The rapid adoption of the CRISPR/Cas9 gene editing technology is evident in the explosion of papers describing the use of the technique for possible use in a variety of applications (e.g., retinitis pigmentosa, Duchenne's muscular dystrophy, HIV infection). As described in earlier posts here, the use of gene editing falls into two broad categories: altering genes in somatic cells (non-reproductive) to treat disease in individuals or altering the germline DNA in embryos to preemptively treat or minimize later-developing disease. It is the latter application that has led to many calls for an official moratorium, a ban on funding, and the convening of a wide public discussion on whether scientists should be able to edit germline DNA, which would create heritable genetic changes passed on to later generations. As reported here earlier, a development biologist in the U.K. applied to the Human Fertilisation and Embryology Authority (HFEA) for permission to use gene editing to study early embryonic development. That application has now been approved:
Our Licence Committee has approved an application from Dr Kathy Niakan of the Francis Crick Institute to renew her laboratory’s research licence to include gene editing of embryos. The committee has added a condition to the licence that no research using gene editing may take place until the research has received research ethics approval. As with all embryos used in research, it is illegal to transfer them to a woman for treatment.
The goal of Dr. Nakian's research is described:
To provide further fundamental insights into early human development we are proposing to test the function of genes using gene editing and transfection approaches that are currently permitted under the HFE Act 2008. We also propose to use new methods based on CRIPSR/Cas9, which allows very specific alterations to be made to the genome. By applying more precise and efficient methods in our research we hope to require fewer embryos and be more successful than the other methods currently used. Importantly, in line with HFEA regulations, any donated embryos would be used for research purposes only. These embryos would be donated by informed consent and surplus to IVF treatment.
The HFEA approval in the U.K. is without precedent and represents the first officially sanctioned use of gene editing on germline DNA. The 2015 publication of a gene editing experiments on non-viable embryos by Chinese scientists was widely condemned and it accelerated the urgency of considering ethical and regulatory aspects of this research as soon as possible. As described here earlier, a recent National Academy of Sciences (NAS) international summit on gene editing technologies had concluded with a consensus statement that it would be "irresponsible" to use gene editing for the purpose of altering germline DNA in the creation of embryos for reproduction. This research does not do that, explicitly. It will use gene editing to study how genetic changes affect embryonic development as its end goal. With regard to the U.S., there is already an NIH-imposed ban on any federal funding for gene editing on human embryos; in addition, the U.S. has no regulatory equivalent of the U.K. HFEA to consider any possible requests for the approval of non-reproductive embryonic developmental studies like the one approved here. The ongoing NAS study committee will convene another public meeting next week (February 11) to consider more impacts of gene editing technologies; details here.
The International Summit on Human Gene Editing, hosted by the National Academies of Science and Medicine (NAS, NAM) and international partners, has just concluded a 3-day meeting (archived webcast available here). This summit was called following the rapid dissemination of human gene editing research using the CRISPR/Cas 9 technology (see earlier posts here and here). The impact of this technology cannot be understated:
The rapid development and widespread adoption of easy-to-use, inexpensive and effective genome-editing methodologies has changed the landscape of biology. The simplicity of the CRISPR–Cas9 system allows researchers and students to make precise changes to genomes, thereby enabling many experiments that were previously difficult or impossible to conduct.
Widespread concern over possible attempts to engineer the human germline (perform gene editing on embryos or gametes for reproductive purposes) led to calls for caution or even a research moratorium (see here). At the conference this week, panels discussed the current technical state of human gene editing, existing and potential governance structures, international perspectives, and social consequences of the technology. The most controversial application of human gene editing – germline editing creating heritable genetic changes – was central to many of the discussions, and the conference oscillated between considering the legitimacy of germline editing and considering the arguably more mundane regulatory control of somatic gene editing. The conference coordinating committee has released a consensus statement that endorses further research on both somatic and germ-line gene editing, subject to existing regulations and oversight mechanisms. The full statement is here. I reproduce the portion of that statement that focuses on the hotly contested issue of germline gene editing:
3. Clinical Use: Germline. Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.
Germline editing poses many important issues, including: (i) the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism); (ii) the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment; (iii) the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations; (iv) the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country; (v) the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively; and (vi) the moral and ethical considerations in purposefully altering human evolution using this technology.
It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.
As reported by David Baltimore, chair of the conference committee, the members did not recommend either a ban or a moratorium on research into germline gene editing, but they state that any use of gene editing in reproduction at this time would be "irresponsible." In the U.S., the NIH has already ruled out federal funding for such research:
However, NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed.
The NAS contemplates ongoing public engagement with the controversies raised by human gene editing, in the form of an upcoming formal NAS study and the establishment of a publicly accessible forum to continue the discussion. More analysis of the conference and the effects on the current research climate will be posted here.
Non-invasive prenatal testing (NIPT) is an alternative to the invasive techniques of amniocentesis or chorionic villi sampling used in reproductive medicine, both of which carry some risk to the fetus. The research demonstrating that fetal DNA could be recovered from maternal serum prompted the development of testing techniques that could simply rely on maternal blood testing in order to recover fetal DNA and perform genetic analysis. The scientists were awarded U.S. Patent No. 6,258,540. Claim 1 of the patent:
A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.
Sequenom, Inc. holds the rights to the patent. It sued Ariosa Diagnostics and several other genetic testing companies for infringement of the patent. In Ariosa Diagnostics, Inc. v. Sequenom, Inc., issued in June, the Federal Circuit ruled that the patent claims to methods for detecting and recovering the fetal DNA from a maternal sample were invalid for lack of patentable subject matter (35 U.S.C. § 101) (see here). That decision followed a sequence of recent Supreme Court cases, AMP v. Myriad (2013) (Myriad) and Mayo v. Prometheus (2012) (Mayo) that each invalidated patent claims in the life sciences for a lack of patentable subject matter. The Federal Circuit relied on the analytic framework from Mayo to dissect the patent claims, summarizing the test as follows:
First, we determine whether the claims at issue are directed to a patent-ineligible concept. If the answer is yes, then we next consider the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application.
The court noted that the presence of fetal DNA in maternal serum was a patent- ineligible natural phenomenon (step 1) and then proceeded to step 2, where it considered whether any other elements of the patent claim (detecting, amplifying) operated to transform the unpatentable natural phenomenon:
Thus, in this case, appending routine, conventional steps to a natural phenomenon, specified at a high level of generality, is not enough to supply an inventive concept. Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art. The claims of the ’540 patent at issue in this appeal are not directed to patent eligible subject matter and are therefore, invalid.
Judge Linn filed a concurrence, but made it clear that he did so because Mayo demanded the application of a fairly unforgiving test that led to an incorrect result in this case. In August, Sequenom filed a petition with the Federal Circuit requesting a rehearing en banc, contending that the panel’s decision wrongly applied the Mayo framework to find a groundbreaking invention unpatentable (see here):
To avoid this absurd result, all the Court must do is reaffirm—as did the Supreme
Court in Mayo—that a combination of known steps that incorporates or is motivated by an unpatentable natural phenomenon is nonetheless patentable if that combination “considered as a whole” was not routine before the patent disclosed it.
Sequenom then described the future impact of the decision as "an existential threat:"
The full Court's intervention is particularly necessary because, if this Court does not step in and draw this line, the panel's rule threatens to swallow many more meritorious inventions along with this one.
Ariosa has recently filed its response to the Sequenom petition. Ariosa argues that the Federal Circuit’s decision properly utilized the Mayo-based framework as an analytic device:
Appellants’ only legal argument (as opposed to their dire policy-based prognostications) in favor of rehearing en banc is that Mayo, Myriad and Diehr must be read as teaching that “a combination of known steps that incorporates or is motivated by an unpatentable natural phenomenon is nonetheless patentable if that combination ‘considered as a whole’ was not routine before the patent disclosed it.” Yet Appellants’ misreading of those precedents amounts to nothing short of a wholesale revision of the Supreme Court’s two-part test for determining whether a claim recites patent-eligible subject matter.
The contrasting arguments of the parties frame a question for the Federal Circuit regarding whether a patent claim embedding a natural phenomenon requires a holistic interpretation (Sequenom) or should be subject to a more splintered analysis (Ariosa). A decision from the Federal Circuit on the petition for rehearing is likely to issue in the next several months; if they do not accept it, the decision could then be appealed to the Supreme Court, which has issued two life science decisions on patentable subject matter in the last three years.
Over the last year, several ad hoc and professional organizations have continued to weigh in on whether the CRISPR/Cas9 gene-editing technology should be subject to any pauses in its adoption as a method of genome alteration or correction (see here). The advent of CRISPR/Cas9 technologies, beginning with the first publication in 2012, has accelerated scientific interest in gene editing because the technique has offered a more efficient approach than previous genome-altering methodologies. Here is an overview of the directions such research can take:
Genome editing has tremendous value as a tool to address fundamental questions of human and non-human animal biology and their similarities and differences. There are at least four categories of basic research involving genome editing technology that can be distinguished: 1) research to understand and improve the technique of genome editing itself; 2) genome editing used as a tool to address fundamental questions of human and nonhuman animal biology; 3) research to generate preliminary development of human somatic applications; and 4) research to inform the plausibility of developing safe human reproductive applications.
However, the CRISPR age is encountering fits and starts. Most controversially, the specter of CRISPR becoming a novel reproductive technology to perform gene editing on a human embryo has raised the most attention and concern. Earlier, this year, two groups of American scientists issued cautionary statements (see earlier post here); the NIH then reiterated its ban on any federal funding of research on gene-editing in embryos. More recently, other international bodies are weighing in. The U.K. Wellcome Trust has now issued a statement:
Research using genome editing tools holds the potential to significantly progress our understanding of many key processes in biology, health and disease and for this reason we believe that responsibly conducted research of this type, which is scientifically and ethically rigorous and in line with current legal and regulatory frameworks, should be allowed to proceed. We will continue to support the use of genome editing in preclinical biomedical research as well as studies that progress and refine these technologies. Within the UK, this research may involve the use of somatic (non-reproductive) or germ cells, including human embryos up to 14 days old - within the confines of the HFE Act 2008 - where appropriately justified and supported by rigorous scientific and ethical review.
Against that backdrop, a U.K. developmental biologist has applied to the Human Fertilisation and Embryology Authority (HFEA), for permission to edit the genome of a human embryo (there is no such agency in the U.S). The goal of the proposed research is to identify what genes in the developing embryo are active in the early post-fertilization stages; the research would use surplus embryos from IVF clinics where permission has been granted for such use. The license may be granted:
The Human Fertilisation and Embryology Authority (HFEA) has yet to review her application, but is expected to grant a licence under existing laws that permit experiments on embryos provided they are destroyed within 14 days. In Britain, research on embryos can only go ahead under a licence from an HFEA panel that deems the experiments to be justified.
In a separate development, The Hinxton Group, an international consortium centered on stem cell issues, published a statement calling for caution in possible reproductive applications, but not a moratorium:
Oversight structures must be in place prior to any attempts to use genome editing in human reproduction. Effective oversight requires the development of appropriate standards for preclinical data (e.g., What are acceptable thresholds for off-target events and mosaicism? What are appropriate methods for determining the impact of off-target events?). Initial attempts should be conducted only in the context of formal clinical research or trials. In addition, the health and well-being of participants, developing fetuses, and pregnancy outcomes should be monitored carefully. The health and well-being of those born should also be monitored in long-term follow-up and research, albeit with a mind toward the burdens this would impose.
Finally, in an event that will likely feature a spectrum of viewpoints, the Chinese Academy of Sciences (CAS) and the Royal Society (the science academy of the U.K.) are joining the U.S. National Academy of Sciences (NAS) to hold a highly anticipated international summit on human gene-editing on December 3, 2015 in Washington, D.C. A preliminary meeting (and webcast) to organize the summit will be held next week on October 5, 2015; details here.
The ongoing legal battles over the scope of reproductive rights protected by the 14th Amendment – with claims of constitutionally protected values of liberty and privacy invoked – continue, going back to the signature case of Roe v. Wade in 1973 and furthered tailored by Planned Parenthood v. Casey (1992), among other cases. Other arguments for the protection of reproductive autonomy are grounded in gender equality. Fast forwarding to the rapidly developing technological landscape of genetic testing, reproductive medicine has steadily refined the options available for prenatal testing to provide prospective parents with ever more accurate – and earlier obtained – medical information. The most dramatic development has been the availability of non-invasive prenatal diagnosis (NIPD) that relies on obtaining fetal DNA (cell-free detal DNA, cffDNA) from maternal blood as early as 4 weeks into gestation and to test for a number of genetic/chromosomal disorders, including Down syndrome (attributed to the presence of an extra chromosome 21, leading to a trisomy). NIPD has reduced the need for invasive procedures, such as chorionic villi sampling and/or amniocentesis. As prenatal testing becomes more sophisticated, an ongoing political battle rages over whether abortion rights should be restricted based on the intent or rationale of the mother for seeking the procedure. This has led to both state and federal efforts to restrict abortion when it is sought on the basis of gender, race or genetic anomaly (e.g., Down syndrome). Currently, a bill, HB 135, is pending in Ohio that would ban any abortion that is sought sought because prenatal testing reveals Down syndrome. North Dakota enacted a similar bill in 2013 (that same bill would have prohibited abortions about as early as 6 weeks; that portion was struck down by the Eighth Circuit in July of this year). To date, there are no reports of enforcement of these selective bans on abortion. Yet they raise not only the most obvious legal issue of whether such laws impinge on the constitutional right enshrined by Roe (or present the “undue burden” prohibited in Casey). They raise a novel issue of whether the legal rights accorded to the mother can vary according to genetic status of a fetus. Beyond that, express litigation over the constitutional concerns of the fetus itself would lead into the legal personhood legal battles that have been fought already (and overwhelmingly seen the defeat of attempted personhood ballot initiatives and legislation) (see earlier posts here and here). Thus, an indirect genetically-determined legal climate of maternal rights emerges if these laws work as intended – with the twist that the relevant genetic information is derived from the fetus. While is appears that these laws are unworkable as a practical matter, these bills can formally require the provider to question the mother about her motives and can impose felony charges on a physician violating the ban. The Ohio bill is likely to pass, and join the North Dakota bill alone in targeting maternal rights on the basis of a fetal genetic anomaly. Proponents of these bills have argued that, for example, the current climate of genetic testing only encourages the elimination of offspring with detectable genetic abnormalities, with the result that Down syndrome births become increasingly uncommon, and they invoke a kind of disability discrimination argument in support of these measures (however, that leads back to the fetal personhood debate). Opponents argue that the Roe-based constitutional right to seek an abortion – while certainly cabined by many modern legislative limitations – is not conditioned on maternal motive or the genetic status of the fetus, but is simply motivated by a desire to limit women's reproductive choices.
In June, the Federal Circuit ruled that a prenatal testing method for detecting fetal DNA in maternal serum was not patentable, violating the prohibition against the patenting of natural phenomena (see here). In the case, Ariosa Diagnostics, Inc. v. Sequenom Inc. (2015), a representative claim from U.S. Patent No. 6,258,540 is as follows:
1. A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.
In the invalidity challenge asserted by Ariosa when the company was sued for patent infringement by Sequenom, Ariosa argued that the method claim effectively covered (or preempted) all uses of the newly observed natural phenomenon - namely, the presence of fetal DNA in maternal blood. The method is centered on that discovery - detect the fetal DNA and perform genetic assessments on that sample, thereby avoiding more risky invasive prenatal procedures. The trial court, and then the Federal Circuit, concluded that the method patent claims were invalid, that they did attempt to patent a natural phenomenon, not an actual invention. As the Federal Circuit stated:
Thus, in this case, appending routine, conventional steps to a natural phenomenon, specified at a high level of generality, is not enough to supply an inventive concept. Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art.
Now, Sequenom has filed a petition at the Federal Circuit, asking for an en banc review of the court's panel decision in June. Sequenom challenges the panel's application of a test for patent eligibility derived from the Supreme Court's 2012 decision in Mayo v. Prometheus. Further, Sequenom argues that the impact of the patent denial on future method patent claims that center on a newly discovered natural phenomena is devastating to future innovation:
The full Court’s intervention is particularly necessary because, if this Court does not step in and draw this line, the panel’s rule threatens to swallow many more meritorious inventions along with this one. The core of nearly every major innovation is the discovery of a fact about the natural world that motivates inventors to combine existing techniques to achieve new practical results. Accordingly, the panel’s test would threaten an invention implementing the discovery that a certain form of Ebola virus provokes an immune response that prevents infection (to take just one timely example). Nearly all vaccines have this problem: The hard part is determining the natural law that a given attenuated virus creates lasting immunity; once you know that, the rest is “routine.” The same goes for future holy-grail discoveries like simple, non-invasive methods of detecting early-stage cancer— ironically, the cheaper and simpler the method discovered, the less patentable it will be. In truth, the problem goes well beyond diagnostics or even medicine: If combining conventional techniques in an unconventional fashion, motivated by a discovery about nature’s laws, is unpatentable subject matter, it is hard to see how any process claim can survive.
The Ariosa decision particularly impacts method claims, not composition of matter claims (which were already severely impacted by AMP v. Myriad in 2013). Whether the Federal Circuit decides to accept the petition and rehear the case en banc is unknown; what is known, however, is that the Ariosa decision does jeopardize the validity of similar method claims to the detection of many biochemical or molecular relationships, just at a time when much of modern biotech research is devoted to uncovering exactly that kind of information.
The rapid dissemination of the publication reporting the use of CRISPR/Cas9 gene-editing technology by Chinese scientists in an attempt at human germline modification has generated quick responses from several official quarters. The National Academy of Sciences (NAS) has announced its upcoming involvement in the scientific, ethical, and policy debate over the use of the CRISPR technology in germline applications:
The National Academy of Sciences and the National Academy of Medicine are launching a major initiative to guide decision making about controversial new research involving human gene editing. Human gene-editing technologies, such as CRISPR-Cas9, may lead to promising new treatments for disease. However, recent experiments to attempt to edit human genes also have raised important questions about the potential risks and ethical concerns of altering the human germline. Future advances are likely to raise new questions.
Our initiative will include an international summit this fall to convene researchers and other experts to explore the scientific, ethical, and policy issues associated with human gene-editing research. In addition, we will appoint a multidisciplinary, international committee to begin a comprehensive study of the scientific underpinnings and clinical, ethical, legal, and social implications of human gene editing. The committee will consider and recommend standards, guidelines, and practices governing the use of gene-editing technologies in biomedical research and medicine. An advisory group to steer the overall initiative will soon be announced.
The NAS initiative has now generated an official reaction from the Obama administration. It is evident that the administration would like to see the scientific community get out ahead of lawmakers in considering how to responsibly handle the potential of CRISPR in reproductive applications. In the White House statement:
The scientific community has a good record of establishing and adhering to ethical principles in genetic technology. In the 1970s, scientists called for a temporary moratorium on gene-splicing technology until the implications and policies could be sorted out. Similarly, this year scientists called for a moratorium on germline-editing research until the safety and ethical issues could be explored by the community.
The advances in health technology over the past century - vaccines, antibiotics, early disease diagnostics, and treatment for countless health conditions - have reduced infant mortality, extended life expectancy, and alleviated suffering for millions. But new technology also brings risks and ethical challenges that require careful consideration. For example, researchers in China recently conducted genome-editing experiments in human embryos of a kind not able to develop into a fetus or a person.
Research along these lines raises serious and urgent questions about the potential implications for clinical applications that could lead to genetically altered humans. The full implications of such a step could not be known until a number of generations had inherited the genetic changes made — and choices made in one country could affect all of us.
It is important that the NAS’ international summit fully explore the implications of germline editing for the current generation and generations to come across the globe, as well as the potential for alternative technologies that do not require germline alteration to deliver similar medical promise. The Administration looks forward to seeing the results of the scientific community’s discussion.
The quiet alarm that underlies these relatively rapid reponses highlights how the use of CRISPR technology application in human reproduction is not just another clinical application, but it goes right to the heart of human potential and scientific power, as well as not insignificantly raising fears of eugenic intent.
In the U.S., we lack a formal regulatory body devoted to oversight of reproductive technologies (unlike, e.g., the UK Human Fertilization and Embryology Authority) so we see a more ad hoc display of responses. The reminder by the National Institutes of Health that no federal funding would be available for gene-editing experiments on the human germline is a kind of de facto ban, since many U.S. scientists rely on federal support.
Following on the recent post, the rush to develop some initial policy statements on the use of genome editing techniques for germline engineering is now understood following the first publication of an attempt to perform germline engineering on embryos using the CRISPR/Cas 9 (CRISPR) system, as reported by Chinese scientists. Several weeks ago, two separate policy statements were issued by experts in genome editing who called for either a moratorium or an ethics-initiated slowdown on any use of the technique on embryos. At the time, there were rumors of an imminent publication, and this was true. The new publication reports that the use of CRISPR to alter the germline of about 86 non-viable embryos had mixed results; some of the embryos accepted the genetic changes, but some did not and “off-target” events were reported, indicating that unintended genomic alterations occurred. These experiments have been widely reported, and have alerted the general public to an issue that they were generally unaware of. Public reaction has followed as well as some official commentary. The journal that published the paper has now issued a statement on its decision to publish:
Protein & Cell has fully realized that this study can provide direct evidences to address some of safety concerns of the CRISPR/Cas9 technique. It may also raise a series of questions and bring further controversies to the field of gene-editing research. In this unusual situation, the editorial decision to publish this study should not be viewed as an endorsement of this practice nor an encouragement of similar attempts, but rather the sounding of an alarm to draw immediate attention to the urgent need to rein in applications of gene-editing technologies, especially in the human germ cells or embryos.
Official responses have also followed the publication of the CRISPR embryo studies. The NIH has issued a policy declaration making it clear that no federal funding is available for research that uses genome modification to the germline of a fertilized egg or embryo. The statement anchors the policy in the already existing legal/regulatory climate:
However, NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.
Practically, there are multiple existing legislative and regulatory prohibitions against this kind of work. The Dickey-Wicker amendment prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed (H.R. 2880, Sec. 128). Furthermore, the NIH Guidelines state that the Recombinant DNA Advisory Committee “will not at present entertain proposals for germ line alteration.” It is also important to note the role of the U.S. Food and Drug Administration (FDA) in this arena, which applies not only to federally funded research, but to any research in the U.S. The Public Health Service Act and the Federal Food, Drug, and Cosmetic Act give the FDA the authority to regulate cell and gene therapy products as biological products and/or drugs, which would include oversight of human germline modification. During development, biological products may be used in humans only if an investigational new drug application is in effect (21 CFR Part 312).
The NIH reiterates the lack of federal funding for any CRISPR (or other technology) attempts at germline engineering. It notes that the combination of existing prohibitions on funding embryo research combined with the ongoing supervision of gene therapy by RAC, supplemented with FDA pronouncements on its jurisdiction over some biotechnology products, create a patchwork of constraints on research in the U.S. RAC considered fetal gene therapy in 1999; as the NIH statement summarizes, the committee was not receptive to this form of prenatal genetic intervention. This new debate, however, focuses on a much more radical genetic intervention. The Chinese experiments were generally not "successful" in the goal of altering the specific gene in the target embryos; this lack of success, while derived from controversial experiments, will only bolster the case for halting any such scientific work, as the recent work validates the safety concerns alone. But what is emerging - despite any enforceable international restrictions - is an urgency to codify resistance into regulation sooner rather than later.
In recent weeks, there has been growing attention to the possibility that recently developed technologies which allow precise editing of genomic DNA could be used for human reproductive purposes, possibly modifying the genomic DNA of a fertilized egg or embryo to create heritable genetic changes. The growing use of the genome editing technology known as CRISPR/Cas9 (CRISPR), first reported in 2012, is permeating much of current genetic research and is driving the policy discussions. A meeting on germline applications held in January of this year at Napa, California, and convened by some of the founders of the original Asilomar conference on recombinant DNA, took up the question of using CRISPR for germline genome engineering. This working group, which included Dr. Jennifer Doudna, an originator of this technology, has now published a call for caution as this technology could be employed to perform germ line editing that would manifest in human offspring. The CRISPR technology allows for more precise and efficient editing in genomic DNA than earlier editing techniques, and has a number of useful applications, both for research and clinical use. According
to several reports, there might be attempts at CRISPR-mediated human germline
modification that are already underway but unknown and that possibility
has stirred the scientific community to action. The participants at the Napa meeting called for further research and more transparent discussions for all stakeholeders. Finally, they called for scientists to refrain from employing CRISPR in any attempts at human germline engineering. The scientists agreed to:
Strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations. (In countries with a highly developed bioscience capacity, germline genome modification in humans is currently illegal or tightly regulated.) This will enable pathways to responsible uses of this technology, if any, to be identified.
In parallel with that statement, a second group of researchers in the field of gene editing called for a complete moratorium on the use of CRISPR for germline genetic engineering. They stated:
In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations. This makes it dangerous and ethically unacceptable. Such research could be exploited for non-therapeutic modifications. We are concerned that a public outcry about such an ethical breach could hinder a promising area of therapeutic development, namely making genetic changes that cannot be inherited. At this early stage, scientists should agree not to modify the DNA of human reproductive cells. Should a truly compelling case ever arise for the therapeutic benefit of germline modification, we encourage an open discussion around the appropriate course of action.
Already, there are published reports of germline modification in monkeys. As for human gene modifications writ large, in 2015, there is the established field of gene therapy, overseen by the Recombinant DNA Advisory Committee (RAC), and slowly embraced by the FDA. These therapies provide genetic alteration to living persons through their somatic cells, so there is no heritability of the changes. RAC was asked to consider fetal gene therapy protocols in the late 1990's, but concluded that the risk/benefit ratio did not justify approval. Current reproductive medicine offers preimplantation genetic diagnosis to prospective parents seeking to avoid transmitting known genetic diseases, but that technique does not involve genome editing. The speed at which CRISPR-based technologies are entering genetic science guarantees that the debate over controversial applications will continue. Not surprisingly, any proposed CRISPR-based reproductive technologies are likely to encounter much more resistance that many other assisted reproductive technologies (ARTs) have encountered to date. Will CRISPR-based reproduction elicit the kind of furious legislative responses to the possibility of human cloning that followed the creation of the cloned sheep Dolly in 1997? Since there are no credible reports of use, the public is not confronted with the issue, but the scientific and bioethical communities can see ahead, and are trying a proactive rather than reactive approach to getting a public debate started.
Federal regulation of the expanding genetic testing marketplace is beginning to take shape. The FDA has issued a formal approval for the marketing of a direct-to-consumer (DTC) genetic test to 23andMe, a leading personal genomics company based in Mountain View, CA. This is the first such decision by the FDA. As discussed here earlier, the FDA has been slowly enlarging its management of in vitro diagnostics to include most genetic tests, which are offered as laboratory-derived tests (LDT). 23andMe has tussled with the FDA over the last several years regarding whether and how its portfolio of DTC tests would be regulated by the FDA. In 2013, the FDA ordered the company to cease its marketing of over 200 unregulated health-related genetic tests through its Personal Genome Service. Finally, 23andMe signed on to FDA involvement by submitting a formal 510(k) application for the Bloom Syndrome Carrier Status test in 2014 (Bloom syndrome is a serious autosomal recessive genetic disorder caused by mutations in the BLM gene). For background on the submission:
Section 510(k) of the Food, Drug and Cosmetic Act requires device manufacturers who must register, to notify FDA of their intent to market a medical device at least 90 days in advance. This is known as Premarket Notification - also called PMN or 510(k).
The 23andMe submission was then converted to a de novo application, signalling the lack of a predicate test for comparison (but now potentially serving as a benchmark for future evaluations). Now, the FDA has announced its approval for 23andMe to market its DTC Bloom syndrome test, taking notice of any potential risk while also identifying the benefit of this type of test:
FDA believes that in many circumstances it is not necessary for consumers to go through a licensed practitioner to have direct access to their personal genetic information. Today’s authorization and accompanying classification, along with FDA’s intent to exempt these devices from FDA premarket review, supports innovation and will ultimately benefit consumers.
In a sign that an overarching regulatory scheme is slowly emerging, the FDA further announced a classification of this subset of genetic tests:
Along with this authorization, the FDA is also classifying carrier screening tests as class II. In addition, the FDA intends to exempt these devices from FDA premarket review. The agency plans to issue a notice that announces the intent to exempt these tests and that provides a 30-day period for public comment. This action creates the least burdensome regulatory path for autosomal recessive carrier screening tests with similar uses to enter the market.
It’s important to note that the Bloom syndrome test is not a test that provides either diagnostic or therapeutic information on which a patient may be making decisions regarding medical care; it is a report on Bloom syndrome carrier status and it will be used in reproductive decisions. The FDA’s concern with 23andMe’s (or other companies) offerings of health-related genetic information was largely focused on the likelihood that consumers would receive their genetic information accompanied by the companies’ assessment of risk or susceptibility, leading them to structure medical decisions (surgery, medications) on shaky or dubious representations. Because the approved test can be sold directly to consumers over the counter, the FDA did attach requirements for 23andMe to make consumers aware of genetic counseling options.
In parallel, the FDA is also building out oversight of foundational technologies that underlie genetic testing and analysis, most directly in its efforts to develop a regulatory program for next-generation sequencing (NGS) (see here). The FDA held its first public hearing on NGS oversight last week.
The U.K. House of Commons approved a bill this week that would allow the use of a novel assisted reproductive technology (ART) to proceed. In current media coverage, the technique has been called three-parent reproduction, and it has been developed to offer a route to reproduction for women who are likely to transmit genetically inherited mitochondrial disease. Offspring inherit their mitochondria from the egg of the mother, and can be at risk from any mitochondrial disease that has occurred to the mother or the maternal family. The proposed intervention is known as mitochondrial replacement therapy. The three parents are the father and two mother donors: the nucleus is removed from the egg of the intended but genetically impaired parent and it is inserted into the egg of a healthy female donor, whose mitochondria are not defective. The reengineered egg undergoes in vitro fertilization with the father’s sperm, and is then implanted. This week, the
U.K. House of Commons approved the use of the 3-parent mitochondrial
replacement technique, in amending the Human Fertilisation and Embryology Act of 2008. The House of Lords is expected to follow suit. Unlike the U.S., the U.K. has an oversight body for ART – the Human Fertilisation and Embryology Authority (HFEA) - which regulates fertility treatments and other reproductive technologies. The U.S. has no specific regulatory agency targeting reproductive technologies, but the FDA claims a regulatory role based on its general regulation of reproductive tissues in commerce (eggs, sperm) and the agency did shut down earlier work using MRT in the late 1990's. In the U.S. the FDA and the Institute of Medicine (IOM) are considering whether the technique should be approved for use in the U.S:
An FDA Advisory Committee (AC) met on February 25 and 26, 2014, to discuss the science regarding assisted reproductive methods involving genetic modification of eggs and zygotes for the prevention of mitochondrial disease. FDA has requested that the Institute of Medicine produce a consensus report regarding the ethical and social policy issues related to genetic modification of eggs and zygotes to prevent transmission of mitochondrial disease.
The FDA committee agreed that any proposed clinical trials with humans could be premature:
The Committee generally agreed that there is not sufficient animal data (particularly with regard to follow-up of offspring) to support the use of the mitochondrial manipulation technologies in first-in-human clinical trials. It was also acknowledged that the use of somatic cell nuclear transfer (SCNT) following by intracytoplasmic sperm injection (ICSI) had to be weighed against alternative methods for preventing the transmission of mitochondrial diseases to offspring, including adoption, oocyte donation, and cytoplasmic/mitochondrial transfer.
The IOM began its study last month, holding its first meeting on the subject. In general, the U.S. is lagging behind the U.K. in considering official approval of this technique; in 1978, in vitro fertilization was first used in the UK before it migrated to the U.S. soon afterward. To date, there are pro and con views on whether MRT could be a viable option for prospective parents. Critics point to safety concerns as well as fears regarding a slippery slope toward allowing other genetic interventions to produce either healthier or “better” offspring. Supporters of MRT point out that the technique offers women with mitochondrial disease to have children that are genetically related but free of the genetic defect imparting serious disease. My own view is that there might be latent genetic incompatibilities that would not be overtly evident but perhaps manifest developmentally or subtly in a way that comprises the health of an MRT-derived offspring. Looking at regulatory moves in the future, there is always the possibility of legislative action that would either allow or prohibit the use of the technique – it’s too early to have such initiatives started, but such moves would echo ongoing Congressional and state responses to the possibility of human reproductive cloning that emerged in 1997, following the creation of the cloned sheep, Dolly.
Genetic counseling services have proliferated in the age of molecular medicine, as health care practitioners increasingly make use of genetic information as a basis for determining risk, diagnosis, treatment and prognosis. The professional field of genetic counseling now encounters the trend of state licensure standards for professional practice. To date, about 15 states mandate licensing for genetic counselors. Licensing is endorsed by the National Society of Genetic Counselors, which publishes model licensing standards and practice guidelines. Virginia has now passed a genetic counselor licensing statute, defining genetic counseling:
"Practice of genetic counseling" means (i) obtaining and evaluating individual and family medical histories to assess the risk of genetic medical conditions and diseases in a patient, his offspring, and other family members; (ii) discussing the features, history, diagnosis, environmental factors, and risk management of genetic medical conditions and diseases; (iii) ordering genetic laboratory tests and other diagnostic studies necessary for genetic assessment; (iv) integrating the results with personal and family medical history to assess and communicate risk factors for genetic medical conditions and diseases; (v) evaluating the patient's and family's responses to the medical condition or risk of recurrence and providing client-centered counseling and anticipatory guidance; (vi) identifying and utilizing community resources that provide medical, educational, financial, and psychosocial support and advocacy; and (vii) providing written documentation of medical, genetic, and counseling information for families and health care professionals.
Virginia is now the first state to incorporate a conscience clause into the licensure of genetic counselors:
Nothing in this chapter shall be construed to require any genetic counselor to participate in counseling that conflicts with their deeply-held moral or religious beliefs, nor shall licensing of any genetic counselor be contingent upon participation in such counseling. Refusal to participate in counseling that conflicts with the counselor's deeply-held moral or religious beliefs shall not form the basis for any claim of damages or for any disciplinary or recriminatory action against the genetic counselor, provided the genetic counselor informs the patient that he will not participate in such counseling and offers to direct the patient to the online directory of licensed genetic counselors maintained by the Board.
Conscience clauses have been added into licensing or accreditation laws since the Roe v. Wade decision in 1973. Such clauses were initially written so that health care professionals or institutions with moral or religious objections to the offering of abortion services were not compelled to do so. In the decades since Roe, conscience clauses have proliferated in both federal and state laws, largely aimed at the delivery of reproductive-related services, including abortion, contraception and sterilization (thus affecting not only direct health care professionals, but pharmacists as well).The rationale for the inclusion of the Virginia statutory provision has not been made explicit, but commentary suggests that the intent is to allow genetic counselors to refuse services to same-sex couples or unmarried persons who seek genetic counseling for reproductive purposes, or to clients who may consider abortion if genetic testing reveals serious genetic disease. It’s not clear when in the sequence of service delivery the counselor may decide to withdraw from the provision of services. The clause includes a provision that removes liability for the counselor for any consequences of denying service or withdrawing from services. What is clear, however, is that this clause would authorize the denying of particular services (the more typical conscience clause) but it would also allow denial of all services to particular individuals or groups, effectively discriminating against certain individuals who seek professional care. That possibility potentially raises the specter of an equal protection challenge as services are denied to classes of individuals based on their identity or status (similar to the recent Arizona legislation that would have allowed frank discrimination by business owners against gay people; it was vetoed by Gov. Brewer). Virginia has already opened the door to denial of professional services to classes of individuals, as it enacted a conscience clause limitation for adoption agencies in 2012 (North Dakota has also done so).Thus, claims of the exercise of religious liberty in the delivery of professional services potentially conflict with established anti-discrimination laws and guarantees of reproductive autonomy. Similar overtones of the clash between claims of religious liberty and legal guarantees of equal access have surfaced in the recent Affordable Care Act litigation over mandates for the coverage of contraception, Sebelius v. Hobby Lobby Stores, Inc. (argued last week at the Supreme Court).
The FDA is considering the merits of an assisted reproductive technology (ART) that has a goal of eliminating the transmission of genetically based mitochondrial diseases. Mitochondria, small DNA packages in the cytoplasm of the cell, are inherited in the maternally-provided egg during reproduction. For women who could transmit mitochondrial disease to offspring, this ART protocol involves the production of an altered egg, which has the nuclear DNA of the mother swapped into the egg of a woman without the genetic disease. Thus the egg is a genetic hybrid. Conventional in vitro fertilization (IVF) follows the manipulation of the egg. This technique has been dubbed "3-parent babies" because the child would inherit DNA from 2 females and one male. Is it safe? In the U.S., the FDA halted the use of a fertility treatment involving cytoplasmic transfer in eggs that was used in 2001, asserting its authority to regulate this technique as part of its ongoing supervision of the production and use of biologic products (e.g. cells, tissues, etc). Although technically genetic material is swapped around in order to “delete” the disease-causing genes, this is not quite the genetic engineering often imagined in which the nuclear genetic material would be deleted, supplemented or rearranged (”designer genes).” In fact, cellular structure makes this technique quite conceptually simple as the mitochondria are cellular organelles that exist outside the nucleus, facilitating a replacement scheme such as the one here. An Oregon scientist, Dr. Shoukhrat Mitalipov, has published experiments documenting success with the use of the technique in monkeys and would like to begin the use of the technique in humans. He would need FDA approval to begin any clinical trials in humans. In two days of open public hearings this week, the Cellular, Tissue, and Gene Therapies Advisory Committee of the FDA invited testimony from scientists and other commenters regarding the scientific, technical and clinical concerns for the use of mitochondrial manipulation technologies. They described their task:
The committee will discuss oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility.
The FDA asserts its authority over the use of this technique as deriving from its role in regulating the production and use of biologic materials, from its ongoing review of protocols that involve genetic manipulation, as well as its goal of insuring the safety of human study subjects. In a briefing document prepared for the hearings, the committee cited a long list of potential safety concerns for both mother and child from the use of the mitochondrial replacement technique:
Potential risks to the women could include: 1) failure to become pregnant; 2) failure to deliver a child; 3) risks associated with the specific mitochondrial manipulation technology procedure; and 4) toxicities of the reagents used in mitochondrial manipulation technologies. Potential risks to their children could include: 1) mitochondrial disease (particularly in women with mitochondrial disease), as a result of carryover of abnormal mitochondria and heteroplasmy; 2) disorders due to nuclear mitochondrial incompatibility; 3) disorders related to aberrant epigenetic modifications ; 4) birth defects and other disorders associated with the specific mitochondrial manipulation technology procedure; and 5) toxicities of reagents used in mitochondrial manipulation technologies. There may be additional risks that are difficult to predict because of limitations in current knowledge.
The FDA will receive public comment on a draft guidance it has issued to those designing protocols for early-phase clinical trials with such techniques. The public comment period closes May 9, 2014. Although fertility clinics in the U.S. are not subject to extensive oversight from the FDA or any other agency, this proposed ART technique comes under FDA purview by its use, manipulation and transfer of biologic products into humans. Effectively, and critically, this technique is a germ-line modification of an embryo, meaning that the genetic manipulation will be carried into future offspring which inherit the replaced mitochondria. That fact heightens the concerns over the safety and ethical dimensions of potential use. Germline modification of embryos is prohibited in at least 40 countries, and there has been a kind of international consensus against use of these techniques. However, in a sign that a more nuanced regulation of certain ARTs may be developing, the UK is also considering whether to approve this use of this ART.
The fetal personhood movement has resurfaced in North Dakota, as the legislature has approved a 2014 ballot measure that will offer the following constitutional amendment: “The inalienable right to life of every human being at any stage of development must be recognized and defended.” This measure aims to establish legal personhood for the fertilized egg, embryo and fetus, with the attendant implications for the assertion of reproductive rights (a bill in the state to directly install fetal personhood by statute failed last week). North Dakota is the first state to approach fetal personhood by legislatively-referred constitutional amendment, in contrast to the citizen-originated beginnings for other state initiatives. Fetal personhood initiatives have been on the ballot before, twice in Colorado (defeated 2008 and 2010) and in Mississippi (defeated in 2011; see here). The Oklahoma Supreme Court invalidated a proposed personhood initiative in 2012 (in a pre-ballot constitutional review), ruling that the initiative was unconstitutional because it could not be reconciled with Planned Parenthood v. Casey (1992) (establishing the “undue burden” standard to assess the legality of measures restricting the exercise of the right to abortion). At the federal level, the Life at Conception Act has been introduced in the Senate and the Sanctity of Human Life Act in the House. The latter states:
[T]he life of each human being begins with fertilization, cloning, or its functional equivalent, irrespective of sex, health, function or disability, defect, stage of biological development, or condition of dependency, at which time every human being shall have all the legal and constitutional attributes and privileges of personhood...
While the fetal personhood movement has largely originated as an attempt to limit reproductive rights, most clearly abortion and certain forms of birth control, the impact of shifting legal personhood to the prenatal stage affects other life science technologies. In vitro fertilization is a commonly used assisted reproductive technology (ART) in which embryos are created in vitro (outside the body) for implantation and pregnancy. In the process, some embryos are either destroyed or unused, and legal personhood for the embryo could potentially upend how IVF is performed, if at all. Fetal personhood further impacts the use of embryonic stem cell techniques, in which stem cells are derived from embryos leftover from IVF procedures and are used to treat various kinds of cellular degeneration (e.g., Parkinson’s disease). Elevating the legal status of the embryo could potentially derail this field of research and medicine. Therefore, fetal personhood strikes at reproductive rights, fertility treatments and stem cell therapies. At the present time, renewed efforts are underway in Mississippi as well as other states to place personhood initiatives on the ballot. The decision from the Oklahoma court on that state’s failed initiative is instructive, because the fetal personhood efforts began in response to the invalidation of many abortion-restricting laws in the country under either Roe v. Wade (1973) or Casey. However, the Oklahoma court applied the same constitutional lens to the proposed amendment that it would apply to more routine abortion restrictions, suggesting that the legal strategy of fetal personhood may be more legally vulnerable than its proponents have hoped.
The use of genetics in reproductive decisions has a long pedigree, as prospective parents consider their genetic background when considering whether children will be born free from disease. As molecular genetics enters medicine, a technique known as preimplantation genetic diagnosis (PGD) has been available for couples at high risk of giving birth to offspring with genetic disease (e.g., two parents that are carriers for the recessive cystic fibrosis). By using in vitro fertilization with genetic screening, PGD offers the possibility of selecting an embryo without disease for implantation. This technique is used in the U.S. as a modality in the general field of assisted reproductive technologies (ARTs), which are largely unregulated by the government here, although subject to professional norms (e.g., American Society for Reproductive Medicine). This past week, the European Court of Human Rights ruled that Italian Law 40 forbidding the use of PGD violated the human rights of a couple that sought to use the technique because of their risk in birthing a second CF child. The law was a violation of Article 8 (right to respect for private and family life) of the European Convention on Human Rights. By analogy to U.S. law, the challenge was a familiar type of assertion for reproductive autonomy against the interference of the state. Italy was ordered to pay damages to the challenging couple. The court noted the "inconsistency of the Italian legal system" - prohibiting the preemptive and avoidant approach of PGD while simultaneously allowing abortion to terminate pregnancy. While the opinion by the ECHR is advisory and does not repeal the law, the ruling will increase pressure on Italy (and possibly Austria and Switzerland, which have similar laws) to reconsider the ban on this ART. Earlier this year, the EHCR ruled that Ireland's abortion ban violated the human rights of a pregnant woman with cancer who could not access abortion services despite her pregnancy-related health risk.
