly, I can grasp the topline story but have trouble digesting all the details.  More sophisticated readers will not be so impaired.  The news report, in the English of the general public, can be read here, the Novartis and Karolinska reports read (but not downloaded or printed) here and here, respectively.

One Man’s Trash is Another Man’s DNA Treasure

Last month, investigators used big data analysis, public DNA genealogy websites and “Discarded DNA” to identify the Golden State Killer (WSJ subscription needed), an individual believed responsible for over 12 murders, greater than 50 rapes and over 100 burglaries in California between 1974 through 1986. While justice may be served if the legal case remains solid, there are some interesting bioethical issues that warrant discussion.

This blog has previously discussed the ethics of searching reportedly anonymized databases and the ability of algorithms to “unanonymize” the data (see HERE and HERE). The current technique used in the Golden State Killer case takes this one step further. Using a public genealogy database site, where individuals looking for distant relatives voluntarily share their personal DNA samples, investigators looked into these databases for partial DNA matches. A partial DNA match means that the investigators were looking for any relatives of the original suspect hoping to gain any identifying information of the relative, leading back to the original suspect. Then, using this narrower group of DNA relatives, investigators literally collected DNA samples this group of people unwittingly left behind, such as skin cells on a paper cup in the trash, so called discarded or abandoned DNA.

One man’s trash is another man’s DNA treasure.

Presently, neither the method of partial DNA search of public voluntary genealogy databases nor the collection of discarded DNA samples violates the 4th Amendment regarding unreasonable search and seizure. Neither the Health Insurance Portability and Accountability Act of 1996 (HIPAA) nor the Genetic Information Nondiscrimination Act of 2008 (GINA) provide protection as none of the data relates to health care records or employment, respectively.

Shouldn’t some law or regulation prevent my personal DNA code from becoming public, particularly if I have not taken steps to publicize it on one of the many public voluntary genealogy sites?

Since your DNA is the ultimate physical marker of personal identity, how much control do you or should you have over it? While you may wish to live a life of anonymity, your extroverted cousin who voluntarily provides her DNA to a public DNA database has just unwittingly publicized some portion of your family DNA as well as traceable personal family data that may allow others to know more about you than you desire. An energetic sleuth dumpster-diving your trash can retrieve your actual DNA. I shred my mail to avoid my social security number or other personal financial information from being obtained and used for identity theft. How do I “shred my DNA” to prevent it from being similarly recovered from my trash?

What may someone do with my DNA information obtained using these techniques. What should someone be able to do?

You could not have convinced me back in 2001 that anyone would spend money to build cars with 360 video equipment and figure out optimal routes that would eventually become what is now Google Street View. Might not someone do the same thing with trash-sourced DNA samples, perhaps Google DNA View?

We already have figured out the garbage truck routes.

More on genetic medicine

The third and final installment from The Code, a series of 3 short documentaries on the internet about the origins of genetic medicine, is entitled “Selling the Code.”  This is about genetic testing to try to predict risks of diseases, among other things.  Doctors use some of this testing in clinical care and a burgeoning amount of research.  A number of companies, such as 23andMe, will, for a (not-too-high) price, sequence your genes, or at least some of them, from a cheek swab sample you send, and then give you a report of what the results are and what they might mean.  In cases where there is a simple connection between a genetic abnormality and a disease—if you have the gene, you get the disease—the approach can be very helpful.  But it’s rarely simple.  Even for known cancer-propensity genes like BRCA1 and BRCA2, there are many variants, and what they mean clinically is far from fully known.  In fact, for most of the common disease we care about, like heart disease, diabetes, and most cancers, the story is complicated indeed.  So what to do with the information is often far from obvious, and careful genetic counseling by a physician who specializes in genetic medicine is a must.

23andMe ran afoul of FDA a couple of years ago, leading to a long process that resulted in FDA acceptance of a more limited menu of testing by the company.

And some companies will sell you “genetic information” for more trivial concerns—presuming to tell you something meaningful about what fitness regimen you should pursue, or what wine you’ll like.  Caveat emptor, I suppose, although the risks are low for some of this.

AND—companies like 23andMe keep anonymized data bases of the genetic information they get for and from their customers, and sell that information to drug companies to support the latters’ research.  An individual can’t be identified in the process (at least, not readily, see my January 2013 post about “DNA research and (non)anonymity”) but the data in the aggregate is valuable to the genetic sequencing company.

These kinds of concerns—particularly what to do with an individual’s information, but also the usefulness of having genetic data on a large group of people to understand disease and help discover new treatments—are germane to an ongoing project of the Hastings Center to assess the implications of genetic testing of the whole genomes of large numbers of babies, to screen for any of several dozen genetic diseases.   Again, most of the babies will be perfectly healthy, and the yield from screening for rare conditions is low.  But people arguably have a right to know about themselves, and parents to know about their newborns.  Yet still, to what end will we use information that we don’t fully understand?  Read a good Los Angeles Times article, that overlaps some of the points in The Code’s video, and provides other useful information in quick-and-easy form, here.

Finally, I was gratified to read that a project to synthesize an entire human genome in the laboratory is being scaled back, at least for now.  Apparently, they can’t raise enough money.  I bet would-be investors aren’t convinced they could own the results and guarantee a return on their money.  I fretted about this in May of 2016 and again in July of the same year.  I encourage readers to click through and read those, as well as the concerns raised by Drew Endy of Stanford and Laurie Zoloth of Northwestern, who criticized both the effort in concept and the closed-door, invitation-only meeting at Harvard to plan it.

That was two full years ago.  A lot is going on under our noses.

New short videos on genetic topics

This week, an email from the Hastings Center promoted The Code, a series of 3 short documentaries on the internet about the origins of genetic medicine.  The three are being released one week at a time.  The first, released this week, briefly (12 minutes) reviews the determination, or sequencing, of the entire human genome, a project conducted in the 1990’s, and completed in 2000, by two labs—one in the government, one private—that initially worked in competition but ended working in collaboration.

It’s a nice review of the key points:

  • A person’s entire genome can be read fast—in a few hours—by an automatic process, at an ever-decreasing cost that now is on the order of $1000.
  • We still are FAR from understanding what the genetic code means for human disease. The number of cases in which there is a reasonably direct link between a single, or a small number, of genetic abnormalities and a gene, in a way that allows us to predict risk of disease or be able to make an enlightened selection of treatment, is still small.
  • With more reading of peoples’ genomes, and more computing power, what amounts to a massive pattern-recognition problem will likely yield more solutions that can be practically exploited to the benefit of human health. Some entities are collecting more peoples’ genomes in a database, for ongoing analysis and, at first, hypothesis generation—that is, “maybe this is a lead that could be acted on for benefit, after the proper follow-on research.”
  • But for now, we should not get carried away—”personalized medicine” is not generally “ready for prime time,” but useful only in a few specific situations, and often most appropriately the subject of new medical research. And one should be careful to get well-informed advice from a medical professional who is expert in genetic medicine, and not over-interpret what a commercial entity might be advising.  (But that, about which this blog has commented in the past, is for another time and another posting.)

This first video does not get into ethical issues—e.g., of justice, privacy, and the like.  But it is a good, quick, engaging overview suitable for the general public.  (BTW, I hate calling non-scientists and non-physicians “lay people,” a term I think best reserved to distinguish most of us from the clergy, and the abuse of which just reinforces the notion of medical scientists as a sort of “priesthood.”)

The second video in the series, due out next week, is on gene editing, and the third, the week after, will address companies that are willing to sequence your genes and tell you, for a price, what they think it might all mean.

Toward true public engagement about gene editing

The March 22, 2018 edition of Nature includes two thoughtful, helpful commentaries about improving the public dialogue around “bleeding edge” biotechnologies.  In this case, the example is gene editing, of which one commentator, Simon Burall from the U.K., says, “Like artificial intelligence, gene editing could radically alter almost every domain of life.”  Burall’s piece, “Don’t wait for an outcry about gene editing,” can be found here.  The other commentary, “A global observatory for gene editing,” by Harvard’s Sheila Jasanoff and J. Benjamin Hurlbut from Arizona State, can be found here, and an umbrella editorial from the editors of Nature is here.  All are open-access and all are worth reading by any citizen who would like to be informed at even a general level about the ethical discussions of biotechnology.

The three share this tone: more inclusiveness, more humility on the part of scientists, and willingness to have difficult conversations are called for—and have been generally lacking in past efforts to engage the public in discussion of the implications of new biotechnologies.  In the view of Jasanoff and Hurlbut, even the much-admired 1975 Asilomar conference that established boundaries on recombinant DNA research and its applications, was too narrow, focusing on technically-definable risks and benefits but not taking time to reflect more deeply on the ultimate ramifications of what the scientists were doing.  The experts dominate, and lecture—gently, but clearly—the “laity.”  This can create a sort of foregone-conclusion effect: getting people comfortable with the research agenda and the scientists’ and technologists’ (including industry players’) goals is the true point.  The possibility that some work simply should not be pursued for a while may scarcely be expressed, much less heeded.  As Hans Jonas said in a reflection about Asilomar, “Scientific inquiry demands untrammeled freedom for itself.”

Burall, Jasanoff, and Hurlbut seem to be saying, repent from that, as it were.  Don’t just have a panel of a dozen scientists or so meet for a single seminar or webinar with a dozen or so non-scientists (with, I might add, the token clergyperson).  Create a clearinghouse for a wide range of views on what gene editing really might mean, and how humans should respond.  Open the dialogue to a large number, not just a few, non-scientists from a wide range of perspectives.  Pay attention to cultures other than the developed West—especially the global South.  Perhaps start with seminars that are cooperatively organized by several groups representing different interests or stakeholders, but don’t stop there—create a platform for many, many people to weigh in.  And so on.

They don’t suggest it will be easy.  And we do have a sort of clearinghouse already—I call it the Internet.  And we’d want to be sure—contra John Rawls—that viewpoints (yes, I’m thinking of God-centered perspectives) are not disqualified from the outset as violating the terms of the discussion.  And, perhaps most importantly, what threshold of public awareness/understanding/agreement would be insisted upon to ground public policy?  Surely a simple popular majority would be suspect, but unanimity—achievable in smaller groups, with difficulty—would be impossible.  And concerns about “fake news” or populist tendencies run amok (the “angry villagers”) would be unavoidable.

But, as Jasanoff and Hurlbut say, “In current bioethical debates, there is a tendency to fall back on the framings that those at the frontiers of research find most straightforward and digestible…[debate must not be limited by] the premise that, until the technical capability does exist, it is not necessary to address difficult questions about whether [some] interventions are desirable…Profound and long-standing traditions of moral reflection risk being excluded when they do not conform to Western ideas of academic bioethics.”

Bingo and amen.  How to make it happen, I am not sure.  Jasanoff and Hurlbut say they are trying to get beyond binary arguments about the permissibility or impermissibility of germline genome editing, for example.  Still, I don’t see how the “cosmopolitan” public reflection they advocate can go on without agreeing on something like a fairly firm moratorium—a provisional “presumption to forebear,” as I like to put it—while the conversation proceeds.  And hey, we’re the Anglosphere.  We’re dynamic, innovative, progressive, pragmatic, visionary.  We don’t do moratoria.   Moratoria are for those Continental European fraidy-cats.  Then again, these writers are seeking a truly global discussion.  And past agreement by assembled nation-states appears to have at least slowed down things like chemical and biological munitions (recent events in Syria notwithstanding).

These authors are doing us a service with their reflections.  Read their articles, give them a careful hearing—and note that their email addresses are provided at the end.  Maybe I’ll write to them.

Resources regarding ethics of gene editing

Recently, two resources have become available regarding gene editing and the issues raised by it.

First, the National Academies of Science, Engineering, and Medicine have made available an archive of its February 22 webinar about human gene editing.  The home page for the Academies’ human gene-editing initiative is here.  A link to the archived webinar is here.  The slides can also just be viewed here.

Second, Issue 1 of Volume 24 of the journal The New Bioethics is dedicated to human gene editing.  The entire issue, or individual articles from it, are available online for purchase, or for viewing if you have access through an academic institution.  Article titles deal with, for example, differentiating gene editing from mitochondrial transfer, comparing ethical issues with gene editing vs embryo selection, and “selecting versus modifying” to deal with disabilities.

I have not been through these materials in any detail, yet.  The webinar looks a smidge promotional, co-sponsored as it was by the Biotechnology Industry Organization (BIO).  But it also recommends the Academies’ report on the status of human gene editing, and summarizes key recommendations, which include limiting efforts (at least for the present!) to editing “somatic,” or, if you will, “adult” cells to make them into cellular therapies for recognized diseases.  This is well within the existing ethical and regulatory regime governing clinical research and treatment development, as opposed to the deeply problematic prospect of heritable gene editing, or attempts to edit genes for human enhancement, both of which the report and the webinar (at least the slides) counsel that we NOT rush into.  The New Bioethics articles look thoughtful and worth reviewing, which I hope to do (and comment on) in the near future.

DIY CRISPR Kits – Gene Editing for the Rest of Us

One might think with the amazing advance of technology and easy access to nearly infinite data via the Internet that we, as a society, would see a reduction in false claims of benefit for novel medical procedures and untested medications. Sadly, it seems to be just the opposite. I seem to be spending gradually more time with my patients reviewing the results of their internet research for new solutions for their chronic back pain. Their efforts are laudable even though the “hoped for” benefits claimed in their researched solutions are woefully lacking. Unfortunately, often this exercise in reviewing the outside data takes valuable time away from the remainder of the office visit.

Reviewing false or confusing information is one thing but preventing patients from self-experimentation with untested medications or unproven treatments is another. Enter the biohacker and companies offering do-it-yourself (DIY) kits claiming to allow anyone to experiment with CRISPR (a method of genetic editing) for self-administration. Emily Mullin covers biohacking and DIY CRISPR very nicely in her recent article in the December Technology Review. To me, this has the feel of the 1980s when a curious kid with some basic programming knowledge, an inexpensive computer and a modem can access previously forbidden government systems, potentially unleashing havoc on the rest of us (WarGames, anyone?) After all, now that we know the human genetic code, all we need is for someone to just provide the instructions and tools for editing that code, then anyone could tweak their own DNA. Easy peasy lemon squeezy, right?

Recently, the FDA has been busy trying to prevent medical clinics from administering untested stem cell treatments (see Neil Skjoldal’s recent November blog entry on (Stem Cell Clinics & the FDA). Imagine the significant increase in the scope of the regulatory problem if individuals can order a DIY CRISPR kit off the Internet!

While we might chagrin at the naiveté required to believe the street-side pitch of the Old West Carter’s Little Liver Pill salesman, that same pitch via a modern tech savvy YouTube video (complete with separate internet links) somehow offers a new level of legitimacy. The Technology Review article speculated that one of the featured companies was preparing not a vaccine but a treatment for herpes. In less than 8 weeks from the article’s publication, Aaron Traywick, CEO of Ascendance Biomedical, publically self-injected himself with his firm’s untested and non-FDA approved “treatment” for herpes. The linked article by Reegan Von Wildenradt in the popular magazine Men’sHealth offered an excellent counter as to why this type of “science” might be suspect, including quotes from ethicist Arthur L. Caplan at NYU in support of the standard FDA process for screening medical treatments.

We often lament in this blog that technology is advancing so rapidly that we fail to have a fair public hearing and discussion of the ethics involved in a particular biomedical advance. Now it seems our time may be better spent speaking out first about the basic risks of the new technology and doing our best to support the FDA in their massive task of policing the Internet to prevent a DIY CRISPR kit from falling into the wrong hands – ours.

P.S. – I’m accepting names for the title of the future Hollywood blockbuster where the son of Matthew Broderick and Ally Sheedy injects himself with his own DIY CRISPR-modified DNA and …

Citizenship, Surrogacy and the Power of ART

A recent LA Times article by Alene Tchekmedyian explores a complicated case involving birthright citizenship, surrogacy and same-sex marriage. Briefly, a California man, Andrew Banks, married an Israeli man, Elad Dvash, in 2010. At the time, same-sex marriage was not legal in the US leaving Elad unable to acquire a green card for residency (via the marriage) so the couple moved to Canada where Andrew has dual citizenship. While in Canada, the couple conceived twin boys, Aiden and Ethan, using assisted reproduction technology (ART) whereby eggs from an anonymous donor were fertilized by sperm from Elad and Andrew and then implanted within the womb of a female surrogate and carried to term. When the US Supreme Court struck down the federal law that denied benefits to legally married gay couples in 2013, Elad applied for and was granted his greed card. The present controversy occurred when Andrew and Elad applied for US passports for the twins. US State Department officials required detailed explanation of the boys’ conception, eventually requiring DNA tests which confirmed Aiden to be the biological son of Andrew and Ethan to be the biological son of Elad. Aiden was granted a US passport while Ethan was denied. The family has since traveled to the US (Elad with his green card and Ethan with his Canadian passport and temporary 6 month visa) where they are now suing the State Department for Ethan’s US birthright citizenship. They are arguing that the current applicable statute places them wrongly in the category of children born out of wedlock rather than recognizing their marriage, thus discriminating against them as a binational LGBTQ couple.

Birthright citizenship is a complicated legal arena and I am no lawyer. The US is even more complicated because we allow birthright citizenship to be conferred jus soli (right of the soil) in addition to jus sanguinis (right of blood). The twins were not born in the US so establishing “bloodline” is needed. The law specifies conditions where one parent is a US citizen and one is not a US citizen, and there is further differentiation depending on whether the children of the US citizen were born in or out of wedlock. They also vary depending on whether the US citizen is male or female, with the law more lenient (easier to acquire citizenship) for the child of a woman than of a man.

While the legal challenge here will almost certainly involve potential issues of discrimination of LGBTQ binational couples, the problem is really with the current legal definitions of parent as it relates to surrogacy in general. The State Department actually has a website dedicated answering questions related to foreign surrogacy and citizenship. The real issue is that the State Department relies upon genetic proof of parentage for foreign surrogacy births. In the present case, the surrogacy occurred outside the US, Elad is the genetic father of Ethan and Elad is not a US citizen; therefore Ethan is not a US citizen. While I’m deep in the weeds here, technically, Aiden and Ethan are not fraternal twins in the usual sense but rather half siblings (and this assumes that the donor eggs are from the same woman; otherwise the boys would be unrelated despite sharing the same pregnant womb through the magic of ART). Had Ethan been physically born via surrogacy in the US, he would have acquired his citizenship via jus soli (see US map for surrogacy friendly states near you).

This problem is just as confounding for heterosexual couples using foreign surrogates, and the problem is global. A more detailed technical legal discussion may be found here. A heterosexual couple using donor eggs and donor sperm and using a foreign third party surrogate would have exactly the same problem establishing US citizenship for “their” child. A similar problem would exist for an adopted embryo gestated in a foreign country by a foreign surrogate. If either the egg or the sperm of the US citizen is used for the surrogate birth, the child would be granted birthright citizenship.

The main difference for homosexual couples is that only one spouse can presently be the biological parent. I say “presently” because with ART it is theoretically possible (and may become actually possible in the future) to convert a human somatic cell into either a male sperm or a female egg. At that point, both spouses within a same-sex marriage could be the biological parents of their child. The present legal issue is not the result of a cultural prejudice against anyone’s sexuality but with the biological prejudice of sex itself. ART has the potential ability to blur the categories of sex as culture is now blurring the categories of gender. Should we consider this a good thing?

Given the present technological limits of ART, the simple issue of US citizenship could be resolved in all these cases if the US citizen parent simply adopted the child. Elad correctly points out that while adoption of Ethan by Andrew would grant Ethan US citizenship, it would not grant Ethan birthright citizenship, a necessary requirement for Ethan to someday run for US president. ART may be forcing us to look at changing our definition of parent but should it change our definition of biology? Ethan is the biological son of Elad. He is able to be the legally adopted son of Andrew and enjoy the benefits of US citizenship as currently does his half brother Aiden. He is not able to become the biological son of Andrew and enjoy the additional benefit of birthright citizenship via jus sanguinis.

Should we change the definition of birthright citizenship because ART is changing our definition of parent?

Update on clinical studies of human gene editing

The January 22 edition of The Wall Street Journal carried an article the essential message of which was, “the Chinese are ahead of us in gene editing.”  Specifically, more human clinical trials are active in China than in the US using gene editing in some form to treat people with specific diseases.  Some of these trials use the “hot, new” CRISPR-Cas9 approach to gene editing.  Almost all of the active ones are in China, although one has recently been approved by regulators to begin in the U.S., at the University of Pennsylvania.  That one appears not yet to be recruiting patients.  In most of these “CRISPR” trials, cells are removed from a patient’s body, altered in the laboratory to make them more likely to treat the disease in question (in this case read: attack a cancer), and injected back into the patient.  They are thus variations on a 30-or-so-year-old approach of using cells that have been modified in some way to treat cancer.

The difference here is that the cells have their genes edited, and that raises potential safety risks, such as, what happens if the wrong genes are “edited,” and the altered cells go nuts and do something undesirable?  Because of this, human trials of gene editing in the U.S. are closely regulated, including having to pass scientific and safety review by the “RAC” (that’s for “Recombinant DNA Advisory Committee,” in case the acronym made any of you think of the Spanish Inquisition…then again, I have had researchers who have had to go through it suggest that the analogy is apt…).

The RAC was established back in the late 1970’s when drugs started being made with recombinant DNA, and trials of gene therapy using genes inserted into viruses were conducted.  A famous case of that work going awry raised concerns about oversight, and slowed things down substantially.  And as it stands now, the U.S. regulatory process for this work is cumbersome.  In China, not so much—a local ethics review board looks at a proposal, and off they go.  The WSJ makes it sound like informed consent for the Chinese studies may be a bit thin, too.  U.S. experts are quoted as saying not that we need less regulation, but that they (the Chinese) need more, to bring them back to our speed.

Perhaps so.  My point here is that this work is going on.  Examples like those cited here seem to me to fall under the existing regulatory regime for human trials, and don’t pose the same sort of ethical issues as the potential for inherited gene edits—that is, editing embryos and babies.  That’s a different kettle of fish.

One Chinese CRISPR trial appears not to alter cells outside the body, but actually try to administer the genetic material to make an edit to a cervical cancer-causing gene.  That poses similar safety concerns to other gene therapy approaches, including some with “zinc finger” editing technology, like a currently-active U.S. study to treat hemophilia, a disorder in which someone has a genetic flaw that makes them susceptible to excessive bleeding and the goal is to repair the offending gene.

In considering this work, I think it’s important to distinguish use of the gene-editing approach for incremental steps to treat human disease, like the cell therapy approaches, or true “gene therapy” approaches in which a “corrected” gene is administered to a patient, from the more problematic possibility of editing individuals in ways that can be inherited.  The latter is what worries me.  I wrote about this last November 9 and November 16.   And yes, the current Chinese work should be more closely regulated.  Doubt we have any control over that.

An FDA blog post from a year ago (by the former FDA Commissioner) provides a useful, brief discussion of the FDA’s approach to regulating various applications of genetic editing.  Worth reading.

Is Your Polygenic Risk Score a Good Thing?

Back in October, Jon Holmlund wrote a blog entry regarding the popular company 23andMe and their collection of your health-related information along with your genetic material. I missed the significance of that relationship at the time. It took a recent article in Technology Review by my favorite technology writer Antonio Regalado to raise my ethical antennae. In his article, he explains the nexus of big data mining of genetic data and health information (such as is collected by 23andMe) and its future potential use to select embryos for IVF, selecting not only against polygenic diseases such as type 1 diabetes but potentially for non-diseases such as height, weight or even IQ.


Pre-implantation genetic diagnosis (PGD) already is used to select for particular embryos for IVF implantation that do not have genetic patterns such as cystic fibrosis or Down syndrome. Diseases that result from multiple genes (polygenic disorders) presently defy current PGD methods used to detect future diseases. Using Big Data analysis of health information compared against linked genetic data, scientists are getting better at accurate polygenic risk scores, statistical models which may more accurately ‘guess’ at an embryo’s future risk for not only juvenile diabetes but also later-in-life diseases (such as heart disease, ALS or glaucoma) or other less threatening inheritable traits (such as eye color, height or IQ) that result from multiple genes (and perhaps even environmental factors). There is confidence (hubris?) that with enough data and enough computing power, we can indeed accurately predict an embryo’s future health status and all of his or her inheritable traits. Combine that further with all of the marketing data available from Madison Avenue, and we can predict what type and color of car that embryo will buy when he or she is 35.

Ok, maybe not the color…

Seriously, companies such as Genomic Prediction would like to see IVF clinics eventually use their expanded statistical models to assist in PGD, using a proprietary technique they are calling Expanded Pre-implantation Genomic Testing (EPGT). Consider the following two quotes from Regalado’s article:

I remind my partners, “You know, if my parents had this test, I wouldn’t be here,” says [founding Genomic Prediction partner and type 1 diabetic Nathan] Treff, a prize-winning expert on diagnostic technology who is the author of more than 90 scientific papers.

For adults, risk scores [such as calculated by 23andMe] are little more than a novelty or a source of health advice they can ignore. But if the same information is generated about an embryo, it could lead to existential consequences: who will be born, and who stays in a laboratory freezer.

Regalado’s last comment is dead-on – literally. Who will be born and who stays in the freezer is another way of saying “who lives and who dies”.

Technologies such as EPGT are poised to take us further down the bioethical slope of choosing which of our children we want to live and which we choose to die. For the sake of driving this point home, let’s assume that the technology becomes essentially 100% accurate with regard to polygenic risk scoring and we can indeed determine which embryo will have any disease or trait. Since we already permit the use of single gene PGD to prevent certain genetic outcomes, should there be any limit to polygenic PGD? For instance:

(A) Should this technology be used to select against immediate life threatening illnesses only or also against immediate mentally or physically permanently crippling diseases that don’t cause death directly?

(B) Should this technology be used to select against later-in-life diseases that are life threatening at the time or also against mentally or physically crippling diseases that don’t cause death directly? (Would it make a difference if the disease occurred as a child, teenager or adult?)

(C) Should this technology be used to select against non-disease inheritable traits that society finds disadvantageous (use your imagination here)?

(D) Should this technology be used to select for inheritable traits that society finds advantageous (a slightly different question)?

Depending upon your worldview, until recently, answering Questions A through D used to be the purview of God or the random result of chance. Are we ready (and capable) to assume that responsibility? Make your decision as to where you would draw the line then review this short list of famous scientists and see how many on that short list your criteria would permit to be born.

Are you happy with that result? Would you call it good?

It would be nice to get this right since it now appears to be our call to make…