Fishing for a major scientific revelation

Scientific invention, per William Kaelin, resembles fishing to a certain extent: You can learn how to bait a hook or cast a line, yet there exists an artistry in knowing where to search for the significant catch. 

Throughout numerous years, Kaelin meticulously unearthed a core physiological mechanism: how cells perceive and react to oxygen quantities. This endeavor resulted in innovative therapies for kidney cancer, and in 2019 garnered him a shared Nobel Prize in physiology or medicine, along with Peter Ratcliffe and Gregg Semenza. 

Kaelin articulates that the groundbreaking investigation, which also bears relevance for treating ailments such as anemia and heart attacks, was rooted in searching in the appropriate direction. 

“Much of science is about identifying connections and potentialities,” stated Kaelin, the Sidney Farber Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School. “I previously assumed it centered largely on mastering intricate techniques, but that is truly of lesser significance. What matters is selecting a worthwhile question to explore and recognizing a potential link that others might have overlooked.”

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Kaelin, born in 1957, reminisces about his childhood fishing with his father along the southern shore of Long Island. His parents nurtured his curiosity in sciences by providing him with chemistry kits, construction toys, and a microscope. “We were caught in the Cold War and the space race,” he observed. “Scientists and engineers were held in high regard.”

He was attracted to mathematics, where solutions have definitive answers, and computer science, where a straightforward command to the mainframe produces a lucid outcome. At Duke University, he pursued a pre-med curriculum and progressed to medical school. During his third year, while conducting research in a lab focused on blood circulation to tumors, he made the pivotal observation that would guide him toward his Nobel-winning journey. “I commenced reading about this peculiar illness known as von Hippel-Lindau disease,” he recounted.

Patients afflicted with von Hippel-Lindau disease, or VHL, develop tumors across various organs. Kaelin learned that these tumors somehow incite an overproduction of new blood vessels, a phenomenon termed angiogenesis.

Years later, as chief medical resident at Johns Hopkins, VHL reappeared in a distinct body of literature, noted as a cause for excessive red blood cell generation.

He recalls pondering: “Here are tumors associated with von Hippel-Lindau disease. Why are they mentioned in this context?”

He was gradually adopting the mindset of a scientist.

Upon establishing his own lab at Dana-Farber, Kaelin revisited the unresolved quandary. His working theory suggested that since increased angiogenesis and heightened red blood cell generation represent two mechanisms tissues employ to cope with low oxygen, perhaps the VHL gene was essential for cells to accurately sense oxygen levels. He reasoned that investigating the VHL gene could illuminate his understanding of angiogenesis, oxygen sensing, and even a prevalent cancer, specifically kidney cancer. This is due to the fact that even non-inherited kidney cancers commonly harbor VHL mutations at some phase in the patient’s life, in contrast to VHL disease, where a mutation is inherited.

There was significant focus on angiogenesis when Kaelin initiated his laboratory, especially due to pioneering efforts from Harvard professor Judah Folkman, who advocated the notion of combating cancers with angiogenesis inhibitors.

“If we were to utilize angiogenesis inhibitors, it was crucial to comprehend the molecular circuitry governing angiogenesis,” Kaelin stated. “It seemed evident that the VHL gene and its protein product must play a role in this, for if it’s defective, an overabundance of blood vessels occurs.”

While it was established that VHL gene mutations caused VHL disease, the mechanism remained unclear. Like most genes, the VHL gene harbors the blueprints for a protein, specifically the VHL protein. Kaelin’s investigation—largely supported by federal funding—validated the hypothesis that the VHL protein is vital for oxygen sensing. In collaboration with others in the domain, his work demonstrated that the protein binds to a protein named HIF-alpha and marks it for degradation, except when oxygen is scarce. In essence, HIF-alpha acts as the primary regulator of the cell’s response to diminished oxygen levels.

In healthy cells, VHL maintains HIF-alpha at levels. However, when the VHL gene is mutated, as occurs in VHL-associated tumors, HIF-1-alpha builds up, improperly igniting the excessive creation of red blood cells and irregular blood vessel development—the signature of VHL disease and numerous cancers.

The discovery elucidated many clinical traits of VHL-associated tumors, but it still raised the inquiry of how the VHL protein “discerns” the presence of oxygen, and therefore whether to target HIF-alpha for destruction. Kaelin and his fellow Nobel laureate Ratcliffe, working independently, demonstrated that a small chemical “flag” is appended to the HIF-alpha protein in the presence of oxygen, signaling the VHL protein to break down the HIF-alpha.

This mechanism is elegantly straightforward, a fundamental balancing act of elements within the body that remained obscure until the correct individual with the appropriate expertise posed the right inquiry. Kaelin expresses satisfaction that the research resulted in the creation of medicines that affect the oxygen-sensing process, yielding new therapies for cancer and for anemia brought on by kidney failure.

“Much of science is about identifying connections and being prepared to recognize a possibility,” he remarked. “Yet, to attain that insight, one must invest in educating individuals, training them, and exposing them to varied ways of thinking and to the work done before them.”

Kaelin is concerned that the reverence for science that propelled him on his journey may not sustain the next generation. While his laboratory thus far has not been impacted by the federal government’s withdrawal of approximately $2.2 billion in research funding to Harvard, he feels heartbroken witnessing its effect on his peers. (A U.S. District Court in September ruled the government acted unlawfully when it rescinded grants, and previously frozen research funds have begun to be released to researchers once again.)

“I was a result of bipartisan endorsement for science and engineering, not just concerning funding, but also in communication—again, honoring scientists and engineers as heroes,” he said. “This established a virtuous cycle, as we attracted talent and invested capital, enabling us to produce exceptional science. This was recognized as a hub for groundbreaking research, which meant we drew more scientific inquiry and additional funding. Presently, it appears we are undertaking actions that could undermine that.”