Whitehead Institute builds scientific bridges to advance human health

Since its inception, Whitehead Institute has driven groundbreaking discoveries in the basic biology of health and disease while training the next generation of biomedical innovators. This past year, its mission of improving human health through foundational research gained new momentum when Whitehead Institute convened physicians and scientists at Boston Children’s Hospital with Whitehead Institute and Massachusetts Institute of Technology researchers, uniting the vibrant research ecosystems on either side of the Charles River.

The idea for this one-of-a-kind research matchmaking event emerged after Whitehead Institute Member Iain Cheeseman shared his lab’s growing interest in rare diseases with Kevin Churchwell, a member of the Whitehead Institute Board of Directors and the president and CEO of Boston Children’s Hospital.

For nearly two decades, the Cheeseman Lab has focused on uncovering the molecular basis of core cellular processes, including how cells grow, proliferate, divide, and function. Recently, Cheeseman began exploring how to apply these discoveries to understand rare diseases, specifically looking at the impact of translational variants—versions of proteins produced from the same gene that have altered functions. However, this shift in focus came with new hurdles.  

“It’s actually surprising how poorly annotated the rare disease space is, making it inaccessible to someone like me who is coming in from the outside,” he said.  

The conversation between Churchwell and Cheeseman sparked an effort to address these challenges. Recognizing the complementary strengths of Boston Children’s Hospital and Whitehead Institute, Churchwell connected Cheeseman with Nancy Andrews, who is the executive vice president and chief scientific officer of Boston Children’s Hospital, a Whitehead alum, and a member of the MIT Corporation.

With Whitehead Institute director Ruth Lehmann’s leadership, Cheeseman worked alongside Andrews and Michael Yaffe, the Director of Clinical Outreach at the Koch Institute and Director of the MIT Center for Precision Cancer Medicine, to organize an event that would help forge new collaborations across the Charles River in an array of scientific areas.

“I have a long history with Whitehead Institute and MIT and I see great potential in joining forces to tackle tough problems in biomedical science,” Andrews said. “This event was fun, exciting, and undoubtedly the start of many rich and productive interactions between our faculties.”

Bridging foundational science and clinical insights

On Nov. 1, 2024, 18 faculty members from Boston Children’s Hospital crossed the Charles River to Whitehead Institute, where they joined 18 scientists from Whitehead and across MIT, including the Koch Institute for Integrative Cancer Research and the Ragon Institute.

The group’s discussions spanned a wide range of topics: an overview of the science being conducted at Boston Children’s Hospital, Whitehead Institute, and MIT, as well as the importance of integrating fundamental and translational science with clinical data.

“The future of biomedical research is rapidly changing,” said Yaffe. “Translating basic science discoveries into clinical treatments—something which used to take a decade—can now happen in months or a few years.  Collaboration between the three institutes [Whitehead, MIT, and Boston Children’s Hospital] will allow their science to make a real difference in the treatment of childhood diseases.”

These discussions were followed by lightning talks, where scientists shared their research with colleagues and pinpointed potential areas for collaborative work across the institutions. The researchers then had the opportunity to engage in one-on-one conversations with scientists they had personally selected, as well as guided matches arranged by the organizers and wildcard discussions.

“Seeing the unexpected connections that have come out of these brief interactions has been so gratifying,” said Cheeseman. “They would’ve never been possible without people speaking directly or if they only had access to lab websites.”

Two weeks following the event, Cheeseman and the organizers received more than half a dozen proposals for “micro grants” intended to stimulate future cross-institution discussions. Lehmann views this as an exciting opportunity for Whitehead Institute researchers—who excel in curiosity-driven science—to gain deeper insights into unmet clinical needs, and hopes that this would be the first of many scientific bridges Whitehead Institute will build in the coming years. 

“As we aspire to make a real difference in human health, we need to be shaped by perspectives that center patients’ needs and experiences and have channels to bring that influence into our work,” Lehmann said. “I believe this framework for building collaborations through targeted interactions can profoundly impact our research.”

Indeed, in the last year, Whitehead Institute scientists and faculty from Boston Children’s Hospital have formed several partnerships. One particular project, from the Cheeseman Lab, sheds light on why patients may exhibit atypical forms of a disease. 

It’s long been thought that each gene codes for one protein. But recent work from the Cheeseman lab and others reveals a more complex reality:  most genes code for more than one protein. This flexibility is attributed to the fact that the cellular machinery tasked with reading DNA can begin working at one of multiple starting points in a sequence. Disease-causing mutations not only affect “known” proteins—they can also change alternate proteins. 

To study the clinical significance of this previously underappreciated biological process, the Cheeseman lab partnered with Mark Fleming, the pathologist-in-chief at Boston Children’s Hospital. The researchers were able to identify two case studies of patients who had a rare anemic disease (SIFD) caused by mutations to the TRNT1 gene. 

Typically, patients with this rare disease have a mutation that impairs both versions of the TRNT1 protein. But in this case, the patients had mutations that affected only one version of TRNT1, while leaving the other version intact. Importantly, both patients have atypical presentations of the disease—supporting the hypothesis that mutations affecting different versions of a protein can have different effects.

Now, building upon this work, researchers at the Cheeseman Lab are developing SwissIsoform—a tool to help clinicians detect mutations in specific protein variants that might otherwise be missed.

“There are many threats to human health, and there’s no magic bullet for them,” said Lehmann. “By coming together, having insightful conversations, and making unforeseen connections, we can inspire collaborations that generate fundamentally new knowledge and paradigm shifts. We have to start somewhere—and we’re starting today.”