Biography of Robert A. Lamb

Robert A. Lamb, a professor at Northwestern University and an investigator for the Howard Hughes Medical Institute, has focused most of his research on influenza and paramyxoviruses, two viral families responsible for many biologically and economically important diseases in humans and other animals. His discovery and elucidation of the functions of several viral proteins have transformed the field of virology (1, 2), providing fundamental insight into viral replication and pathogenesis. By analyzing the molecular basis of viral processes, such as membrane fusion (3–5) and ion channel activity (6–8), Lamb's research has laid the groundwork for developing new vaccines and therapeutic drugs. His viral studies have also advanced basic understanding of how cells work.

Figure 1.

Robert A. Lamb, photograph taken in 2003.

Lamb's dedication to furthering scientific knowledge extends outside the laboratory as well, as is evidenced by his dedication to teaching and his commitment for the past 9 years as editor-in-chief of the journal Virology. He has won numerous awards for his accomplishments, including the 1990 Wallace P. Rowe Award for Excellence in Virology Research and consecutive 1987 and 1997 MERIT awards, all presented by the National Institutes of Health. This year, Lamb was elected to the National Academy of Sciences. His Inaugural Article, titled “Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion,” is featured in this issue of PNAS (9).

Mentorship, then Partnership

Lamb's uncle, a successful chemist, encouraged Lamb from a young age to follow in his footsteps. By the time he had entered high school, Lamb's curiosity and ability as well as the family's guidance had steered him to the field of biochemistry. He chose to attend the University of Birmingham (Birmingham, U.K.) for his undergraduate degree, he says, because the college had the best biochemistry department in Britain at that time.

Lamb's interests gradually narrowed to virology while he was in college. Upon his graduation, he immediately entered a Ph.D. program in virology at the University of Cambridge (Cambridge, U.K.). “I decided that I wanted to work on viruses from a self-interest point of view. They infect humans and they cause human disease, and I thought there would always be employment in this,” said Lamb.

Unlike the American Ph.D. system, which allows students a flexible amount of time to complete their degrees, the British system provides funding for only 3 years. Within these time constraints, Lamb completed a doctoral thesis under the mentorship of virologist Brian Mahy (10). The thesis defined proteins produced by Sendai virus, a mouse pathogen closely related to the virus that causes measles and mumps, and helped elucidate how Sendai virus replicates.

Upon graduating with his doctoral degree in 1974, Lamb began a postdoctoral program in virology at The Rockefeller University in New York under Purnell Choppin. Lamb stayed at Rockefeller for 8 years, first as a fellow and then as an assistant professor. During this time, Lamb was unfettered by teaching or administrative responsibilities and thus could pursue his own research interests. “You were encouraged to be independent and think creatively. (Choppin) had a big checkbook, and he paid for the experiments, so you could do what you wanted. I thought this was a great life,” said Lamb.

Together, Lamb and Choppin published 22 papers. The pair focused their research on sequencing viral genes, including the neuraminidase gene of influenza B (11), and identifying and characterizing several viral proteins, such as the influenza A virus M2 protein (12). M2, which spans the viral membrane, remains a focus of Lamb's current research efforts. Lamb's studies have shown that this protein is an ion channel (6), shuttling protons across the viral membrane to dissociate protein interactions inside the virus.

M2 was the first, and until recently the only, ion channel ever seen in an animal virus; Lamb's laboratory discovered just this year that BM2, a membrane protein of influenza B virus, is also an ion channel (13). Both proteins are imperative to influenza A and B virus infectivity and replication, and drugs that inhibit them have the potential to effectively treat influenza. For example, Rimantadine, a licensed antiviral drug that targets M2, can prevent or treat influenza. Lamb and other scientists continue to study M2 and BM2, not only for the development of other therapeutic drugs but also as a model for other ion channels in viruses and cells. “They really alter the way we think about how these viruses work,” said Lamb.

Close-Knit Collaborations

During his time at Rockefeller, Lamb took part in several productive collaborations and forged other influential relationships, including meeting his future wife, fellow virologist Reay Paterson. “She came to Rockefeller for a visit, and shortly afterward she decided to come to the USA from Scotland to work with me,” said Lamb. In the early 1980s, Lamb received an offer that would lure him away from Rockefeller, an associate professorship at Northwestern University in Evanston, IL.

Lamb felt his interests would mesh well with the school's other faculty, and he was excited about the possibility of running his own laboratory. However, with his limited knowledge of the U.S., he had never previously considered moving to the Midwest. “Actually, I wasn't quite sure where it was. I assumed everyone who did scientific research lived on the coasts, more or less,” he said. A visit to the campus gave Lamb more geographical and personal perspective, leading him to accept the offer, and his laboratory at Northwestern has been operating now for just over 20 years.

Lamb's dislike of long-distance collaborations inspired him to gather a strong group of in-house collaborators, both within his laboratory group and in other departments at Northwestern. One of his most frequent collaborators, Northwestern neuroscience professor Lawrence Pinto, has studied ion channel proteins with Lamb for 11 years. Several members of Lamb's own research group have worked at the laboratory for at least 10 years, including Paterson, who has been a part of Lamb's laboratory since its inception. The group's longevity has lent the laboratory a sense of stability. “When you've got a sort of institutional memory of what was done in the lab years ago and where reagents are that might still be useful, it's really a tremendous asset,” said Lamb.

Figure 2.

George P. Leser, Charles J. Russell, and Makoto Takeda are currently collaborating with Robert Lamb.

Thwarting the Viral Mission

Each member of Lamb's laboratory studies viruses, with specific focuses on the structure and function of integral membrane proteins, such as M2, and the mechanisms of viral infection and replication of influenza and paramyxoviruses. Members of these two families consist simply of a single strand of the nucleic acid RNA enclosed in a lipid envelope. Although viruses are not considered alive by common standards, their one “mission,” if the word applies, is to create additional copies of themselves. To do this, a virus must get its RNA inside a cell and commandeer the cell's machinery, converting it into a temporary factory that churns out viral copies. When the new viruses leave the original cell, they infect more cells, and the cycle starts anew.

Scientists have long understood these basic tenets of viral infection and replication; however, many of the molecular mechanisms that drive each step, RNA entry, viral assembly, and viral exit, remain unresolved.

Lamb's research has made great strides in elucidating how viruses work at the molecular level throughout every point of the cycle. For example, in 1997, Lamb's group devised a way to prevent new influenza viruses from leaving their host cell, effectively holding the viruses hostage at the end of their replication cycle (14). Unlike some viruses, which forcefully explode from host cells when replication is complete, influenza viruses peacefully bud from the cell surface. Earlier research had highlighted the importance of two viral membrane proteins, hemagglutinin and neuraminidase, exiting from host cells. After genetically disabling either of the proteins, the researchers found these viruses had slight difficulty budding from cultured cells. However, when both proteins were disabled, the number of viruses exiting from the cells dropped by 90%, with remaining escapees severely deformed. Because the deformed viruses were much less likely to infect new cells, this research suggests that hemagglutinin and neuraminidase are critical to continuing the viral replication cycle.

Later, in 1999, his group gathered key structural evidence to show that the “fusion protein” of paramyxoviruses, a membrane protein needed for these viruses to fuse with and enter cell membranes, is strikingly similar in paramyxoviruses, influenza, and HIV (5). His laboratory, together with Northwestern biochemistry professor Ted Jardetzky, created a detailed picture of the paramyxovirus fusion protein by using x-ray crystallography. Although the different viruses are unrelated in terms of genetic makeup or disease, this research hints that they share a common mechanism for fusing viral and cellular membranes.

Lamb adds another piece to the viral exit puzzle in his Inaugural Article (9), in which he continues research on influenza hemagglutinin. For more than 30 years, researchers have known that hemagglutinin tends to associate with clumps of lipids, now known as “lipid rafts,” which float on host cell surfaces. To determine whether this association is necessary for budding, Lamb and his colleagues genetically altered some influenza viruses such that their hemagglutinin was no longer attracted to the rafts. Much like the 1997 experiment, these mutants bud less effectively from cells. Because hemagglutinin has proven to be an essential part of viral escape and entry, Lamb suggests that this protein gathers at lipid rafts to provide a sufficient concentration in the budding viruses, resulting in efficient entry into the next target cell.

Foundation for the Future

Throughout the course of his career, Lamb's research has gradually shifted from sequencing viral genes and characterizing protein structure to making use of this material through data-mining techniques. Most of Lamb's current research efforts, including his Inaugural Article (9), rely heavily on the extensive body of his own previous work. As new viral threats surface, including the potential use of smallpox as a bioterrorist weapon and “emerging” viruses such as Ebola and West Nile, Lamb's findings take on renewed importance.

Despite the value of current knowledge, Lamb emphasizes that many viral functions are still not yet understood, leaving much work to be done. “At the end of the day, we're trying to understand how viruses work,” he said.