A Chicago family
Howard Robert Horvitz was born in Chicago on May 8, 1947. Both his parents were the American-born children of Jews who had left Eastern Europe around 1900. His mother’s father came from Oster, near Kyiv, and his mother’s mother from a town in Galicia that is now Dębica in Poland; her father and at least three of her siblings were later murdered by the Nazis. His father’s father had been born Solomon Gourevitch in a Jewish village near Minsk, worked as a garment presser in Chicago and was blacklisted for joining a famous 1910 strike. Horvitz’s first name, Howard, honoured a great-grandfather, Hersch, who had been shot by the Nazis a few years before his birth.
His father, Oscar, a would-be chemist who could not afford the schooling, became a certified public accountant and eventually treasurer of a Chicago trucking company. His mother, Mary, was a schoolteacher and later a guidance counsellor. Bob, as the family called him, grew up from age five to twelve in a mostly Jewish neighbourhood on Chicago’s north side, where the novelist Saul Bellow’s father lived a few doors away, and then in suburban Skokie. He had severe asthma as a child, which kept him out of most sports but, he believed, made him determined and fearless. For a ninth-grade science fair he bred fruit flies in his mother’s bathroom to reproduce Gregor Mendel’s ratios of inheritance.
From mathematics to biology
Horvitz went to the Massachusetts Institute of Technology in 1964 and studied mathematics and economics, spending his summers working for IBM. In his senior year, wanting to do something relevant, he took his first biology course and loved it. He asked the professor whether it was crazy to apply to graduate school in biology after six weeks of the subject; the professor, a physicist turned biologist, told him he was starting early.
At Harvard he earned his doctorate in 1974 in the laboratory of James Watson and Walter Gilbert, studying how a virus takes over a bacterium’s machinery for reading genes. He then went to the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, England, to work with Sydney Brenner on a tiny transparent worm, Caenorhabditis elegans. Before leaving, on Watson’s advice, he took three Cold Spring Harbor summer courses in neurobiology in a row, which he was told no one had done before.
Tracing every cell in a worm
C. elegans is about a millimetre long, and every individual develops in exactly the same way. In Cambridge Horvitz worked with John Sulston to follow, under the microscope, every cell division that takes place as the worm grows from larva to adult, publishing a complete description in 1977. The map revealed something striking: during development the worm makes 1,090 cells, and exactly 131 of them die, always the same ones, at the same time. Cell death was not an accident. It was part of the plan.
Life at the Laboratory of Molecular Biology suited him. Morning coffee, afternoon tea and lunch in the top-floor cafeteria run by Gisela Perutz, wife of the structural biologist Max Perutz, were occasions for constant scientific conversation, a contrast to the more solitary, sink-or-swim culture he had known at Harvard. With Sulston and Martin Chalfie he began hunting for mutants in which particular cell lineages went wrong, and in 1981 they described lin-4, a gene that changes the timing of cell fates. That gene later became famous in its own right: two of his postdoctoral fellows, Victor Ambros and Gary Ruvkun, used it to discover microRNA.
Horvitz joined the MIT faculty in 1978, arriving with more than 500 strains of worms. His approach was to use genetics to find the genes behind each biological process: hunt for mutant worms in which something goes wrong, then work out which gene is broken and how the genes fit together into a pathway.
He set out deliberately to give each young scientist in his laboratory a distinct problem and the freedom to follow it, believing that training outstanding scientists would of necessity produce outstanding science. One early graduate student, Eun-chung Park, found that worms carry many genes whose loss has no obvious effect, a finding that surprised mammalian geneticists when they rediscovered it years later in the first knockout mice. Another, Hilary Ellis, took on the genetics of programmed cell death.
The genes that decide when a cell dies
With his graduate student Hilary Ellis, Horvitz searched for worms in which the 131 doomed cells survived. In 1986 they identified the first two true death genes, ced-3 and ced-4, and showed that both must work for a cell to die. His laboratory then found ced-9, a gene that protects cells from death by holding the other two in check, along with genes that control how dead cells are cleared away. In 1993 the laboratory showed that ced-3 resembles a human enzyme, and in 1994 that ced-9 is the worm version of the human gene BCL-2, which keeps cells alive and was already known to be overactive in some lymphomas. The Nobel committee noted that most of the genes controlling cell death in the worm have human counterparts.
This was the genetic foundation of the field of apoptosis, or programmed cell death. Our bodies make and destroy enormous numbers of cells every day, and the balance matters. Too little cell death lets damaged cells survive and can lead to cancer and autoimmune disease; too much contributes to neurodegenerative disorders, stroke and heart attack damage.
From worms to cancer medicine
Knowing that cancer cells often survive by over-using the cell’s own brakes on death, drug developers set out to release those brakes. The result was a new class of drugs that block BCL-2, the human counterpart of the worm’s ced-9. In April 2016 the US Food and Drug Administration approved venetoclax, the first BCL-2 inhibitor, for chronic lymphocytic leukaemia; its approved uses have since widened. It works by switching the death program back on in cancer cells.
Horvitz has spoken of three hats: basic research on worms at MIT, medical research on disease and advising companies that turn biology into drugs. He was persuaded to take the third by a fellow worm biologist, Jonathan Hodgkin, who asked him whether he ever wanted to do anything useful. He has also worked with groups studying Huntington’s disease since 1979.
A father’s illness and the search for ALS genes
In 1986 Horvitz’s father was diagnosed with amyotrophic lateral sclerosis, the fatal paralysing disease also known as motor neurone disease. Oscar Horvitz came to Boston to be seen by the Massachusetts General Hospital neurologist Robert Brown, and Horvitz and Brown began a collaboration to find the genetic causes of ALS, with members of Horvitz’s group working in Brown’s laboratory. In 1993 that effort, together with the work of other researchers, identified the first gene for inherited ALS, SOD1, which encodes the enzyme copper-zinc superoxide dismutase.
The discovery opened the way to animal models of the disease and to treatments aimed at its genetic causes; in April 2023 the FDA granted accelerated approval to tofersen, a drug designed to lower production of the faulty SOD1 protein, for people with SOD1-related ALS. Oscar Horvitz died of ALS in 1989. His son and daughter funded the publication of an ALS resource book for patients and families in his memory.
Jewish roots
Horvitz has written about his Jewish family history in detail: grandparents who fled poverty and persecution in the Russian Empire and Galicia, relatives murdered in the Holocaust, a grandmother who escaped the Tsar’s police in 1905 by pretending she could not read. He describes his childhood home as quite secular, though his sister Carol took up lighting Sabbath candles and went to a Hebrew summer camp. His mother long supported the National Council of Jewish Women. He named his daughter in memory of his father, whose Hebrew name was Asher.
Family illness shaped his science as well as his life. His aunt Ann, his mother’s eldest sister, died of Alzheimer’s disease, one of the personal reasons he gives for his interest in neurodegenerative disorders, and his father’s death from ALS drew him directly into research on that disease.
Mentor, husband and father
Horvitz has always made training young scientists a central goal, giving them freedom to follow their own discoveries. Among those who passed through his laboratory is Gary Ruvkun, who shared the 2024 Nobel Prize for the discovery of microRNA. Horvitz is the David H. Koch Professor of Biology at MIT, a member of its McGovern Institute for Brain Research and an investigator of the Howard Hughes Medical Institute. He served as president of the Genetics Society of America in 1995 and has chaired the board of trustees of the Society for Science, which runs major science competitions for students.
Since 1991 he has shared his life with the neuroscientist Martha Constantine-Paton, now his wife, and her two sons; their daughter, Alexandra, was born in 1993. He cooks, plays the piano about as well as his daughter, and keeps orchids. He shared the 2002 Nobel Prize in Physiology or Medicine with Sydney Brenner and John Sulston.
His story shows how studying a worm that almost no one had heard of can lead, decades later, to medicines for leukaemia and new hope for people with ALS.
Sources & further reading
H. Robert Horvitz, Biographical, NobelPrize.org · Press release: The Nobel Prize in Physiology or Medicine 2002, NobelPrize.org · FDA approves venetoclax for chronic lymphocytic leukaemia, The Pharmaceutical Journal · FDA approves treatment for ALS associated with a mutation in the SOD1 gene, US Food and Drug Administration · H. Robert Horvitz, The Horvitz Lab, MIT · H. Robert Horvitz, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
A life of tikkun olam. This is part of tikkun olam, the Jewish idea of repairing the world, and every one of us can add to it.