Of Mice and Men: How Paul Allen's Giving Set the Stage for an Ambitious Effort to Map the Human Brai

[Inside Philanthropy] Of Mice and Men: How Paul Allen's Giving Set the Stage for an Ambitious Effort to Map the Human Brai

Paul Allen, the Microsoft co-founder who passed away in 2018, and whose science philanthropy was driven by equal parts curiosity and a willingness to take on difficult questions, created the Allen Institute for Brain Science back in 2003, with a commitment of $100 million. Its first mission: to build the Allen Brain Atlas, a complete map of a mouse’s brain and how it functions, combining the disciplines of neuroscience and genomics. It was the first step in a broader goal to understand the mammalian brain, the better to help scientists researchers make important leaps in general knowledge and medical advances.

In the two decades since, the institute — operating as a nonprofit research center — has taken on a life of its own, building a track record of solid science, developing new streams of government and private funding, and playing an increasingly valuable role in the accelerating field of brain biology. The Allen Institute recently announced its latest milestone, one that would no doubt have gratified Paul Allen himself. The National Institutes of Health has awarded the research organization $173 million in grants to lead a global, multi-institutional effort to create a complete atlas of the cells of the human brain by their type and function, as well as macaque and marmoset brains that are also used in brain research.

While the initiative is a government-funded effort and highly collaborative, it’s notably building on Allen’s legacy of science funding, being literally rooted in the Allen Institute he created, but also carrying on the late donor’s dedication to big, collaborative projects that tap into multiple sectors and pools of expertise. The project’s broad buy-in, and generous funding from a government agency, are in one sense a testament to the philanthropy Allen did in his lifetime, including his commitment to a certain approach to science funding and a mission to better understand the workings of the brain.

That’s a scientific pursuit that likely has no end, but this project marks its latest ambitious chapter. The human brain is a galaxy of interconnected cells, an estimated 100 billion to 200 billion of them, with upward of a 100 trillion connections. And much of the way the brain functions remains unknown, including the causes of the various neurological and psychiatric disorders that doctors can’t cure or treat effectively. Scientists believe such fundamental understanding of the brain’s architecture, gene expression and function, which the new project is designed to provide, will be a valuable tool for researchers developing needed treatments for brain-related disorders. As with all of the Allen Institute’s work, the brain atlas information will be freely available to all researchers, everywhere.

The brain atlas project is being funded by the NIH, through its BRAIN Initiative Cell Atlas Network (BICAN). It’ll be led by Ed Lein, Ph.D., senior investigator at the Allen Institute for Brain Science, and Hongkui Zeng, Ph.D., executive vice president and director of the Allen Institute for Brain Science. The project includes subprojects by an international roster of researchers from 17 institutions in the U.S., Europe and Japan — with the Allen Institute managing and coordinating the effort.

What makes this project unique?

Why is this brain atlas project important — and why now? After all, scientists have been studying the brain for a long time. And in more recent decades, the development of functional MRI and other imaging technologies have enabled scientists and doctors the ability to view brain activity noninvasively in living animals and people. The answer is that new and ongoing advances in the study of cells and genes and gene expression are enabling scientists to develop a vastly more detailed understanding of how the brain and its cells work. And from that knowledge, they hope to also open the door to understanding what can go wrong to cause disease, and how such issues might be addressed therapeutically. In other words, the ability to create an atlas of the human brain simply wasn’t possible until recently.

“We’re actually going cell by cell, using the genes in individual cells to determine their identity,” said Luke Esposito, senior director, scientific operations for the brain science team at Allen Institute. “And that single-cell technology is actually quite new.” The ability to isolate the gene expression in a single cell is also a relatively new development, he added, and it’s central to the BICAN mission.

Scientists are calling the BICAN atlas the brain equivalent of the Human Genome Project, which sequenced nearly the entire human genome, (as well as several other non-human organisms used in research). But the BICAN brain atlas effort is also building atop of the foundation of knowledge created by the genome project. The Human Genome project created a complete list of all the genes, but not every gene is used, or expressed, by the cells. Some gene expressions are beneficial; some can lead to disease. The BICAN project seeks to find out which of the many available genes are being expressed by the brain cells. Once the initiative is completed, scientists will be able to see which genes are being expressed in any given cell and will then be able to know which genes are associated with healthy function or disease.

A different approach to science funding

What makes the Allen Institute a reasonable choice to manage such a massive, global project as BICAN? Much of it has to do with the track record and model to which the Allen Institutes committed since Paul Allen seeded that first initiative 20 years ago. Since then, the Allen Institute footprint and mission has expanded: It now includes the Allen Institute for Cell Science, the Paul G. Allen Frontiers Group, the Allen Institute for Immunology, and the Allen Institute for Neural Dynamics. The teams collaborate with researchers at institutions around the world on any number of biological and medical challenges, including the biology of addiction, neurodegenerative disease ALS, blindness and eye disease, epigenetics, cancer and immunology, and more.

The NIH chose the Allen institute for project, in part, explained Esposito, because of its demonstrated ability to successfully handle NIH grants going back several years — these include 2014 NIH awards to lead a consortium to study cell synapses, as well as another BRAIN initiative grant that had the institute collaborating with scientists at the California Institute of Technology and the Howard Hughes Medical Institute. But it also goes back to Paul Allen’s original vision for the institute: a scientific center that would combine elements of academic research labs, business, and publicly oriented government labs.

Compared to most labs, the 250 scientists of the Allen Institute are comparatively more interdisciplinary. “We have larger teams focused on a common goal, so we have cell biologists working next to molecular biologists working next to engineers working next to software engineers working next to data analysts,” said Esposito. And ultimately, baked into the Allen Institute is the goal to disseminate information and knowledge to scientists everywhere. 

From a funding perspective, this new brain atlas endeavor — and the human genome project before it — are also significant because they diverged from the way most science research is supported. Traditionally, research is funded on a hypothesis-driven basis: A scientist applies for a grant to study a specific question. The goal is to generate with that study some specific, concrete advance in knowledge for the field under study. The human genome and the brain atlas, however, aren’t discrete, hypothesis-driven efforts. They are massive, globally scaled, multi-institutional and interdisciplinary efforts to generate basic scientific knowledge.

It was not always clear if such big projects would be worth the investment. But the human genome project showed that these large projects could be of great value to biological and medical research; not only was it scientifically useful, but according to one study, the genome project generated an economic return of $800 billion on the initial $3.5 billion investment. Allen clearly recognized the potential of funding more science using this model.

It’s similarly hoped that the BICAN brain mapping project will be a launchpad for other scientists, including those seeking to develop treatments for brain and neurological conditions like Alzheimer’s and serious mental illnesses. For philanthropic funders of science philanthropy, it’s worth considering what role they might play in such emerging, nontraditional “big science” efforts to generate human knowledge — and how they might live on well beyond a donor’s lifetime.