Organoids, Chimeras, Ex Vivo Brains – Oh My!

By Henry T. Greely

Image courtesy of Wikimedia Commons

At about the time of the birth of modern neuroethics, Adina Roskies usefully divided the field into two parts: the neuroscience of ethics, what neuroscience can tell us about ethics, and the ethics of neuroscience, what ethical issues neuroscience will bring us (1). At some point, in my own work, I broke her second point into the ethics of neuroscience research and the ethical (and social and legal) implications of neuroscience for the non-research world. (I have no clue now whether that was original with me.)

The second part of Roskies’ division of neuroethics, the ethics of neuroscience research, has always had a special place in my heart because early work in it really helped mold the field we have today. In the early ‘00s, groups that mixed scientists, physicians, and ethicists, largely through the efforts of Judy Illes, explored what to do about abnormal brain scans taken from otherwise healthy volunteers. (See, e.g., 2, 3) It had become clear that, in the computer-generated imagery of a brain MRI, more than 20 percent of “the usual subjects” (college undergraduates, usually psychology majors) and about half of “mature” subjects had something “odd” in their brains. These could be variations of no clinical significance, such as “silent” blockages or benign tumor to potentially very serious problems, such as malignant tumors or large “unpopped” aneurysms. Happily, only small fractions of those oddities held clinical significance, but this still posed hard questions for researchers, many of whom were not themselves clinicians. What, if anything, should they tell, and to whom? And so, working together, scientists, clinicians, and ethicists talked with each other, learned from each other, and came up with useful answers, usually involving both changes to the consent process and a procedure for expert review of some worrisome scans.



That model of close and fruitful interaction between the neuroscience researchers and people with ethics or legal expertise has, I think, largely persisted in neuroethics, at least in North America. The early conversations about the disclosure of results deserve significant credit for that. 

Ethical issues in neuroscience research have continued to appear, on questions from confidentiality to consent. But largely without me. I’ve thought of my neuroethics work as almost entirely on the ethical, legal, and social effects of neuroscience outside the research setting.  Until now.* 

Last April, Nature published a comment written by Duke University’s Nita Farahany, me, and 15 others, including 11 scientists (4).  The piece, The Ethics of Experimenting with Human Brain Tissue, grew out of a May 2017 workshop held at Duke by its Science and Society Initiative with help from the NIH BRAIN Initiative.  It dealt with…wait for it…organoids, chimeras, and ex vivo brains, things I call “human brain surrogates”, and pointed out the dilemma they embody. Ethical constraints limit what we can do to the brains of living people, leading us to create surrogates for people’s brains – but the closer the surrogate comes to the living brain, the more we back into those same ethical constraints.

Image courtesy of Flickr

The best way to study how a human brain works is by studying a living human brain in a living human being. But this has problems. Humans are terrible lab animals – we disobey, we lie, and we can call lawyers. Researchers can’t “sacrifice” us at the right moment in the research and then carefully examine slices of our brain.  We hold rights that make much intrusive and risky, but potentially illuminating, research ethically (and legally) impossible. So, researchers look for surrogates for living human brains in living human beings, surrogates that do not have such an inconvenient moral status. Mouse brains in mice, monkey brains in monkeys, thin slices of human brains in Petrie dishes – all these have research value. But we know, from decades of disappointment in moving those findings to humans, that, although similar in some ways, none of them is the same as, or perfectly predicts, a living human brain in a living human. 

Enter three new or improved technologies. (For more information on any of these technologies, see the Nature Comment; for much more information, read its references.)

1) “Organoid” is the term generally used to refer to a small ball of human cells grown in cell culture from stem cells (human stem cells for human organoids). The stem cells may be embryonic stem cells, induced pluripotent stem cells, or other types of stem cells, but the effort has been to get cells that will all become one or more cell types found in an organ. Thus, there are human liver organoids, kidney organoids, gut organoids…and yes, brain organoids. The human neural organoids have been grown for over three years – and some of them have survived for over two years (4). They have diameters of about 4 millimeters (or a sixth of an inch), about the size of a very small pea (4). They have no vasculature and so the cells need to be in contact with the oxygen and nutrient bearing (and waste bearing-away) culture media. Currently human neural organoids have about two to six million neurons (no other brain cells so far, just neurons). They self-organize, grow synapses, fire, and continue to get more and more complex as time goes on. Still, by comparison, the human brain is estimated to contain approximately 86 billion neurons (5). 

2) Chimeras – in this case, human/non-human brain chimeras – are creatures with some human brain cells and some non-human brain cells. (Thus far, in brains at least, they are always non-human animals with some human cells, not humans with some non-human cells.)  Chimeras have been used in research for many years, though organoids are opening new possibilities: such as transplanting human organoids into rodent brains – which turn out to grow blood vessels for them (6). 

3) Researchers have also long used human brain tissue kept alive outside the body – ex vivo tissue – but what is used and how is, like chimeras, becoming “new and improved.” Instead of keeping flat sheets of human brain cells alive in a dish, researchers are keeping alive and studying larger and larger chunks of human brains, taken from neurosurgical discards or from the recently dead. There are even some efforts, so far only in non-humans, to keep whole brains from dead animals “alive” apart from their bodies (7). 

Other than being creepy, what do these all have in common? They are efforts to understand human brain function, and ultimately human brain diseases, better by making human brains that do not have the rights of human “persons” and hence can be used more broadly, and more roughly, in labs.  But as noted below, there’s a dilemma: the closer the surrogate comes to the living human brain in a living human, the more questions it raises about whether the surrogate has a moral status – and, if so, what status?

A retinal organoid

Image courtesy of Flickr

The Comment lays out some, but by no means all, of the questions these surrogates raise – lays them out but does not answer them. Some of those questions are about the fully human persons whose cells or tissues are used in the research and some are about the “thing” being studied itself.  

There is much work to be done on the ethics of this kind of neuroscience research, but, like the work on disclosure of MRI findings to subjects, it is work that requires the union of scientific, medical, ethical, legal, and other expertise. To know what to think of a human neural organoid, it is important to know something at least of what, if anything, that organoid can sense, perceive, do, or, possibly at some point, think. But the science is only a start to the question. We know mice, rats, and monkeys sense, perceive, do, and think things but we will allow some research with them. The ethical questions need to inform the scientific questions about these things; the scientific findings need to inform the ethics answers.

Happily, this is happening. The authors of the Comment, scientists and ethicists, recognized the appropriateness of concern about this research – not so much as it exists today but for what it may (or may not) become in five or ten years. And they recognized the need to work together. This kind of collaboration, indeed, is built into the NIH BRAIN Initiative, an effort that, at heart (and brain) is fundamentally about creating new tools for neuroscience research, and ultimately brain treatment. Its Multi-Council Working Group, made up of directors and outside advisory council members from 10 NIH Centers and Institutes as well as some at-large representatives (I’m one). It contains a Neuroethics Division (8), chaired by Dr. Christine Grady, chair of the Bioethics Department at the NIH Clinical Center, and myself. That division includes both scientists and ethicists among its members and the Duke workshop had its origin in some of the Division’s work. 

But there is much more to be done, on these topics and others, by that group and many others. Think about possible issues raised by using CRISPR to modify non-human primates by giving them human versions of some genes. (A National Academies of Medicine forum will do so this October (9)).  Or the questions of another human brain surrogate, an in-silico version, if it approaches close enough to consciousness to prompt concerns about its moral status. 

All scientific revolutions are ultimately based on revolutions in tools. The MRI, fMRI, animal models, thin slices, and other tools have taken us far but the next generation of tools is coming. It will make possible much scientific progress, but will undoubtedly raise many ethics issues, issues that will be important, complicated, and (usually) fun. Come and play!

P.S. And join the International Neuroethics Society! Our Annual Meeting on November 1 and 2, 2018 in San Diego features a panel on these issues: http://www.neuroethicssociety.org/2018-annual-meeting-program.



*Actually, I was wrong about that, a mistake it may be useful to explain. I have been an author, from 2003 to 2017, on six pieces involving human/non-human chimeras (10-15), at least two of which were specifically about brain chimeras. (11, 12) But, in spite of being involved in neuroethics since its modern birth, I put those in a different category – they were part of my stem cell work with some connections to my “weird life forms” interests. I – and we – need to remember to define neuroethics broadly.

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Hank Greely is the Deane F. and Kate Edelman Johnson Professor of Law at Stanford University, where he directs its Center for Law and the Biosciences as well as the Stanford Center for Neuroscience and Society. He began serving a two-year term as president of the International Neuroethics Society in November 2017. He chairs the California Advisory Committee on Human Stem Cell Research; and serves on the Neuroscience Forum of the National Academy of Medicine; the Committee on Science, Technology, and Law of the National Academy of Sciences; and the NIH BRAIN Initiative’s Multi-Council Working Group, whose Neuroethics Division he co-chairs. And he likes playing (doubles) tennis even though he is, to be charitable, not very good.

REFERENCES

1. Roskies, Adina L., 2002, “Neuroethics for the New Millennium”, Neuron, 35(1): 21–23. doi:10.1016/S0896-6273(02)00763-8

2. Kim, B.S., Illes, J., Kaplan, R.T., Reiss, A., Atlas, S.W. Neurologic findings in healthy children on pediatric fMRI: Incidence and significance, 23 Am J Neurorad.1674 (2002);

3. Illes, J., Desmond, J., Huang, L.F., Raffin, T.A., Atlas, S.W. Ethical and practical considerations in managing incidental neurologic findings in fMRI,  50 Brain and Cognition 358 (2002).

4. Nita A. Farahany, Henry T. Greely, et al., The Ethics of Experimenting with Human Brain Tissue, NATURE, 556:429-32 (April 26, 2018)

5. Society for Neuroscience, BRAIN FACTS at 5 (2018), available for download at file:///Users/hgreely/Downloads/Brain%20Facts%20Book%202018%20PDF.pdf, accessed July 12, 2018.

6. Mansour, A. A. et al. (2018) An in vivo model of functional and vascularized human brain organoids Nature Biotechnol. 36:432041, https://doi.org/10.1038/nbt.4127.

7. Antonio Regalado, Researchers Are Keeping Pig Brains Alive Outside the Body, Technology Review (April 25, 2018), https://www.technologyreview.com/s/611007/researchers-are-keeping-pig-brains-alive-outside-the-body/

8. The BRAIN Initiative, Neuroethics Division of the BRAIN Multi-Council Working Group, https://www.braininitiative.nih.gov/about/neuroethics.htm, accessed July 12, 2018

9. Forum on Neuroscience and Nervous System Disorders, National Academy of Medicine, Transgenic and Chimeric Neuroscience Research: Exploring the Scientific Opportunities Afforded by New Nonhuman Primate Models – A Workshop, at http://nationalacademies.org/hmd/Activities/Research/NeuroForum/2018-OCT-4.aspx, accessed July 12, 2018

10. Henry T. Greely, Defining Chimeras – and Chimeric Concerns, American Journal of Bioethics, Vol. 3, issue 3:17-20 (2003)

11. Mark Greene, et al., Moral Issues of Human–Non-human Primate Neural Grafting, Science 309:385-386 (July 15, 2005)

12. Henry T. Greely, Mildred K. Cho, Linda F. Hogle, Debra M. Satz, Thinking About the Human Neuron Mouse, American Journal of Bioethics:  NEUROSCIENCE 7:(5) 25-40 (May/June 2007)



13. Henry T. Greely, Human/Nonhuman Chimeras: Assessing the Issues, in Oxford Handbook of Animal Ethics (ed. Tom Beauchamp and R.G. Frey, Oxford Univ. Press, 2011)

14. Henry T. Greely, Academic Chimeras?, The American Journal of Bioethics, 14:2, 13-14 (2014)

15. Jun Wu, et al., Stem Cells and Interspecies Chimeras: Past, Present, Future, Nature 540:51-59 (Dec. 1, 2016)

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Greely, H. (2018). Organoids, Chimeras, Ex Vivo Brains – Oh My! The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2018/09/organoids-chimeras-ex-vivo-brains-oh-my.html

Participatory Neuroscience: Something to Strive For?

By Phoebe Friesen

Image courtesy of Pixabay.

In the last few decades, there has been an increasing push towards making science more participatory by engaging those who are part of or invested in the community that will be impacted by the research in the actual research process, from determining the questions that are worth asking, to contributing to experimental design, to communicating findings to the public. Some of this push stems from the recognition that research is always value-laden and that the values guiding science have long been those of an elite and unrepresentative few (Longino, 1990). This push also has roots in feminist standpoint theory, which recognizes the way in which marginalized individuals may have an epistemic advantage when it comes to identifying problematic assumptions within a relevant knowledge project (Wylie, 2003). Additionally, many have noted how including the voices of those likely to be impacted by research can support the process itself (e.g. by identifying meaningful outcome measures) (Dickert & Sugarman, 2005). As a result, participatory research is becoming widely recognized as having both ethical and epistemic advantages. The field of neuroscience, however, which takes the brain as its primary target of investigation, has been slow to take up such insights. Here, I outline five stages of participatory research and the uptake of neuroscientific research in each, discuss the challenges and benefits of engaging in such research, and suggest that the field has an obligation, particularly in some cases, to shift towards more participatory research.

The first and lowest stage of participatory research is represented by most scientific projects, in which all power and decision-making lies in the hands of the investigators. The vast majority of neuroscientific research takes place at this stage of participation (Robertson, Hiebert, Seergobin, Owen, & MacDonald, 2015).

The second stage is best exemplified by citizen science projects, in which the parameters of a research project are established by investigators and then the content of the project is filled in by many non-scientists. In some cases, there are opportunities for participants to become more involved (and even to be given credit for discoveries and publications), but this does not always occur (Wicks, Vaughan, Massagli, & Heywood, 2011). There is a significant amount of neuroscientific research taking place at this stage, often in the form of games that allow investigators to crowdsource many hours of tasks related to identification that the human eye can perform better than algorithms (e.g. EyeWire, Mozak). Research at this stage can also be derived from social networks for patients that collect vast quantities of data recorded by preferences (e.g. PatientsLikeMe) (Suresh, 2016).

The third stage gives some say to those who are impacted by the science, offering those impacted by the research an opportunity to shape the data set being collected, through their words or interpretations of their own experiences, or through commenting on the research design before it is implemented. Some neuroscientific research takes place at this stage, particularly that which involves qualitative data or community consultation (Klein et al., 2016; Stratford et al., 2016).

The fourth stage can be found in methodologies such as critical participatory action research and community-based participatory research, in which a community contributes to the research design from start to finish and is given ownership of data and authority over how that data is communicated to others. Central to this stage is the premise that power is shared between scientists and community members throughout the entire research process. This form of research appears to be very rare within neuroscience. One neuroscientific project which investigates the influence of colors on learning resembles these models in some ways and was inspired by and continues to involve high school students from Catalonia (Ruiz Mallen et al., 2016).

Members of a citizen science team

Image courtesy of Wikimedia Commons.

The fifth and final stage of participatory research is exemplified by user-led research, in which a scientific project is entirely conducted by individuals outside of industry or the academy (e.g. survivor research in mental health) . I have found no examples of research within neuroscience that takes place at this stage.

Taking this all into account, it looks like neuroscience is not very participatory, and when it is, the community members’ role is primarily as free laborers. Why might this be the case? Part of the answer is likely to be the many challenges that participatory research involves, some of which are unique to the field of neuroscience and some of which are seen across scientific endeavors. Those unique to neuroscience include the background and technical knowledge required, the expensive tools involved that are difficult to attain and operate, and the hype that frequently surrounds findings within the field (Stratford et al., 2016). Similarly, there is often a significant distance between neuroscientific research and the communities that might be impacted by that research, making applications or implications of the research less easy to foresee or understand. This distance might also mean that only a small subset of the population is interested in engaging in participatory neuroscientific research or that there is a greater risk of “wandering terminology,” which occurs when terms used in one epistemic realm are misapplied within another (e.g. see (Tekin, 2017)).

There are also several structural challenges that prevent researchers, in any field, from engaging in participatory research. Funding structures may not support these forms of research, especially since building relationships with impacted communities and engaging in this form of research can take a significant amount of time (Price, Chatterjee, & Biswas, 2014). Relatedly, reward systems within institutions, including the pressure to publish and bring in funding, can deter investigators from engaging in participatory research and from sharing data, decision-making power, or publications with additional collaborators (Choudhury, Fishman, McGowan, & Juengst, 2014). Additionally, systems of research oversight (e.g. IRBs, RECs), which are not constructed on the basis of participatory research, are often unable or uninterested in accommodating research which frequently cannot be entirely specified in advance and includes individuals from outside of academia in data collection and analysis (Boser, 2007; Noorani, Charlesworth, Kite, & McDermont, 2017).

Additional challenges to engaging in participatory research are epistemic, including the risks of self-selection bias and collecting variable data in citizen science projects (Kelling et al., 2015). It is also not unusual for investigators and those impacted by research to be interested in different kinds of research questions and to have different expectations related to what good research looks like (Ottinger, 2010). Ethical challenges arise as well, including the risk of engaging in tokenism, where participants are merely invited to participate in a symbolic sense (Stratford et al., 2016), or failing to fully inform the community regarding how their contributions are being used or sold (e.g. Lumosity – see (Purcell & Rommelfanger, 2015)), especially since “the allure of participation in a scientific study [can] be used as a Trojan horse to entice individuals to part with information they might not otherwise volunteer” (Janssens & Kraft, 2012, p. 1).

Given these challenges, it is hard not to ask: why bother? Are there good reasons that neuroscience should strive to be more participatory, or should it simply continue as is, reaping the rewards of participation when humans can outperform algorithms, but otherwise remaining within the ivory tower?

Participatory action research

Image courtesy of Flickr.

An answer to this question requires a look at the benefits that participatory research can produce, which are largely captured by three Rs: Rigor, Relevance, and Reach (Balazs & Morello-Frosch, 2013). Participatory research enhances scientific rigor through encouraging both reflection and transparency during the process; community members may also contribute to the identification of assumptions and issues, including those stemming from various conflicts of interest. Participatory research can also increase the relevance of research, because topics neglected in mainstream research are more likely to be taken up and results that will directly benefit those impacted by the investigation are often pursued. Finally, the reach of the knowledge is expanded, in the community may have the ability to access people or places that scientists could not, both during recruitment and during the transmission of results, which can lead to both larger and more diverse data sets, which in turn, improves generalizability (Cooper, 2017).

Taking these benefits into account, it appears that the field of neuroscience has a lot to gain from including more non-investigators in the research process, not just during data collection, but while asking larger questions regarding methodologies and goals. Keeping in mind the challenges discussed above, it is likely that some neuroscientific projects are better off remaining in the halls of the academy, but particularly in cases where neuroscientific research involves vulnerable communities or when a drug or device is being developed for clinical application, significant benefits may result from engaging in participatory research (e.g. through ensuring that an intervention meets the needs of its users). Within participatory research, misleading assumptions can be identified and excluded early on, applications of the science can be kept in mind throughout the process, and scientists can be given the opportunity to learn what matters most to the individuals impacted by their work. This shift will require buy-in not only from investigators, but also from institutions and regulators, who often restrict participatory research through reward systems and systems of oversight that are based on a narrow conception of what constitutes science.

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Phoebe Friesen is a post doctoral fellow at the Ethox Centre at the University of Oxford. She recently received a PhD in philosophy from the CUNY Graduate Center after completing her doctoral work, which focused on theoretical and ethical issues related to the placebo effect. She works primarily on questions within the realms of research ethics, bioethics, and psychiatry.

References

Balazs, C. L., & Morello-Frosch, R. (2013). The three Rs: How community-based participatory research strengthens the rigor, relevance, and reach of science. Environmental Justice, 6(1), 9-16. 

Boser, S. (2007). Power, ethics, and the IRB: Dissonance over human participant review of participatory research. Qualitative Inquiry, 13(8), 1060-1074.

Choudhury, S., Fishman, J. R., McGowan, M. L., & Juengst, E. T. (2014). Big data, open science and the brain: lessons learned from genomics. Frontiers in Human Neuroscience, 8(239). doi:10.3389/fnhum.2014.00239 

Cooper, R. (2017). 9 Classification, Rating Scales, and Promoting User-Led Research. Extraordinary Science and Psychiatry: Responses to the Crisis in Mental Health Research, 197.

Dickert, N., & Sugarman, J. (2005). Ethical goals of community consultation in research. American Journal of Public Health, 95(7), 1123-1127.

Janssens, A. C. J., & Kraft, P. (2012). Research conducted using data obtained through online communities: ethical implications of methodological limitations. PLoS Medicine, 9(10), e1001328.

Kelling, S., Fink, D., La Sorte, F. A., Johnston, A., Bruns, N. E., & Hochachka, W. M. (2015). Taking a ‘Big Data’approach to data quality in a citizen science project. Ambio, 44(4), 601-611.

Klein, E., Goering, S., Gagne, J., Shea, C. V., Franklin, R., Zorowitz, S., . . . Widge, A. S. (2016). Brain-computer interface-based control of closed-loop brain stimulation: attitudes and ethical considerations. Brain-Computer Interfaces, 3(3), 140-148. doi:10.1080/2326263X.2016.1207497 

Longino, H. E. (1990). Science as social knowledge: Values and objectivity in scientific inquiry: Princeton University Press.

Noorani, T., Charlesworth, A., Kite, A., & McDermont, M. (2017). Participatory Research and the Medicalization of Research Ethics Processes. Social & Legal Studies, 26(3), 378-400. 

Ottinger, G. (2010). Buckets of resistance: Standards and the effectiveness of citizen science. Science, Technology, & Human Values, 35(2), 244-270.

Price, A., Chatterjee, P., & Biswas, R. (2014). time for person centered research in neuroscience: users driving the change. Annals of Neurosciences, 21(2), 37-40. doi:10.5214/ans.0972.7531.210201

Purcell, R. H., & Rommelfanger, K. S. (2015). Internet-based brain training games, citizen scientists, and Big Data: ethical issues in unprecedented virtual territories. Neuron, 86(2), 356-359.

Robertson, B. D., Hiebert, N. M., Seergobin, K. N., Owen, A. M., & MacDonald, P. A. (2015). Dorsal striatum mediates cognitive control, not cognitive effort per se, in decision-making: An event-related fMRI study. Neuroimage, 114, 170-184.

Ruiz Mallen, I., Riboli-Sasco, L., Ribrault, C., Heras, M., Laguna, D., & Perié, L. (2016). Citizen science, engagement and transformative learning: a study of the co-construction of a neuroscience research project in Catalonia.

Stratford, A., Brophy, L., Castle, D., Harvey, C., Robertson, J., Corlett, P., . . . Everall, I. (2016). Embedding a Recovery Orientation into Neuroscience Research: Involving People with a Lived Experience in Research Activity. Psychiatric Quarterly, 87(1), 75-88. doi:10.1007/s11126-015-9364-4

Suresh, A. (2016). The Science Behind WeCureALZ: A Participatory Research Project Tackling Alzheimer’s Disease. Retrieved from http://blogs.plos.org/citizensci/2016/04/22/science-behind-wecurealz-citizen-science-alzheimers/

Tekin, (2017). 11 Looking for the Self in Psychiatry: Perils and Promises of Phenomenology–Neuroscience Partnership in Schizophrenia Research. Extraordinary Science and Psychiatry: Responses to the Crisis in Mental Health Research, 249.

Wicks, P., Vaughan, T. E., Massagli, M. P., & Heywood, J. (2011). Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm. Nature Biotechnology, 29(5), 411-414.

Wylie, A. (2003). Why standpoint matters. Science and other cultures: Issues in philosophies of science and technology, 26-48.

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Friesen, P. (2018). Participatory Neuroscience: Something to Strive For? The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2018/06/participatory-neuroscience-something-to.html