Structural Biology, Virology
Dr. Lamb is also John Evans Professor of Molecular and Cellular Biology at Northwestern University, Evanston, and professor of microbiology-immunology at Northwestern University Feinberg School of Medicine.
Structure and Replication of Influenza Virus and Paramyxoviruses
Robert Lamb attributes his interest in science to his uncle, a chemist who studied volatile organo-fluorine compounds. "Whenever his experiments went wrong," Lamb says, "two [safety] walls of the lab dissolved."
But what impressed Lamb most was that his uncle, though he did not discover the compound, found the conditions to create the first block of Plexiglass (Lucite) ever made. Yet the successful chemist advised Lamb to take a slightly different career path. Lamb recalls, "He said go on and be a biochemist. It's the up-and-coming field."
So Lamb studied biochemistry as an undergraduate at the University of Birmingham in England, then virology as a Ph.D. student at the University of Cambridge. He is now a leading expert on influenza viruses and the paramyxoviruses, the latter a group of viruses that cause measles and mumps and many respiratory diseases in humans, canine distemper in dogs, and Newcastle disease in chickens. These viruses threaten agribusinesses and human health on a global scale. His quest to understand them, Lamb says, has kept his research interesting and relevant.
Through his studies of virology, Lamb addresses problems that impact the general population and relate to many scientific fields. "Viruses make people sick, and humans are selfish. We'll find ways to cure ourselves," Lamb says. He collaborates with cell biologists, electrophysiologists, and protein crystallographers to supplement his area of expertise. "I've worked on viruses since 1974, but I've been all over the place—that's what keeps you alive intellectually. You've got to keep moving, and when new types of technologies come along, you embrace them."
When Lamb began his Ph.D. program at Cambridge in 1971, he studied Sendai virus, a paramyxovirus that affects rodents. Lamb worked with Brian Mahy, whom he remembers as a young, enthusiastic mentor. "He taught me that you can do things apart from science, and do them well," Lamb says. Following Mahy's advice, Lamb became the chairman of his college's junior common room—the British equivalent to the head of the college's student body. The position taught him to represent the interests of a diverse group of people, a skill that he uses now when he manages his lab.
As a Ph.D. student, Lamb learned about slab gel technology, a method invented at the Laboratory of Molecular Biology in Cambridge to separate protein molecules, which is now a standard procedure in every biological science lab. As a young virologist, Lamb used slab gels to separate the proteins of paramyxoviruses; information about the viral makeup guided further research and, eventually, treatment. When Lamb moved to the Rockefeller University to start his postdoc, he brought slab gel technology with him.
At Rockefeller, Lamb worked with Purnell Choppin. (Choppin would become the president of HHMI in 1987.) In 1981, Lamb and Choppin discovered a protein, which they called M2, that Lamb later showed was the first known ion channel in an animal virus. The influenza virus uses M2 to reproduce and infect a host. Lamb and his collaborator, Lawrence Pinto, found that the drug amantadine, which doctors were using to treat influenza, works by blocking this channel. Lamb and others can now use M2 as a model for ion channels in viruses and cells, and to improve drugs like amantadine that obstruct these channels.
In 1983, Northwestern offered Lamb a tenured position, which he took. The university was a good fit—it had abundant financial resources, which allowed Lamb to be creative with his research. He focused on viral membrane proteins and viral reproduction. Typically, the influenza virus infects a host cell, cannibalizes the cell's mRNAs and hijacks the cell's protein synthesis system to produce more viruses, then buds out of the cell membrane to infect other healthy cells. In 1997, Lamb and his lab members discovered that if they disabled two viral membrane proteins, they prevented the influenza virus from leaving an infected cell. Lamb has continued to build on this work to develop an influenza vaccine.
By 2007, Lamb and his colleague Ted Jardetzky at Northwestern had mapped the structure of the protein that paramyxoviruses use to fuse to a cell in the first stage of infection. Once they knew its structure, they could tell that the viral protein completely changes form when fusing. It first reaches out, hooks, then pulls back the host cell's membrane, morphing its own shape in the process. The viral fusion protein gains energy as it folds, like a compressed spring, but somehow holds this unstable state for long enough to bind to a host cell.
Lamb wants to know how the virus knows to sacrifice stability of the viral fusion protein so that later it can do the work of fusion, and how it knows when to activate the fusion protein. If it doesn't reach, hook, and pull at the right place at the right time, the process terminates, and the virus can't infect. Further studies of paramyxovirus fusion could guide vaccine development by helping researchers understand how other viruses enter cells.
While Lamb spends most of his spare time helping his children with their homework or watching their soccer games, sometimes he stays late in the lab to learn more about other proteins in the paramyxoviruses he studies. He likes going to the big synchrotron (at the Argonne National Laboratory, in a Chicago suburb) and watching the beamline—a long, pipe-like apparatus that shoots a shaft of light at particles that have been crystallized. Lamb watches the diffraction pattern of the light as it hits a crystalline form of a paramyxovirus protein—though all he really sees is lines and numbers on a computer monitor, the disjointed building blocks of the viral structures that he and his colleagues will later piece together. Lamb explains, "I'm there for moral support," (his postdoc and his collaborator Ted Jardetzky usually work the device), "but mostly it's just fun seeing the data collected."