Whitehead Institute Members Iain Cheeseman and Siniša Hrvatin receive Bose Research Grants

Whitehead Institute Members Iain Cheeseman and Siniša Hrvatin have each received a Professor Amar G. Bose Research Grant, which supports ambitious MIT faculty research that may be too early, exploratory, or unconventional for traditional funding.

Cheeseman will use the grant to study the hidden proteome, a large and poorly understood set of protein variants produced by human cells. The work could help researchers better understand cancers and rare genetic diseases to which these hidden proteins contribute. It could also eventually improve how some disease-causing mutations are interpreted, leading to better diagnostics and care for people with these diseases.

Hrvatin will use the grant to lay groundwork for cryopreservation, the long-term freezing and storage of living cells and tissues. His lab will explore whether survival strategies found in freeze-tolerant animals, including tardigrades, can be adapted to help human cells better withstand freezing.

The grants are named for the late Amar G. Bose, an MIT professor, inventor, and founder of Bose Corporation, and reflect his belief that important discoveries often begin with questions whose outcomes are not yet clear.

“The Bose award represents a powerful opportunity to be bold in taking new directions,” says Cheeseman, who is also a professor of biology at MIT. “This unique framework, which is also very much in the spirit of Whitehead Institute, provides the ability to be more prospective than retrospective. It was really fun to think about where we are today, where we’re going, and how we hope to use this information to impact health and disease, as well as our core understanding of how cells work.”

For Hrvatin, who is also an assistant professor of biology at MIT, the grant offers a chance to pursue a project that grows out of his lab’s work on biological states of stasis, such as torpor and hibernation, while moving into a new area of research.

“Most funding rewards you for continuing what you’ve already proven you can do,” Hrvatin says. “The Bose Grant asks for the opposite—to pursue a bold idea that may run contrary to mainstream approaches. We believe that nature has evolved powerful solutions to the problem of cryopreservation. The Bose Grant gives us the freedom to explore whether human cells can be taught to use them.”

Uncovering the hidden proteome

Cheeseman’s project builds on a basic question raised by the Human Genome Project: now that scientists know the complete sequence of the human genome, how do they determine what cells actually make from those instructions?

For decades, researchers have often relied on a simplified model in which each gene provides instructions for one protein. That framework has supported enormous progress, but it leaves out a substantial part of what cells produce. Cells can begin reading genetic instructions at different starting points, generating alternate versions of a protein from the same gene. These variants can differ from the more familiar version by only a few amino acids, or by much larger sections, and those differences can change where the protein goes in the cell, what it interacts with, and what it does.

Together, these overlooked proteins make up the “hidden proteome.” 

“The rules that govern how our cells make proteins were established in the 1950s and ’60s,” Cheeseman says. “For most of the work that we do, we dramatically oversimplify things. Even though we know there can be different starting points, people have basically ignored that for most studies of health and disease.”

The hidden proteome was not the focus of Cheeseman’s lab when he began working at Whitehead Institute. The lab encountered it while studying cell division, after finding a protein variant that could not be explained by the standard rules for how a gene is read. That result led the lab to ask whether similar complexity existed elsewhere.

With the Bose grant, Cheeseman’s lab will specifically expand its work on the hidden proteome in cancer and rare genetic disease. In cancer, the lab will investigate whether tumor cells use alternate protein production to adapt, including as they become resistant to drugs or evade immune responses. The lab will also study whether mutations that currently have no known connection to disease may instead affect hidden protein variants that have not yet been incorporated into standard genetic interpretation.

“When you start thinking about how you want to understand what a cancer cell is doing, or how you want to identify rare disease mutations, if you don’t actually consider what’s being made from our genomes, you’re never going to get that right,” Cheeseman says.

Advancing cryopreservation

Hrvatin’s project also begins by questioning a long-standing assumption. Current cryopreservation methods still rely heavily on chemicals such as DMSO, which help protect cells during freezing but can also be toxic. These methods work well for some cell lines, but many of the cell types scientists and clinicians most want to store—including neurons, liver cells, pancreatic islets, tissues, and organs—remain difficult to freeze and revive reliably.

“The field has historically treated this mainly as a physics and chemistry problem: cool quickly and develop cryoprotectants that suppress ice formation,” Hrvatin says. “Those approaches are hitting diminishing returns. We are looking at the problem from a biologist’s perspective and asking: How do animals that survive being frozen, such as tardigrades, manage it, and can we give human cells the same tools?”

Hrvatin’s lab studies how animals enter and survive states in which biological activity slows dramatically. The Bose-funded project extends that work from cold tolerance to freezing itself. The lab will use genetic screens to search for genes and pathways that make human cells more resilient to freezing and to the chemicals used in cryopreservation. The researchers will also study tardigrade proteins that appear to help the animals survive freezing and explore whether related, human-compatible molecules could help protect human cells.

The long-term goal is to preserve sensitive human cells and tissues more safely and reliably. These advances could improve research that depends on banked cell samples and lay groundwork for better preservation of transplantable tissues and organs—which currently have only a short lifespan before they become unusable for transplant.

The two projects reflect Whitehead Institute’s commitment to research that follows unexpected biological questions into new, groundbreaking territory. With support from the Bose grants, Cheeseman and Hrvatin will continue to pursue fundamental questions that could open new paths toward understanding and treating disease.