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					Pramod K. Srivastava

The Scientist
By LAILA KAIN

I

n India, Ganesha is the God of Beginnings. He is the son of the god Shiva and his consort. His elephant head evokes wisdom, his belly, prosperity. He can, worshippers say, remove any snag, any hindrance, any obstacle that endangers

the start of any project. He is sometimes shown strong as the elephant trampling the forest, wily as the rat robbing food from the kitchen. Ganesha protects writers, poets and students, because for them, life is a never-ending stream of beginnings: a blank page, an open book, a new lesson to learn.

A tiny statue of this Hindu protector guards the computer belonging to Pramod K. Srivastava, Ph.D., in his office on the sixth floor of the Research Building at the University of Connecticut Health Center in Farmington. It's a fossil-colored, windowless study, littered with the debris of academic inquiry -papers strewn on every surface, charts tacked onto the walls, photos, poems, books everywhere. To the right, a moveable electronic whiteboard big as a blackboard stands scribbled with notes; a wide-screen videophone, on a rolling cart, rests just a few feet away. Lab coats hang on the door. Coffee cups sit, abandoned, on shelves. A framed map, half unwrapped, leans against a leather armchair. "Welcome to the bus station," Srivastava says, at least half in jest, waving away any possibility of his ego being taken too seriously. A gentle man with lively eyes, he's dressed in a long, loose, light Indian shirt, tan slacks, wool socks and sandals. Yet each item in view is a clue that he is more, much more than meets the eye. The papers, charts and scribbles on his smart-screen speak to his engagement with the problems and schedules of his work as professor of medicine and director of the UConn Center for Immunotherapy of Cancer and Infectious Diseases. For more than two decades, he has worked in the forefront of cancer immunotherapy -- using the body's defense system against the disease. His use of common heat-shock proteins (HSPs) is unique in the field of individualized vaccines. The results of his research are being tested across the United States, in Great Britain and Europe. His vaccines are moving into stages II and III of the three-step clinical

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trial process. A chief supplier of these therapies is Antigenics, the company he helped found and where he also serves as chairman of the Scientific Advisory Board. The half-wrapped map in his office details all biotech companies in the Boston area, including Antigenics. The videophone offers instant access to his offices in Boston and New York and to conferences worldwide. The lab coats are on-call for research work; the tie's there in case visiting dignitaries or photographers arrive unexpectedly. The chair opens into a sleeper in case he doesn't make it home at night. Why then, would this worldly man of wide accomplishment want Ganesha close at hand? Because this scientist, businessman and father of a seventh- grader has gone back to school. Medical school. At age 48, Srivastava is a second-year student at UConn medical school, just another student with a doctorate in biochemistry, a master's in paleontology, undergraduate degrees in botany, zoology, chemistry and English; just another student who speaks English, Hindu, Urdu, Bengali, basic Japanese and reads elementary French and German; just another student who runs a research center. Ask him how school's going, and he pauses, closes his eyes in thought, then confesses, "The first year was painful, very painful. It's better now." The pain, he explains, was caused by the sheer volume of work and the way it clashed occasionally with his habits as a researcher. Taking tests, for example, requires only the most probable answers, he says. "They want to know is the answer a, b or c? Being who I am, I find myself wondering whether the answers might be x, y or z. In research, a quick answer is a bad thing." Actually, his entry into medical school is a return to the career he fled in India. "At 17, I thought it was a torment," he remembers. Times change. Today he looks forward to "learning the language of patient care" as well as better understanding the workings of the human body, disease and medicine. He looks forward to years three and four, then a residency in his field of choice. "It's weird, isn't it? I thought he was kidding when he talked about med school," says Dr. Zihai Li, Ph.D., M.D., a former student, longtime friend and now fellow professor. "Then he surprised everyone, even myself.

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"I should have known better. There's nothing conventional about him. That he can do so many things at once is amazing; he's multi- dimensional." An understanding of this protean quality, in the eyes of another longtime friend, may be cultural. "Western culture teaches you to be linear," says Rajiv Chandawarker, M.D., an independent surgeon and researcher at the cancer center and Pramod's friend since the early 1990s. "Western food, for example is served in courses, first, second, third. "In the Far East and Asia, we see things laterally and all at once: Indian food, for example, is multi-flavored and complex. "Success may be the balance between the two -- and Pramod may be the embodiment of that balance.

An Indian Childhood In an unhurried pace, Srivastava begins the story of his life in the town of Allahabad, northern India, where he was born in 1955. A major pilgrimage center, the ancient city was the site of the first Indian National Congress in 1885, and the birthplace of Mahatma Gandhi's nonviolent movement in 1920. His father was a civil servant and retired Army officer. His mother died when he was 2 1/2 years old. The youngest of four children (joined later by a stepsister), Srivastava remembers being raised by his father and elder sister Urmila. His brother Vinod grew up to be a neurosurgeon. Accomplishment was expected as a member of the Srivastava family, belonging to the Kayastha caste in India, in ancient times comprised of clerks and scribes, today including doctors, lawyers, civil servants and other professionals. As a child, he recalls the first time his Indian values came into contact with another way of thinking (and his first images of the United States). "It was a summer afternoon; I was 10 or 12 years old and looking for something to read in my uncle's house," he remembers, speaking his memories aloud, as if only to himself. "What I found was a U.S. Information Agency booklet, illustrated with stunning American landscapes and describing the nation's history and government. "I remember being amused but intrigued by the idea that the American Constitution was premised on the belief that `all men are created equal.'

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"Although I was by then fully conversant with the Hindu belief that all creation, including all sentient beings, are manifestations of the same consciousness, I had never considered that idea as the basis of a political document and became very, very curious" about a country that would create political instruments based on such beliefs. "That intense interest in and curiosity about America has never left me. It still quickens my pulse." Curiosity was his constant companion as a child. "Whenever I heard a new word, I wanted to know what it meant; I wanted to learn its origin." His fascination with words drew him into the realm of poetry in a public as well as a private way. "When I was growing up, the entire town used to show up when famous poets arrived," he explains. "Our poetry began at 8 o'clock in the evening and often lasted until 3 in the morning." Brief by comparison, the summer Sunken Garden Poetry Festival at the Hill-Stead Museum in Farmington is nevertheless valued deeply by Srivastava, who continues to read and occasionally write poetry on his own. Among the few personal items in his office at UConn is a framed copy of Seamus Heaney's "The Republic of Conscience." Like the Nobel Prize-winning poet from Ireland, Srivastava, believes that, "There is no life without poetry." To this day, he requires the reading and dissemination of a poem at the end of weekly lab meetings on Monday afternoons. "Poetry comes from the heart, not the mind," he says slowly, as if just discovering the thought. "And while we must use our minds wisely, we must never forget our hearts."

Science: A Shining City Like poetry, science was prized in the world that raised him. "When I was growing up, my local newspaper carried biographies of scientists in every weekend edition." Science and mathematics were the jewels in the crown of Indian history. Long before the European Renaissance, India had grasped key concepts such as the idea of zero, the decimal system and the correct measurement of pi. Indeed the numbers we refer to as "Arabic" (1-9 and beyond) entered the Arab world via Indian sources, and

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thence to Europe. The idea of abstract numbers, refinements of trigonometry, calculus and even the concept of infinity can be traced to Indian sources. "When I was a child, science seemed a glorious thing to do," Srivastava remembers. "It was the shining city on the hill." He remembers the very moment when he knew he would reside in this shining world for life. "I was not yet 13 and it was evening when my father and I took our customary after-dinner walk around the university grounds in Allahabad. It was nearly midnight, and we noticed that all the buildings were dark, except for one laboratory in the physics department. "A lamp poured bright light into the night and onto a desk where a lone man was working. I was mesmerized; the desire to be a scientist tugged forcefully at my young heart." Eventually, he would work similar hours in a similar lab, headed by the demanding paleontology Professor Pant. (Divya Darshan Pant was chairman of the Department of Botany at the University of Allahabad.) The hours were long, the work intense, "and I was charmed," Srivastava recalls. "There was energy in the air. It was vibrant, vibrant." During the days and nights working in Professor Pant's labs, Srivastava grew curious as to the reasons behind the evolution shown so clearly in the fossils at hand. To learn more, he pursued graduate work in genetics and biochemistry, studying at Kolkata University's Bose Institute in eastern India, at the Center for Cellular and Molecular Biology in Hyderabad, southern India, and at Osaka University in Japan.

Cancer, at First Glance It was in Hyderabad that a casual invitation changed the course of his life. In a nearby lab, a friend working with a scanning electron microscope asked Srivastava if he'd ever seen a cancer cell. "No." "Well, come look." He did. He was astonished by what he saw.

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"I couldn't get over how weird, and strange, the cancer cells looked, how different from the normal cells, how wildly disorganized, bizarre they were," he remembers. Intrigued, he wondered if the very composition of cancer cells was different from normal ones; experiments showed this was not the case. In reading recent works in this area, he came across longstanding results in the field of vaccination. "Mice and rats had been vaccinated against cancers just as easily as one vaccinates against smallpox and polio." "The ability to vaccinate suggested that the cancers themselves contained something that made the vaccine possible," he says. This vaccine concept -- that the seed of success lies within the disease itself -- is basic to immunological thinking. The next step was to find the mysterious entity within cancer cells that could make vaccination possible. Srivastava started searching for answers: harvesting tumor tissues, shredding them into tiny shards, testing each shred as a possible vaccine, documenting the results, all as a side project to his graduate work. In 1982, he identified heat-shock proteins (HSPs) as possible ingredients for success. Present in every cell of the human body, HSPs function like modern-day soccer moms: keeping the cellular "household" in working order, tidying up other proteins, folding them in line, even driving them from one place to another. In Srivastava's experiments, the HSP-based vaccines extracted from cancer tissues seemed to succeed, while the same HSP vaccines extracted from normal tissues did not. The question was why. As the answers eluded him, another opportunity opened -- returning him to his earlier specialty: genetics. In Search of the Best Meeting Professor Alan Garen of Yale University led to a post- doctoral fellowship in the United States at Yale. The idea delighted him. "I knew that the best science anywhere was being done in America," he says. "I could hardly wait to see the country I had read about as a child." He also longed to return to genetics. Setting his HSP work aside, he headed for New Haven and began working with Garen, whose fruit-fly study is still considered a landmark in genetics research. At Yale, he remembers being "a happy fellow on campus," inspired by the university community, its concerts, lectures, movies and more. In the lab, it was dismally

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different. "Everything felt so mechanical, so driven by the need for generating data -so seemingly devoid of intellectual inquiry." Seeking change, he sent a copy of his HSP research to Lloyd J. Old, M.D., at the Sloan-Kettering Institute in New York, the physician and researcher best known for bringing immune-system science squarely into the world of cancer research. Srivastava waited one week, two weeks for the doctor's reply. When none came, "I felt offended. I tried calling him at his office but could never get beyond the wall of secretaries." So he called him at home. (Srivastava is now amused by his brashness at age 26.) At 8 o'clock on a Saturday morning, Old answered on the first ring. "He knew who I was immediately; he remembered my study in surprising detail and was immensely curious about the data," Srivastava remembers. "It was the beginning of a conversation that would last a lifetime," he says softly, lost in the memory. Encouraged by Old, Srivastava returned to cancer research, first at Sloan-Kettering Institute, and a faculty position in Mount Sinai School of Medicine in New York, then faculty and research positions at Fordham University. In 1997, he moved to Farmington, Conn., where he founded the Center for Immunotherapy of Cancer and Infectious Diseases at the UConn Health Center, bringing all of his lab colleagues with him. The UConn Connection Today, 20 years after his first experiments with HSP vaccines, Srivastava understands why those based on cancer-derived tissues succeed where others fail: With today's HSP vaccines, each patient's own cancer tissue teaches the immune system how to recognize its own cancer antigen. Like a fingerprint at the crime scene, this information tells the T-cells what to look for, search and destroy. "It's like dialing 911," he explains. "The police won't come until you call and tell them who you are, what's wrong and where to find you." The strength of this approach is drawn from its specificity, says Peter J. Deckers, M.D., dean of the UConn School of Medicine, also a prominent breast cancer surgeon. In an e-mail message, Deckers explains that HSP-derived vaccines appear to allow "the specific, definitive recognition of the foreign antigen by the immune system - - and the direction of the immune system specifically against that enemy antigen."

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Judith Kulko, whose past 20 years have been spent caring for cancer patients, sees the appeal of individualized vaccines in a different light -- for their ease on each patient's body. "The side effects are minimal," she says. "They're mostly localized -- a rash, a headache, little more." Kulko is nursing director for clinical and translational research at the UConn Cancer Center. "Under Pramod's leadership, this institution is leader of the pack in the field of immunotherapy," says Carolyn D. Runowicz, M.D., director of the UConn Comprehensive Cancer Center. "Pramod is a thought-leader in the field. With molecular-based strategies, we'll no longer need to slash, burn or poison our way out of cancer," she adds, referring to surgery, radiation and chemotherapy. "I hope to be put out of a job soon. I want this [cancer] to be gone, like polio." The road to curing cancer is strewn with broken promises. But if and when Runowicz's wish comes true, it may well be due in part to the trials currently underway at the UConn Health Center. Among those now open are studies on kidney cancer and melanoma that relate to Srivastava's work with heat shock proteins and customized vaccines.

ON A RECENT SATURDAY IN AVON, Srivastava and Chandawarker engaged in the following conversation as they spent the morning together, as is their custom. "Pramod, will our work change the way we treat cancer?" "That's not what we're about, Rajiv. We're about understanding how things work, by understanding how our immune system works, good things may happen, on the side. From understanding comes all else." In the silence of the research wing, a world of curving hallways, dozens of labs and offices running day and night, men and women sit on stools and chairs at tables and desks, eyes on data, thoughts in inquiry mode. Several are Srivastava's former students, whose doctorates he mentored, women and men still with him, still guided by him, as they pursue a wider, deeper understanding of the human immune system, questions that will help manage treatment, illuminate understanding "We can't be biased towards only finding a cure; we have to find out what's going on," says Sreyashi Basu, Ph.D., a post-doctorate researcher, recently examining the role of fever on the immune system. "Everyone gets a fever, but no one's probed deeply or methodically, until now, whether it's a good or a bad thing, whether fever may, in fact, help make you well."

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Research work is methodical, precise, sometimes discouraging. Srivastava's prime role, his colleagues say, is one of unfailing support. "He is always encouraging me, always pushing me, always asking if I am happy inside," says Robert Binder, Ph.D., now completing his four-year fellowship at UConn. "Failure is not the worst thing, he tells me, if it also leads to understanding." The Teacher as Student In a way, medical school is setting Srivastava free from the four walls of his office and the rabbit warren of his research labs, opening doors to the world of large auditoriums, small classrooms, new professors and the 20-something culture of the student world. In lecture halls, he mixes easily with classmates, tossing jokes back and forth, preferring to sit in the more anonymous back row seats. In the hallways, he talks, laughs, encourages. Together, they take on the challenges of problem-based learning classes, clinical assessments and patient care. What was "torment" 30 years ago -how the body works and why -- seems intriguing today. Why? Perhaps medical school itself may be another kind of experiment for this seasoned researcher with a restless mind. Take the Atkins Diet, for example. It was in class that he gained an understanding of visceral fat and its dangers. In response (and thanks to the gift of a protein bar from Chandawarker), he was convinced that the Atkins program might work. Ever the scientist, he also saw this as a chance for research. "I'm experimenting on myself," he says, saving samples of pre- diet blood for later comparison, modifying diet foods to his own taste, and observing with increasing curiosity the food-mind-body connection. "I've already lost 10 pounds, mostly around the middle," he says proudly. "But what interests me most are the molecular answers: Why does this work, and how does it work on the molecular level." "He will figure this out. He'll take it to the next step," says Chandawarker. "Actually, I expect wonderful things from this `experiment,' as I call it. Imagine having a mind like that in school, looking at medicine anew, refreshed, without the worries of youth or the confusion of those too long in the profession. "I am extremely curious to hear his observations. He's one of the smartest minds I know. A complete ace."

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Back in his office and clearly at ease by end of day, Srivastava slips off his sandals and settles into his favorite chair, the stresses of the day visible only in the shadows beneath his eyes. He says he sleeps little, rises daily about 4 a.m. and uses before-dawn time to make overseas telephone calls, read, write and meditate. "I try to never miss a sunrise," he says, almost reverentially. "I'd feel the day wasted if I did." By 8 a.m. he's in school, just another student making rounds, taking notes, interviewing patients and learning the role of healer in the 21st century. He won't be done till dark. On weekends, he spends time with his son Vasishth, 12, who is growing up in their family home in Avon with Jasmine Shah, his wife of 14 years. When asked what he wants most for his son, Srivastava pauses before this reply: "Joy -- keeping the joy of learning alive. That is the true challenge of education." And for himself? Perhaps the same, perhaps something more, perhaps something new? Closing his eyes, he pauses before this unhurried reply. "In the mall the other day, in the Apple store I saw this quote: `The noblest joy is to understand.' How beautiful, because from understanding comes all else; from understanding comes great joy. "Perhaps it was insane to go to medical school at this point in my life, but I am proud that I had the courage to do so. And my learning continues. It is a great joy." Ganesha, god of students, take note.

Copyright The Hartford Courant 2004) More information is available by calling 860-679-2835 and 800-535-6232, or at the following websites: www.uchc.edu http://cancer.uchc.edu http:// immunotherapy.uchc.edu www.cancerresearch.org www.Antigenics.com
[Illustration] COVER PHOTO: COLOR, PHOTOGRAPH BY MICHAEL MCANDREWS PHOTOS 1-2: COLOR, PHOTOGRAPHS BY MICHAEL MCANDREWS PHOTOS 3-5: (B&W), PHOTOGRAPHS BY MICHAEL MCANDREWS; Caption: PHOTOS 1-2: On some afternoons, Pramod Srivastava drives to the office of Dr. Jeffrey M. Kagan in Newington to watch him examine patients and to take patient histories. The short white jacket is the traditional uniform of a medical student. Srivastava juggles attending classes at the UConn Medical School with directing the UConn Health Center's Center for Immunotherapy of Cancer and Infectious Diseases and working as chairman of the scientific advisory board of Antigenics, a company he founded. In the top photo, he hangs on late into a three-hour class. PHOTO 3: Second-year medical student Casey Kuwada, right, jokes with classmate Pramod Srivastava as Srivastava checks in with his office between classes at the UConn Medical School in Farmington. Srivastava, 48, has a doctorate in biochemistry. PHOTO 4: Srivastava settles in for an 8 a.m. lecture on the effects of illicit drugs on the brain. He is finishing his second year at the UConn Medical School in Farmington. PHOTO 5: "Poetry comes from the heart, not the mind," says Srivastava, who grew up in a culture where the whole town turned out to hear famous poets. "And while we must use our minds wisely, we must never forget our hearts."

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