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Aviv Regev, PhD

Applying Mathematical Order to the Human Cell

 

As computational and systems biologist Aviv Regev, PhD, maps the trillions of cells that comprise the human body for the Human Cell Atlas, she is driven always by her lifelong passion to discover the complex language that cells “speak” and how they make their decisions.

“This international collaboration is moving ahead rapidly, and in the next five years, we are targeting a ‘first draft’ of the atlas,” says Regev, a pioneer in single-cell genomics. “This comprehensive reference map of all human cells will serve as a basis for both understanding human health and diagnosing, monitoring, and treating disease.”

Regev is the founding co-chair of the Human Cell Atlas, which has as its goal charting the body’s some 37 trillion cells. It is an audacious project, and it is a significant factor in FASEB selecting Regev for its 2020 Excellence in Science Mid-Career Investigator Achievement Award.

Regev is Professor of Biology at the Massachusetts Institute of Technology (MIT), a Howard Hughes Medical Institute Investigator, and the Chair of the Faculty and Director of the Klarman Cell Observatory and Cell Circuits Program at the Broad Institute of MIT and Harvard. Her Organizing Committee Co-Chair is Sarah Teichmann of the Wellcome Trust Sanger Institute.

The Human Cell Atlas is destined to be groundbreaking. Regev herself has called it a “periodic table of our cells.” Already, the emerging map is transforming our understanding of both the fundamentals of biology and how cellular processes and tissue function can go askew in common disease and cancer, helping uncover disease mechanisms, devising drug screens, avoiding toxic side effects, and refining blood tests.

The first sparks of Regev’s passion for genetics were struck in her freshman year at Tel Aviv University. There, she was one of a small corps of students who were chosen to design and pursue their own course of study. The Interdisciplinary Program for Outstanding Students, which is now known as the Adi Lautman Interdisciplinary Program for Outstanding Students, emphasizes intellectual curiosity and excellence.

“Entering university, I did not yet want to narrow myself to a single area, so this fit me very well,” says Regev. “I took a genetics class my first semester and was fascinated by the mathematical challenge of finding order in the complex, interconnected networks of proteins and genes within each cell. This was very early, my first year as an undergraduate, and I am still fascinated by and in love with this problem.”

Geneticist and evolutionary biologist Eva Jablonka’s genetics class had a deep and lasting influence on Regev’s career. She first met Jablonka when she interviewed for the interdisciplinary program, and that prompted Regev to take her genetics class, which was taught in a style now known as the “inverted classroom.” Regev was drawn to the very conceptual nature of genetics, which also drew her to biology, a topic she had not studied before.

It was Jablonka’s innovative approach to science that also inspired a novel approach to mentorship that still deeply influences Regev today. “Eva, in thinking like a theorist, is the truest type of mentor. I had my own research problem to solve, which was not at all her problem. She mentored me through this, which is quite different from a mentor/advisee working on a biological question together – the more common form of advising, at least in biology. That was the biggest impact [of her mentorship].”

Regev says mentorship is important for every postdoc, graduate student, and undergraduate, especially for those who have come from groups that have been historically underrepresented in science. Diversity of experience, background, and thought is essential for creativity and open-minded exploration at the heart of scientific research, says Regev.

“Mentorship is a special part of every scientific endeavor – a mentor does not simply teach known knowledge – because science is about discovering and understanding what is not yet known,” says Regev. “Because learning to become a research scientist is about learning how to look at the abyss of the lack of knowledge and figuring out how to navigate it into knowledge. Thus, a mentor plays a critical role in chaperoning and guiding an individual, not only through advice and example but often through simple listening.”

In 2002, finishing up her doctoral work, Regev skipped another traditional career step when she was able to establish her own independent group as a Bauer Fellow at Harvard’s Bauer Center Genomics Research – without first training as a postdoc. It was a remarkable opportunity. In her lab, she and her colleagues, using modeling cell circuitry, developed algorithms and computational tools to recover cellular modules, their regulation, function, and evolution.

With her reputation for hard work and independence, Regev has always taken her own research path. In 2006, she joined MIT and the Broad Institute as a faculty member. From this platform, she gained a far deeper understanding of cells, chiefly those of the immune system. She not only continued to develop her cell circuitry modeling algorithms but embarked on matching them with new experimental approaches to generate data that is better suited to learning such models and systematically testing them.

Regev sees great prospects in the intersection of biology and computer science. Until recently, biology and disease have appeared as too big to efficiently wrangle. With so many genetic variants, disease-associated loci, cell types, and their combinations, scientists have chosen to be very selective in how to approach disease, looking at specific genes and cells or narrowly focused experiments. No longer.

“We are at the cusp of an inflection point, where this ‘bigness’ becomes a remarkable strength,” says Regev. “We found ways now – including single cell genomics – to make our data and experiments so big that we can use the power of computational methods not just to analyze data, but to do biology in a new way,” she adds, noting that cell circuitry explorations allow scientists to learn how variants lead to function or dysfunction in cells, tissues, and organs.

Regev says another key factor facing science today is ensuring ethics, diversity, and equity are paramount in the scientific enterprise. These are some of the core values for the Human Cell Atlas, and comprises securing genetically and geographically diverse data for study and safeguarding that the scientific community itself is diverse, open, and equitable.

Regev’s history of conceptual thinking while also getting things accomplished accounts for many of her awards. She is a recipient of the National Institute of Health’s Director’s Pioneer Award, a Sloan fellowship from the Sloan Foundation, the Overton Prize from the International Society for Computational Biology (ISCB), the Earl and Thressa Stadtman Scholar Award from the American Society of Biochemistry and Molecular Biology, the ISCB’s Innovator Award, and the Paul Marks Prize, and she is an elected member of the National Academy of Sciences.

The future looks to be equally as bright. Beyond the Human Cell Atlas, her work is proceeding in three areas – deciphering genetic circuits in cells, discovering how cells come together in tissue to maintain homeostasis, and devising a roadmap of human disease from the level of genes to that of modules in cells and in tissues.

“In all of these endeavors we are propelled by ‘design for inference,’ which is our paradigm to devise new experiments driven by our abilities to learn the structure and function of biology from data,” says Regev. “It’s an exciting road ahead.”

(Photo courtesy of Casey Atkins Photography)

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