Vishva Dixit

Vishva Mitra Dixit is a Kenyan-born physician of Indian origin who is the current Vice President of Discovery Research at Genentech. He is best known for leading one of the first teams that elucidated the role of caspases in apoptosis and inflammasome pathways, and for uncovering the signaling pathways of death receptors of the TNF receptor superfamily. He is a leading international authority on the science of cancer and related therapies, and one of the most highly cited scientists in the world. His research on apoptosis is now commonly found in introductory biomedical textbooks.

Dixit has been a member of the National Academy of Sciences since 2013.

Early life and education

Vishva Dixit was born in Kisii, Kenya in 1956. His parents were both physicians, working for the British colonial authorities. The family moved to Kericho, Kenya, where Dixit attended primary school. After the end of colonial rule, he transferred to the new desegregated “European schools”.

Dixit was fascinated by science from an early age, and his parents encouraged him to pursue a career in medicine. He studied the sciences in university, and he graduated from medical school in 1980 with an MD from the University of Nairobi.

Once his medical degree became recognized in the United States, Dixit secured a residency in the Department of Pathology at Washington University in St. Louis. He became an American citizen in 1987.

Academic career and Genentech

During medical school Dixit was published by journals including Developmental Medicine and Child Neurology and The Lancet.

Following medical school, Dixit began work at the Washington University School of Medicine where between 1981 and 1986 he completed a residency in the Department of Pathology. He specialized in hemostasis and thrombosis during his last year of clinical training. Dixit told Nature that he decided to pursue pathology because he has always been fascinated by death and because he wanted to “do something in science that would influence the lives of people.”

From 1986 to 1997 he was associated with the University of Michigan Medical School, Ann Arbor, where he rose through the ranks from assistant professor to associate and then full professor.

In 1997 Dixit became the Director of Molecular Oncology at Genentech, a company known for focusing on high-quality research in an informal atmosphere and viewed as a cross between academia and industry.

In 2007 he then took over the leadership of the Department of Physiological Chemistry at the company. He later became the Vice President of Discovery Research, while maintaining responsibility for the Department of Physiological Chemistry. He also oversees Genentech’s postdoctoral program.

Influential research discoveries

Dixit has contributed to major discoveries that are highly cited and appear in introductory biomedical textbooks. In 1996, Dixit was the second most highly cited scientist in the world. The discovery in 1997 of MyD88 (25) as a central conduit for signals emanating from the interleukin-1 receptor was recognized in later years; in 2013, it was mentioned as a “Pillars in Immunology” contribution by the Journal of Immunology.

Early research on thrompospondin

While at the University of Michigan, he received funding from the National Institutes of Health to support research into thrombospondin, a protein in the extracellular matrix.

Caspases and apoptosis

In 1991, Dixit was inspired by an article in Scientific American to study how tumor necrosis factors, which are responsible for regulation of immune cells, are related to cell death.

Dixit switched research tracks and began investigating cell death mechanisms. His lab became famous for elucidating, in a series of landmark papers, what happens during cell death. The research identified each component of the cell-death pathway and explained how they were all connected.

In 1996 he published research that showed the first indication of a mammalian deathase. The work on death receptor-induced apoptosis was notable as prior to that time cell surface receptors were thought to signal by functioning as ion channels or by altering intracellular phosphorylation. Death receptors, however, are signaled by a new mechanism, namely the recruitment and activation of a death protease. In other words, the second messenger emanating from a death receptor was a protease.

Together with Guy Salvesen’s group at the Burnham Institute, Dixit’s group proposed the model of proximity-induced autoactivation to explain how the first proteolytic signal is generated after clustering of the inactive caspase precursors at death receptors.

RIP kinases, NF-κB signaling and necroptosis

At Genentech, Dixit formed a team with the goal of working to unravel the complex interplay between cell death and inflammation at the molecular level. During his work with the company, he has worked on regulatory components of the innate immune system. In 1999, his team at Genentech discovered RIPK2 and RIPK3, which later were shown to be key mediators of NF-κB signaling and necroptosis, respectively.

His work has included focusing on the pro-inflammatory NF-κB pathway and he contributed to the discovery of a core complex composed of three proteins: CARD11, BCL10 and MALT1/paracaspase that enabled antigen receptors to activate the canonical NF-κB pathway. Furthermore, Dixit discovered the protease activity of MALT1, which has a role in T cell activation and MALT lympoma’s, and they described the family of metacaspase proteases in plants in a paper published in 2000.

In a series of landmark papers between 2016 and 2020, Dixit and his colleagues at Genentech also worked out the complex molecular mechanisms that regulate activity of caspase-8, OTULIN, RIPK1, RIPK3 and other proteins that modulate inflammation, apoptosis and necroptosis signaling by death receptor and TLRs.

Inflammasomes and pyroptosis

Dixit was among the first scientists to demonstrate that other immune caspases besides death caspases are incorporated into the activating scaffold called the inflammasome. In particular, caspase-1 activates cytokines of the interleukin-1 family, which are immune effectors that initiate an immune attack.

In 2004 and 2006, Dixit provided unequivocal genetic evidence by identifying the NOD-like receptors NLRP3 and NLRC4 as components of inflammasomes, which are responsible for caspase-1 activation. The research showed that inflammasomes distinguish between pathogenic attacks, such as differentiating between types of bacteria, through the use of different adaptors.  More specifically, the intracellular protein NLRC4 was identified as a sensor for Salmonella that triggered assembly of an inflammasome complex. NLRP3 and the inflammasome adaptor ASC, on the other hand, were found to be required for activation of the inflammasome by diverse pathogenic agents, including microbial toxins, and Gram-positive bacteria such as Staphylococcus aureus or Listeria monocytogenes.

In 2009, his group at Genentech followed up on these findings with the discovery of the first small molecule inhibitors of the NLRP3 inflammasome. Derived analogs of this sulfunonylurea class of compounds are currently in clinical development for inflammatory and neurodegenerative diseases.

Dixit’s team discovered and described the non-canonical inflammasome pathway, publishing three separate papers in 2011, 2013, and 2015.

The 2011 paper showed that mice lacking the gene that encodes caspase-1 also carry a mutation in a neighboring caspase gene, caspase-11 or caspase-5 in humans, which is responsible for some of the effects that had been attributed to caspase-1, including sensitivity to sepsis.

The 2013 paper clarified the role of Toll-like receptor 4 and caspase-11 in inducing innate immune responses to Lipopolysaccharide. The research showed that recognition of intracellular LPS by innate immune cells leads to pyroptosis and activation of the NLRP3 inflammasome. They showed that these mechanisms do not depend on TLR4, but were mediated by caspase-11, which was significant because for years it was assumed that TLR4 was solely responsible for cellular responses induced by LPS.

In the 2015 paper, they used mice subjected to random mutation to find mediators of caspase-11-dependent non-canonical inflammasome signaling. This led to the discovery that caspase-mediated cleavage of the protein GSDMD creates an amino-terminal fragment that induces pyroptosis. The advances contributed to firmly establishing the sequence of events leading from inflammasome activation to pyroptosis, DAMP release and lethal septic shock.

Using a similar research strategy, in 2020 they reported NINJ1 as a mediator of plasma membrane rupture and DAMP release from pyroptotic cells. They showed that NINJ1 also mediates secondary necrosis of apoptotic cells, which was significant because it settles a decades-long discussion whether secondary necrosis constitutes a biochemically regulated process.

Ubiquitin signaling (A20, LUBAC, OTULIN)

In 1990 Dixit’s lab at the University of Michigan discovered tumor necrosis factor (TNF)-inducible genes in endothelial cells, including A20/TNFAIP3. They found that the pro-inflammatory cytokine TNF efficiently converted the anticoagulant surface of endothelium to one that supported coagulation, allowing blood to clot readily, which is an important part of vascular health. In later years, A20/TNFAIP3 would achieve prominence as a modulator of inflammation.

In 2004, Dixit’s group at Genentech discovered “ubiquitin editing” as a complex form of cellular signal transduction that deploys post-translational attachment of ubiquitin to proteins, in various linkage configurations, to regulate protein function and stability.

In 2018, his group showed that OTULIN regulates cell death and inflammation by removing linear ubiquitin chains from LUBAC, which promotes its activity.

Board work and fellowships

Dixit is a member of the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and a Foreign Member, European Molecular Biology Organization. He has also served on the boards of the Bill & Melinda Gates Foundation, Howard Hughes Medical Institute, and the Keystone Symposia on Cellular and Molecular Biology.

In 2016, Dixit received The Gutenberg Research Award at Gutenberg Research Award Seminar in Munz, Germany. He also received the G.H.A. Clowes Memorial Award from the American Association for Cancer Research and the Dawson Prize in Genetics from Trinity College Dublin.

In 2017, Dixit participated in The Harvey Lecture Series, held by the Harvey Society at The Rockefeller University in New York City. In 2017, he was elected Fellow of The American Association for Cancer Research.

In 2018, Dixit received the Cell Death & Differentiation (CDD) Jurg Tschopp Prize at Clare College in Cambridge, United Kingdom.

Citations and media coverage

Dixit is one of the world’s most cited scientists, with some of his publications garnering more than 2,000 citations.

Dixit’s work on apoptosis is now commonly found in introductory textbooks for both biology and medicine. Upon his induction into the National Academy of Sciences, the citation noted that “he is known for the breakthrough discovery that a cysteine protease (caspase) is a component of the death receptor-induced apoptotic pathway - a finding that allowed his laboratory and others to then elucidate the entire 'death cascade.’”

Dixit’s work has also received attention from books and media outlets. In 2008, he was interviewed in Nature magazine about his contributions to science and motivations for research, including his decision to move to Genentech. He was also interviewed for “The Cancer Solution,” a 2015 book authored by Dr. Jack C. Westman, to comment on the use of xenografts in academia. Dixit explained that mouse models are heavily used, because they are “very convenient” and “easily manipulated,” since tumor size can be assessed easily.

Dixit’s work has been written up multiple times in The Scientist, including his papers on apoptosis, signal transduction, the duality of ubiquitin and inflammasome activator.