So, it finally happened: the genome of human embryos was modified and children with such modifications allegedly were born and will pass those edits on to future generations. The world is outraged, pretending to be surprised, when nobody really should be. According to press reports, suddenly, the World Health Organization (WHO) announced creation of a panel “to examine gene editing issues.” SCIENCE magazine quotes NIH Director and geneticist, Francis Collins, MD, and CRISPR co-inventor Jennifer Doudna, PhD, to have not only condemned the use of CRISPR-Cas9 for human embryo editing by Chinese investigators but (like many others) as having made the somewhat surprising statement that “they have difficulty in coming up with any genetic disorder that should even be considered for germline editing now.”
The source of all of this commotion was in China, which has become the Wild West of human medical experimentation, not only when it comes to germline editing of human embryos but also in many other areas of medicine. There are currently in China hundreds of clinical trials underway in oncology, rheumatology and other specialty areas, involving treatment modalities, which in the U.S. and elsewhere in the developed world are still in approval stages (and/or have, indeed, been rejected for trials) because of ethical and/or scientific concerns, even though the scientific groundwork for proposed treatments was developed in these countries.
As much more openly discussed in the U.S. and other countries recently, China is highly proficient (indeed, likely too proficient) in acquiring new technologies, initially developed in the West. It now also is no longer a secret that the Chinese government is not only complicit in, but also in many cases central to the management of the process of stealing Western technologies in an openly announced attempt to become the world’s leading economic power in all important industrial areas. And medicine is, of course, a crucially important industry, representing a highly significant, and quickly growing, portion of every country’s gross domestic product (GDP).
Acquiring state-of-the-arts medical knowledge, in contrast to other industries, usually does not even require sophisticated spy craft because such scientific breakthroughs, as CRISPR-Cas9 genome editing, are published in very much detail in the scientific literature, and Western patents, of course, matter little in China.
One, therefore, cannot help but wonder why governments and media now pretend to be surprised that a Chinese scientist, He Jiankui, PhD, reported the birth of the world’s first allegedly genetically “edited” human newborns. As everybody with international connection in the world of reproductive biology has known for some time, it was only a matter of time for this to happen. As these words are written, other laboratories in China are, undoubtedly, also in the process of editing genes in human embryos.
Chinese government's pronouncements condemning He’s actions are, likely, just as much ruse as the government’s routine denials of unfair trade practices in other economic spheres. What He did is just a first step in a government-supported attempt to assume control of yet another cutting-edge “industrial” area with enormous growth potential, as “medical tourism” has become a very rapidly growing industry and is already actively pursued by China in quite a number of medical specialties.
Over 100 Chinese scientists, according to a report in the New York Times, have allegedly denounced He’s research. The same report also quoted China’s Vice Minister of Science as stating that He’s scientific activities would be suspended. One wonders whether that will really be the case and, if so, for how long? At a genome editing conference in Hong Kong, He announced “with pride” his accomplishment and his intent “to continue manufacturing babies” that would not be vulnerable to HIV infections--in itself, a completely absurd clinical concept.
Only a few years ago, California- and Massachusetts-based scientists announced what may become one of the most consequential recent discoveries in science (undoubtedly destined to win a Nobel Prize), the so-called CRISPR-Cas9 system.
CRISPR (standing for Clustered Regularly Interspaced Short Palindromic Repeats) are DNA sequences found in the genome of bacteria and other prokaryotic organisms, left behind from viruses that had affected them, now used by prokaryotes to detect and destroy the DNA from similar viruses. In other words, CRISPR is the primitive adaptive immune system of bacteria and prokaryotes.
Cas-9 (standing for CRISPR-associated-9) is an enzyme that utilizes CRISPR sequences as a guide in helping to recognize and cleave specific DNA regions, complementary to a CRISPR sequence.
Combined, CRISPR-Cas9 can, therefore, edit (cut out and even replace) specific sections of genes within organisms, offering wide-ranging applications in biotechnology, agriculture and, of course, medicine for editing of genomes. In the human experience, CRISPR-Cas9, for example, can theoretically eliminate from zygotes (the fertilized egg before its first division) an abnormal mutation leading to a single gene disease, like sickle cell disease, Tay-Sachs or cystic fibrosis. As hundreds of single gene diseases are known by now, contrary to the above-noted alleged statements from Collin’s and Doudna’s, potential targets for CRISPR-Cas9 genome editing, therefore, are definitely not lacking.
Once an abnormal gene is eliminated at the 1-cell stage and replaced by a healthy gene (i.e., is “edited”), all subsequent cells of the embryo will inherit the edited gene. The embryo and the subsequent newborn will, therefore, if everything goes well, have a normal gene in all bodily cells and not be affected by the single gene disease. Even more importantly, the so-born person will now transmit into future generations only the healthy gene. In other words, assuming everything does go well, the abnormal disease-causing gene in such a case has been eliminated from that person’s family tree.
However, where current knowledge stands, everything does not always necessarily go well. For example, in some very preliminary experiments, CRISPR-Cas9 editing also resulted in unwanted off-site edits, which can potentially cause significant harm by creating chimeric embryos. Also, significant confusion and controversy still exists regarding a paper that reported successful edits at the zygote stage over the authors’ explanation of how such edits are even physiologically possible.
Much of what really happened in this Chinese case is actually still either not known or may not have been correctly reported by the scientist who performed the CRISPR-Cas9. What is alleged to have happened is that CRISPR-Cas9 was used on zygotes from couples where the husband was HIV-infected, but the woman was not. The goal was elimination in the embryos of a gene that facilitates entry of the HIV virus into cells (i.e., facilitates HIV infections). By eliminating this gene from embryos, they would become resistant to HIV infections. Why such resistance was required when the woman who was trying to conceive was not infected with HIV, is, however, unclear.
The “editing” of embryos was allegedly successful; edited embryos were transferred into the uterus, implanted and resulted in the reported twin delivery. Another patient is apparently still pregnant. As of this point it is, however, unclear whether the already born offspring and the still in utero pregnancy were appropriately tested to determine whether the desired gene was really eliminated from all cells. Maybe even more importantly, it is unclear whether the twin newborns and the ongoing pregnancy were tested for unwanted “edits” at off-sites, where no such “editing” was intended. Preliminary CRISPR-Cas9 work reported in the literature on human embryos that were not transferred into women (interestingly, some of this work, which also was severely criticized at the time, was also performed in China), strongly suggested that such undesired “edits,” indeed, occurred quite frequently.
Let’s assume the not uncommon scenario that a couple desirous of pregnancy comes to CHR for fertility treatment, the female HIV-negative but the male HIV-positive. Further assuming that the male is in long-term treatment and, as is now fairly often the case, shows zero viral HIV load on testing, the risk of female and/or offspring being infected from the male’s semen used in an IVF cycle is basically zero. One, therefore must ask: What was the real purpose of He’s intervention into the germline of embryos in these couples? Even assuming He’s interventions succeeded and eliminated the facilitating gene for HIV entry into cells in those embryos/offspring, what was the purpose, why was the procedure really done? As it stands, the procedure does not appear to serve any clinical purpose.
Every unnecessary medical intervention is, in principle, unethical! Considering the ethical as well as biological/medical concerns expressed all over the world about such treatments, unnecessary medical interventions affecting the human germline go far beyond only being “unethical.” At current knowledge levels, they must be considered dangerously ignorant and harmful to so-treated women and their offspring. This accusation is further strengthened by the above-noted New York Times report, which also suggested that the informed consents He obtained from his patients were woefully inadequate.
The world’s first alleged attempt at clinical germline editing was, thus, apparently performed for no reasonable medical indication, whether it was technically correctly performed and whether it was successful is unknown and, even more importantly, whether “editing” resulted in unwanted off-site edits with potential dangerous consequences, apparently, has also not been determined. What further aggravates the potential misconduct in this case, is that the desired intervention, while preventing entry of the HIV virus into cells, may actually increase influenza risks. The lifelong risk of contracting influenza is, of course, many times the risk of being infected with HIV.
The closer one looks on He’s alleged intervention, the more likely this whole episode, therefore, either appears the product of incredible scientific ignorance, is serving some still unknown commercial interests or is simply the product of a delusional mind. Whatever finally will reveal itself, in some ways, however, matters little because all three of these explanations do not explain how such an experiment can publicly recruit patients, as reported by the New York Times, obtain government funding, and can establish necessary laboratory facilities, without colleagues or superiors of sane mind and/or with deeper knowledge intervening.
He is neither a reproductive biologist nor a physician by training but graduated from a Chinese university as a physicist. According to the New York Times, He, indeed, saw himself at the time “as China’s Albert Einstein.” Despite exuding very obvious self-confidence, he, therefore, was not exposed to the basic training of a reproductive biologists and the medical insights of physicians. Since this project was conducted in secret, He apparently also did not seek appropriate professional advice, which may be the explanation why he pursued a senseless clinical goal.
After arriving in the U.S. for further training on a Chinese government grant, He decided to abandon his desire “to become China’s Einstein” and, instead, switched, at Rice University in Houston, into the field of biophysics, where he for the first time came across CRISPR-Cas9 gene editing. Following one year of postdoctoral research at Stanford University in California (allegedly completely unrelated to CRISPR-Cas9), He returned to China and obtained a position at the Eighth Affiliated Hospital of Sun Yat-sen University in the southern city of Shenzhen.
It is there that He appears to have developed an interest in treating AIDS with gene therapy. He, indeed, in 2017 published a paper in which he developed an in vitro model to knock in and knock out the HIV-1 co-receptor CCR5, on which the HIV virus depends for entry into cells [He et al., Protein Cell 2017; 8(11):848-852]. This paper also included as one of three authors a scientist from the Division of Biological Sciences, University of California Sand Diego, La Jolla, CA (Zhang T). Nothing in this paper, however, suggested that this technology would in the future be used for editing the germline of human embryos, nor does this paper offer a rational why such an attempt would even make sense as a clinical strategy in couples where the male, but not the female, is infected with HIV. As noted before, the risk of an offspring to be HIV infected if the father is HIV-positive (with zero viral load) and the mother is not infected, is basically zero.
The VOICE has on many prior occasions discussed the very special position reproductive medicine and, especially reproductive biological research, occupy: Clinicians and basic scientists in our field on a daily basis face ethically often highly controversial issues and, therefore, are rightly constrained by professional guidelines and, sometimes, even subject to legislative restrictions.
We, however, have also repeatedly pointed out that, at least in the U.S., the practice of IVF has, mostly successfully, been self-regulated via professional guidelines and, thereby, has avoided strict government regulations. This, of course, does not mean that the U.S. government was in any way supportive of IVF; to the contrary, evidenced by the fact that since its inception IVF has been almost completely excluded from all federal funding, the government has under Democrat as well as Republican administrations expressed considerable hostility toward the field.
For the longest time, the government, nevertheless, allowed the almost unrestricted development of IVF, as long as funding came from private sources. This hands-off approach in recent years has, however, increasingly eroded, as mounting concerns about crossing the germline of human embryos induced Congress to legislatively prohibit the Food and Drug Administration (FDA, the federal agency charged with overseeing the practice of IVF in the U.S.) from considering all research applications for approval that threatened to modify the human genome, even with intent to prevent diseases.
We in these pages a number of years ago reported on our and other investigators’ attempts to approach the FDA about the possibility of performing plasma exchange procedures via either spindle cell or nuclear transfer in attempts to prevent mitochondrial genetic diseases and improve female infertility especially in older women. Since such treatments would create so-called “three-parent babies” (with an egg donor providing roughly 1% of all DNA, the so-called mitochondrial DNA, to the baby), the FDA was not even willing to grant a meeting with CHR investigators on the subject. Such treatments have, with government permission, been going on for over two years in the UK and are publicly advertised by IVF centers in Ukraine, China and other countries.
As long as human embryos are not transferred into the uterus and certain other conditions are met, genomic embryo editing was recently approved in Japan (Science 2018;362;134). In some European countries, all embryo editing is prohibited, even if embryos are not transferred. As just noted by Eli Y. Adashi and Glenn Cohen in the December 3 issue of JAMA (doi:10.1001/jama.2018.18270), a British bioethics council (Nuffield Council on Bioethics) recently released its long-expected report on social and ethical issues raised by heritable genome editing (accessed December 3, 2018) and, quite surprisingly, found genomic editing of human embryos “ethically acceptable” if “intended to secure and are consistent with the welfare of a person who may be born as a consequence,” while rejecting drawing distinctions between different indications for such editing (therapeutic vs. heritable genome editing for cognitive or physical enhancements).
In the U.S. it is possible to pursue genetic editing research on human embryos under similar conditions to those in Japan, though not defined by law and not funded by federal grants. But, as the FDA in a cease and desist letter to a New York City-based IVF center recently again reemphasized, it considers any crossing of the germline to be under its administrative authority and, since the agency currently is prevented by Congress from even considering such projects, such activity is not considered permissible.
As we now know, embryo editing in China is apparently not only done for research but also for clinical purposes, even if as far-fetched as in the recently announced interventions by He. One can further speculate that, as of this moment, in China and elsewhere, multiple laboratories and IVF clinics are in active pursuit of crossing the germ line clinically. It seems to us only a matter of (rather short) time before investigators somewhere in the world, announce the utilization of CRISPR-Cas9, this time in hopefully clinically valid interventions, properly documented and successful.
It may be cliché but, if highly qualified serious investigators are prevented from pursuing clinical progress, less competent and poorly qualified scientists and clinicians will fill the void. The above-noted British ethics council in our opinion correctly concluded that genomic editing of human embryos is ethically acceptable. We are somewhat less certain that indications for such editing should not matter, but that is not subject of this article.
The motivation for this piece was to convey CHR’s opinion that He’s announcement, whether factual or not, clearly demonstrates that human genome editing is here to stay. We for the longest time have been making the argument that, like in all other medical fields, progress in reproductive medicine is unavoidable (and, indeed, should be welcomed) and, therefore, should be carefully facilitated rather than be left to the pursuit of underground scientists like He.
The response to the not only ethically, but likely also clinically, inappropriate interventions by He and co-workers, therefore, should not be handwringing about the inability of science to exert self-control as, likely, will be the medias’ response, but the recognition that this kind of irresponsible science is not what leading research laboratories produce, if permitted to conduct responsible research under the control of institutional review boards. Despite many nay-sayers at different stages, this model has proven itself over 40 years of clinical IVF practice. Responsible research laboratories and clinical IVF centers can be trusted to perform responsible basic as well as clinical research, which automatically removes opportunities and incentives for unethical and incompetent underground research.
In the U.S., the He episode, therefore, should be a wake-up call to FDA as well as Congress to remove the shackles that have been placed on responsible researchers. This is by no means a call for removal of FDA oversight but a suggestion that the FDA be allowed by Congress to reinitiate discussions with leading researchers in the field on how responsible progress can be achieved. If responsible U.S. researchers are not allowed to press on with research, as we have witnessed, more irresponsible ones will do it elsewhere. U.S. patients who will not be able to receive state-of-the-arts treatments in the U.S. will then have to travel to China or other countries, as, currently, patients from all over the world travel to CHR and other U.S. centers if they failed to conceive locally.
This is a part of the December 2018 CHR VOICE.
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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