Biography of Rafi Ahmed
Before publication of a 1994 paper in Nature, most immunologists thought of Rafi Ahmed as a virologist, even if one beginning to work in the emerging field of viral immunology. Ahmed’s Harvard PhD and his Scripps postdoctoral work had been entirely in microbiology and, specifically, how individual viruses behave. Soon after joining the faculty at UCLA, however, he had realized “the really interesting questions are how our bodies attain and maintain immunological memory, regardless of the virus involved.”
Soon after joining the faculty at UCLA, however, he had realized "the really interesting questions are how our bodies attain and maintain immunological memory, regardless of the virus involved."
Ahmed made himself an immunologist. The Nature paper – one that started to answer one of the basic questions in immunology -- made him a famous one. In the early 1990s, the immunological world began watching the newcomer to the field closely. So did Emory University and the Georgia Research Alliance, jointly committed to creating, from the ground up, a world-class vaccine center in Atlanta.
But that is getting ahead of our story.
Coming to America
Rafi Ahmed grew up in Hyderabad, India. His father worked for the state government, his mother an active community volunteer, focused on improving the lives of women. Hyderabad was renowned for its culture, cuisine, and hospitality. The Ahmed house was always filled with company and activity. At its center of hubbub was young Rafi, an only child until he was 20, already away in school, when his parents adopted baby sister Kulsoom, who now lives in Toronto.
The household language was Urdu, but Rafi learned English at four, at the Most Holy Rosary Convent kindergarten, one of the nun-run Catholic schools then popular in India. He continued speaking English at Saint George’s Grammar School. (He still attends reunions of Saint George graduates living in the United States.) At 12, he entered a boarding school, which, like many schools based on the English system, required students to live in dormitories and not see their parents, except for holidays, for more than an hour per weekend.
It was there that Ahmed became fascinated by his first microscope. He also liked chemistry, reading both comic books and history, but his forte was racquet sports and also cricket. He was a good spin bowler, a position like pitcher in baseball.
After graduating from Osmania University in his hometown, he moved in 1970 – choosing the place for no particular reason other than it was somewhere in America -- to Pocatello, Idaho, a town a fraction the size of Hyderabad and many times colder. Ahmed’s university education in India had focused entirely on biology and chemistry. As a student at Idaho State University, he filled in the chemistry, physics, mathematics and other courses needed to enter an American graduate program in microbiology.
His mountaineer roommate, Paul Ahart, with whom he is still in touch, took him camping. He learned to ski. He spent Thanksgiving, Christmas, and other holidays with an American host family in Pocatello, Roger and Donna Boe, with whom he also remains close.
Becoming a virologist
In 1974, with Idaho State bachelor’s and master’s degrees in hand, Ahmed moved to McGill University in Montreal to begin a doctorate in microbiology. But after two months working with bacteria, he felt unsure of his direction. He decided to withdraw from school and work while he thought about his future. Virologist Angus Graham, chair of biochemistry at McGill, offered the young dropout a position as a low-level research assistant. He also kept an eye on him and he liked what he saw. Within a month, Graham had assigned Ahmed his own research project.
Graham encouraged his protégé to go back to school -- to the best school that would admit him. Homesick for the United States, Ahmed chose Harvard. Before moving to Boston, he flew to Karachi, Pakistan, where he met and married the woman his parents had chosen as perfect for him. Their instincts proved good.
So did his choice of Harvard, “very special years,” he recalls, smiling. In 1981, after four years in the laboratory of famous Harvard virologist Bernard Field, Ahmed got his Ph.D. and headed to Scripps Institute in La Jolla, California for postdoctoral studies. Because by now he had become interested in viral immune responses, Michael Oldstone’s laboratory seemed – and turned out to be– the perfect place.
Three months after settling into his postdoctoral training, he received a call from UCLA’s new chair of microbiology and immunology Jack Stevens. Stevens was looking to recruit an expert in immune responses to viruses. When Ahmed demurred – “I just started my postdoc” – Stevens told him to finish whatever training he thought he needed. UCLA would hold the job. Three years later, in 1984, he, wife Lala, and infant son Hasan moved to Los Angeles, which still ranks at the top of their favorite cities. Daughter Fatima was born a year later.
Ahmed recalls, "It was my first introduction to a real research lab, my first exposure to virology, and my first opportunity to see the life of a scientist up close. Everyone was so excited, having so much fun. I knew I had found what I wanted to do."
Focusing on T-cells
At UCLA, Ahmed began working with T-cells, a type of white blood cell, able to recognize and destroy invading pathogens like viruses and intracellular bacteria. In 1988, he published a paper in the Journal of Experimental Medicine that focused on the ability of the T-cells to respond more quickly and more vigorously to pathogens they have encountered before than to those they are seeing for the first time. The paper showed that this immune T-cell memory, as it is called, turns out to be much longer-lived than anyone had thought. Although the paper did not cause a particularly big splash, as many of his later papers would do, it irrevocably turned Ahmed’s research interest toward the surprising persistence of immunologic memory.
The article also paved the way for the groundbreaking paper that appeared in Nature six years later, titled “Cytotoxic T-cell memory without antigen.” Authors with Ahmed were his graduate students Lisa Lau and Beth Jamieson (first author of the earlier long-life T-cell paper described above), and T. Somasundaram. This paper showed, also surprisingly, that T-cell memory was not only long-lived but could persist on its own, independently of whether or not antigens were still present. This was the first demonstration that longevity of memory was a cell intrinsic property.
If the first T-cell paper had turned Ahmed’s research interests in new directions, this paper changed the direction of numerous immunology laboratories.
Making the Emory gamble
Ahmed had become an immunological superstar almost overnight, and a number of prestigious institutions came knocking on his door. But he had no interest in leaving UCLA. The department was supportive, and his wife and children loved Los Angeles as much as he did. Little wonder colleagues and friends were surprised when he even accepted the invitation of Emory microbiology and immunology chair Richard Compans to visit the Atlanta campus. And they thought he had completely lost his mind, recalls Ahmed, when he announced he was giving up the status of UCLA for a smaller, less-recognized school that didn’t even have a building for the vaccine center its leaders were talking about so grandly.
But Ahmed followed his gut. His work on the fundamental question of immune memory, the basis of vaccination, made a vaccine center a perfect match for his interests. And, even if his colleagues couldn’t see them, he saw the signs for success at Emory.
First, he was impressed by the enormous commitment to creating an internationally-regarded vaccine center, a commitment not only by Emory but also by state leaders. The Georgia Research Alliance had been established to work with Georgia research universities to build the research infrastructure needed to make Georgia a leading center for bioscience and technology. A key part of the plan was to attract some of the world’s most brilliant scientists to Georgia, then provide them with the tools and facilities they needed to succeed. If Ahmed would come build Emory’s vaccine center and serve as its director, he would be among the first group of Georgia Research Alliance Distinguished Professors. The Governor himself assured Ahmed that the GRA would provide him with every resource possible. The GRA president secured spots for the Ahmed children in the city’s best schools and tried to allay the (considerable!) doubts of his family about the possible move.
The second appeal of Emory for Ahmed was the potential partners for the vaccine effort. The Centers for Disease Control and Prevention literally abuts the University, with CDC and Emory faculty strolling back and forth between the two campuses where they often hold joint appointments and share research projects, many in infectious diseases. The new but rapidly growing Rollins School of Public Health was another resource, one that would help with biostatistics and public policy. And, perhaps most importantly of all, Emory has one of the country’s eight National Institutes of Health-funded regional primate research centers, providing non-human primate models for vaccine development.
Tom Insel had just been recruited as Yerkes Regional Primate Research Center director, coming from the NIH’s National Mental Health Institute, to which he would later return as director. Before either of them arrived in Atlanta, Ahmed’s and Insel’s phone conversations back and forth determined that the new Emory Vaccine Center – at the moment little more than a name – would be located on the Yerkes campus, a short leafy walk from the Emory medical campus, and that the initial, primary focus of the center would be HIV/AIDS.
Working by phone, Ahmed, Insel and Yerkes research director Tom Gordon put together a construction grant proposal. The National Institutes of Health awarded them $1.25 million, to be matched by $1.25 million from Emory. It was a good start, but hardly enough for a facility needed for the vaccine center plans growing daily. True to its word, the GRA provided an additional $2.5 million, which Emory again matched. With the new facility on the drawing board scheduled, Ahmed began recruiting some of the most outstanding people in the country, many still there (see http://www.vaccines.emory.edu/faculty/index.html).
Discovering exhausted T-cells - and how to re-energize them
While building the Vaccine Center, Ahmed continued his own work. The cascade of papers were a roadmap to a new understanding of how T-cells function and how this functioning could be improved.
- Immune response to an acute infection is an immediate and intense battle with the host winning. But what happens when the infection becomes chronic, going on and on and on? Ahmed’s lab was the first to demonstrate t-cell exhaustion in chronic infection. A 1998 paper with postdoc Allan Zajac reported the discovery that T-cells remained present after long periods of infection (it had been wrongly assumed that the infection had wiped them out) but, exhausted from their long fight against infection, were no longer able to function. This work done in mice was quickly extended by other labs in chronic human infections such as HIV, HCB, and HBV. This observation was also seen in cancer, as t-cells that infiltrate tumors – presumably trying to eliminate them – also become exhausted.
- If T-cells become exhausted and lose function, as the Ahmed laboratory had now demonstrated, the big question naturally was whether or not strategies could be devised to restore function. The paper for which Ahmed is being recognized as a Game Changer, published with Dan Barber, in Nature in 2006, definitively showed that it could.
PD-1, a real Game Changer
The team then set out to discover the difference between functional T-cells and exhausted, non-functioning ones. To do this, the laboratory analyzed the genes expressed in virus-specific T-cells of mice chronically infected with the lymphocytic choriomeningitis virus compared with the gene expression of functioning T-cells in mice that had cleared an acute infection. When the gene profiling data came back to Ahmed’s lab, showing that the expression of Programmed Death 1, or PD1 for short, was higher in exhausted cells than in functioning cells, Ahmed had to go back to the literature and read up on exactly what PD1 was and did.
PD1 is an inhibitory receptor, a kind of brake on the immune system. If PD1 was the brake, could it be removed?
Yes, said Ahmed. The 2006 Nature paper describes how using antibodies to block this inhibitory receptor enhances flagging T-cell function. Ahmed considers the paper, written with then graduate student Daniel Barber, one of the most influential papers of his career. He is not alone. This paper linking T-cell dysfunction with the PD-1 inhibitory receptor and showing that removal of this brake can rejuvenate exhausted T-cells has been highly influential in the clinical development of PD-1 directed immunotherapy for the treatment of human chronic infections and cancer.
Today the biggest excitement in terms of translational and clinical implications, says Ahmed, lies in the data coming out in oncology clinical trials, with extremely promising results of PD1 blockades in patients with melanoma and non-small cell lung cancer. He believes that PD1 blockade treatments will be licensed within the next year or two for these particularly virulent and hard to treat cancers.
The Emory Vaccine Center: from dream to pre-eminence
And that vaccine center that was in the late 1990s was little more than a dream and determination looking for a leader? Mike Cassidy, current president and CEO of the Georgia Research Alliance, says the GRA knew it was recruiting a talented and visionary scientist, but the GRA and Emory got even more than they could have hoped for.
Under Ahmed’s continuing leadership, the Emory Vaccine Center is now the largest academic vaccine research center in the world, with more than 30 faculty 250 (including five GRA Eminent Scholars) and a research staff of nearly 250, laboratories in New Delhi as well as Atlanta, and more than $500 million in research funding over the past 15 years alone. Not only the largest vaccine center, the Emory Vaccine Center is also the most comprehensive, spanning the entire spectrum from basic vaccine discovery science, to nonhuman primate studies, to clinical trials and vaccine evaluation in humans through the Hope Clinic headed by Mark Mulligan and public policy vaccine work headed by Walt Orenstein.
Originally best known for its extraordinary contributions related to the development of vaccines for HIV/AIDS, the Emory Vaccine Center is now recognized for additional strengths in vaccines against hepatitis, malaria, tuberculosis and influenza (playing a big role in identifying antibodies in highly conserved regions of flu virus with the idea of developing a flu vaccine universally affective). Recent work focuses on rejuvenating the exhausted immune response to chronic viral infections and cancer. Ahmed believes the most powerful future of PD1 therapy lies in cancer vaccines, a combination he believes will be transformative.
And, as the organizers of GRA had hoped its scientists would do, in 1992, the Emory Vaccine Center also spun off the biotechnology company GeoVax, based on work done by Harriet Robinson, specializing in the creation, development, and commercialization of human vaccines to combat HIV/AIDS. GeoVax has generated more than 100 jobs, millions in research funding, and 15 patents as of 2014. GeoVax currently is involved in phase two clinical trials (the phase that tests whether a drug shown to work in animals has a biological effect in humans) of a drug developed at Emory that holds significant promise in the prevention and treatment of AIDS.
Ahmed has never regretted his gamble on Emory, and the move turned out well for his family as well. After completing his BA in economics at the University of Chicago, son Hasan returned to Emory to complete a MPH in biostatistics at the Rollins School of Public Health. He now works at the Fred Hutchinson Cancer Research Center in Seattle. Daughter Fatima did her bachelors in English at Emory and is now working on a masters of fine arts in creative writing at Florida State University. When the children left the nest, wife Lala also returned to school and is now a Montessori teacher.
For Ahmed himself, honors continue to pour in, from a distinguished professorship at Emory to induction in the National Academy of Science. He is sought after worldwide as a consultant and lecturer. But the best part, he says is watching his work, his students and colleagues, and the Emory Vaccine Center continue to change how infectious disease and cancer can be treated and prevented.