Grounding ethics from below: CRISPR-cas9 and genetic modification

By Anjan Chatterjee

The University of Pennsylvania

Anjan Chatterjee is the Frank A. and Gwladys H. Elliott Professor and Chair of Neurology at Pennsylvania Hospital. He is a member of the Center for Cognitive Neuroscience, and the Center for Neuroscience and Society at the University of Pennsylvania. He received his BA in Philosophy from Haverford College, MD from the University of Pennsylvania and completed his neurology residency at the University of Chicago. His clinical practice focuses on patients with cognitive disorders. His research addresses questions about spatial cognition and language, attention, neuroethics, and neuroaesthetics. He wrote The Aesthetic Brain: How we evolved to desire beauty and enjoy art and co-edited: Neuroethics in Practice: Mind, medicine, and society, and The Roots of Cognitive Neuroscience: behavioral neurology and neuropsychology. He is or has been on the editorial boards of: American Journal of Bioethics: Neuroscience, Behavioural Neurology, Cognitive and Behavioral Neurology, Neuropsychology, Journal of Cognitive Neuroscience, Journal of Alzheimer’s Disease, Journal of the International Neuropsychological Society, European Neurology, Empirical Studies of the Arts, The Open Ethics Journal and Policy Studies in Ethics, Law and Technology. He was awarded the Norman Geschwind Prize in Behavioral and Cognitive Neurology by the American Academy of Neurology and the Rudolph Arnheim Prize for contribution to Psychology and the Arts by the American Psychological Association. He is a founding member of the Board of Governors of the Neuroethics Society, the past President of the International Association of Empirical Aesthetics, and the past President of the Behavioral and Cognitive Neurology Society. He serves on the Boards of Haverford College, the Associated Services for the Blind and Visually Impaired and The College of Physicians of Philadelphia. 

In 1876, Gustav Fechner (1876) introduced an “aesthetics from below.” He contrasted this approach with an aesthetics from above by which he meant that, rather than defining aesthetic experiences using first principles, one could investigate people’s responses to stimuli and use these data to ground aesthetic theory. Neuroethics could benefit with a similar grounding by an ethics from below, especially when ethical concerns affect public policy and regulation.

We are in the middle of a scientific revolution (Doudna & Charpentier, 2014) that will transform biological research by profoundly affecting agriculture, animal husbandry, and medicine. It also has profound implications for neuroethics. Genetic modification using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeat–CRISPR-associated protein), a system of adaptive immunity discovered in bacteria, has become feasible and cheap. Described in 2015 as “Science’s breakthrough of the year”, CRISPR-Cas9 offers promises as well as perils. In addition to modifying somatic cells, we can now modify germline cells. We might be able to eliminate single gene neurological disorders like Huntington’s disease, among many others. At the same time, intentional selection of genes for physical and mental traits might reify social inequities and resurrect the possibility of eugenics. Specifically, genetic manipulation could become a deep tool for cognitive and mental enhancement that selects and manipulates genes that contribute to intelligence, attention, memory, and even creativity.

Image courtesy of Wikimedia Commons.

Scientists and ethicists are aware that the public should be involved in discussions about these technologies and their applications. Think tanks, bioethics groups, and scientific societies call for public engagement. For example, in December 2015, the US National Academies of Sciences, Engineering and Medicine held a summit on the regulation of CRISPR-–Cas9 gene-modifying technology (Travis, 2015). PHD physicist and Congressman Bill Foster (D-IL) opened the summit with a reminder that gaining public acceptance of what can be done with CRISPR-Cas9 is critical. The meeting opined that it would be irresponsible to proceed with germline modification without broad societal consensus about the appropriateness of possible uses. The final report from the National Academy of Sciences (National Academies of Science, 2017) walked back from their early call for broad societal consensus (Baylis, 2017), but did offer condition under which germ line genetic modification might be considered. Nonetheless, the report advocates for public involvement as stated on pages 7-8,

“Public engagement is always an important part of regulation and oversight for new technologies. As noted above, for somatic genome editing, it is essential that transparent and inclusive public policy debates precede any consideration of whether to authorize clinical trials for indications that go beyond treatment or prevention of disease or disability (e.g., for enhancement). With respect to heritable germline editing, broad participation and input by the public and ongoing reassessment of both health and societal benefits and risks are particularly critical conditions for approval of clinical trials.
At present, a number of mechanisms for public communication and consultation are built into the U.S. regulatory system, including some designed specifically for gene therapy, whose purview would include human genome editing. In some cases, regulatory rules and guidance documents are issued only after extensive public comment and agency response.” 

Given CRISPR-Cas9’s technical ease, low cost, and potentially wide spread application, knowing current public opinion is crucial to ongoing engagement. The “public” is not a monolithic entity, and understanding how different groups differ in their attitudes becomes critically relevant to any outreach efforts. 

Public opinion on In Vitro Fertilization (IVF) has changed

dramatically since its introduction.

Image courtesy of Flickr user Image Editor.

With these considerations in mind, we investigated what “the public” thinks about genetic modification research by querying 2,493 Americans of diverse backgrounds (Weisberg, Badgio, & Chatterjee, 2017). Respondents were broadly supportive of conducting this research. However, demographic variables influenced the robustness of this support– conservatives, women, African Americans, and older respondents, while supportive, were more cautious than liberals, men, non African American ethnicities, and younger respondents. Support for such research was also muted when the risks, such as unanticipated mutations and possibility of eugenics, were made explicit. We also presented information about genetic modification with contrasting vignettes, using one of five frames: genetic editing, engineering, hacking, modification, or surgery. The media, it turns out, uses different framing metaphors than academics when describing this technology. Journalists, more often than scientists, use “editing” as a metaphor, perhaps not surprising in so far as they are professional writers. It would be useful to know if these metaphors affect people’s opinions. In the context of our vignettes, the contrasting frames did not influence people’s attitudes. Our data offer a current snapshot of public attitudes towards genetic modification research that can inform ongoing engagement. 

Our observations are hardly the last word on the topic. Rather, they are an initial survey of a dynamically changing landscape. Will public attitudes evolve as more people become aware of the possibilities and problems of these technologies? What do we make of demographic differences? Conservatives, women, African Americans, and older people do not group together in an obvious way. Surely the reasons for caution among these groups vary. We did not find an effect of metaphoric framing in our study. This absence of an effect is reassuring in so far as journalists and scientists typically write about genetic modification using different organizing frames. Perhaps the lack of effect was because of an insufficient “dose” of framing language. If we presented more extensive descriptions and reinforcing language, might we have found an effect of framing? The point is that the implications of our results are subject to ongoing refinement, further testing, and continuing discussion as is true of most empirical studies. 

In a rapidly changing world in which biological sciences have the potential to profoundly affect our physical and mental and cognitive lives, public opinion assessed from below may be critical to grounding policy shaped from above. 

References 



Baylis, F. (2017). Human germline genome editing and broad societal consensus. Nature Human Behavior, 1. Retrieved from doi: doi:10.1038/s41562-017-0103



Doudna, J. A., & Charpentier, E. (2014). The new frontier of genome engineering with CRISPR-Cas9. Science, 346(6213), 1258096.



Fechner, G. (1876). Vorschule der Aesthetik. Leipzig: Breitkopf & Hartel.



National Academies of Science, E., and Medicine. (2017). Human Genome Editing: Science, Ethics, and Governance The National Academies Press Retrieved from http://go.nature.com/2ooO6jx.



Travis, J. (2015). Inside the summit on human gene editing: A reporter’s notebook. Retrieved from doi:https://doi.org/10.1126/science.aad7532



Weisberg, S. M., Badgio, D., & Chatterjee, A. (2017). A CRISPR New World: Attitudes in the Public toward Innovations in Human Genetic Modification. Frontiers in Public Health, 5, 117.

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Chatterjee, A. (2017). Grounding ethics from below: CRISPR-cas9 and genetic modification. The Neuroethics Blog. Retrieved on
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A CRISPR View of Life

By Shweta Sahu

Image courtesy of Wikimedia Commons

We now live in a society where many are trying to get a leg up where they can, whether it be through pharmacological neuroenhancement (like Ritalin and Adderall) or other neurotechnologies (like transcranial direct current simulation). Technology also allows us to exert an even earlier influence on neurodevelopmental disorders through prenatal genetic testing for fetuses. Such technologies include amniocentesis and chorionic villus sampling, that screen for Down’s, Edwards’ and Patau’s syndromes, and give parents the chance to decide whether they would like to terminate or continue with their pregnancy. One article even claims 53% of all pregnancies were aborted following prenatal diagnoses of Down’s Syndrome, though there is still much dispute over the exact numbers.

More recently, research has turned to looking into how to intervene at even earlier stages with gene editing of embryos. CRISPR (clustered regularly interspaced short palindromic repeats) is a naturally occurring bacterial defense mechanism, that when combined with certain enzymes, like “Cas” (CRISPR associated proteins), enable scientists to manipulate the gene sequence of an organism. CRISPR technology brings to life the idea that we can edit genes by either inserting or cutting out specific DNA sequences. Among the vast, exciting biomedical applications of this CRISPR/ Cas system are some promising leads, such as developing CRISPR based disease models. Diseases like schizophrenia and autism involve many genes and using CRISPR, one lab has been able to recreate the genetic mutations and investigate the “faulty” neurons that play a role in these conditions in animal models more efficiently. Whereas this previously took a couple years (requiring the time consuming method of trial-and-error to find the specific sites of mutation) projects like this take only a couple months with the help of CRISPR due to its ability to target sequences in an efficient, site-specific manner. 

Moreover, using genome engineering technologies like CRISPR has the potential to increase our ever-growing knowledge of disease processes and subsequent treatments. More specifically, this ability allows us to treat diseases involving muscle differentiation, cancer, inflammation, fetal hemoglobin, and Epstein Barr in animal models and some hope to potentially be used to eliminate gene mutations from the human population. One example of this includes a special birth case. This year, a 3-parent baby was born via a technique called “spindle nuclear transfer”, where mitochondrial genes from a donor woman were added to the mother’s own egg, and consequently fertilized by the father’s sperm. This reproductive technology was prompted by the desire to avoid Leigh syndrome, a fatal neurologic condition affecting one in 40,000 newborns. The mother had previously given birth to 2 babies with this condition, and thus looked to the 3-parent embryo technique as the answer. Because the Food and Drug administration (FDA) banned such a technique in the US, the procedure was performed in Mexico, where no such FDA exists.

Further yet, this CRISPR/ Cas technology may be the first stepping stone to applying these as therapies for neurological diseases. Many genetic disorders of the nervous system are caused by trinucleotide repeats, and recently, the CRISPR/ Cas system has been used in editing the mutations that cause conditions such as Huntington’s Disease (HD) and Fragile X Syndrome (FXS) in cell models. The CRISPR/ Cas system, in conjunction with single guide RNA (sgRNA) targets a specific sequence of DNA and induces a site-specific double stranded DNA break that can subsequently be either altered—resulting in a silenced gene—or deleted—resulting in a null allele. These small cuts in the DNA lead to larger changes in the gene, which affects function of subsequent proteins. When this procedure is applied to mutated genes throughout the genome of an organism, it can restore proper gene/ protein function. In this way, gene editing has the potential to provide the basis for successful therapy for neurodevelopmental disorders.

However, today's debate concerns not so much the research itself, but rather its ethical implications and the clinical applications that result in permanent changes to the human gene pool. For example, one article cites the example of a seven-time Olympic medalist in cross-country skiing whose genetics, the author claims, enabled the medalist to excel in his chosen sport. Might it be possible some athletic-oriented parents wanted the same for their child and genetically edited their child’s genome so as to introduce the overactive erythropoietin gene that confers high oxygen-carrying?

Genetically modifying genes opens doors to another major ethical concern: designing babies that carry permanent allele alterations implies heritable changes to the human germline DNA. Traits that society deems “unfit” would be eliminated from the population by selecting for the “better” alleles of the “fit” population; in turn, these “fit” alleles would be fixed into the population with gene editing technologies. The “unfit” alleles would eventually be lost from the population because genetic modification would prevent them from ever being passed on. Is it possible that one day in the near future clinicians and physicians will use CRISPR to decide which beneficial alleles get passed on? This would allow us to bypass natural selection in totality. 

Image courtesy of Prezi

Among similar lines, one study done at Yerkes in the Dias and Ressler lab opens yet another door to the realm of epigenetics and how ancestral sensitivity to certain stimuli can be transferred to subsequent generations. One notable example of this transgenerational information transfer includes the “Dutch Hunger Winter” in 1944, during which the F0 generation experienced the famine conditions and the F1 generation, in utero at that time, later developed astonishing rates of diabetes and obesity, as did their offspring (F2 generation). Similarly, another study found that a nutrition-linked mechanism through the male line seems to have influenced the risk for cardiovascular diseases and diabetes mellitus mortality. Taken further, maybe one day we can use CRISPR to edit our genes so that such unfavorable traits are not passed along in this way.

Might this be uniquely ethically complicated as we discuss editing genes related to brain function? One lab in China has genetically engineered more than 12 monkeys with a version of autism, in hopes of testing treatment for autism in humans. The reasoning for using monkeys in this study is that we share a more developed prefrontal cortex (a brain area where many psychiatric disorders seem to be impacted) and this should enable more generalizable results and translatable treatments.

Françoise Baylis, Canadian bioethicist and philosopher, posed the following questions. If you have a patient with Huntington’s, why treat just their symptoms, “allow them to reproduce and have children with Huntington’s, and we just have to do this over and over and over again? Why not fix it once and for all?!” This question of hers addresses the issues with the balance of “to do” or “not to do.”

Kevin Esvelt, an assistant professor at Harvard delves more into the delicate balance between the benefits and costs of using such technology and expands on the future directions for neurodiversity. He states, “if you give parents the option of zero autism risk in exchange for a certain loss of creativity or unusual talents, I expect almost all of them would take it — to the detriment of humanity.”

Image courtesy of the Genetic Literacy Project

That brings me to my next question, that of responsibility. Whose decision is it? Who decides what a “beneficial gene” is and who all should receive such modifications? A recent poll conducted by Harvard T.H Chan School of Public Health, researchers asked about “changing the genes of unborn babies: who should decide?” The results indicated that 53% of responders said “scientists, physicians, and technological experts” while 9% said “government officials and policy makers” (31% answered neither, presumably the potential parents). Some argue that parents should have complete authority when it comes to gene editing, a process they likened to that of autonomy in choosing sperm donors. However, a contrasting view argues that “parental autonomy must be weighed against the interests of future generations who cannot consent to the genetic modifications their flesh will be heir to.”

Does this mean that the social injustice will deepen and the gap between the classes will widen or perhaps we’ll have an even more rampant view of “normalizing” and less appreciation of neurodiversity? According to one source, in Israel, their national health system provides its citizens with preimplantation genetic diagnoses, such that “any Israeli citizen can now fertilize multiple embryos with in vitro fertilization (IVF) and then choose to implant the one that seems to have the best genetic health.” But it’s unclear if everyone would agree what “best genetic health” would mean and how that would be interpreted by neurodiversity advocates.

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 Sahu, S. (2017). A CRIPSR View of Life. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2017/01/a-crispr-view-of-life.html

The Ethical Implications of Harvesting Human Organs from Pigs

By Anayelly Medina

This post was written as part of a class assignment from students who took a neuroethics course with Dr. Rommelfanger in Paris in Summer 2016.

Anayelly is a rising Senior at Emory University majoring in Neuroscience and Behavioral Biology.

The Chimera is a Greek mythological fire-breathing monstrosity composed of multiple animal parts with the head of a lion, the body of a goat, and the tail of a snake. Not surprisingly, in the realm of science, chimera is also the name given to an organism or embryo containing a mixture of cells from two species. Recently, the world has learned of the current research efforts being made towards growing human organs in other animals, specifically pigs [2,3,4,5]. From these efforts, the human-pig chimera has been developed and so have ethical questions concerning the process and outcomes of this research.

According to the United Network for Organ Sharing, in the United States, about 22 people die each day while waiting for an organ transplant. This shortage of organ transplants has played a role in fueling researchers’ interests in developing alternative methods to solve this problem. One proposed method [5], by Pablo Ross, involves creating a human-pig chimera embryo, inserting it into the uterus of a pig, allowing it to develop, and having an end result of the growth of a human organ as the chimera develops. The process of creating the chimera, in this case one that will potentially develop a human pancreas, first involves removing the DNA in a pig embryo that would allow it to grow a pig pancreas. This removal process is conducted through a gene editing technique known as CRISPR. The CRISPR process involves utilizing a protein molecule such as CAS9 to cut out the targeted DNA section from a DNA strand. The CAS9 enzyme includes a guide RNA (gRNA) that matches up to the target DNA section and removes it. The removal of the pig’s DNA section creates what is called a “niche” (void) in the DNA strand; human induced pluripotent stem cells, or iPS, are then injected into the embryo when it’s just a few cells in a petri dish [2]. Researchers then hope that these injected human stem cells will take advantage of the void in the DNA and result in the development of a pig fetus growing a human pancreas. This human organ would then be compatible with a human patient from whom the iPS cells are derived, reducing the risk of organ rejection by the body. The potential ability to grow human organs inside of other animals in order to solve the organ donor/transplant shortage seems like a proposal without faults. Nevertheless, the future of this technology could lead to the purposeful growth of a human brain in a different species. Purposefully growing a human brain in a different species would raise a multitude of questions regarding their placement/personhood on the human/ animal scale. Furthermore, there are questions surrounding the ethics of such a procedure that must be addressed.

The mythical chimera, courtesy of Flickr user Eric Parker

One of the concerns that arises when dealing with interspecies embryos is determining their value. These embryos contain both pig and human DNA; as such, at what point do we determine whether such an organism “counts more” as an animal or a human? As professor Stuart Newman states, “you’re getting into unsettling ground that I think is damaging to our sense of humanity” [4]; furthermore, bioethicist Jason Robert states that “one of the concerns that a lot of people have is that there's something sacrosanct about what it means to be human expressed in our DNA” [4]. For individuals who believe that human nature and our humanity lies in the sequencing of our genes, the idea of having animals containing human DNA may result in them questioning their “personhood”. Are they less of a person or are the animals now more like a person? As stated by Regalado, “the worry is that the animals might turn out to be a little too human for comfort” [3].

Another main concern of this research involves the process of inserting human genes into the pig embryo but then having some of these genes migrate into the developing pig’s brain. The concern is that this migration of human stem cells into the brain of the animal could result in chimeras acquiring a cognitive state [2] and make them more human [3]. Once again, the deontological issue of determining what side of the human/nonhuman side these animals are on arises. As stated by Imam, “mental condition is an intrinsically human experience” [2]; if these chimeras were to develop a cognitive state, what would occur in terms of continuing with the procedure? Would these chimeras now hold autonomy? Researchers, such as Lowe, offer a solution, stating that “with every organ we will look at what's happening in the brain and if we find that it's too human like, then we won't let those fetuses be born" [5]. Lowe’s proposed solution has its own issues. At what point in the developmental stage are these chimeras considered to hold a cognitive state (if a human brain were to show signs of development). Ultimately, the old question of what “counts” as life arises once again. Furthermore, when considering humans, according to Farah, we wouldn’t sacrifice one healthy human for five life-saving organs [1]; if these chimeras were to develop a cognitive state, would such a notion hold true for them as well?

The concern surrounding these ethical issues, especially that of altering cognitive function, is evident through the National Institute of Health’s (NIH) refusal to fund this research in the United States [1] [Ed. note: this may be changing]. In other locations, such as the UK, guidelines for research involving animals containing human genetic material have already been established. Finally, what must also be considered in this research are the rights of the animals since the procedure requires surgical techniques and alterations of their genetic code that are yet to be fully understood. In addition, if such a technique were to function, then the development of organ farms would also be concerning to both humans and animals. The possible development of “organ farms” would raise further questions regarding the ethics of creating a new market for human organs.

References

1. Farah, M. 2015. An Ethics Toolbox for Neurotechnology. 86: 34-37.

2. Imam, J. 2016. Human organs grown in pigs may help transplant patients, scientists say. Cable News Network (CNN). June 9. Available at: http://edition.cnn.com/2016/06/09/health/human-organs-chimera-irpt/index.html (accessed June 11, 2016).

3. Regalado, A. 2016. Human-animal chimeras are gestating on U.S. Research Farms. MIT Technology Review. January 6. Available at: https://www.technologyreview.com/s/545106/human-animal-chimeras-are-gestating-on-us-research-farms/ (accessed June 11, 2016).

4. Stein, R. 2016. In Search For Cures, Scientists Create Embryos That Are Both Animal And Human. NPR. May 18. Available at: http://www.npr.org/sections/health-shots/2016/05/18/478212837/in-search-for-cures-scientists-create-embryos-that-are-both-animal-and-human (accessed June 12, 2016).

5. Walsh, F. 2016. US bid to grow human organs for transplant inside pigs. BBC News. June 6. Available at: http://www.bbc.com/news/health-36437428 (accessed June 12, 2016).

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Medina, Anayelly. (2016). The Ethical Implications of Harvesting Human Organs from Pigs. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2016/08/the-ethical-implications-of-harvesting.html