A family of refugees and physicians
Bruce Alan Beutler was born in Chicago on December 29, 1957. All four of his grandparents had come to the United States to escape persecution as Jews, and he was reminded of it often as a child. His mother’s parents came separately from Kiev around the turn of the twentieth century and met in Chicago; his grandmother, whom the children called Bubbie, lived with the family when he was small and spoke with a strong Yiddish accent. His father’s parents, Alfred and Käthe Beutler, were both physicians in Berlin, he an internist and she a paediatrician whose patients included children of prominent gentile families. Käthe did not foresee the Holocaust, but she saw that her children would have no future in Nazi Germany, and in 1935 she pushed the family to emigrate.
His father, Ernest Beutler, born in Berlin in 1928, raced through the University of Chicago and became a medical doctor at 21 and one of the leading academic haematologists of the twentieth century; among other things he discovered random X chromosome inactivation in humans in 1962. His mother, Brondelle May Fleisher, studied mathematics at Chicago. Beutler later wrote that he, his siblings and cousins all felt the recent history of antisemitism in Europe keenly, and probably felt a need to excel partly because of it.
A Californian naturalist
When Bruce was two the family moved to Arcadia, near Los Angeles, where his father became chairman of medicine at the City of Hope Medical Center. He grew up raising dogs, ducks, rabbits, mice, chameleons, fish, turtles and finches, hiking and birdwatching in the San Gabriel Mountains, and marvelling at the similarity of living things to people. At Polytechnic School in Pasadena he found brilliant friends and, at fifteen, heard a live performance of Bach’s St. Matthew Passion that made Bach the centre of his musical life.
In high school he started working in his father’s laboratory, learning to measure red blood cell enzymes, and at seventeen he published research on the selenium-containing enzyme glutathione peroxidase. He finished high school at sixteen, raced through the University of California, San Diego, in two years, and worked in the laboratories of the fruit-fly geneticist Dan Lindsley, the infectious disease specialist Abraham Braude, where he first heard of bacterial endotoxin, and the geneticist Susumu Ohno. In 1977, at nineteen, he entered the University of Chicago medical school, graduating in 1981, then trained in internal medicine and neurology at the University of Texas Southwestern Medical Center in Dallas.
Isolating TNF
In 1983 Beutler joined the laboratory of Anthony Cerami at Rockefeller University in New York to study cachectin, a mysterious substance released by immune cells called macrophages when they are exposed to lipopolysaccharide, or LPS, the toxic molecule on the surface of many bacteria also known as endotoxin. Within a year he had purified cachectin, something no one had managed before, and raised antibodies against it. In a decisive experiment, mice given the antibody survived a lethal dose of LPS while untreated mice died, showing that cachectin was a key cause of the deadly shock that bacterial infections can trigger.
When he compared its sequence with that of human tumour necrosis factor, or TNF, a protein just cloned by the company Genentech, he saw that cachectin was simply the mouse version of TNF. Scientists had been excited about TNF as a possible cancer treatment. Beutler showed that it was in fact one of the body’s most powerful drivers of inflammation. TNF went on to become one of the most studied proteins in all of biomedicine, and blocking it turned out to be far more useful to patients than giving it.
The molecule that became Enbrel
In 1986 Beutler moved back to Dallas as an investigator of the Howard Hughes Medical Institute at UT Southwestern. One of his first goals was a practical way to block TNF in the body for long periods. His MD/PhD student David Crawford and postdoctoral fellow Karsten Peppel built a hybrid protein that joined the part of a TNF receptor that grabs TNF to part of an antibody molecule. The result was stable, did not provoke the immune system and neutralised TNF extremely potently.
Beutler and his colleagues patented the protein and licensed it in 1995 to the Seattle biotechnology company Immunex, later acquired by Amgen. As etanercept, sold as Enbrel, it was approved in the United States in November 1998 for moderate to severe rheumatoid arthritis, and later for juvenile arthritis, psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Along with other TNF blockers, it transformed the treatment of these diseases, letting many patients who had faced progressive joint destruction and disability lead active lives. Etanercept is listed by the World Health Organization as an alternative on its List of Essential Medicines.
Hunting the endotoxin receptor
Beutler’s deeper question was how the body knows it is infected in the first place. LPS triggered TNF and inflammation, but nobody knew what receptor on the cell sensed it. Two strains of mice were known to ignore LPS completely because of mutations at a genetic location called the Lps locus. Beutler became convinced that finding the mutated gene would reveal how the immune system recognises microbes, a question unanswered since Pasteur and Koch had shown that germs cause disease.
From 1993 his laboratory set out to find the gene by positional cloning, breeding and analysing 2,093 mice to narrow down its location, then searching a stretch of DNA of at least 5.6 million base pairs with slow, hand-loaded sequencing gels. For five years they found nothing. Colleagues thought the effort too risky; his own father urged him not to put all his eggs in one basket; and in 1998 the Howard Hughes Medical Institute told him his funding would end. On the night of September 5, 1998, reviewing the day’s computer searches, he saw a match to a real gene: Tlr4, a relative of the fruit-fly gene Toll. Within days the team found a single-letter mutation in one resistant strain, and later showed the gene was deleted entirely in the other. Their paper in Science in December 1998 has been cited thousands of times.
A window on innate immunity
The discovery showed that TLR4, a Toll-like receptor on the surface of immune cells, is the sensor that detects LPS, and it suggested that other members of the same family detect other molecules from microbes. That proved true: researchers, above all Shizuo Akira, soon showed that different Toll-like receptors recognise the signatures of most kinds of bacteria, viruses and fungi, raising the first alarm of the innate immune system within minutes of infection. Jules Hoffmann had shown in 1996 that fruit flies with mutations in Toll die because they cannot fight off bacterial and fungal infections.
In 2011 the Nobel Assembly at the Karolinska Institutet awarded half of the Nobel Prize in Physiology or Medicine jointly to Beutler and Hoffmann for their discoveries concerning the activation of innate immunity, and the other half to Ralph Steinman for discovering the dendritic cell. The Toll-like receptors are now central to research on sepsis, on vaccines and the substances added to them to strengthen immune responses, and on autoimmune diseases such as lupus, in which Beutler and his Scripps colleague Argyrios Theofilopoulos found that TLR7 plays an essential role in mouse models.
Taking the immune system apart
In 2000 Beutler moved to the Scripps Research Institute in La Jolla, where he set out to take innate immunity apart gene by gene. Using a chemical called ENU to create random mutations in mice, his laboratory screened for animals with abnormal immune responses and then found the responsible mutations with software written by his colleague Yu Xia, eventually identifying as many as 50 mutations a year, compared with one in five years a decade earlier. As DNA sequencing became vastly faster, his group identified hundreds of mutations affecting immunity.
In 2011, just as the Nobel Prize was announced, he returned to UT Southwestern in Dallas to found the Center for the Genetics of Host Defense, where he continues to study how the body protects itself against infection and how immunity turns against the body in autoimmune and inflammatory disease. He was elected to the National Academy of Sciences and the Institute of Medicine in 2008.
Family, faith and legacy
Beutler has written of his paternal grandmother’s regret that the family went to America rather than Palestine, so that she could not take part in building the State of Israel, and of her relief that her children did not have to fight in Israel’s wars. In 2019 the Jewish Theological Seminary awarded him an honorary degree. He married Barbara Lanzl in 1980, and they had three sons, Daniel, Elliot and Jonathan, before divorcing in 1988; he brought Daniel and Elliot to Stockholm for the Nobel ceremony. His father, who died in 2008, lived to see most of his son’s honours, though not the Nobel Prize.
Beutler describes himself as obsessive and proud of it, and he advises young scientists to choose an undervalued but important question and pursue it relentlessly. Two very different kinds of people benefit from that persistence: patients with rheumatoid arthritis, psoriasis and other inflammatory diseases who take the TNF blocker his laboratory invented, and scientists everywhere who now understand how the body first recognises the microbes that invade it.
Sources & further reading
Bruce A. Beutler, Biographical, NobelPrize.org · Press release: The Nobel Prize in Physiology or Medicine 2011, NobelPrize.org · Etanercept, Wikipedia · Bruce Beutler, 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.