Ivan Oransky

Gunther S Stent

Gunther Stent credited his interest in biology to the fact that he met Sol Spiegelman at a party in 1945. Stent was a graduate student at the University of Illinois, where Spiegelman—who would go on to develop nucleic acid hybridisation and win a Lasker Award for other work—was a visiting seminar speaker. Stent read one of Spiegelman’s papers. “On the fi rst two pages of that paper I was amazed to fi nd an inelegant derivation of the same standard equations which, in my sophomore year, I had to derive in a few minutes on an exam in the Doc’s physical chemistry course”, Stent later recalled in his self-published 1998 memoir, Nazis, Women and Molecular Biology. He asked a friend: “Wouldn’t microbiology be a good fi eld for me to get into if it takes so little to have a paper published?” Stent’s memoir, and his life, was full of that kind of selfdeprecation. (His memoir is also fi lled with a seemingly endless list of women he pursued and eventually lost.) Born Gunther Siegmund Stensch in Berlin, in 1924, he had emigrated to the USA when he was 14 years old. Landing in Chicago, he earned a bachelor’s degree in chemistry from the University of Illinois in 1945, and then began his graduate studies, with a year spent screening technical documents in Germany after the war. He earned his PhD in physical chemistry from the University of Illinois in 1948. After meeting Spiegelman, he read Erwin Schrodinger’s What is Life? Like Seymour Benzer the book led him to Max Delbruck’s laboratory at Caltech, in Pasadena, on a postdoctoral fellowship. There and at Cold Spring Harbor Laboratory, where he took Delbruck’s famous phage biology course, he was surrounded by other like-minded scientists who would become giants in the burgeoning fi eld of molecular biology: James Watson, Salvador Luria, Alfred Hershey, and Renato Dulbecco. Stent’s fi rst project was an attempt to fi gure out why a particular bacteriophage, strain T4, did not attach to its bacterial host unless it came into contact with tryptophan. In 1952, he moved to the University of California, Berkeley. He used radiolabelled bacteriophage to confi rm DNA’s double helix structure in 1954, a year after Watson and Francis Crick published their famous report. In 1957, he helped found the school’s department of virology. In 1963, Stent wrote Molecular Biology of Bacterial Viruses, which Watson told The New York Times was “the textbook that became the most exciting tool for the study of molecular genetics following the fi nding of the double helix”. He trained a number of leading scientists, including Sydney Brenner, who shared the 2002 Nobel Prize in Medicine or Physiology for his work on developmental genetics. Over the next decades, he turned his attention to philosophy. He argued in The Coming of the Golden Age: A View of the End of Progress that scientists had learned everything they could about molecular biology. When John Horgan, author of The End of Science, interviewed him in 1992, he acknowledged that biologists still had a lot to learn. “But I think the big picture is basically over”, he said. Evolutionary biology in particular “was over when Darwin published The Origin of Species”. Many of his colleagues, of course, disagreed. He also studied neuroscience, using the leech as a model. (He also shared a patent on hementin, an anticoagulant derived from leeches.) One of his most-cited papers was a 1973 study of what happens at the synapse during learning (Proc Natl Acad Sci USA 1973; 70: 997–1001). Stent wrote or edited several other books, including the reissue of Watson’s The Double Helix: a Personal Account of the Discovery of the Structure of DNA, and Phage and the Origins of Molecular Biology. His 2002 book Paradoxes of Free Will won the 2002 John F Lewis Award of the American Philosophical Society. Stent chaired Berkeley’s department of molecular biology from 1980 to 1986, and then founded and chaired the department of molecular and cell biology from 1987 to 1992. He retired in 1994, having also spent time at the University of Copenhagen, the Institut Pasteur, and Harvard University. Stent is survived by his second wife, Mary Ulam; a son, Stefan Stent; and two stepsons, Alexander Ulam and Joseph Ulam. His fi rst wife, Inga Loftsdottir Stent, died in 1993.

Katharina Dorothea Dalton

Katharina Dalton began her career as a chiropodist, and even wrote a textbook on the subject, but is best known for her work describing premenstrual syndrome (PMS). Robert Frank had described “premenstrual tension” in 1931, but Dalton, along with Raymond Greene—Graham Greene’s brother—published the first paper on PMS in the BMJ in 1953. Soon after that, she established the world’s first PMS clinic at University College Hospital, London, UK. The 1953 BMJ paper was the first of many published by Dalton on PMS, based on research with tens of thousands of patients. Because she didn’t do placebo-controlled studies, some have questioned her results, although hardly anyone doubts her critical role in convincing the medical establishment that PMS was a real condition. For example, one of her beliefs—that progesterone would be an effective treatment for PMS—has not been borne out by scientific scrutiny. For the few patients for whom progesterone worked, it was probably not because of regulation of levels of the hormone itself, according to University of California, Los Angeles professor of obstetrics and gynaecology Andrea Rapkin, but because one of its metabolites, when given as a suppository, acts at the GABA receptor and has a stress-modulating effect. “Part of the problem was that she wasn’t rigorous”, Rapkin told The Lancet. “In that way it was logical to criticise her. But on the other hand, being able to say that premenstrual behaviour was really not related to women wanting to get pregnant or have sex or whatever men were saying at the time was important.” “She was a pioneer”, said Uriel Halbreich, professor of psychiatry and gynaecology at the State University of New York at Buffalo, “and pioneers are not necessarily the ones providing the definitive answers”. She was “a really persistent and effective advocate of the recognition of PMS” in the UK, and her work was quite well accepted there, he said. It was less accepted by US physicians, he added, but she was admired by many women and garnered much publicity. Some of the publicity was due to high-profile court cases in which Dalton served as an expert witness. She turned down several cases in which attorneys were planning a “PMS defence” because the women didn’t have a cyclical pattern of behaviour that responded to treatment. But in 1980, she took the cases of Sandie Smith, who had convictions for crimes such as arson and assault and was charged with threatening to kill a police officer, and Christine English, charged with murder. Smith got probation after Dalton showed her crimes had occurred at monthly intervals, and English was allowed to plead guilty to manslaughter due to diminished responsibility. The cases were the first successful uses of the PMS defence. Dalton later took similar cases, but was strict about the ones she accepted, concerned that the plea was not abused. “The genuine cases are few and far between”, she wrote, “it is important to ensure that PMS is not made a universal defense”. In 1978, Dalton published Once a Month: Understanding and Treating PMS. Much of its advice would today be thought quaint—eg, avoiding driving tests and work stress at certain times—and was toned down in later editions. It was a family affair; Dalton’s daughter Wendy Holton, the founder of PMS Help, co-wrote several editions, and a granddaughter, Jennie, wrote a chapter in the 1999 edition. The book recommends a diet in which women “eat small starchy snacks every three hours during the waking hours and within one hour of waking and retiring to bed”, along with “adequate protein and plenty of fruit and vegetables”. It is intended to prevent the blood level of progesterone dropping, which has been shown to happen, in some studies, after a large meal. Dalton later turned her attention to postpartum depression, which she attributed to fluctuations of the same hormones as she did PMS. She also, with her son Michael, studied the effects of vitamin B6 toxicity, and their study formed part of the basis of the 1997 UK Committee on Toxicity restriction of the sale of the vitamin to 10 mg per day. The study was later questioned by The Lancet (1998; 351: 1523) and by some researchers (1998; 352: 62). Dalton started medical school at the Royal Free Hospital after her first husband, Wilfred Thompson, was killed in combat in World War II. She qualified on the day in 1948 in which the NHS began its existence. Her second husband, Tom Dalton, predeceased her in 1992. She is survived by her four children.

Joan Wright Goodman

Joan Wright Goodman’s important work on stem cells was done at a time when few women worked in research laboratories. When Goodman’s husband, Charles, joined the Oak Ridge National Laboratory, Oak Ridge, TN, USA, as a nuclear physicist in the early 1950s, she was off ered a position working with Charles Congdon, who ran the mammalian recovery group laboratory. “We had been working on bone marrow transplant, and she came and worked in our laboratory. We were trying to develop programmes in diff erent aspects of bone marrow transplant—cell separation, protein separation, and others”, Congdon told The Lancet. Goodman teamed up with Norman Anderson to work on protein separation, but found the method wasn’t particularly useful for cells. She then turned her attention to isolating stem cells. Others had previously shown that stem cells were present in the spleen, in leukemoid blood, and that tumours undergo “tremendous transformation”, Congdon said. When Goodman and her colleague George Hodgson began their work, the question of stem cells in the peripheral blood was “as old as histology itself”, they wrote, “for the description of the haemocytoblast is equivalent in most accounts to that of the large lymphocyte or lymphoblast. Despite the fact that large lymphocytes and, at least in some species, occasional lymphoblasts are found normally in the peripheral circulation, the presence of stem cells is generally not accepted.” But Goodman and Hodgson would be the fi rst to isolate stem cells from normal peripheral blood in healthy animals. They reported this fi nding in a 1962 paper (Blood 1962; 19: 702–14). The paper, along with work by others including James Till and Ernest McCulloch, who won the 2005 Lasker Award for basic research, “paved the way for the development of the studies on the physiology and pathophysiology of ‘blood stem cells’ as an integral system of the homeostasis of blood cell formation”, Theodor Fliedner, of the Medical Center of the University of Ulm, Germany, wrote in 1998. Although it would be quite a few years before anyone began using peripheral blood as a supply of stem cells, Congdon said, the study is still frequently cited. Goodman, who graduated from Barnard College, New York, and then earned her PhD in physiology from the University of Rochester, New York, also studied the use of bone marrow transplantation to mitigate radiation damage, and the role of the thymus in the formation of red blood cells. Congdon called Goodman “the most competent bench scientist with whom I had an association” during his more than 30 years in research. “Every experiment was repeated enough and so carefully carried out that the work stood on its own merits. She was personally involved in every eff ort.” Goodman was “a very dynamic person who sort of created a group of people around her—from technicians to postdocs—everyone in the lab”, Congdon remembered. “She was a kind of informal leader.” With the backing of Hollander—who, according to Congdon, gave women opportunities to work at Oak Ridge National Laboratory, particularly in positions as senior geneticists and molecular biologists—Goodman became “particularly concerned about women being treated equally in the laboratory and that wasn’t quite easy at that time”. Goodman was willing to speak out “about that inequity in science, and she had a great influence on us all, including me”, Congdon told The Lancet. The Goodmans moved to the Lawrence Berkeley National Laboratory in 1978. She retired in 1985, at which point she decided to go to law school at the University of San Francisco and later passed the bar, practising life sciences intellectual property law for a short time. Later, she and her husband became active supporters of the arts in the Bay Area and elsewhere. Goodman is survived by her husband; a son, Henry Nicholas; a daughter, Diana Goodman; and a brother, Arthur Wright.

Lawrence M Brass

It didn’t take long after meeting Lawrence Brass, in the late 1980s at the Yale School of Medicine, New Haven, CT, USA, for Ralph Horwitz to recognise, as others did, that “collaborating with him would be enormously benefi cial, and fun as well”. Brass initiated a collaboration with Horwitz, then chair of medicine at Yale, Walter Kernan, and Catherine Viscoli to study the potential risks of phenylpropanolamine. There had been reports of spontaneous brain haemorrhage in people taking this compound, especially in young women, and manufacturers were coming under increasing pressure to undertake sponsorship of studies of the drug. “He was aware that the FDA was growing increasingly concerned about the potential risks of phenylpropanolamine as an ingredient in diet aids and cold remedy products”, said Horwitz, now dean of Case Western Reserve University’s School of Medicine, Cleveland, OH, USA. The collaboration would eventually become known as the Yale Hemorrhagic Stroke Project. When it was completed, in 1999, it proved that phenylpropanolamine was in fact linked to strokes. “I think it was a surprising result for all of us”, Horwitz said. “Larry came with a strong belief that phenylpropanolamine was not likely to increase the risk of stroke, and the rest of us believed that as well.” “Larry had a very agile intellect, and a very comprehensive approach to research and science”, Horwitz told The Lancet. “He had a very deep knowledge of the fi eld—not just of neurology, but also the basic science of vascular disease.” One of Brass’ most infl uential trials was the Women’s Estrogen for Stroke Trial (WEST), according to Marc Fisher, a collaborator at the University of Massachusetts, Worcester, MA, USA. Results of the trial, published in 2001, showed no benefi t for oestrogen supplementation. Brass’s recent work involved a national stroke database. Because the database is young, not many papers have emerged out of it yet, but the work will continue, Horwitz said. Brass was also very interested in quality of care and quality improvement in stroke care. “There are very few people that I knew who were as admired, respected, and beloved as Larry was across the spectrum of people working in academic life, whether you talk to people at the FDA, the NIH, or colleagues in academic medicine, even people with whom his own work or ideas may have confl icted”, Horwitz said. Brass was gregarious, and was a “very eff ective colleague and collaborator”, he said. Brass attended the University of Pennsylvania, Philadelphia, PA, then the Tufts Medical School, Boston, MA. He trained in medicine at the Newton-Wellesley Hospital in Massachusetts, then in neurology and stroke at the Neurological Institute of New York at Columbia University. In 1987, he joined Yale, where he established a stroke service. Brass frequently sat on data safety monitoring boards, and was “very important in educating younger stroke doctors”, Fisher said. He was “very much involved with teaching, patient-oriented research, and was a real advocate for improving stroke awareness”, said Ralph Sacco, who trained with Brass at Columbia and is now a professor of neurology there. “He was also a good role model for younger people as a teacher, and as an educator and a researcher. Younger people in the fi eld looked up to him.” Brass was “a real gadget person”, Sacco said. “He was the one who fi rst turned me onto computers. He was a real Macintosh enthusiast, and always the fi rst one to have the best new gadget on the block. He thought it was a good way to integrate technology into clinical medicine, research and education.” He was also “a big guy who liked to eat”, Fisher said, and Brass once won a contest to become a judge of a bourbon company-sponsored barbecue contest. Brass was also an accomplished amateur magician. Once Fisher found this out, he asked Brass to perform after dinner at a neurology meeting, where “he put my wife in a box”, Fisher said. “He was a great hit.” Brass was very dedicated to his family and is survived by his wife, Lori Ann Brass; two sons, Zachary and Schuyler; his parents, Melvin and Joyce Brass; and two sisters, Jill Brass and Susan McInerney. “We had a lot more to expect from Larry”, Sacco said. “This was a shock to all of us.”

Watching the detectives

The Los Angeles Police Academy diner is not where you’d expect to find a Canadian forensic accountant having lunch. It’s more of a sanctuary for the men and women who share the bond of policing the 470 or so square miles that comprise Los Angeles, arguably America’s most challenging and highprofile law enforcement beat. Outside the ’50s-style diner, an almost smogless February blue sky serves up a steady diet of warm sunshine. Inside, the large room is festooned with framed pictures of ages-old graduating police classes and various weaponry, such as polished wooden nightsticks from years gone by. The booths are crammed with officers, both in and out of uniform, chomping on generous

George Widmer Thorn

5.99 specials.

The art of medicine : Narrative humility

George Thorn’s love of the kidney and its upstairs neighbour, the adrenal gland, began when he was a medical student. Working in Frank Hartman’s laboratory at the University of Buffalo in the late 1920s, Thorn developed “the first workable assay for adrenal cortical extract activity”, according to George Cahill, a former student and colleague, who is now Emeritus Professor of Medicine at Harvard Medical School. This work earned Hartman and Thorn the Gold Medal of the American Medical Association in 1932. When Thorn moved to Johns Hopkins University in 1936, doctors still had only crude animal adrenal extracts with which to treat the adrenal gland disorder Addison’s disease. Some of the patients who received these treatments “just felt awful”, Cahill told The Lancet. In the late 1930s, desoxycorticosterone was first synthesised by several laboratories. Thorn showed that subcutaneous pellets of the corticosteroid could be used to correct adrenal insufficiency in dogs, and eventually in people. Thorn also reported on the effects of cortisol (17-hydroxycorticosterone) and related corticosteroids on the adrenals, which was critical to having cortisol adopted as a mainstay of Addison’s treatment. This work was only possible because Thorn, 10 years earlier, when working as a doctor at a summer camp, had treated Edward Kendall. Kendall, who would win the 1950 Nobel Prize for his work on adrenal hormones, sent Thorn the synthetic glucocorticoids he had been working on. After moving to the Peter Bent Brigham Hospital (now Brigham and Women’s) in 1942, Thorn became one of the original editors of the 1946 first edition of Harrison’s Principles of Internal Medicine. That year, he also reported the first routine direct test of the adrenal gland response using adrenocorticotropic hormone (ACTH). Over the next few years, Thorn showed that ACTH could be used to stimulate the adrenal gland to diagnose Addison’s. His prowess gave the Brigham an international reputation, as Thorn treated patients with Addison’s including Spencer Tracy, Robert Frost, and Judy Garland. It was on Thorn’s watch that the Brigham became a pioneer in kidney transplantation. In 1945, surgeons grafted a donor kidney onto the arm of a woman with acute tubular necrosis to give her temporary renal function until her kidneys recovered. The woman began to secrete urine, and eventually left the hospital with her own kidneys intact, although it is unclear what the direct effect was of the graft. Even as physician-in-chief, Thorn could not convince surgeons to allow the operation to proceed in a regular operating room. Instead, it took place in a hospital ward, recalled Joseph Murray—who shared the 1990 Nobel prize for his work on kidney transplantation—in his Nobel lecture. But Thorn, who invited Dutch dialysis pioneer Willem Kolff to lecture at the Brigham in 1947, spurred the development of the artificial kidney—the dialysis machine— under the direction of John Merrill. In 1954, this machine made possible the first successful human kidney transplantation, which was performed at the Brigham by Murray. After meeting the aviation pioneer and philanthropist Howard Hughes in the 1940s, Thorn took an active role in the US national research agenda. Their relationship led to Hughes’ first donations of money for medical research, which in turn, in 1953, led to the creation of the Howard Hughes Medical Institute. Thorn presided over some of the institute’s earliest, but also most difficult times: as Director of Research beginning in 1955; as President from 1981 to 1984; as Interim President from 1987 after the forced resignation of his replacement over financial irregularities; and as Chairman from 1990. Thorn also had a critical role at the Massachusetts Institute of Technology (MIT), Cambridge, USA, according to MIT President Emeritus Paul Gray. In the 1960s, when MIT and Harvard created the Health Sciences and Technology joint programme, Thorn was drawn in as an early adviser, Gray said, and had a significant role in shaping the programme. After Thorn was appointed to the executive committee of MIT’s governing board, he was instrumental in MIT creating a full-service health maintenance organisation in 1973 for faculty, staff, and students. Cahill recalled Thorn’s smile and imagination. “George Thorn would walk in the room and everyone would feel better”, he said. Thorn and his wife Doris would have students out to their beach in Manchester-by-the-Sea for picnics. He also restored original woodland in his town by planting several hundred trees in a plot now known as the Thorn Arboretum. Thorn is survived by his son, Weston, and two stepchildren, Alan Steinert and Susan Poverman. His first wife, Doris Weston, died in 1984; and his second, Claire Hyman Steinert, died in 1990.