The CEIRS Website is excited to announce a new column, Behind the Bench (BTB). BTB publishes articles written by CEIRS network graduate students and postdoctoral fellows sharing their perspective on influenza-related news, scientific accomplishments, and other issues of interest to the influenza community. Our inaugural column is written by Dr. Jeremy Jones, a postdoctoral fellow in Dr. Robert Webster’s laboratory at St. Jude Children’s Research Hospital. As one of Dr. Webster’s last mentees before his retirement, Jeremy took the opportunity to sit down with him and discuss his early life as a scientist, his contributions to the field of influenza, as well as advice for budding researchers and some insight into his personal life.
There are few who have contributed as much to their field of study as Robert Webster. With over a half century’s worth of research experience, his research has revealed some of the central principles by which we understand influenza viruses today. Fresh off of an amazing retirement celebration in January that featured a symposium with an international panel of influenza experts (many of whom studied under Dr. Webster), I had the opportunity to sit down and chat with him. He reflected on his life, his career, and how in so many ways, influenza has been a major influence.
From the farm to the laboratory
I asked Dr. Webster to start at the beginning and to tell me how he became interested in science. He grew up on a small farm near Balclutha, New Zealand, with 12 siblings, but quickly realized the farm could not support all of them. He made the decision early to go to college and find a career away from the agricultural community where he was raised. However, the farm left an indelible mark on him. “I think the farm formed some of the basis for the rest of my life,” he mused, remarking that it led to many of his ideas on the interactions between animals, humans, and disease. His mother wanted him to become a banker, but having an older brother who was a chemist heavily influenced his decision to enter the sciences. It was during a college lecture series highlighting the role of microbes in human health at the University of Otago that his career focus fully switched to microbiology.
A brilliant discovery
Dr. Webster was introduced to influenza research as a graduate student in Canberra, Australia. That is also where he helped to develop a laboratory reagent now widely used throughout the world. Frustration with trying unsuccessfully to quantify the interactions of influenza viruses with antibodies led Dr. Webster and his advisor, Dr. Stephen Fazekas, to contact the local wool industry seeking various dyes that might be useful in protein staining. “We went through these one after another and found Coomassie [Blue] stained most brilliantly of all of the dyes,” he told me. In 1963, Webster and Fazekas published their results in the journal Biochimica et Biophysica Acta. [Biochim Biophys Acta, 1963].
The bird flu hypothesis – a walk on the beach and the importance of colleagues
I asked Dr. Webster to recount the story of the “beach walk” that led to the discovery that influenza viruses that infect humans originated in animals – most commonly birds. Before recounting the story, he said he would like to talk a little bit about the importance of research colleagues and how one in particular contributed to the tale. In the early 1960’s, Webster worked with his friend, chemist Graeme Laver. “Laver and I were successful because I did the biology and he did the chemistry,” Dr. Webster said, clearly advocating for collaboration. Together, they developed the first influenza subunit vaccine (a vaccine developed using pieces of the virus rather than the whole virus) [J. of Immunology, 1966]. This approach helped to ease side effects associated with early “whole-virus” vaccines and remains the basis of influenza vaccines used today. Not only were the two successful research partners, Drs. Webster and Laver also vacationed together with their families. During one trip, while walking along the beach, they found it littered with dead muttonbirds (shearwaters). Both men, somewhat jokingly, speculated that perhaps the birds died of influenza, as they had recently read the virus had been found in seabirds in South Africa.
Together, they attempted to secure funds to go “flu hunting” at The Great Barrier Reef, a site they knew to be populated with muttonbirds. “It was a great place to visit, fish, go on holiday with the family, and do a little science on the side,” Dr. Webster said with a smile. Laver’s department head felt differently, saying, “You’re out of your mind…if you think I’m going to spend money for Webster and Laver to go to the Reef for holiday!”
Ultimately, Drs. Webster and Laver secured WHO funding to go on their flu hunt. At the Reef, they found birds with antibodies against influenza that were able to neutralize or “attack” human influenza viruses. Later, the pair demonstrated that blood from human flu patients also neutralized avian viruses. The work established a link between human influenza and the infection in birds. This link served as the basis for our understanding of the ecology of influenza viruses today and the recognition of birds as a reservoir from which influenza viruses originate. The research also helped to establish that influenza viruses from different species can mix-and-match their genes, and that such genetic reassortment can trigger pandemics. In addition, viruses collected during Webster and Laver’s early “flu hunts” contributed to the development of neuraminidase inhibitors (such as Tamiflu), one of the few types of influenza therapeutics available today.
Mixing vessel hypothesis
Several years later, Dr. Webster joined the faculty of the newly opened St. Jude Children’s Research Hospital in Memphis, TN. Here, with his colleague and friend Dr. Allan Granhoff, Dr. Webster further explored the concept that influenza viruses from birds and humans could reassort genes to yield pandemic viruses. The two scientists would also introduce the pig as a critical player in this process. St. Jude did not yet have the facilities to work with pigs, but they found suitable space in laboratories at Plum Island, NY. In a series of groundbreaking experiments, they found that avian and human influenza viruses could swap genes inside pigs. The viruses that came out of the pigs were novel, had altered virulence, and could spread to un-infected pigs. Dr. Webster admits they didn’t have much faith that the experiments would work, but these experiments changed the way we think about influenza, particularly how species like pigs serve as a “mixing vessel” for flu to facilitate the viruses’ ability to jump from a bird to a human. The manuscript series describing these experiments was published in the journal Virology [Virology 1971]; however, it was first rejected by the Journal of Experimental Medicine. Dr. Webster often uses this as an example for young researchers running into difficulties with publishing.
The future of influenza research
I asked Dr. Webster to speculate on the future of influenza research and pandemic preparedness. If you’ve heard him speak at a lecture recently, you’ll know he advocates for increased integration of genomics into influenza research, and pushes for more influenza surveillance in animal populations where influenza viruses originate. But one issue that troubles him is the current hold on gain-of-function experiments, which he believes is delaying answering important questions about the threat posed by influenza viruses. He asserts that the moratorium on gain-of-function research must be resolved in such a way that we do not overstate the threat or cause undue fear in the general public. “We are faced with viruses that have potential…they are out there and could transmit into humans and learn to transmit human to human,” he said.
Mother Nature is likely making such viruses on her own, Dr. Webster often says. His message is that we must be vigilant and learn as much about the potential of these viruses as possible. To this end, several groups including the collaborating CEIRS Centers are tasked with characterizing influenza viruses from around the world in a wide variety of experimental models. This risk assessment seeks to understand the threat of emerging influenza viruses to humans. Ultimately, these data will help inform us in the pre-pandemic planning process that includes vaccine development and antiviral stockpiling. “What is the risk of the viruses in the aquatic bird reservoir? Which ones matter? Which ones have potential? What constitutes a virus that will move from one host to another and what constitutes a pandemic virus?” he asked, admitting “the molecular mechanisms are not fully resolved.”
The CEIRS program is playing a key role in answering these questions in great part due to the sharing of viruses, reagents, and knowledge among the collaborating centers, notes Dr. Webster. He recalls the important role CEIRS has played in the past including the response to the 2009 H1N1 pandemic. One example he noted was that the speed at which the vaccines seed stocks were prepared, and the speed at which virus was characterized was due to the work undertaken by the CEIRS Centers. “The strength of the CEIRS network has already been established. The expansion into multiple Centers speaks for itself. The interactions that are going on are really fantastic.”
Personal success and advice for new researchers
When asked to talk about the keys to a successful career in science and what advice he might offer young researchers, Dr. Webster immediately credits his colleagues, collaborators, and the “many, many young people” he’s worked with throughout the years.
“The network of people you set up is absolutely essential to your success,” he noted. “Look at the field and try and find the people who you think have been successful and try to get into their labs. It’s who you know that matters a great deal.” If you train in a good lab, “some of the mentor rubs off on you.”
He also stresses the importance of this being a two-way street. “Really it comes down to be prepared to get in there and work hard and have your ideas accepted as well. Bring your ideas to the table; look for the opportunity to do things for yourself.”
Finally, publish, publish, publish. “You’ve got to publish; everything may not go into a top-rate journal, but you must be disciplined and write up everything you do.” He does have concern about the current level of research support from public and private sources. He recalled early in his career it was much easier to secure funding, and admits young researchers face a different world. Successful funding “will require cross-field and cross-entity research, incorporating academic and private research,” he said.
It is easy to see how family has played a big role in Dr. Webster’s life. Some of his most famous flu stories are intertwined with family vacation. When asked what he does when not thinking about flu, traveling with the family is one of his favorite activities. He’s also an avid fisherman and gardener, the latter of which he attributes to his upbringing on the farm in New Zealand. “It’s a much bigger garden than I need, by far,” he said. However, none of us [his lab members and co-workers] would ever complain, as we often benefit by taking home the excess produce. His sweet corn harvest and summer corn parties are always a hit, and I myself have made a trip to his garden to pick some of the best blackberries, raspberries, and blueberries you’ve ever tasted.
When asked what’s up next for him, he replied, “Persuading myself not to come into work every day. It will be hard because St. Jude has been such a fantastic place to work, lots of good young people to work with and lots of exciting things going on with influenza.” It’s obvious that it will be hard for him to leave the research behind, but he admits it’s time for a change.
The pages needed to fully document Dr. Webster’s life and career exceed what I have available. There are many great tales and scientific accomplishments I’ve glossed over or skipped completely (>700 publications, numerous prestigious fellowships, and the recent establishment of an endowed chair in his name at St. Jude). Luckily, we may not be far from a thorough retelling of his stories. “At my age, if I want to write a book about anything, now’s the time to do it,” he said. In the coming months, he plans to do some traveling with his wife Marjorie in the southern hemisphere, and after that, he’ll go into “semi-isolation” to begin writing.
As I finished up the interview at Dr. Webster’s office table, over which countless influenza projects and experiments have been pondered, I couldn’t help but to also reflect. It’s this same table where we had our first meeting more than 5 years ago. I, a fresh-faced but admittedly nervous postdoc, was sitting down and discussing science with someone I knew was a giant in the influenza field. I came to his lab with a background in influenza and found it surreal to be sitting there with him knowing that he had authored the very first manuscripts my graduate PI had me read. I remember leaving that first meeting feeling privileged to work with him and excited to get started. But there was also a bit of trepidation because I had sheepishly admitted to him that I’d never held a bird of any kind, and he was proposing a set of poultry vaccine experiments that would require using many chickens. It’s likely that this news made him nervous, too. He never showed it and encouraged me onward with the birds. My postdoctoral fellowship with Dr. Webster has just recently come to a close, and I think of the influence he’s had on me as a scientist by imparting new knowledge, a great deal of confidence, and the right amount of independence to grow. For all this, I am very grateful. I imagine many of those who’ve had mentoring or research interactions with Dr. Webster will also recall their time learning from him, reflecting on how he’s made us grow as scientists, and hopefully recalling a few humorous stories and experiences here and there. Should all of these finally end up in a book, I hope to be first in line for an autographed copy.
Fazekas de St. Groth S, Webster RG, Datyner A (1963). Two new staining procedures for quantitative estimation of proteins on electrophoretic strips. Biochim. Biophys. Acta 71, 377-391.
Webster RG, Laver WG (1966). Influenza virus subunit vaccines: immunogenicity and lack of toxicity for rabbits of ether- and detergent-disrupted virus. J. of Immunology 96(4), 596-605.
Webster RG, Campbell CH, Granoff A (1971). The “in vivo” production of “new” influenza A viruses. I. Genetic recombination between avian and mammalian influenza viruses. Virology. 44(2):317-28.
Images of Dr. Webster and Drs. Jones and Webster courtesy of St. Jude Children’s Research Hospital; all other images sourced from Wikimedia Commons.