William Kaelin Jr.

William G. Kaelin Jr.
Born	23 11, 1957
Birthplace	New York City, New York, U.S.
Nationality	American
Occupation	Physician-scientist, professor
Employer	Dana–Farber Cancer Institute, Harvard University, Howard Hughes Medical Institute
Known for	Discovery of how cells sense and adapt to oxygen availability; research on tumor suppressor proteins
Education	Duke University (BS, MD)
Spouse(s)	Carolyn Scerbo
Awards	Albert Lasker Award for Basic Medical Research (2016) Nobel Prize in Physiology or Medicine (2019)
Website	[Kaelin Lab at Dana–Farber Official site]

William George Kaelin Jr. (born November 23, 1957) is an American physician-scientist and Nobel laureate whose research transformed the scientific understanding of how cells sense and respond to changes in oxygen levels. A professor of medicine at Harvard Medical School and an investigator at the Dana–Farber Cancer Institute and the Howard Hughes Medical Institute, Kaelin shared the 2019 Nobel Prize in Physiology or Medicine with Peter J. Ratcliffe and Gregg L. Semenza for their collective discoveries concerning the molecular mechanisms by which cells adapt to oxygen availability. His laboratory at Dana–Farber studies the function of tumor suppressor proteins, and his foundational work on the von Hippel–Lindau (VHL) tumor suppressor gene provided critical insights into the oxygen-sensing pathway that has broad implications for the understanding and treatment of cancer, anemia, and other diseases. Kaelin's path from a self-described mediocre undergraduate research student to a Nobel Prize winner is a story marked by persistence, intellectual curiosity, and the pursuit of fundamental biological questions with profound medical relevance.

Early Life

William George Kaelin Jr. was born on November 23, 1957, in New York City, New York. Details regarding his parents and upbringing in New York are limited in publicly available sources, though Kaelin has spoken in various interviews about his early interest in science and mathematics. In a 2018 autobiographical account, Kaelin recalled his early experiences with laboratory research during his undergraduate years, noting that he received a C+ grade for his first research laboratory course in college — an inauspicious beginning for a future Nobel laureate. A professor's written observation at the time suggested that Kaelin's talents might lie elsewhere. Despite this early setback, Kaelin persisted in his scientific education and ultimately pursued a career that combined clinical medicine with laboratory research.

Education

Kaelin attended Duke University in Durham, North Carolina, where he earned both his Bachelor of Science degree and his Doctor of Medicine (MD) degree. His undergraduate experience, including the difficult C+ in his first research laboratory, did not diminish his interest in pursuing scientific inquiry alongside medicine. After completing his medical degree at Duke, Kaelin went on to complete his clinical training in internal medicine and subsequently pursued a fellowship in medical oncology, a path that would ultimately lead him to the intersection of cancer biology and molecular research.

Career

Clinical Training and Early Research

After receiving his MD from Duke University, Kaelin completed his residency training in internal medicine. He then pursued a fellowship in medical oncology, during which time he became increasingly drawn to laboratory-based research focused on understanding the molecular underpinnings of cancer. His clinical training in oncology provided him with firsthand exposure to the devastating effects of cancer and motivated his desire to uncover the fundamental mechanisms driving tumor formation and progression.

Kaelin joined the Dana–Farber Cancer Institute and Harvard Medical School, where he established his own laboratory and began his independent research career. He was appointed to the faculty at Harvard Medical School, eventually rising to the rank of Sidney Farber Professor of Medicine. He also became an investigator of the Howard Hughes Medical Institute (HHMI), one of the most prestigious designations for biomedical researchers in the United States, which provided long-term funding to support his laboratory's work.

Research on Tumor Suppressor Proteins and VHL

The central focus of Kaelin's research career has been the study of tumor suppressor proteins — proteins that normally function to prevent cells from growing and dividing in an uncontrolled manner. When tumor suppressor genes are inactivated through mutations, the loss of their protective function can contribute to cancer development. Kaelin's laboratory at Dana–Farber has been particularly focused on understanding how tumor suppressor proteins function at the molecular level and how their loss leads to oncogenesis.

Kaelin's most consequential scientific contribution centered on the von Hippel–Lindau (VHL) tumor suppressor gene. VHL disease is a hereditary condition caused by mutations in the VHL gene, which predisposes affected individuals to the development of tumors in multiple organs, including highly vascularized tumors such as hemangioblastomas and renal cell carcinoma. Patients with VHL disease also frequently develop tumors that overproduce vascular endothelial growth factor (VEGF) and other factors normally induced by low oxygen conditions, a finding that pointed toward a connection between VHL and the cellular oxygen-sensing pathway.

Kaelin's laboratory made the critical discovery that the VHL protein plays a central role in the cellular oxygen-sensing machinery. His work demonstrated that the VHL protein is part of an ubiquitin ligase complex that targets the transcription factor hypoxia-inducible factor (HIF) for degradation under normal oxygen conditions. When oxygen levels are adequate, specific proline residues on the HIF-α subunit are hydroxylated by prolyl hydroxylase enzymes. This hydroxylation serves as a molecular signal that enables the VHL protein to recognize and bind HIF-α, leading to its ubiquitination and subsequent destruction by the proteasome. Under low-oxygen (hypoxic) conditions, the prolyl hydroxylases cannot function effectively, HIF-α escapes VHL-mediated degradation, and it accumulates in the cell, where it activates the transcription of genes involved in adaptation to hypoxia — including genes encoding erythropoietin (which stimulates red blood cell production), VEGF (which promotes blood vessel formation), and metabolic enzymes.

This mechanism explained why VHL mutations in cancer lead to the constitutive activation of hypoxia-response genes even in the presence of normal oxygen levels — because without functional VHL protein, HIF-α cannot be degraded and continuously drives the expression of pro-angiogenic and pro-growth factors. Kaelin's elucidation of this pathway was complementary to the independent discoveries of Gregg L. Semenza, who had identified the HIF transcription factor and characterized its role in the oxygen-sensing response, and Peter J. Ratcliffe, who had studied the oxygen-dependent regulation of erythropoietin gene expression and the role of HIF in diverse cell types.

Together, the work of Kaelin, Ratcliffe, and Semenza revealed a fundamental mechanism of cellular oxygen sensing that operates across virtually all animal cells. The Nobel Committee described their collective discovery as one that "established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function" and noted that this oxygen-sensing machinery "has already stimulated the development of promising new strategies to fight anemia, cancer and many other diseases."

Translational Impact

The discoveries made by Kaelin and his co-laureates have had significant translational consequences for medicine. The understanding of the HIF-VHL pathway led directly to the development of a new class of drugs known as HIF prolyl-hydroxylase inhibitors, which stabilize HIF and stimulate erythropoietin production. These drugs have been developed for the treatment of anemia, particularly anemia associated with chronic kidney disease. Additionally, the insights into how VHL loss drives tumor angiogenesis contributed to the development of anti-angiogenic therapies for renal cell carcinoma and other cancers.

Kaelin's work has also informed the broader field of cancer biology by demonstrating how the loss of a single tumor suppressor can deregulate an entire physiological pathway, providing a molecular rationale for targeted therapeutic approaches. His laboratory continues to investigate the functions of tumor suppressor proteins and the mechanisms by which their inactivation contributes to cancer, with ongoing research exploring new therapeutic strategies based on these fundamental insights.

Academic Service and Engagement

In addition to his laboratory research, Kaelin has served in various advisory and leadership roles within the cancer research community. He has been a fellow of the American Association for Cancer Research (AACR), which recognized his contributions to the field. In 2024, he was invited to deliver the commencement address at Baylor College of Medicine, reflecting his standing as a prominent figure in the biomedical sciences.

Personal Life

Kaelin married Carolyn Kaelin, a breast cancer surgeon at Brigham and Women's Hospital and Dana–Farber Cancer Institute. Carolyn Kaelin was herself diagnosed with breast cancer and later with a brain tumor. She died on August 5, 2015, at the age of 54. When the Nobel Prize was announced in October 2019, Kaelin expressed that he wished his late wife could have been present to share in the recognition. He later married Carolyn Scerbo.

Kaelin has spoken publicly about the impact of his wife's illness and death on his perspective as both a cancer researcher and a person affected by the disease, underscoring the personal dimension of his decades-long commitment to understanding and combating cancer.

Recognition

Kaelin's contributions to biomedical science have been recognized with numerous awards and honors from institutions around the world.

In 2014, Kaelin was awarded the Wiley Prize in Biomedical Sciences by the Ludwig Institute for Cancer Research, recognizing his contributions to understanding the molecular mechanisms of oxygen sensing.

In 2016, Kaelin received the Albert Lasker Award for Basic Medical Research, often considered the most prestigious American biomedical research prize and sometimes regarded as a precursor to the Nobel Prize. He shared the Lasker Award with Ratcliffe and Semenza for their work on the oxygen-sensing pathway. That same year, he received the AACR Princess Takamatsu Award.

Kaelin has also been awarded the Canada Gairdner International Award, another major international prize in biomedical science. He has received the Massry Prize from the Keck School of Medicine of USC. He was further honored with a prize from the Institut de France.

On October 7, 2019, Kaelin was awarded the Nobel Prize in Physiology or Medicine, jointly with Peter J. Ratcliffe and Gregg L. Semenza, "for their discoveries of how cells sense and adapt to oxygen availability." The Nobel Assembly at the Karolinska Institutet cited the trio's collective work in establishing the molecular mechanisms underlying cellular oxygen sensing as one of the most fundamental adaptive processes in biology.

Kaelin is a member of the National Academy of Medicine.

In 2024, Kaelin was recognized with the Stanley P. Reimann Honor Award from Fox Chase Cancer Center in Philadelphia, further acknowledging his contributions to cancer research.

Legacy

Kaelin's elucidation of the VHL–HIF oxygen-sensing pathway represents one of the most significant advances in the understanding of cellular physiology in the late 20th and early 21st centuries. The pathway he helped to characterize is now recognized as a fundamental mechanism that governs how virtually all multicellular organisms detect and respond to changes in oxygen concentration — a process essential to embryonic development, adaptation to high altitudes, immune function, wound healing, and metabolic regulation.

The therapeutic implications of Kaelin's work extend across multiple areas of medicine. The development of HIF prolyl-hydroxylase inhibitors as treatments for anemia represents a direct clinical translation of the basic science discoveries made by Kaelin and his colleagues. In oncology, the understanding of how VHL loss drives the HIF-mediated overproduction of VEGF and other pro-angiogenic factors has informed the design of targeted therapies for kidney cancer and contributed to the broader development of anti-angiogenic strategies in cancer treatment.

Beyond the specific clinical applications, Kaelin's career has served as an illustration of the value of basic science research driven by curiosity about fundamental biological mechanisms. His trajectory from a student who received a C+ in his first laboratory course to a Nobel laureate has been cited as an example of the unpredictable and nonlinear path that scientific discovery often follows. His advocacy for rigorous, reproducible science and his emphasis on understanding the mechanistic basis of disease have influenced a generation of physician-scientists.

As the Sidney Farber Professor of Medicine at Harvard Medical School and a continuing investigator at Dana–Farber and HHMI, Kaelin remains an active researcher, training the next generation of scientists in his laboratory and pursuing new questions about the biology of tumor suppression and cellular adaptation.