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
, from http://www.theneuroethicsblog.com/2017/07/grounding-ethics-from-below-crispr-cas9.html

Would a Therapy for Down Syndrome Change Lives For Better or For Worse?

By Sarika Sachdeva

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

Sarika Sachdeva is an undergraduate junior at Emory studying Neuroscience and Behavioral Biology and Economics. She is involved with research on stimulant abuse and addiction under Dr. Leonard Howell at Yerkes National Primate Research Center.

Researchers around the world are working to develop treatments and cures for all kinds of genetic disorders and abnormalities, but what happens when the people affected by the condition don’t want it taken away? New breakthroughs in treatment are often controversial for non-fatal conditions such as Down Syndrome, which causes inhibited neural communication and leads to learning delays as a result of an extra copy of chromosome 21 (Rochman, 2015).

Recently, a study from the Boston University Medical Center claimed to have identified differences in gene expression that are found in people with Down Syndrome. Previously it was thought that most of the effects of Down Syndrome occurred prenatally, but comparisons between toddlers and adults with the disorder revealed that changes in white matter levels in the brain are actively occurring during development. People with Down Syndrome have defects in their oligodendrocytes, a type of brain cell that forms white matter. This defect causes people with Down Syndrome to have less white matter than unaffected individuals. White matter insulates nerve fibers and facilitates communication between brain cells; thus, decreased white matter formation slows signal transmission and leads to the learning delays associated with Down Syndrome. This finding could be a significant step in the search for a treatment that promotes brain functioning. Instead of working on a genetic cure for Down Syndrome to stop the extra chromosome from ever having an effect, researchers may now shift their focus to finding therapies that increase oligodendrocyte formation and improve neural communication in people with Down Syndrome.

Proponents claim that a treatment of this kind will increase the quality of life for people with Down Syndrome. On the other hand, many parents of affected children argue that their child is perfectly normal and happy the way they are; they say that their children would not be the same if their disorder were removed (Becker, 2016). This leads to two interesting and as of yet unanswered questions: does treating someone with Down Syndrome remove the essence of who they are by affecting their brain, which “skirts close to intervening with the self”? Or would treatment retain the identity of the affected individual but with better cognitive functions (Becker, 2016)?

Image courtesy of Wikimedia

The uncertainty of the aftereffects of any potential “therapy” makes it difficult for parents to accept scientific breakthroughs with enthusiasm; some even say they would be more likely to support research for treating heart problems found in people with Down Syndrome instead of treating the cognitive neurodevelopmental components of Down Syndrome (Rochman, 2015). Even if treatments were to be given only to babies or fetuses with trisomy 21 before their sense of self and consciousness might have had the chance to develop, there are still important ethical considerations involved. Would treating the child make a difference in who they grow up to be, creating some sort of inauthentic self? Would this alteration have any potential risks, and at what consequence is it still worth attempting to prevent Down Syndrome? Because Down Syndrome is not fatal, any viable treatment options would have to be reliable and safe in order to guarantee that the affected individual would not end up with a potentially worse condition.

If we as a society decide that Down Syndrome is something that must be eliminated as soon as possible, we dismiss any immediate concerns about equality and social acceptance for those with Down Syndrome. When we focus on ways to change or alter these diseases, we are ignoring the contributions people with these conditions are making to society and implying that their presence is not valued. At the same time, the goal of medicine is to develop treatments to improve peoples’ lives and, in this case, to make Down Syndrome a disorder of the past. It seems counter intuitive that researchers are investing time and money into treatments that people may not even want; however, the idea is not to create a treatment for every single person with Down Syndrome regardless of what it may do to their self, but to give people with Down Syndrome and their families more options about how to live with the disorder. Whether they choose to improve cognition or not is up to them, but having that ability represents a significant leap forward in their autonomy. The question of whether Down Syndrome can and should be treated is tied to a larger discussion about how disabilities are viewed on a daily basis, but working towards a cure and working to remove the stigma surrounding people with disabilities do not have to be mutually exclusive.

References

Becker, A. J. 2016. A Pill for Down Syndrome. The Atlantic, March 15. Available at: http://www.theatlantic.com/health/archive/2016/03/down-syndrome-mother/473832/ (accessed June 10, 2016).

Boston University Medical Center. "Discovery of key abnormality affecting brain development in people with Down syndrome." ScienceDaily. www.sciencedaily.com/releases/2016/02/160225135608.htm (accessed June 10, 2016).

Rochman, B. 2015. A Change of Mind. MIT Technology Review, December 16. Available at: https://www.technologyreview.com/s/544531/a-change-of-mind/ (accessed June 10, 2016).

Seibel, B. 2015. Behind the Stigma: How the label of Down Syndrome keeps us from understanding the people who have it. Vantage, April 27. Available at: https://medium.com/vantage/how-the-stigma-of-down-syndrome-separates-us-from-the-people-who-have-it-99e1a36091a6#.qbtd9x6mq (accessed June 10, 2016).

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Sachdeva, Sarika. (2016). Would a Therapy for Down Syndrome Change Lives For Better or For Worse? The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2016/07/would-therapy-for-down-syndrome-change.html

23andMe: The Ethics of Genetic Testing for Neurodegenerative Diseases

by Liana Meffert



The following post is part of a special series emerging from Contemporary Issues in Neuroethics, a graduate-level course out of Emory University’s Center for Ethics. Liana is a senior at Emory University majoring in Neuroscience and Behavioral Biology and Creative Writing (poetry). She is currently applying to Public Health graduate schools and considering a future in medicine. In her free time she enjoys running, reading, and her research on PTSD at Grady Memorial Hospital.

23andMe logo 

The face of genetic testing and counseling is in the midst of a major overhaul. Historically, a patient had to demonstrate several risk factors including familial and medical health history or early symptoms in order to be tested for the likelihood of developing a neurodegenerative disease. For the first time, the public has unrestricted and unregulated access to the relative probability of developing certain neurodegenerative diseases.

So why is finding out you may develop a neurodegenerative disease in later years different than learning you’re at high risk for breast cancer? Neurodegenerative diseases are unique in that they essentially alter one’s concept of “self.” Being told you may succumb to cancer at some point in your life is a much different scenario than being told your memories will slowly deteriorate or that the way you relate to your loved ones, or even the very things you enjoy, may change. For the first time in history, the potential for these drastic changes in your “future self” are available at the click of a button.

“23andMe” was* one such DTC (Direct-to-Consumer) genetic testing service providing information for individuals to learn about and explore their genetic susceptibility. When the service was originally launched in 2008, anyone willing to submit a saliva sample and pay a fee could receive a report containing health-related genetic information. I was one of the customers of the original genetic testing service. After several weeks, the time it takes to process a sample, I could go online and view my health-related genetic information. What did I learn? To name a few things: I have a reduced risk of Alzheimer’s and Parkinson’s (possibly), my genetic makeup suggests I am very unlikely to have red hair (true) or enjoy the taste of cilantro (also true).

But what if I had a high probability of developing an untreatable neurodegenerative disease? One that would negatively influence my quality of life in later years? Information such as this leaves the individual in a precarious position, yet the news may not be as detrimental as one would expect. Studies on quality of life after predictive testing for Alzheimer’s Disease (AD), Huntington’s Disease (HD), and ataxias have shown that: “(a) extreme or catastrophic outcomes are rare; (b) consequences commonly include transiently increased anxiety and/or depression; (c) most participants report no regret; (e) many persons report important benefits from receiving the genetic information” (Paulsen, 2013).

flickr user Alice Bartlett

Great, right? Not so fast. All of these studies were done in a typical genetic counseling environment, likely equipped with clinical geneticists, genetic counselors, and psychotherapists. As Roberts (2013) addresses in his paper on the practical and ethical issues of genetic susceptibility testing: “the impact of testing on people without post-test counseling is unknown because it is considered standard of care to deliver predictive genetic test results within the traditional genetic counseling model—.” Essentially, the outcomes for DTC genetic testing are unknown. This is a concerning phenomenon that needs to be addressed. 

Furthermore, we know relatively little about how our genes interact with our environment, so those official-looking results you get on the internet may not be as “official” as they seem. It may be that a woman in Atlanta with a specific genotype identified by “23andMe” develops a chronic illness, while a woman living on a farm in Iowa with a similar genotype does not. We don’t know. The ability to accurately predict the phenotype (how our genes are actually expressed) is limited. At best, it’s an informed estimate that remains open to interpretation. This is a hard thing to explain over one page on the Internet. Roberts also addresses these concerns in his paper: “APOE [the risk allele in this gene has some predictive value] testing has limited predictive value, and there are currently no proven prevention options for AD; for these and other reasons (e.g., potential psychological and social harms), the medical community has recommended against its use.”

I propose an intermediary: someone to review and screen the results, sharing pertinent information with the patient and putting the results in context when necessary. As of August 2011, two out of thirteen of the companies offering genetic susceptibility testing for neurodegenerative diseases required results to be given through a physician (Roberts, 2013). This is what needs to change, particularly since testing for neurodegenerative diseases is becoming increasingly accessible. In 2013, “nine companies market DTC genetic tests related to risk for AD, nine for MS, three for PD, three for ALS, two for PSP, one for Niemann-Pick disease, one for CJD, and one for vascular dementia (Paulsen, 2013). “23andMe” is one of many, and an increasing number, of companies that will have to negotiate the line between helpful and harmful health information.

Remind me again why neurodegenerative diseases present a special case of ethics?

Neurodegenerative diseases are unique in that they have the potential to change an individual’s sense of self: the discussions surrounding neurodegenerative diseases necessitate a certain level of expertise to guide patients through the appropriate steps in dealing with, and responding to, their results. Regulations should be put in place to prevent consumers, “patients,” from viewing the results of neurodegenerative diseases online, instead re-routing the information to a doctor, genetic counselor, or some other licensed professional. The emotionally laden aspects of neurodegenerative diseases is paramount: person-to-person is much more comforting than your computer screen, or even a “live chat.” The necessity of structured support surrounding such a life-altering disease is ten-fold when it is not just a discussion of how to die, or when to die, but rather, how to live.

*As of September 2013, the FDA suspended “23andMe” from releasing any results of genetic testing out of concern for consumers. The FDA cited concerns of false negatives and positives and overall lack of validity of some of the tests. Similar concerns are addressed in this paper. 

References

Paulsen, J. S., Nance, M., Kim, J. I., Carlozzi, N. E., Panegyres, P. K., Erwin, C., ... & Williams, J. K. (2013). A review of quality of life after predictive testing for and earlier identification of neurodegenerative diseases. Progress in Neurobiology, 110, 2-28.

Roberts, J. S., & Uhlmann, W. R. (2013). Genetic susceptibility testing for neurodegenerative diseases: ethical and practice issues. Progress in Neurobiology, 110, 89-101.

Robillard, J. M., Federico, C. A., Tairyan, K., Ivinson, A. J., & Illes, J. (2011). Untapped ethical resources for neurodegeneration research. BMC Medical Ethics, 12(1), 9.

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Meffert, L. (2015). 23andMe: The Ethics of Genetic Testing for Neurodegenerative Diseases. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2015/05/23andme-ethics-of-genetic-testing-for.html

Predicting Alzheimer's Disease: Potential Ethical, Legal, and Social Consequences

By Henry T. Greely, J.D.





Henry T. (Hank) Greely is the Deane F. and Kate Edelman Johnson Professor of Law and Professor, by courtesy, of Genetics at Stanford University. He directs the Stanford Center for Law and the Biosciences and the new Stanford Program in Neuroscience and Society  SPINS). He is also a member of the AJOB Neuroscience Editorial Board.



Would you want to know the date and time of your death? Life-Line, the first published fiction by Robert A. Heinlein, one of the giants of 20^th century science fiction, explored that question. The story’s protagonist, Hugo Pinero, had invented a machine that could tell precisely when individuals would die, but, as Pinero found to his distress, he could not intervene to change their fates.



Would you want to know whether you would be diagnosed with Alzheimer disease (AD)? This question is rapidly leaving the realm of science fiction; indeed, it already has for some unlucky people. Our ability to predict who will suffer from this evil (and I chose that word carefully) condition is proceeding on several fronts and may already be coming into clinical use.



This post will briefly note the ways in which AD prediction is advancing and what some of the ethical, legal, and social implications of such an ability would be, before asking “should we care?”

Via the BBC

Science



Several different techniques are providing information about an individual’s risk of being diagnosed with AD, including genetics, biomarkers, and neuroimaging.



Genetics can predict AD with great confidence for about one person in a thousand. People who carry a mutated version of the PS1 gene (or, much more rarely, mutated versions of the PS2 or APP genes) are nearly certain to be diagnosed with AD, unless they die earlier from something else, and with an early onset version that typically strikes in one’s 40s or 50s. People with two copies of the APOe4 allele, about one to two percent of the population, have a very high risk (at least 50 percent, perhaps as high as 80 percent) of being diagnosed with AD in their sixties or seventies. People with one APOe4 allele and one APOe2 or APOe3 allele – that’s about 20 percent of the population – have two or three times the AD risk of people without an APOe4 allele. Other alleles of other genes have also been found to confer higher risk of AD, and some single nucleotide polymorphisms have been associated with higher risk of the disease.



Other researchers have identified biomarkers that are associated with risk of AD, both in the cerebral spinal fluid (CSF) and in the blood serum. Thus far, the CSF methods have looked for levels of the protein beta amyloid (42), which forms plaques on dead and dying neurons of those with AD, and the protein named “tau,” which forms tangles in the bodies of those neurons. Some of the blood work has looked at those biomarkers; others have looked at a range of different proteins in the blood. None of these methods is ready for clinical use; some of the published research has claimed nearly 90 percent accuracy in predicting relatively near-term AD diagnosis.



Recently, the FDA approved a radio ligand that attaches to the amyloid plaque in the brain and allows the existence of amyloid plaque to be seen by positron emission tomography (PET). The approved labeling is for use in diagnosing AD, not in predicting it, but the off-label use doctrine allows doctors to prescribe it for any purpose. Other researchers are trying to find ways to image tau tangles, though currently the only method for detecting them is through a brain biopsy (not an easy technique!). It is also known that magnetic resonance imaging (MRI) scans of brains can see changes in grey matter density in certain parts of the brains of people with AD; efforts are under way to use that method to predict AD diagnoses.



These various methods need not be used in isolation. They could be used together, in an effort to provide greater accuracy than any one test would do on its own. We are only at the beginning of efforts to assess those possibilities.



The FDA has not approved any of these methods (yet) for clinical use in predicting AD and professional groups have recommended against such use. It remains unclear how good any of these methods are alone or in combination, or at what age or ages they are useful. (A genetic cause may be strongly predictive even before birth; amyloid plaque levels may – or may not – be relevant only for people over 60.) Their accuracy might also vary between completely cognitively normal and those showing some minor signs of cognitive problems (which, for many people, would not progress to AD).



Importantly, these methods were not discovered in order to use them for clinical prediction. They are the results of basic research, of efforts to understand the natural history of the disease, in hopes of ultimately finding preventions or treatments. Their first use in humans has been in AD research, stratifying research subjects into high and low risk groups in the hope of making clinical trials faster and cheaper. But nothing prevents a physician from ordering the tests for a worried patient (with money to pay for tests that insurance will not reimburse).

Via Next Avenue 

Effects



Let’s assume that people did begin to get fairly accurate tests for their AD risks. What would follow?



If we had good interventions to prevent or treat the disease, much good might come from such testing, but we don’t (beyond “chicken soup” kinds of recommendations like “exercise”.) So how and why will people use these predictions and what non-medical consequences can we expect?



Some people will use the information for financial planning. A friend of mine is an “elder lawyer,” who spends a good amount of his time in financial planning for the elderly. He says that if we had a test that was 90% accurate, he would urge all of his clients to get such a test so they can plan how to use (and preserve) their assets for their struggle with AD.



On the other hand, some will worry about the effects of getting tested. Being at high risk for AD might lead to all the usual discrimination suspects – employment, health, life, and disability, plus one special one, long term care insurance. The relatively old ages at which AD strikes (except for the roughly 1% of cases that are early onset) mitigate, but do not eliminate, the number of people who would risk employment and health insurance discrimination. Most people will not be employed when they are diagnosed with AD. And, at time of diagnosis (and hence of increased health care costs), most of those affected will be over 65, and thus will have Medicare for health coverage (whatever may happen to Obamacare). Ironically, though, whether GINA, the Genetic Information Non-discrimination Act, protects them will depend on whether their risks were predicted using genetic methods or other methods. (The consequences of the use of mixed methods are not clear.)



A few special cases of possible “employment” discrimination might be noted. Every four years Americans “employ” someone as President. Would the public want to know the AD risks of the candidates? Not too long ago, President Ronald Reagan was diagnosed with AD only a few years after the end of his second term. The public, acting largely through the press, might want AD risk information from future candidates. (Teneille Brown has explored these issues in more depth¹.)



Similarly, sitting presidents may well want that kind of information about candidates for appointment to jobs with life tenure – federal judges, and particularly Supreme Court justices. In 2009, Judge Karen Williams, Chief Judge of the United States Court of Appeals for the Fourth Circuit, retired from the bench at the age of 57 because of early onset AD. All things being equal, presidents want the judges they appoint to sit, and influence the law, for decades after the president’s term is over.



It is not clear that life insurers would care much about AD risk; the disease process is so long that the age at death, though somewhat reduced, may not be change significantly. But private disability insurers should care, as AD patients who are employed at the time of diagnosis may end up claiming on such policies.



And long-term care insurers, should care, a lot. AD patients will often need years of long-term care. The private long-term care market is relatively new and small. It is a policy initiative to try to deal with the upcoming huge cost of long term care for Baby Boomers, care that is not significantly covered by Medicare or private health insurance. If people were able to test for their AD risk and then, if they test positive, buy long-term care insurance on the same terms, the resulting “adverse selection” will cause insurers either to lose money or to raise their rates. Either outcome, in this young and relatively fragile market, could end long-term care insurance. On the other hand, if insurers can take AD risks into account (at least when the customer knows those risks), people at high risk will often find long term care insurance unaffordable, even though – and especially because – they will need it.



But other, less tangible, consequences may follow. Consider the effects on family dynamics. Will the children take away Dad’s car keys sooner if he has been predicted to be at high risk for AD? Will they take away his checkbook, and control over his finances? How will the relationships within the family change when spouses, partners, and children expect an AD diagnosis?



And, of course, what will be the effects on people predicted to be at high risk? They may face depression or other psychological consequences. They might even make plans for suicide.



These issues, of course, are not new – they occur already with an AD diagnosis. But an AD prediction may move the opening point of these concerns forward several years, years that otherwise might not have been clouded by the knowledge, or fear, of AD.



Should We Care?



In a different sense, none of these issues is new. They already exist with fatal diseases that can be confidently predicted, like Huntington disease, as well as fatal diseases once they are diagnosed. But AD is, in some ways, distinctive. Instead of striking one person in 20,000, like Huntington disease, it will strike an estimated 10% to 15% of the population. And its memory, and ultimately personality, destroying characteristics lead to special challenges, as well as, for some people, to special horror. What, if anything, should we do about it? For now, I will make only two suggestions: assurance of the accuracy of the predictions and a requirement for counseling.



The accuracy of the tests, alone and in combination, needs to be assessed carefully, and for people of different sexes, ethnicities, and other possibly relevant possibilities. I believe some kind of public assessment of accuracy, akin to (and possibly including) FDA approval, should be required before the testing is allowed.



Then, both before the test is taken as well as after any positive results are returned, we should require skilled counseling. The first session will help make sure that the individual understands the advantages and risks of taking the test. The second will help high risk people deal with the shock of the prediction – and with its longer-term consequences.



Conclusion



Pinero’s “life predictor” never existed and never will. That would have been good for the fictional Pinero: in the short story thugs paid by life insurance companies murdered him, on the very date his machine had predicted



Widespread, accurate (or even inaccurate) AD prediction is not yet here. It will be soon. As a common, expensive, and severe disease, its predictability will bring some foreseeable challenges, as well, no doubt, as some unforeseeable ones. We need to work to understand, and cope with, those challenges. And we need to start yesterday.





Reference



1) Teneille Brown, Double Helix Double Standards: Private Matters and Public People, J. Hlth Care L. & Pol. 11:295-376 (2008).

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Greely, H. (2014). Predicting Alzheimer Disease: Potential Ethical, Legal, and Social Consequences. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/06/predicting-alzheimer-disease-potential.html

Stress Rx: Chant two Ommsss, with food, twice daily

How can and should meditation be used to restore physical and mental health in a clinical setting?  That is the question that Emory University neuroscience graduate student Jordan Kohn posed to begin the latest Neuroethics Journal Club.  The discussion thereafter centered on Black et al.’s 2013 Psychoneuroendocrinology paper entitled “Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial.”¹ This paper laudably attempts to bridge the mind-body gap and suggests a biological, and perhaps more importantly, a genetic mechanism to explain how yoga can apparently help relieve stress, protect against depression, and restore immune function in caregivers.  The implications of this line of investigation could be widespread as the scientific and medical communities grapple with our fundamental understanding of the mind and body and how to integrate what used to be considered fringe or alternative approaches into the mainstream.



Caregivers for dementia patients have been widely studied because they experience high levels of chronic stress and in turn suffer high rates of depression and other mental and physical health problems.² Both acute and chronic stress can drastically alter immune system function³ and, not surprisingly, dementia patient caregivers show marked impairments in immunological measures.⁴ The connection between the immune system and mental health is increasingly studied for its apparent bi-directionality.  Sickness behavior – characterized by fatigue, poor sleep, irritability, and lack of appetite – closely resembles major depression.  In fact, pro-inflammatory cytokines, which are up-regulated during an infection, can induce depression.⁴





In this study, participants were randomly assigned to practice the Kirtan Kriya Meditation, guided by an audio CD, for only 12 minutes per day, or to listen to a CD of relaxing music for the same amount of time each day.  After 8 weeks, nearly two thirds of the meditators had improved depression scale scores of at least 50% and most of them also scored 50% better than they had at baseline on a cognitive test.  Significantly fewer music listeners improved by 50% in either of these measures. These data had actually been, in part, reported previously⁶ but in this study the authors sought to determine whether meditation modulated gene expression in an attempt to understand how yogic meditation mechanistically elicits these beneficial effects.  Black and colleagues assessed genome-wide expression levels at baseline and post-treatment for both groups and also performed more focused analyses on genes related to immune system function or under the control of the well-known transcription factors NF-κB and IRF-1.⁹  They found that there was a significant reduction in the expression of genes that respond to NF- κB and an increase in those that can be activated by IRF-1 which, together would suggest a decrease in pro-inflammatory cytokines and a better functioning immune system.



This paper, along with a growing literature on the clinical benefits of meditation, raises the question of how ecologically valid such studies are and how one would, on a practical level, implement such interventions.  For one thing there is the issue of standardization.  Several high-profile meta-analyses have been performed to try to answer the question of whether meditative interventions actually improve clinical measures but only a fraction of relevant studies can be included in any one analysis due, at least in part, to the heterogeneity of interventions and study designs.^7,8 This has led to poor power which has made it difficult to determine what effect these interventions actually have.⁹ A second question is in what contexts should meditation be most appropriately prescribed? Our journal club facilitator, Jordan Kohn, noted that meditation has been shown to be useful for people incarcerated in prison and perhaps uniquely beneficial for training the military to cultivate their ‘Warrior Minds’ (though there may be additional ethical concerns for some). However, there may not be a one-size-fits all approach to meditation. While there might be benefit for stress reduction in Alzheimer’s caregivers, or cultivating compassion in those who are incarcerated, or creating sharper minds for our military personnel, Jordan mentioned that there may be some individuals who would not find benefit and might actually be harmed, by certain kinds of meditation. For example, individuals who suffered PTSD might only relive their trauma more vividly during their meditation sessions.



An important issue that this paper speaks to indirectly is the apparent necessity to have biological data to support psychological findings.  This is undoubtedly an important pursuit as it may lead to new therapeutic targets, but it also seems to be missing the point.  Does a psychological or mind-based intervention absolutely need to affect biological measures (in the body) in order to be valid?  In this case, the reported effect is most likely indirect where meditation helps to relieve perceptions of stress which may allow hormone levels to normalize and the immune system to get back to business as usual.  Since the authors do not report effects on any of the biological “levels” between the mind and gene transcripts in immune tissue, their genetics results serve mainly to support the aforementioned psychological data but do not really extend the findings.  However, in the public one can easily find alternative medicine skeptics as well as enthusiasts who are already mesmerized by the exoticism of meditative traditions and alternative medicine. Having a biological marker as compelling as genetic data might convince skeptics that meditation has true validity and is worthy of future funding and integration into clinical care.



Another question along these lines is whether biological measures – which can be altered by meditation – can shift a sense of disease responsibility?  It is well known that not every individual who is exposed to trauma or put under stress will develop a stress-related pathology.  Some people seem to be resilient.  If the remedy for those who are not resilient is a drug that alters neurochemistry, then one would think that the susceptibility must have been due to a pre-existing chemical imbalance – a biological deficit so to speak.  But if the prescribed therapy is to train yourself in mindfulness, then does that mean the disease is the result of a character or personality flaw?  That is, if a patient can just use his/her mind to reduce stress through meditation should the patient just summon the moral fortitude to not be so affected by stress to begin with?  One wonders if prescribing something like a pill versus meditation, indicates that the patient needs “real” medicine for their illness because it is something out of the patient’s control.  These and other issues are likely to be continually discussed as alternative approaches including meditation are increasingly studied and expanded into clinical settings.





References



1.  Black, D. S. et al. Yogic meditation reverses NF-kappa B and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology 38, 348-355, doi:DOI 10.1016/j.psyneuen.2012.06.011 (2013).

2.  Pinquart, M. & Sorensen, S. Differences between caregivers and noncaregivers in psychological health and physical health: A meta-analysis. Psychol Aging 18, 250-267, doi:Doi 10.1037/0882-7974.18.2.250 (2003).

3.  Dhabhar, F. S. & McEwen, B. S. Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: A potential role for leukocyte trafficking. Brain Behav Immun 11, 286-306, doi:DOI 10.1006/brbi.1997.0508 (1997).

4.  Lovell, B. & Wetherell, M. A. The cost of caregiving: Endocrine and immune implications in elderly and non elderly caregivers. Neurosci Biobehav Rev 35, 1342-1352, doi:DOI 10.1016/j.neubiorev.2011.02.007 (2011).

5.  Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature reviews. Neuroscience 9, 46-56, doi:10.1038/nrn2297 (2008).

6.  Lavretsky, H. et al. A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity. International journal of geriatric psychiatry 28, 57-65, doi:10.1002/gps.3790 (2013).

7.  Goyal, M. et al. Meditation programs for psychological stress and well-being: a systematic review and meta-analysis. JAMA internal medicine 174, 357-368, doi:10.1001/jamainternmed.2013.13018 (2014).

8.  Grossman, P., Niemann, L., Schmidt, S. & Walach, H. Mindfulness-based stress reduction and health benefits. A meta-analysis. Journal of psychosomatic research 57, 35-43, doi:10.1016/S0022-3999(03)00573-7 (2004).

9.  Bartlett, T. "Wait, So Does Meditation Actually Work or Not?" in Percolator  (Chronicle.com, 2014).

10.  NF-κB and IRF-1 are transcription factors which, when activated by an extracellular signal, can induce the expression of a variety proteins in order to mount a cellular response. NF-κB is typically associated with an increase in pro-inflammatory cytokines whereas IRF-1 induces interferon beta, an antiviral cytokine.







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Purcell, R. (2014). Stress Rx: Chant two Ommsss, with food, twice daily. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/04/stress-rx-chant-two-ommsss-with-food.html

Ethics, Genetics, and Autism: A Conversation with Dr. Joseph Cubells

Dr. Joseph Cubells

Dr. Joseph Cubells is an Emory psychiatrist who focuses on working with adults with developmental and behavioral disorders, especially Autism Spectrum Disorders (ASD). He is on the cutting edge of using molecular genetics to identify genetic anomalies in his patients with the aim of improving and refining treatment packages. I spoke with Dr. Cubells about his work and the ethical implications of the use of genetic microarray tests with patients. After providing more details about how he uses molecular genetics in his practice, I will focus on our discussion of two primary issues related to his work: (1) the communication of genetic testing procedures and results to families and, (2) the role of health care systems in the widespread use of these tests. 

Dr. Cubells is primarily engaged in clinic work. He has over 200 cases and works exclusively with adults (he does not see patients under the age of 16). Molecular genetics is one technique used in his patient management strategies: “I am very interested in the role of molecular genetic testing in the care of people with neurodevelopmental disabilities. Not so much establishing a diagnosis of autism though because autism is a behavioral diagnosis.” In other words, because there is no genetic or otherwise biologically based test currently available for autism, Dr. Cubells and his team are interested in diagnosing other genetic differences, such as Phelan McDermid Syndrome which occurs when a chromosome is deleted after conception (de novo) and can lead to a variety of physical and developmental disabilities. This condition, and many other genetic anomalies, may contribute or directly lead to the development of autistic characteristics. Most professionals, including myself and Dr. Cubells, now agree that there is not a single ‘autism’ but, rather, many different ‘autisms’ with many different causal pathways, both genetic and environmental.

Last November, Dr. Cubells and his team presented a paper on their use of molecular genetics in direct patient care at the American Society for Human Genetics. They sent chromosomal microarray tests¹ to be analyzed for 44 of their patients. Seven of these tests “came back with definitely clinically relevant differences that had not been previously diagnosed.” This is a rate of 16%, which, for Dr. Cubells, is “a substantial and important rate.” This rate may seem small but the impact of these findings are critical. For example, among those seven, one adult male’s test showed a deletion of the monoamine oxidase (MAO) A and B gene. This effects of this deletion are similar to the effects of taking a MAO inhibitor (MAOI), a type of pharmacological treatment for depression. Both this medication and this genetic deletion can lead to a fatal hypertensive crises if a person consumes tyramine (found in many aged or fermented foods, foods high in protein, and some alcoholic beverages) or in the presence of sympathomimetic drugs, which mimic transmitters such as catecholamines (i.e., epinephrine, norepinephrine, and dopamine). Because this genetic deletion was identified, the patient now wears a medic alert bracelet stating that he must be treated as a patient on a MAOI to avoid unexpected drug reactions. This knowledge is potentially life-saving.

These microarray genetic analyses can help refine patient management; however, the actual purpose and results of tests are difficult to accurately communicate to families. Dr. Cubells related another story of an adult who has significant autistic characteristics for whom his team identified another type of anomaly: a 15q13.3 deletion for which a small part chromosome 15 is deleted in each cell. They discovered that this participant’s mother has the same deletion, however, unlike her son, does not show any of the developmental delays. The man’s grandmother, however, also has the deletion and exhibits some developmental delays. This patient’s cousin is recently married and is wondering if he should be tested for this deletion. I asked Dr. Cubells what, in cases like this, a genetic counselor or clinician is ethically responsible to communicate to families regarding the implications of obtaining the tests and the implications of the results. This issue is an important concern for eventual pre-natal diagnoses of autism as well as for the project I am working on as the current Neuroethics Program Scholar, which involves considering the implications of using eye-tracking technologies for early, presymptomatic screening of ASD.

The gene copy number (also "copy number variants" or CNVs) is the number of copies of a particular gene in the genotype of an individual.

Dr. Cubells responded that “the first thing you have to make clear is there is a lot of uncertainty.” For cases like the one described above, he would start by explaining that the test will only tell him whether he carries the deletion. If he does not, then there is an “infinitesimally small” likelihood that his future children would have that deletion. However, if he does carry the deletion, things are a much more complicated. There is a big chance that this gentleman’s children would have learning or developmental difficulties, however, as the patient’s mom exemplified, there could also be no discernible influence. “And so the range of possibilities ranges from very challenging to fine.” Regardless, at this stage, Dr. Cubells believe that with this particular chromosomal variation, or copy-number variant (CNV), there are “reasonable odds” that there will be challenges but the field is not ready to be quantitative about it. This is the kind of information, he says, of which genetic counselors must be aware.

There are significant differences in the understanding of risk between the lay public and professionals.² Explaining probabilities to patients or families is difficult, but Dr. Cubells urges that the physician’s role is “to be helpful when he can and to give them [the family and patient] as much information as he can to explain things.” This information should include an explanation of the meaning and difference of variable penetrance and variable expressivity. The former is the proportion of people who carry a particular gene that also expresses and particular trait, or phenotype. The latter describes the differences within this expression, or the ranges of phenotypes linked to a particular gene or genetic anomaly. This information is often confusing for patients and families to understand. It is critical that patients understand these terms in order to  consent to taking part in a microarray test and for comprehending the consequences of test results. Given that the responsibility of making decisions lies with the patient and family, this information needs to be communicated clearly and reliably.

We also discussed issues related to the cost of these genetic arrays and resource allocation. Dr. Cubells explained that genomic micro-arrays cost, at a minimum, around $800. If the company wants to stay in business and possibly make a profit, then they need to charge around $1400. He admits that this amount of money can be also used towards valuable and efficacious behavioral or psychological treatment. And so where should we put our resources? He admits that, despite the obvious benefits of the work he is doing, he is “ambivalent about pushing the importance of genetics in autism because [he] spends a lot of time explaining what ought to happen but the resources aren’t there.” This is a large debate in the field. Many self-advocates and family members struggle, knowing that there is a lack of funding for research on quality of life issues and services, especially for adults who lose a host of services, such as instruction on daily living skills as well as occupational and speech therapies, once they age out of the public school system at the age of 21.³

“But on the other hand,” Dr. Cubells explains, “we do need to understand things at the level of etiology. We need to know if a person has Phelan McDermott versus 15q versus 22q11⁴ because even now there are clinical implications for that.” Dr. Cubells sees a problem in the lack of reimbursement for genetic counselors who see patients with psychiatric problems; insurance companies do not have to pay for this kind of consultation. He says this situation needs to change, but the only way this change will happen is for politicians and professionals to work towards changing the minds of insurance and health care administrators. 

Cost is a real barrier to access to emerging medical technologies like this for many families. This means that critical information will potentially not be available to many patients unless these tests become a mandated part of health care coverage. It is also possible that tests like these will become part of standard pre-natal check-ups, in which case a host of other ethical concerns arise. Disability activists, especially those adherent to neurodiversity, see pre-natal diagnostics of disabilities as an attempt to eradicate disability and difference from the human population—a eugenic enterprise. Additionally, as was discussed in my last post, cultural and faith-based backgrounds of families may mean less acceptance of the use of these technologies. Families may rely on more spiritually-based explanations of disabilities and so may not be open to discussions of genetic causes, which can be seen as more chronic and stigmatizing. Finally, for many of the genetic anomalies identifiable by these tests, no reliable treatments are available. There are educational and behavioral therapies for autism and related disorders; however, there is no guarantee that any intervention will dramatically change behavior or if, given the variability of autistic manifestation, any intervention will even be necessary! These issues will be discussed more fully in my next blog post, where I describe the impact of the use of eye tracking technologies to identify autistic markers in infancy. 

This discussion reminded me of a recent op-ed in the New York Times in which the columnist, Nicholas Kristof, called for more attention in the media and government on mental health. We may be working in the right direction as the Affordable Care Act does include mental health care, but costs remain high and the consequences of these costs are having real effects on real lives. Bringing the impact of psychiatric, intellectual, and developmental disorders has on the quality of life of diagnosed individuals and their families into the public realm is imperative to obtaining more funding for services and more research on how to develop, implement, and distribute these services most effectively. As genetic testing and prescreening for psychiatric conditions continues to become more advanced, I agree with Mr. Kristof and Dr. Cubells. Improving coverage for psychiatric services should be a high priority issue for politicians, health care administrators, scientists, physicians, and, most importantly, families.

Dr. Joseph Cubells is a psychiatrist whose clinical and research interests lay in molecular genetic factors of developmental and behavior disorders, such as autism, schizophrenia, and major depression. He is the Medical Director and Attending Psychiatrist at the Emory Autism Center where he work with adults on the autism spectrum and with genetic and chromosomal disorders that lead to various psychiatric disorders.

References

1. A chromosomal microarray test is a new method of detecting alterations in a person’s DNA. Specifically, these tests look for areas on the DNA with too many or too few copies of genetic material. This method is more specific than earlier genetic tests, thereby allow for more exact maps of the DNA and, ostensibly, the ability to identify more anomalies. For more information, see The American College of Obstetricians and Gynecologists’ Committee Opinion on the use of this test in prenatal diagnosis here: http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Genetics/The_Use_of_Chromosomal_Microarray_Analysis_in_Prenatal_Diagnosis.


2. For example, see: Hamepl, J. (2006). Different concepts of risk - A challenge for risk communication. International Journal of Medical Microbiology, 296(S1): 5-10; Miller, A.M, Hayeems, R.Z, & Bytautas, J.P. (2010). What is a meaningful result? Disclosing the results of genomic research in autism to research participants. European Journal of Human Genetics, 18: 867-871; McMahon, W.M., Baty, B.J., & Botkin, J. (2006). Genetic counseling and ethical issues for autism.  American Journal of Medical Genetics Part C (Semin. Med. Genet.), 142C: 52-57; Slovic, R. (1987). Perception of Risk. Scienze, 236(4799): 280-285.


3. For more explanation of this perspective, see this report by the Autistic Self Advocacy Network (ASAN), “ASAN expresses concern regarding new HHS report on autism research” at http://autisticadvocacy.org/2012/07/asan-expresses-concern-regarding-new-hhs-report-on-autism-research/.


4. These are all genetic disorders associated with autistic phenotypes. Phelan-McDermid is “the result of a disruption of the SHANK3/ProSAP2 gene on the terminal end of chromosomee 22,” according to the website for the Phelan-McDermid Syndrome Foundation (www.22q13.org). 15q  and 22q11 refers to partial deletions of chromosomes 12 and 22 that leads to a variety of developmental disorders.

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Sarrett, J. (2014). Ethics, Genetics, and Autism: A Conversation with Dr. Joseph Cubells. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/04/ethics-genetics-and-autism-conversation.html