Profile of Vishva M. Dixit

Vishva Dixit and his team work to reveal foundational insights concerning cell death, inflammation, and the innate immune system that further the knowledge of disease-related cellular signaling and inspire therapeutic development. Dixit, Senior Fellow and Vice President of Early Discovery Research, Physiological Chemistry at Genentech, was elected to the National Academy of Sciences (NAS) in 2013 and in 2022 received the Vilcek Prize in Biomedical Science, the Dr. A.H. Heineken Prize for Medicine, and the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology. He says, “I always wanted to discover something fundamental—to reach a level of immortality, because, if you discover something fundamental, it’s going to last as long as mankind lasts; and if you discover something that’s fundamental and it helps people—that’s even more important (1).”

Portrait of Vishva Dixit. Image credit: The Royal Society.

Childhood in Post-Colonial Kenya

Born in 1956 in Kenya, East Africa, Dixit was raised in Kericho, where his physician parents Raj and Lila ran a clinic. Originally from India, the couple was sent to Kenya as part of the Colonial Service that administered Britain’s overseas territories. Lila was one of the first women doctors in the region whose population included members of the Kalenjin and Maasai tribes. The work was challenging, the physicians developed close relationships with locals, sometimes dining with them, along with their daughter and two sons.

Following Kenya’s independence in 1963, Dixit was one of the first youths of color to attend a European-run school in the country. “There was tension, but it dissipated over time”, he says. Dixit recalls reading history and Time Life science books. “As a 10-year-old, I was fascinated by the prospect that one could still be an explorer—a discoverer of new worlds using the tools of science”, he says (2).

While Dixit initially envisioned becoming a research chemist or physicist, his parents steered their children toward the medical field, which they viewed as rewarding in all respects. When Raj died of cancer decades later in a local hospital, numerous former patients, many living in poverty, donated money to pay his bill before Dixit even saw it.

Mentors at Medical School, Residency

Dixit in 1975 entered the University of Nairobi, where he earned his MD in 1981 after spending an internship year at Kenyatta National Hospital (KNH). Physiology professor Edward Hettiaratchi—who memorably taught that the foundations of biology rest on naturalist Charles Darwin’s evolutionary theory and biologist Claude Bernard’s hypothesis that all systems are engineered to maintain homeostasis—was his mentor (3). Dixit coauthored his first two peer-reviewed papers with Hettiaratchi: the first on hyperlipidemia (4) and the second on the use of antithyroid therapy in treating neoplastic conditions (5). Dixit’s third paper, for which he was the sole author, addressed the cause of depression in chronic scurvy (6). Scurvy, largely eliminated in Western countries, was among the diseases treated during his internship in KNH’s tropical medicine unit run by Philip Rees. With Rees, Dixit saw patients suffering from a mysterious wasting illness later believed to have been HIV/AIDS. Due to a lack of funding, patients often shared beds. Troubled by the government’s response to medical needs, Dixit decided to focus on research.

His decision was influenced by his first visit to the United States in 1977, when he traveled to see his brother Rajiv, who was then in residency in the internal medicine program at Washington University (WU) in St. Louis. Rajiv took him on rounds, where he met young leukemia patients given months to live. “That impressed on me that research in medicine is just as important as research in the hard sciences”, Dixit says. He also desired to live in the United States, attracted by its opportunities and freedom. Rajiv was instrumental in securing a residency for him from 1981 to 1986 in WU’s Department of Laboratory Medicine at Barnes-Jewish Hospital.

Dixit also served as a postdoctoral fellow and research associate from 1982 to 1986 in the WU School of Medicine Department of Biological Chemistry. There he worked as an apprentice for biochemist William Frazier and conducted research on the role of thrombospondins, which modulate blood cell adhesion and affect tumor progression. Dixit coauthored several papers on glycoproteins, including one detailing a thrombospondin amino acid sequence (7). This work and Frazier’s support led to numerous offers for assistant professorships. In 1986, Dixit accepted a position in the University of Michigan Medical School Department of Pathology, where he became an associate professor in 1991 and a full professor in 1995.

Identification of a Key Apoptosis Mediator

Although Dixit’s work on thrombospondin was well funded, he grew frustrated by its incremental advances, and he desired change. He collaborated with Rory Marks, a Ward postdoc, on a study concerning the effect of tumor necrosis factor (TNF) on endothelial cells (8). Researching TNF, Dixit learned that the process of noninflammatory programmed cell death known as apoptosis could be induced by TNF in cancer cells. “Hurriedly, I wrote to Genentech to obtain recombinant TNF and they supplied me with a veritable ton of material”, Dixit shared in a 2010 article for Nature Cell Biology (9). He and MD/PhD student Muneesh Tewari began a series of experiments on the receptors for TNF and a related receptor termed Fas.

The Massachusetts Institute of Technology lab of molecular biologist Robert Horvitz during this time identified the first known cell death gene, ced3, in Caenorhabditis elegans. The gene encoded a protein homologous to the mammalian cysteine protease ICE, which Dixit and Tewari suspected was in the death receptor pathway. Dixit and Tewari transfected an inhibitor of ICE, crmA, into cancer cells to see if it would block TNF and Fas-induced apoptosis. In a 2019 interview for Cell Death & Differentiation, Dixit recalled the dramatic moment when he and Tewari realized crmA had blocked cell death (10).

The observation set the stage for a series of classic, highly cited papers published in 1995 concerning apoptosis. The first, reporting the crmA inhibition of apoptosis (11), was followed by a groundbreaking paper on the identification of the mammalian counterpart of ced3, which Dixit and colleagues named “Yama” after the Hindu god of death but is now called caspase-3 (12).The discovery not only helped connect Horvitz’s finding to human developmental biology, but also established a focal point for identifying other death pathway components, such as additional caspases and the death domain-containing adapter protein FADD. This protein, also termed MORT1, is the primary conduit for the flow of death signals from death receptors to the cell’s interior (13).

A New Cellular Signaling Mechanism

In 1996 Dixit unveiled another molecular component of the death signaling pathway: FLICE/caspase-8, determined to be a member of the ICE/ced-3 family and homologous to FADD (14). Using a new analytical tool, nano-electrospray tandem mass spectrometry, he and his colleagues identified a novel cellular signaling mechanism whereby receptors recruit and activate FLICE. The findings were later incorporated into what Dixit termed “the induced proximity model”, holding that inactive protein precursors of caspases can autoprocess to active forms.

Genentech asked Dixit in 1997 if he would be interested in serving as the company’s director of molecular oncology. Impressed by Genentech’s postdoctoral program rooted in academia, Dixit later accepted the offer. He became the vice president of molecular oncology in 2003 before assuming his present role in 2005.

Genentech opened doors for collaboration, such as with fellow department member Avi Ashkenazi, a pioneer in death receptor signaling research. Shortly after starting his lab at Genentech, Dixit coauthored two seminal reviews concerning signaling and modulation in apoptosis (15). His group in 1997 was among the first to show that the death domain-containing molecule MyD88 is a key adaptor in interleukin-1 (proinflammatory cytokine) signaling (16). Dixit and colleagues also identified two ancient families of caspase-related proteins, paracaspases and metacaspases, with the former found to play a central role in MALT (mucosa-associated lymphoid tissue) lymphoma (17).

Discovery of the Noncanonical Inflammasome Pathway

Another Dixit lab research focus concerns inflammasomes, innate immune system receptor/sensor proteins that recruit and activate proinflammatory caspases in response to triggers. His team established that NOD-like (nucleotide-binding oligomerization domain) receptors with a death fold structural motif are critical components of the inflammasome pathway, which the team theorized is coupled with the cell death pathway (18). The researchers additionally found that the adaptor cryopyrin is essential for inflammasome assembly (19).

A breakthrough occurred in 2011 when Dixit and his team discovered the caspase-11 driven noncanonical inflammasome pathway (20). Activated by the bacterial endotoxin intracellular lipopolysaccharide (LPS), it was found to be surprisingly independent of toll-like receptor 4, the only known sensor for LPS. Engagement of the pathway was shown to mediate pyroptosis, a form of necrotic programmed cell death, and subsequent endotoxic shock.

Marking yet another advance, the Dixit group showed that proinflammatory caspases mediate necrotic death by cleaving a single substrate, the protein Gasdermin D (21). As necrosis plays a fundamental role in numerous diseases, Gasdermin D is now a target for pharmacological approaches to inhibit it. The protease OTULIN, revealed by Dixit and colleagues to limit cell death and inflammation via ubiquitin (regulatory protein) modification (22), is another potential therapeutic target. Still others are certain receptor-interacting protein kinases, whose roles have been elucidated by Dixit’s team (23–26) and NEDD4-binding protein 1, which the researchers identified as a potent suppressor of cytokine responses (27). These and many other inhibitors identified in Dixit-led research are either currently in preclinical or clinical trials.

Extended Family

Many Dixit team members have worked with him for decades. “I think of them as an extended family”, he says. Genentech principal research associate Karen O'Rourke has worked with him for 39 years, and scientists Kim Newton and Nobuhiko Kayagaki have each been in his team for 21 years. Dixit has mentored approximately 60 postdocs.

Dixit’s family mirrors many of his passions: his son Naveen is an immigration attorney, helping individuals who dream of living and working in the United States; his daughter Nisha volunteers for the Cheetah Conservation Fund (CCF), with a mission to save the wild cheetahs of Africa; and his wife Manjul, a retired pediatrician, supports the CCF with her husband, along with other nature conservation efforts.

In addition to never forgetting Africa’s natural wonders, Dixit still thinks about the patients whom he met there, including those who perished from sepsis, a condition that kills 11 million people around the globe each year (28). Reducing this death toll is now his primary objective. Dixit says, “If we can even scratch the surface in providing effective pharmacological therapies for sepsis, then in my mind’s eye, I would have accomplished one of my missions. I would have genuinely gone from bench to bedside.”