Using a virus as an experimental system, Kaiser made fundamental discoveries that were instrumental in ushering in the era of recombinant DNA technology, often known as gene splicing.
June 23, 2020 - By Bruce Goldman
Dale Kaiser, PhD, a Lasker Award-winning professor emeritus of biochemistry and of developmental biology at the Stanford University School of Medicine, died June 5 at his home in Stanford, California. He was 92.
Kaiser’s pioneering research on a virus that infects bacteria was instrumental in ushering in the era of recombinant DNA, or gene splicing, technology. Gene splicing allows scientists to study genes by stitching them into the DNA of cells. It also enables biotechnologists to produce proteins by the batch in bioreactors. This, in turn, has enabled the bulk production of drugs ranging from antibodies to insulin.
“Dale Kaiser’s discoveries transformed the fields of molecular biology and genetics,” said Lloyd Minor, MD, dean of the School of Medicine. “His research also advanced scientists’ understanding and appreciation of signaling mechanisms in developmental biology. He was renowned for his teaching, and he was praised by all for his towering scientific integrity. We will all miss him.”
“Dale was one of the founders of molecular genetics during the time the field emerged,” said Roeland Nusse, PhD, professor and chair of developmental biology, Virginia and D. K. Ludwig Professor in Cancer Research and Reed-Hodgson Professor in Human Biology. “He was a creative and original scientist. He was also modest and very kind. Few people who met Dale casually would have guessed that much of our current understanding of molecular genetics originated from his brilliant insights.”
Kaiser, the Jack, Lulu and Sam Willson Professor of Biochemistry, emeritus, worked six days a week throughout his 61 years at Stanford, said Lucy Shapiro, PhD, professor of developmental biology and director of the Beckman Center for Molecular and Genetic Medicine. He would walk daily from his home on campus to his office in Beckman Center until just a year or so ago, when complications of Parkinson’s disease made it impossible, she said.
“Dale had a razor-sharp mind and avid curiosity about the natural world,” said Shapiro, the Virginia and D. K. Ludwig Professor, who has known Kaiser since 1968. “There was no way to turn his brain off. Everybody who knew him looked up to him, confided in him.”
In 1980, Kaiser shared the Albert Lasker Award for Basic Medical Research with Paul Berg, PhD, now professor emeritus of biochemistry; Stanley Cohen, MD, professor of genetics and of medicine; and Herbert Boyer, PhD, then a professor of biochemistry at the University of California-San Francisco, for their work on gene splicing.
“Dale was a delight to have as a colleague,” said Berg, the Robert W. and Vivian K. Cahill Professor of Cancer Research, Emeritus. “He was brilliant. It’s an enormous loss to our department and to me that he’s gone.”
As a prospective graduate student, Seung Kim, MD, PhD, now a professor of developmental biology, first met Kaiser in 1985 and became his doctoral trainee.
“I’m proud to have been a student of Dale Kaiser,” Kim said. “We all tried to emulate Dale. He was insightful, patient, polite and empathetic. His door was always open, and he was a great listener. He was a remarkable teacher and mentor, training multiple generations of students who’ve gone on to advance biomedical research.”
Native of Ohio
Born Armin Dale Kaiser on Nov. 10, 1927, in Piqua, Ohio, the young Kaiser displayed two hallmark features of a budding scientist: a propensity for making explosives and a deep-seated drive to fix broken radios.
After serving in the Army Signal Corps from 1945 to 1946, the 6-foot-2-inch veteran attended Purdue University, graduating in 1950 with a degree in biophysics. He earned a PhD in biochemistry in 1955 at the California Institute of Technology, where he met his future wife of 67 years: Mary Durrell, a technician in his lab.
At Cal Tech, Kaiser became interested in a bacteriophage — a virus that infects bacteria — called lambda. This bacteriophage could develop, by some mysterious switching mechanism, in either of two directions after invading E. coli. Like all viruses, lambda could commandeer the cell’s replicative machinery to generate multiple copies of itself.
Alternatively, like some but not all viruses, lambda could sew its own tiny genome into that of its bacterial host. There it would sit, replicating only as a feature of the dividing cell’s own genome, until some environmental signal indicating stress on the part of the cell awakened the dormant phage and rendered its host a factory for viral proliferation.
Kaiser’s curiosity about how this switching happens turned him into a world-class expert on the lambda genome, whose relative simplicity made it an ideal experimental system.
Hired by Arthur Kornberg
After a postdoctoral fellowship at the Pasteur Institute in Paris from 1956 and 1957, Kaiser was hired as an instructor by Arthur Kornberg, MD, then chair of Washington University’s department of microbiology, to become the department’s resident virologist.
Another member of that department was Berg, who received the Nobel Prize in chemistry in 1980 for his recombinant-DNA-associated research. “We met every day for lunch,” Berg recalled. “Everybody knew what everybody else was doing. Nobody held anything back.”
In 1959, the department — all six faculty members — moved as a unit to the Stanford School of Medicine to establish its Department of Biochemistry. Kornberg, who received the Nobel Prize in physiology or medicine that year, was its chair. Kaiser rose from assistant professor to associate professor in 1961 and to full professor in 1966. He served as departmental chair from 1984 to 1989, when he became a founding professor of the medical school’s Department of Developmental Biology.
Kornberg had purified DNA polymerase, the molecular machine that we now know copies every living species’ genetic material, and had shown that DNA polymerase could indeed make DNA copies from genomic templates. But it was Kaiser who proved that DNA polymerase faithfully replicates the encoded message of DNA.
A DNA molecule is a lengthy sequence of four chemical units, or bases, often referred to by the initials A, T, G and C, that hook up one after another like links in a chain. Two of these bases, A and T, have a chemical attraction to one another; the other two, G and C, likewise share a mutual attraction.
Like the DNA in our chromosomes, lambda DNA is double-stranded. But at each end of its lone linear chromosome, one of the strands extends a bit farther than the other, stretching for 12 additional bases beyond its partner.
These tails on opposite ends of the lambda chromosome had been shown to have an affinity for one another, and their fusion turned the linear lambda chromosome into a circular ring.
Kaiser and postdoctoral scholar Ray Wu showed why this happens by painstakingly figuring out the identity of each base composing these protruding ends. Kaiser and Wu showed that the two “sticky ends” of the lambda chromosome — among the first-ever DNA sequences to be deciphered — were ordered so that when they lined up, their constituent bases faced one another in pairs with opposites-attract relationships, and lambda’s linear chromosome closed up into a circular ring.
Splicing strands of DNA
Kaiser and his graduate student Peter Lobban devised a general way of using enzymes to create sticky ends on arbitrary DNA stretches. Researchers could then not only join two pieces of the same DNA strand, but splice unrelated DNA strands together to form a whole new entity — the conceptual basis for recombinant-DNA technology.
“That fundamental finding forever changed biology from simply the study of existing living entities to creation of new ones,” Shapiro said. The era of genetic engineering was born.
Kaiser also invented an efficient new way to introduce bits of DNA into bacterial cells to see how they affected the cells’ behavior. By doing this, he could discern the roles of individual lambda genes.
In the early 1970s, Kaiser shifted his focus to the study of soil-dwelling bacteria called Myxobacteria. These one-celled organisms travel in microbial “wolf packs”: orchestrated swarms of tens of thousands of individual cells. Swarming enables the extracellular accumulation of enzymes required to digest insoluble organic substances in the soil.
When nutrients become scarce, Myxobacterial cells band together to form aggregates called fruiting bodies. Initially rod-shaped individual cells curl up as long-lived, low-maintenance spherical spores, riding out the hard times. Once conditions improve, the cells germinate and resume their swarming wolf-pack ways.
Kaiser’s lab succeeded in identifying numerous molecular signals that guide Myxobacteria toward one or another of these alternative lifestyles. The discoveries have provided clues for understanding tissue formation and cell-to-cell communication in complex organisms.
“How one-celled creatures manage to act as a multicellular one is the crux of developmental biology,” Shapiro said.
The co-author of roughly 400 peer-reviewed papers, Kaiser was a meticulous writer. Kim recalled Kaiser’s returning 23 serial drafts of the same paper to him for revision.
He was also a great explainer. “His lectures were models of clarity,” said Berg, who co-taught a course with Kaiser. “He was meticulous in preparation and as clear as a bell.”
Kaiser won the U.S. Steel Award in Molecular Biology in 1970, the Waterford Prize for Basic Medical Research in 1981 and the Genetics Society of America’s Thomas Hunt Morgan Award in 1992. He was president of the society in 1993 and 1994. He was a member of the National Academy of Sciences, of the American Academy of Arts and Sciences, and of the American Society of Biological Chemists.
Besides his wife, Kaiser is survived by a son, Christopher Kaiser, of Cambridge, Massachusetts; and a daughter, Jennifer Lee, of Maricopa, California.
No memorial service is planned.
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