Posts Tagged ‘bioethics’
By: Samuel Porter, PhD
In 2012, a pair of studies were published in Nature and Science weeks apart igniting one the biggest national debates about science in recent memory. These studies demonstrated that a few mutations in the highly pathogenic H5N1 strain of influenza virus (colloquially known as “bird flu”) could enable it to be transmitted through the air to mammals. At the heart of controversy was the question of whether scientists should be creating more virulent and/or pathogenic strains of deadly viruses in the lab. This controversial research is known as “gain of function” studies.
Critics claimed that the research was too dangerous that the risk of an accidental or deliberate release of these lab strains was far greater than the scientific and public health benefits. In an attempt to respond to the growing concern over their work, the community of researchers working with these pathogens voluntarily agreed to suspend this gain of function research for 60 days to discuss new policies on conducting the research safely.
But that was not enough to satisfy critics of the research, who continued to lobby the Obama administration to take official action. On October 17, 2014 the White House Office of Science and Technology Policy (OSTP), abruptly announced a pause on all U.S. Government funding of gain of function research on influenza, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS) coronavirus until the National Science Advisory Board for Biosecurity (NSABB) could make recommendations for policy regulating the research going forward. The NSABB was formed in 2005 (in the wake of the anthrax attacks in 2001), and is composed of scientists from universities around the nation, and administrators from 14 separate agencies in the federal government. The board reports to the Secretary for Health and Human Services (HHS) and is tasked primarily with recommending policies to the relevant government entities on preventing published research in the biological sciences from negatively impacting national security and public health.
The move drew harsh criticism from researchers in the field, many of whom thought that it was too broad. They claimed it would jeopardize their ability to predict, detect, and respond to potentially emerging pandemics. In the private sector, several companies said that the order would prevent them from working on new antiviral drugs and vaccines. Furthermore, many young scientists worried that an inability to do their experiments could jeopardize their careers. In an effort to bring attention to the issue, many scientists (including the two flu researchers whose research triggered the pause) formed the group Scientists for Science, which advocates against blanket bans on research. In addition, researchers were especially upset by the recommendation of the NSABB to censor the publications resulting from the experiments due to fears that this research could have a “dual use” that would threaten national security. However, not all researchers in the field support gain of function research (the opposition group is called Cambridge Working Group) and maintain that the risks of the research outweigh benefits.
The moratorium lasted until January 9th, 2017, when the OSTP released the guidelines for funding this research in the future. The new rules are essentially the same recommendations put forth by the NSABB seven months earlier. The NSABB had concluded that these studies involving “potentially pandemic pathogens” (PPP) do indeed have important benefits to public health, but warranted additional screening prior to funding approval. It directed federal agencies to create a pre-funding review mechanism using eight criteria (including whether the pathogen is likely to cause a naturally occurring pandemic, and if there are alternative methods of answering the scientific question). The results of these reviews must be reported to the White House OSTP. Importantly, the policy was implemented in the final days of the Obama administration rather than leave it to the incoming Trump administration, who, as of this date, has yet to fill nearly any top science positions, and may not have issued guidance for months, if at all. Researchers welcomed the decision to finally lift the ban, but questioned when the projects would be allowed to resume.
What can we learn from this situation from a science policy perspective? First, we must learn not to overreact to hysteria regarding the risks of this type of research. Indeed, there are risks in performing research on potentially pandemic strains of influenza and other pathogens, as there are with other types of research. But issuing overly broad, sweeping moratoriums halting ground breaking research for years is not the answer, nor is government censorship of academic publication. While in the end, the studies were given the green light to resume, and were published without modification, there is no making up for the lost time. These studies are not machines than can simply be turned on and off on a whim without repercussions. When we delay research into learning how viruses become pandemic, we hurt our ability to detect and respond to naturally occurring outbreaks. Additionally, when American scientists are prevented from doing research that other countries are still pursuing, American leadership in the biomedical sciences is at a competitive disadvantage. (The European Academies Science Advisory Council also recently updated its recommendations for PPP research in 2015, but did not institute a moratorium.) What we learn from these studies could potentially save countless lives. Secondly, the freedom to publish without any government censorship must be valiantly defended in any and all fields, especially with a new administration with an aggressively anti-science and anti-climate stance. Lastly, the scientific community must do a better job educating the public both on the importance of these studies from a public health perspective, and on the precautions put into place to ensure that these studies are conducted safely.
In the future, there will inevitably be debates over the safety or ethics of the latest experiments in a particular field. In attempting to wade through the murky waters of a complex controversy, science policy makers should make decisions that balance public health, safety, and ethics, rather than reactionary policies like censorships and moratoriums.
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By: Courtney Pinard, Ph.D.
In one of the most impressive feats of synthetic biology so far, researchers have harnessed the ability of bacteria to fight and destroy viruses, and have been able to precisely and cheaply edit genetic code using a genetic technology called clustered, regularly-interspaced short palindromic repeats (CRISPR) and CRISPR-associated endonuclease protein 9 (Cas9). CRISPR has been used to find and detect mutations related to some of the world’s most deadly diseases, such as HIV and malaria. Although CRISPR holds great promise for treating disease, it raises numerous bioethical concerns, which were sparked by the first report of deliberate editing of the DNA of human embryos by Chinese researchers. Previous blog posts have described scientific discussion surrounding the promise of CRISPR. At least three scientific research papers per day are published using this technique, and biotech companies have already begun to invest in CRISPR to modify disease-related genes. However, the use of CRISPR, or any genetic editing technology, to permanently alter the genome of human embryos is an issue of concern to a much broader range of stakeholders, including clinicians, policymakers, international governments, advocacy groups, and the public at large. As CRISPR moves us forward into the realm of the newly possible, the larger global, social and policy implications deserve thorough consideration and discussion. Policies on human genetic editing should encourage extensive international cooperation, and require clear communication between scientists and the rest of society.
There is no question that CRISPR has the potential to help cure disease, both indirectly and directly. CRISPR won the Science Breakthrough of the Year for 2015, in part, for the creation of a “gene drive” designed to reprogram mosquito genomes to eliminate malaria. Using CRISPR-Cas9 technology, investigators at the Universities of California (UC) have engineered transgenic Anopheles stephensi mosquitoes to carry an anti-malaria parasite effector gene. This genetic tool could help wipe out the malaria pathogen within a targeted mosquito population, by spreading the dominant malaria-resistant gene in 99.5% of progeny. The gene snipping precision of CRISPR can also treat certain genetic diseases directly, such as certain cancers, and sickle cell disease. CRISPR can even be used to cut HIV out of the human genome, and prevent subsequent HIV infection.
There are limitations of CRISPR, which include the possibility of off-target genetic alterations, and unintended consequences of on-target alterations. For example, the embryos used in the Chinese study described above, were non-viable, less than 50% were edited, and some embryos started to divide before the edits were complete. Within a single embryo, some cells were edited, while other cells were not. In addition, researchers found lack of specificity; the target gene was inserted into DNA at the wrong locus. Little is known about the physiology of cells and tissues that have undergone genome editing, and there is evidence that complete loss of a gene could lead to compensatory adaptation in cells over time.
Another issue of concern is that CRISPR could lead scientists down the road to eugenics. On May 14th 2015, Stanford’s Center for Law and the Biosciences and Stanford’s Phi Beta Kappa Chapter co-hosted a panel discussion on editing the human germline genome, entitled Human Germline Modification: Medicine, Science, Ethics, and Law. Panelist Marcy Darnovsky, from the Center for Genetics and Society, called human germline modification a society-altering technology because of “the potential for a genetics arms race within and between countries, and a future world in which affluent parents purchase the latest upgrades for their offspring.” Because of its potential for dual use, genetic editing was recently declared a weapon of mass destruction.
In response to ethical concerns, the co-inventor of CRISPR, Dr. Jennifer Doudna, called for a self-imposed temporary moratorium on the use of CRISPR on germline cells. Eighteen scientists, including two Nobel Prize winners, agreed on the moratorium. Policy recommendations were published in the journal Science. In addition to a moratorium, recommendations include continuing research on the strengths and weaknesses of CRISPR, educating young researchers about these, and holding international meetings with all interested stakeholders to discuss progress and reach agreements on dual use. Not all scientists support such recommendations. Physician and science policy expert Henry Miller disagrees on a moratorium, and argues that it is unfair to restrict the development of CRISPR in germline gene therapy because we would be denying families cures to monstrous genetic diseases.
So far, the ethical debate has been mostly among scientists and academics. In her article published last December in The Hill Congress Blog, Darnovsky asks: “Where are the thought leaders who focus, for example, on environmental protection, disability rights, reproductive rights and justice, racial justice, labor, or children’s welfare?” More of these voices will be heard as social and policy implications catch up with the science.
In early February, the National Academy of Sciences and National Academy of Medicine held an information-gathering meeting to determine how American public attitudes and decision making intersect with the potential for developing therapeutics using human genetic editing technologies. The Committee’s report on recommendations and public opinion is expected later this year. One future recommendation may be to require Food and Drug Administration (FDA) regulation of genetic editing technology as a part of medical device regulation. Up until recently, the FDA has been slow to approve gene therapy products. Given the fast pace of CRISPR technology development, guidelines on dual use, as determined by recommendations from the National Academies, should be published before the end of the year. So far, U.S. guidelines call for strong discouragement of any attempts at genome modification of reproductive cells for clinical application in humans, until the social, environmental, and ethical implications are broadly discussed among scientific and governmental organizations.
International guidelines on the alteration of human embryos are absolutely necessary to help regulate genetic editing worldwide. According to a News Feature in Nature, many countries, including Japan, India, and China, have no enforceable rules on germline modification. Four laboratories in China, for example, continue to use CRISPR in non-viable human embryonic modification. Societal concerns about designer babies are not new. In the early 2000s, a Council of Europe Treaty on Human Rights and Biomedicine declared human genetic modification off-limits. However, the U.K. now allows the testing of CRISPR on human embryos.
In a global sense, employing tacit science diplomacy to developments in synthetic biology may mitigate unethical use of CRISPR. Tacit science diplomacy is diplomacy that uses honesty, fairness, objectivity, reliability, skepticism, accountability, and openness as common norms of behavior to accomplish scientific goals that benefit all of humanity. The National Science Advisory Board for Biosecurity (NSABB) is a federal advisory committee that addresses issues related to biosecurity and dual use research at the request of the United States Government. Although NSABB only acts in the U.S., the committee has the capacity to use tacit science diplomacy by providing guidance on CRISPR dual use concerns to both American citizen and foreign national scientists working in the U.S.
Under tacit science diplomacy, scientific studies misusing CRISPR would be condemned in the literature, in government agencies, and in diplomatic venues. Tacit science diplomacy was used when the Indonesian government refused to give the World Health Organization (WHO) samples of the bird flu virus, which temporarily prevented vaccine development. After five years of international negotiations on this issue, a preparedness framework was established that encouraged member states to share vaccines and technologies. A similar preparedness framework could be developed for genetic editing technology.
Institutional oversight and bioethical training for the responsible use of genetic editing technology are necessary, but not sufficient on their own. Tacit science diplomacy can help scientists working in the U.S. and abroad develop shared norms. Promoting international health advocacy and science policy discussions on this topic among scientists, government agencies, industry, advocacy groups, and the public will be instrumental in preventing unintended consequences and dual use of genetic editing technology.
By: Daniël P. Melters, Ph.D.
DNA is a very ubiquitous molecule, sufficient to span the observable universe at least 20 times. Most of this DNA comes from viruses, either in the form of active viruses or in its inactive form incorporated in viral, bacterial, plant, fungal, and animal genomes. To limit the spread of viruses, it is not surprising that evolution has created many ways to contain the spread of these inactivated viruses. We have adopted some of these antiviral mechanisms for our own use.
The discovery of the first bacterial antiviral system, the restriction enzyme, led to the founding of Genentech and thereby the modern biotechnology industry. Despite the ease with which restriction enzymes can be used to cut and paste pieces of DNA together, they are currently limited to use in test tubes (in vitro).
A few years ago, a new genetic tool was discovered that could modify genetic material in living creatures (in vivo). Again, it was a bacterial anti-virus mechanism. This new technology is called CRISPR and its in vivo use brings with it the possibility to edit DNA in order to correct genetic diseases in patients themselves. Just as a slew of restriction enzymes with unique cutting characteristics have been found, a similar scenario seems to be happening with CRISPR with the discovery of more nucleases used to cut specific DNA sequences. The original nuclease used with CRISPR is cas9, but recently another nuclease (cpf1) was discovered. Where cas9 is efficient in deleting genes, cpf1 seems to be good for making small modifications. In the foreseeable future more cas9-like nucleases will be discovered, each with potentially their own unique characteristics, in addition to ongoing efforts to genetically engineer a better cas9 nuclease.
Ethical questions about the use of CRISPR in humans, especially in human sperm and eggs, have arisen. On December 1-3, 2015, the U.S. National Academy of Sciences in collaboration with the Chinese Academy of Sciences and the UK Royal Society, hosted a three-day international summit on the use of CRISPR in human embryos. Although germline editing is strongly discouraged pending continued technological and ethical deliberations over the next few years, it remains a scientific possibility. Based on a single Chinese study, it is still unclear if this route is realistic. After all, cloning mammals has proven much harder than feared in the 1990s, as has creating a petrol-producing algae by genetic editing. Nevertheless, this has not stopped genetic entrepreneurs like Google and Bill Gates from jumping on the CRISPR bandwagon to kick-start the second revolution in biotechnology. One big unknown factor that still remains looming over the development of both the technology and any regulation is the potential misuse of any do-it-yourself CRISPR kits.
In addition to making individual genetic changes at will like those with CRISPR, forces that work on population genetics can be employed. Again they have their roots in evolution. One such potential powerful force is gene drive. Gene drive is caused by a genetic sequence that does not obey the Mendelian inheritance rules (where there is a 50-50 shot for a gene to be passed on from parent to offspring). It is therefore possible to introduce a gene that could, for example, get rid of the malaria parasite by introducing a few GMO mosquitoes into a population of natural mosquitoes. Through gene drive over time the entire population of mosquitoes will carry the malaria-fighting gene. The implication would be that the malaria parasite would not be able to passed on to humans and thus malaria would be eradicated. This sounds like a dream scenario!
However, using gene drive on mosquitoes to eradicate malaria does open a new can of worms. Both for the good – as the need to fumigate would be reduced also reducing the creation of fumigation-resistant insects, including mosquitoes – and for the bad, namely unwanted ecological consequences as a result from for instance horizontal gene transfer. Another unwanted consequence of the gene drive technology would be the near-certainty that it will spread across political borders. To handle such foreseeable international disputes, international regulatory collaboration will be required. One solution to overcome these unwanted consequences of gene drive could be use genetically engineered mosquitoes that would not be able to produce any off spring.
Whatever happens on the side of technology development, genetically modifying organisms remains controversial for the time being. Just think about the hype surrounding the recent FDA approval (after 19 years) of faster-growing “Frankenfish” for human consumption. Part of the problem resides in the highly technical details and extensive use of jargon that permeate the biological sciences. At times, it can be challenging for even scientists to keep up with the fast pace of development in the field of genetics. Once can only imagine what must then be demanded of the public and policy makers. Just look at what CRISPR itself stands for: clustered regularly interspaced short palindromic repeats. From the acronym alone, it is not clear what CRISPR does or means. Only through extensive communication between scientists and the public can a bridge be made that allows for exchange of knowledge about both the technical details and sincere concerns. The absence of many scientists on social media does not help this and actually widens the knowledge gap.
Nevertheless, various scientists have raised their voices about the potential power of gene drive as well as their professional concerns. Sure, gene drive can be used to do many things such as immunize animals that carry human diseases, control insect-borne diseases, spread pest-specific pesticides and herbicides, reduce populations of rodents and other pests, control invasive species, and aid threatened species. Yet, the power of gene drive also brings with it the fear for the unknown. What happens if a gene “goes wild” and crosses the species barriers through horizontal gene transfer? Will we be able to detect this quick enough to control it? What damage will it do if we can’t control it? Will there be any damage? For instance, cross-pollination between GMO crops and natural variants has been observed, albeit their incidences are relatively low and its broader ecological effect mostly unknown. To help curb these concerns, some solutions have been brought forward to help contain gene drive such as by designing it like Lego pieces, where only a complete set would be functional.
These concerns were considered so great that the U.S. National Academy of Sciences felt the need to create a workshop focused specifically on gene drive, in addition to the earlier international summit about the ethics of human genome editing. In short, the meeting showed that while gene drive has potential promises, both scientific and regulatory uncertainties remain, as well as fear about its potential irreversibility if it were to go wild. In other words, more research is needed covering all aspects of gene drive, including educating the public across the globe about the pros and cons.
Just as atomic energy produces both electricity and atomic bombs, thereby bridging the worlds of physics and societal needs, bacterial immune systems and evolutionary forces bridge basic biological research with applied biotechnologies. Society as a whole is moving more and more towards a society where genetics is a driving force for change – in medicine, global health, agriculture, pest-control, the judicial system and in combating terrorism. Understanding the basic principles of biology, genetics, and evolution are a must for policy makers of today and even more so of tomorrow. How else will they be able to support or debate a bill that is guided by or deals with genetic information and manipulation? After all, selective breeding and building a highly interconnected world have resulted in new species (of pets, livestock, and crops) and forced other species to adapt to changes in the environment we made (such as geographical barriers like roads and deforestation, and climate change). Therefore, careful ethical consideration of the wise use of powerful genetic tools and forces is critical, both for use in human, as well as any potential ecological implications. Gene drive as a tool has great potential, since after all, most of the DNA on earth came from the driving forces of selfish genetic elements. Evolution has provided us with many powerful tools and with great power comes great responsibility.