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Living Tissues Propel Ethically Responsible Brain Research

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Living tissues provide high-resolution images of the human brain, which cannot be offered by MRI or postmortem tissue. | Courtesy of Ed Lein

The study of brain tissue from living donors – patients who continue to live after their donation – will reveal the structure and function of the human brain at unprecedented depths, but the data collected from these research efforts must be ethically regulated, said scientists convening at a February 13 news briefing at the 2020 AAAS Annual Meeting.

The speakers presented the latest updates from their work, which fall under the international BRAIN initiative, a project jumpstarted by the Obama administration aiming for accelerated understanding of the human brain. Similar initiatives have since materialized in Canada, the EU, Japan, Korea, China and Australia – altogether forming the International Brain Initiative.

“We’ve been able to show that the brain is extremely cellularly complex, but at the same time finite and definable,” said Ed Lein, director of Human Cell Types Program at Allen Institute for Brain Science. “And now using living brain tissue, we are able to describe it at a fine level of granularity in a way that has never been possible before.”

Exploring living brain tissues can advance understanding of neurological diseases and conditions by delving into the brain’s higher-level functions. These include sensory perception, cognition, generation of motor commands, spatial reasoning and language – all of which have been difficult to study in the past, mainly because brain tissue donations are not common. Brain tissues currently available to research labs are usually postmortem.

By contrast, in Lein’s lab, brain tissue samples come from individuals with epilepsy or cancer, for whom regular biopsies are part of standard procedure for diagnosing and monitoring the disease. The tissues extracted are still healthy, and the cells within the organ remain intact. In this way, living tissues provide high cellular resolution of the human brain, which cannot be offered by current imaging techniques like MRI or by studying postmortem tissue.

“Neuroscience is where the field of immunology was at several decades ago,” said Ed Lein, part of the multi-national Human Cell Atlas Project, which aims to map and understand all the cells of the human body. Far from the early days of immunology, it’s now well known that the immune system runs on a complex network of many different cell types. Lein hopes to attain this level of cellular resolution in neuroscience.

One critical insight revealed by his analysis of living tissue is the striking difference between human and mouse brains that highlight the complexity of the human nervous system. He has found there are differences between the variety of cell types, specialized properties of these cells – like the way serotonin receptors signal on cell surfaces – and gene expression.

These differences might pose issues for the use of rodents to model human neurological diseases and conditions. It would be ineffective to develop drugs on an animal model that doesn’t use genes or cells in the same way as humans, said Lein.

Mouse models are still relevant, he added, but one of his hobbyhorses is to find a model that recapitulates the human, rather than assuming that the mouse brain – in sharing similar genes – is likely to function exactly like the human brain.

To do this, Lein hopes to obtain many more living tissues in a rigorous, standardized way that accounts for large variations in age, disease, and differences in surgical procedures. This requires a well-organized network among researchers, clinicians and patients to set up access to tissue as soon as it’s available.

Karen Rommelfanger and Ed Lein spoke to reporters at the AAAS Annual Meeting. | Robb Cohen Photography and Video

To probe inside the human brain also poses a question of ethics. The unique organ is a reservoir of precious and private data – like memories and emotions – that define what it means to be human.

“The whole reason why the field of neuroethics exists is because there is something special about the brain,” said Karen Rommelfanger, director of neuroethics program and professor of neurology, psychiatry and behavioral sciences at Emory University. “Patients want to donate their tissues … but they need to know of how their tissue will be used in the future, and how the data is going to be used.”

Rommelfanger presented a series of ethical questions neuroscientists must incorporate into research that uses live brain tissue, such as a living patient’s consent or East-West cultural frameworks of the human brain. To answer these questions, Rommelfanger calls for a strong collaboration among neuroscientists, industry leaders, policymakers and the patients themselves – across national borders.

“Policymakers and industry leaders in charge of regulating cutting-edge neurological treatments or research resulting from live brain tissue donation need to prepare to be the first to know about ethics issues, not the last,” she said. “They must move beyond the belief that compliance and regulatory checkboxes are proxies for ethics.”

To actively incorporate neuroethics into research investigations, scientists should start by collecting data from families of patients undergoing brain tissue extraction, documenting their perspective on how they would like the tissues to be used, without discouraging them from donating.  Both top-down and bottom-up models for creating a platform and gathering funds for neuroethics inquiries are already available to neuroscientists around the world, noted Rommelfanger.

“We have ourselves in an ethical conundrum – the closer we get to an approximation of the human brain, the more ethically fraught it becomes,” said Rommelfanger. “So, we need philosophical questions to inform better science.”