Stanford biochemist David Hogness, a founder of genomics, dies at 94

David Hogness, PhD, a Stanford biochemist who helped found the field of genomics, died Dec. 24 at his home on campus. He was 94.

Hogness conceived of and conducted an influential series of experiments in the 1970s and 1980s that bridged the gap between molecular biology and genetics, and that played a key role in launching the fields of molecular genetics and genomics. The research techniques he developed in his Stanford laboratory, and the insights derived from his studies, served as the bedrock for the Human Genome Project and have been used to identify thousands of disease-associated genes.

 “It’s impossible to overstate the magnitude of Dave Hogness’ founding contributions to the fields of developmental biology and of genomics,” said Lloyd Minor, MD, dean of the Stanford University School of Medicine. “His legacy includes not just his scientific discoveries, but the scores of researchers who trained in his lab who have become leading scientific thinkers. His influence is far-reaching, his loss will be deeply felt, and his impact on medicine enduring.”

A meticulous writer, Hogness was reluctant to publish many of his most important findings as he mulled over concepts and word choices that would best convey his discoveries. This perfectionism, together with a seeming indifference to fame and deadlines and a mischievous impulse for rule-breaking, often kept him out of the wider public spotlight. It also sometimes rankled trainees eager for publications and letters of reference with which to launch their careers.

“Dave was famous for not publishing many papers,” said Roel Nusse, PhD, professor of developmental biology at the School of Medicine and the Virginia and Daniel K. Ludwig Professor in Cancer Research. “Not everyone was happy about it, because you typically need to publish papers to establish your career. But those papers he did publish were excellent, and his reputation was so strong that even those trainees with a pretty thin publication record would get jobs just because they came out of his lab.”

“Dave was truly beloved by everyone who worked with him,” said Rockefeller University President Richard Lifton, MD, PhD, who studied under Hogness. “He was a person fascinated by big ideas and filled his lab with people who had interesting thoughts about what could be done in science. He encouraged really audacious projects and was very supportive of his trainees. All of us who came out of Dave’s lab left thinking ‘Wow, science is so cool. What are the most important questions I can tackle next?’”

‘Amazing vision’

Hogness’ many trainees and colleagues remember a man with a towering and wide-ranging intellect eager to tackle big-picture questions, be they scientific or philosophical, that appeared out of reach to many of his contemporaries.

 “Dave conceptualized a whole field of research long before the necessary technical capabilities to accomplish it existed,” said Stanford professor of developmental biology William Talbot, PhD, a former graduate student in the Hogness lab, now senior associate dean for graduate education and postdoctoral affairs at the School of Medicine. “He knew exactly what he was doing and what he wanted to be able to do from at least the early 1970s. He had amazing vision.”

Hogness’ seminal research in the 1970s and 1980s united the fields of molecular biology and genetics, allowing researchers for the first time to identify the position of particular genes along the chromosome and to begin to understand exactly how mutations in key genes affect the embryonic development of the fruit fly. His discoveries revealed that genes of higher organisms can include intervening sequences called introns and showed that their activity is controlled by noncoding promoter sequences, including a stretch of DNA known as the TATA box that serves as a starting point for transcription of many genes.

The realization that many developmental and regulatory pathways are shared across species is a key reason that the field of developmental biology exists today. He also was a key participant in discussions in the mid-1970s about the safety of combining the DNA of different species in one organism in a process known as recombinant DNA technology.

Outside the lab, Hogness enjoyed traveling and hiking and spending time with his family, friends and many dogs — usually Labrador retrievers. He was keenly interested in politics and matters of social justice. He enjoyed studying topics as diverse as architecture, history and dog training. He was fascinated not only by the idea of mapping genes but by historical and contemporary maps in general. He owned a blue Chevy Suburban on which he had a professional sign painter inscribe “Bartholomew’s Equal Area Projections: Land and Lakes Survey” on the doors. It served on occasion as the perfect vehicle for sneaking onto logging roads usually off-limits to the public.

Long summer holidays to places like Puget Sound and Glacier National Park to hike, camp and kayak with his family each year helped him to disconnect from the day-to-day work of the lab and focus on the bigger questions in his field.

The big questions

Hogness was born on Nov. 17, 1925, in Oakland, California, and grew up in Chicago, where his father, Thorfin Hogness, PhD, was a professor at the University of Chicago. He was tackling big questions as early as high school, when he considered whether to follow in the footsteps of his father, who served as the director of plutonium research for the Manhattan Project at the end of World War II, or instead aim to become a Supreme Court justice.

In the end, science trumped law. Correspondence with his father, who advocated after the war for the civil control of atomic energy research, revealed him toying as a college student with the idea of merging the fields of chemistry and biology as early as the 1940s. He earned a bachelor’s degree in chemistry from the California Institute of Technology in 1949 and a PhD in biology and chemistry there in 1952.

As a postdoctoral scholar in the laboratory of biochemist Jacques Monod at the Pasteur Institute in Paris, Hogness studied how the bacterium E. coli induces the expression of the enzyme beta-galactosidase in the presence of lactose. Together with immunologist Melvin Cohn, PhD, Hogness showed that the enzyme was assembled from scratch from its constituent amino acids rather than from preexisting inactive protein subunits. The discovery was a foundational step in Monod’s studies of how bacteria genetically control enzyme synthesis, for which he later shared the Nobel Prize in Physiology or Medicine.

But Monod, who was active in the French Resistance during World War II and a noted musician and philosopher, also inspired Hogness in his personal life.

“Jacques Monod was a real mentor to Dad as a scientific thinker and in so many other ways,” recalled Peter Hogness, David Hogness’ son. “He admired how Monod was engaged with art, culture and political questions throughout his life.” David Hogness and his wife, Judith, whom he married in 1948, frequently contributed to political races and causes advancing human rights and racial justice.

Hogness returned to the United States to join the Washington University in St. Louis in 1955, first as an instructor in microbiology and then as a member of the faculty. While there, he studied the genetic organization of a virus that infects bacteria, bacteriophage lambda, and created the first physical maps of genes along DNA. In 1959, he joined the Stanford faculty with biochemist Arthur Kornberg, MD, and three other members of the microbiology department at Washington University — Paul Berg, PhD, A. Dale Kaiser, PhD, and Robert Lehman, PhD — to populate Stanford’s newly formed biochemistry department.

Designing family home

After the move, Hogness applied himself to the role of amateur architect when he designed his family home on the Stanford campus under the auspices of Joseph Eichler, known for popularizing the midcentury modern style of home to Northern California. “He drew out some plans and showed them to Eichler,” recalled his son, Chris Hogness, MD. “Eichler looked at it and liked it.”

With Kaiser, Hogness continued to work on understanding how the bacteriophage lambda genome functions and is organized, helping to generate the first maps of the physical positions of genes on DNA. But in the late 1960s, he wanted to branch out into other model systems like the fruit fly Drosophila that were more amenable than viruses to the study of genetic regulation of development.

In 1968 he spent his sabbatical year traveling to key Drosophila labs around the world, including Edward Lewis’ laboratory at CalTech, James Peacock’s lab at CSIRO in Australia and Wolfgang Beerman’s lab at the Max-Plank Institute in Germany.

Hogness settled on Drosophila due to a remarkable feature — the existence of what are known as polytene chromosomes in the fly’s salivary glands. These chromosomes are repeatedly replicated but never segregated into daughter cells. As a result, the chromosomes clump together along their lengths, generating distinct dark and light bands that serve as genetic signposts.

“Dave’s genius was to realize that the recombinant DNA technologies newly developed at Stanford, which allowed researchers to isolate and replicate to very high copy numbers distinct segments of DNA, could be used to map the locations of those DNA segments to specific bands on the polytene chromosomes,” said Philip Beachy, PhD, professor of developmental biology and the Ernest and Amelia Gallo Professor at Stanford. “He also figured out how to use randomly generated overlapping segments from the Drosophila genome to ‘walk’ along the chromosome to identify distant genes.”

“Dave had the completely novel vision of unifying the genetic and physical maps of genomes, allowing us to find any gene for which we have a phenotype,” said Lifton.

Hogness described the concept of chromosome walking, and what would come to be known as positional cloning, in an extraordinary grant proposal in 1972 that many people consider to be the foundation of the field of genomics. When he published the proof of principle in a landmark paper in 1974, identifying for the first time the location of specific DNA segments on polytene chromosomes, his colleagues were staggered.

“You could see the future in that paper,” Lifton said.

TATA boxes and introns

Hogness went on to develop a technique known as colony hybridization, which allowed researchers to identify a single bacterial colony out of thousands that was expressing any gene of interest, and to subsequently identify a DNA sequence called the TATA box that prompts the expression of a gene into a protein in nearly all higher organisms — a discovery for which he is well-known but which he never published. He also showed for the first time that genes of higher organisms contain noncoding sequences called introns.

All of these discoveries set the stage for his examination of Ultrabithorax, one of the key genes critical to the development of Drosophila. Certain combinations of mutations in this gene caused the duplication of an entire body segment, resulting in flies with four wings rather than two, and eight legs rather than six. The rough location of the region had been localized to specific bands on the polytene chromosome, but biologists were stymied in their efforts to learn exactly where the gene was or how it functioned.

“Dave figured out a way to find the gene based on isolating the DNA sequences within that region of the genome,” said Stanford professor of biochemistry Mark Krasnow, PhD, who was a postdoctoral scholar in Hogness’ lab at the time. In the early 1980s, Hogness published a detailed description of the positional cloning of the Ultrabithorax gene, which he went on to show as a master regulator of development.

“This paper demonstrated the ability to clone the gene underlying any genetic trait, and simultaneously proved there were genes specifically devoted to regulating normal development. It’s one of the great papers in the history of biology,” Lifton said.

“It was immediately apparent how profound this would be for the future of the field,” said Krasnow, who holds the Paul and Mildred Berg Professorship. “It brought a precision and beginning of a molecular understanding that led to the transformation of developmental biology. It was like meeting your pen pal for the first time. These were genes that people had been studying for decades and that had a profound effect on the development of a whole organism. And when we began to understand that these pathways were conserved through evolution — that is, we now had the key to understanding at a molecular level development in all organisms — that was a real ‘oh my goodness’ moment.”

Gentle encouragement, hands-off guidance

Along the way, Hogness recruited and trained countless young scientists with the same particular blend of gentle encouragement and hands-off guidance that he used in raising his sons.

“He was a bit of a laissez-faire parent, in that he let me do whatever he thought I could safely do,” Chris Hogness said. “When I was 14, he let me bike with an older cousin from Stanford to Seattle during the summer. As he did with his trainees, he gave us a fair amount of freedom. He wanted us to develop our own confidence.”

By the late 1980s, Hogness felt that Stanford needed a new department focused solely on developmental biology. He made his case by writing an 11-page white paper outlining his reasoning. He prevailed. One of his first moves was to convince noted researcher Lucy Shapiro, PhD, then chair of the microbiology department at Columbia University, to chair the new department — a position that he had no interest in filling himself. To do so, he flew across the country unbidden, and walked into Shapiro’s lab bearing a dozen yellow roses and a sheaf of blueprints for Stanford’s as-yet-unfinished Beckman Center for Molecular and Genetic Medicine.

“And just like that, I was coming to Stanford,” Shapiro recalled.

Hogness was awarded the Thomas Hunt Morgan Medal by the Genetics Society of America in 2003 and the International Prize for Biology in 2007. He is also the recipient of a Lifetime Achievement Award from the Society of Developmental Biology, the March of Dimes Prize of Developmental Biology and a Genetics Society of America Medal.  

 In 2013, he shared the Warren Alpert Foundation Prize with Stanford professor of genetics and of biochemistry Ron Davis, PhD, and former Stanford professor David Botstein, PhD, for their seminal contributions to the creation of a human genetic map leading to the discovery of thousands of disease genes.

Hogness is survived by his sons.

A celebration of his life is planned for early 2020 at Stanford.