Richard Axel: One of the Nobility in Science

Dr. Axel with postdoc Allan Wong, Ph.D., in the 2-photon imaging room of the Axel lab
PHOTOGRAPH BY CHARLES MANLEY
Dr. Axel with postdoc Allan Wong, Ph.D., in the 2-photon imaging room of the Axel lab

BY ROBIN EISNER
WHEN RICHARD AXEL, M.D., LEARNED HE WAS TO SHARE THE 2004 Nobel Prize in Physiology or Medicine with his former postdoctoral fellow, Dr. Linda B. Buck, his immediate thoughts turned to the many other fellows and students, past and present, from his lab. It was, after all, their efforts being saluted by the most prestigious honor in science.
"Scientists donít work in a vacuum," says Dr. Axel. "We work within a scientific community with a common goal and passion to do science. I have been blessed over the years with a remarkably strong and exciting group of students and fellows who actually did much of the work. I feel an enormous debt of gratitude to them. I feel very good that their work has been appreciated in so profound a way."
Dr. Axel also feels a deep appreciation to the teachers who inspired and challenged him and the institutions ó Columbia University, its College of Physicians & Surgeons, the National Institutes of Health, and the Howard Hughes Medical Institute ó that provided the resources, space, and a creative milieu for the research to flourish.
Without question, a Nobel Prize is a crowning achievement in a scientistís career and Dr. Axel says he is humbled by it. But, he adds, awards are not the goal of science. He and the members of his laboratory "do science" 10 to 12 hours a day because they love the process of learning and discovery, even with its frustrations and failures. "I find the intellectual process enjoyable," he says. "The reward is in obtaining the result of an experiment. Getting the Nobel now allows me and my students to return to the lab with an even greater intensity." Indeed, after the hoopla, press conferences, parties, and ceremonies celebrating the prize, Dr. Axel relishes being in his office on the 10th floor of the Hammer Health Sciences Center in the city he loves, sitting on his soft grey leather couch analyzing data from recent experiments, and living up to his irreverent and formidable reputation.
Feeding a compelling curiosity has driven Richard Axel for almost 40 years of his life as a scientist and continues to motivate him. That self-defined "inquisitiveness" led, in the late 1970s, to fundamental discoveries with colleagues about how to introduce genes into mammalian cells in an efficient way. It was an impressive result for an assistant professor at P&S and a springboard for a revolution in molecular biology and biotechnology that earned Columbia millions of dollars in licensing revenues from patents. (See accompanying article.)
His laboratory in the 1980s continued to perfect methods to isolate and understand the regulation of genes and succeeded in cloning several genes important in medicine, such as the receptor for HIV and the neurotransmitter receptor for serotonin.
At that time, though, Dr. Axel says, he was "bored" with cloning and approached Eric Kandel, M.D., 2000 Nobel Laureate in Medicine and University Professor of Physiology and Cell Biophysics, Psychiatry, Biochemistry and Molecular Biophysics, to use molecular biological techniques to study behavior. Their collaboration led to the identification of a gene important in egg-laying behavior in the model organism Aplysia and contributed to the development of a new field: molecular neurobiology. Dr. Axel then became interested in using genetic technologies to understand how the brain perceives the "colors, forms, shapes, texture, sounds, smell, and tastes" of the physical world. He thought olfaction was a good way to study perception and behavior, as very little was known about the sense of smell at the time. The Nobel Prize he shares with Dr. Buck, who now works at the Fred Hutchinson Cancer Research Center in Seattle, represents more than 10 years of work in both identifying the genes for odor receptors and elucidating the organization of the olfactory system. (See accompanying article.) Dissecting how higher brain centers generate a "percept," say, of the scent of a lilac, or coffee, or a skunk, which then causes an organism to behave in a certain way, continues in his laboratory.
Igniting a Genetic Revolution
During the biological dark ages, some 25 years ago, before cloning and sequencing genes became routine, scientists did not know how to put genes into cells from higher organisms. Drs. Richard Axel, Michael Wigler (then a graduate student at P&S and now a professor at Cold Spring Harbor), and Saul Silverstein, now professor and chairman of microbiology at P&S, changed all that. The trio developed a fundamental set of tools to insert foreign genetic material into mammalian cells.
Although the research answered basic science questions, the tools have had enormous commercial implications, such as allowing the creation of cells that express therapeutic proteins and glycoproteins. Columbia University holds a series of patents on these genetic engineering technologies, which have been licensed to pharmaceutical, biotechnology, and agricultural companies. Drugs developed from the technologies have been used in breast cancer, kidney failure, cystic fibrosis, infertility, and other conditions. Genetically engineered seeds also have been developed. Licensing revenues from the patents have generated a substantial amount of money for Columbia.

By his own admission, Dr. Axel says his adult accomplishments were not necessarily predicted by his early life. Born on July 2, 1946, Richard Axel grew up in Crown Heights, a relatively poor neighborhood in Brooklyn. His parents had immigrated from Poland in 1937. "They had a respect for education, but they were not very educated people," Dr. Axel says. His dad was a tailor. Young Richard went to P.S. 161 and Lefferts Junior High School. "I was a good student, but not a top student," he says. He was to attend George W. Wingate High School, a local school, but an assistant principal at his junior high suggested he take the test to go to Stuyvesant High School, a school in Manhattan for gifted boys. (It is now co-ed.) He got in and took the subway from Brooklyn to school every day. "I learned to sleep standing up," he says, and to absorb the culture and aesthetics of Manhattan. That world included art, books, and music ó especially music.
The young man first heard opera, now a passion, in high school. The aria that his teacher played which so inspired him was "The Letter Duet" from "The Marriage of Figaro" by Mozart. "It was extremely beautiful, so perfect musically," Dr. Axel says. "Hearing it was the beginning of a long love affair with opera, which today borders on obsession." As a high school student, he would pay 50 cents twice a week for standing room tickets at the Metropolitan Opera. He could afford the extravagance, he says, because he had a high school job appraising diamonds at a pawn shop. Dr. Axel still goes to the opera at least once a week.
He also read voraciously at Stuyvesant. "I was essentially self-educated," he says. "I went to the library and started at the As and tried to read straight through. I didnít get far." He graduated with straight As from Stuyvesant but says he never felt particularly smart among so many good students. "The students there were extremely bright."
Beauty, which he first cultivated in high school, is important to Dr. Axel in science. "At its best, at rare moments, doing science is like great art and beautiful music," Dr. Axel says. "Data can be extremely beautiful. There have been many moments when I have sat in my office and my mind has been embraced by the elegance of an experiment or of a result."
Dr. Axel also discovered in high school the lesson of humility in the face of natureís powers. He says his most notable moment at Stuyvesant was when he played two games as starting center on the schoolís basketball team against Power Memorial Academy High School. Dr. Axel is 6 feet 3 inches tall. His opponent was a young Lew Alcindor, later known as Kareem Abdul-Jabbar. "Alcindor scored 54 points in the first half of one of the games," Dr. Axel recalls. "They creamed us. He went on to be the best basketball player ever. I became a competent researcher."
LEFT: Richard Axel as he receives his Nobel Prize in December 2004 in Stockholm from Swedenís king, Carl XVI Gustaf
BELOW: The Nobel diploma

Modesty notwithstanding, his high school academic record earned him a full scholarship to Columbia College. "I started at Columbia in the early 1960s when findings about how the information encoded in DNA could direct the activity of cells were first being described," he says. "The world of molecular biology and genetics fascinated me, but I was torn between literature and science." Professors, however, discouraged his literary ambitions. As an undergraduate, he obtained a job washing glassware in the laboratory of Dr. I. Bernard Weinstein, M.D., D. Sci. (Hon.), Frode Jensen Professor of Medicine, and director emeritus of the Herbert Irving Comprehensive Cancer Center at P&S. He was fired because he kept breaking test tubes, but Dr. Weinstein rehired him to do research. In a short time he published three papers, two as first author. Although he wanted to attend graduate school, he had been drafted, and the government at the time had ended graduate school, but not medical school, deferments. With his 1967-minted bachelorís degree in chemistry, he went to medical school at Johns Hopkins in Baltimore. P&S had not accepted him.
Dr. Axel obtained a medical degree in 1970 but says it was given to him if he promised never to practice on live patients. "I was a terrible medical student," Dr. Axel says. So he came back to Columbia as a resident in pathology, where he worked on tissues and autopsies. The legend continues that the pathology chairman would give Dr. Axel board certification in pathology only if he promised never to practice on dead patients. He didnít. He pursued a fellowship in pathology at Columbiaís Institute of Cancer Research, working in the microbiology laboratory of Dr. Sol Spiegelman, who died in 1983. "Sol had a flare for experimental design, which in my experience is unmatched," Dr. Axel says. "He spent an enormous amount of time with me, and with him I learned how to dissect a scientific problem." From 1972 until 1974, as part of his deferment, he worked in the National Institutes of Health laboratory of biophysicist Dr. Gary Felsenfield, an expert in chromosomal structure and gene expression. "I learned from Gary that technology should not be feared, and that one should embrace all techniques necessary to solve a problem," he says.
Dr. Axel returned to Columbia in 1974 as an assistant professor of pathology in the Institute of Cancer Research and has been at Columbia since, now in the Department of Biochemistry and Molecular Biophysics, the Department of Pathology, the Institute of Cancer Research, and the Center for Neurobiology and Behavior. He became a Howard Hughes Medical Investigator in 1984 and was named a University Professor, Columbiaís highest academic title, in 1999. He was elected to the National Academy of Sciences in 1983, and he prides himself in the fact that many of the graduates of his laboratory also are NAS members. He serves on the advisory boards of several academic institutions and has been an associate editor of Cell since 1976.
He is a scientific adviser to Sentigen, a New Jersey-based company that utilizes findings from olfaction receptors to develop drugs, an "electronic nose" for use in homeland security applications, and pesticides based on understanding the attraction of insects to human odors.
Besides being devoted to Columbia, Dr. Axel cannot imagine ever leaving New York. "When you walk in the city, you see fire in peopleís eyes," he says. "You have a sense that New York City is a place where things are created, not just exhibited. The city is not a museum. Itís dynamic, changing, and crazy. And I love it."
Making Sense of Sensation
For the past 15 years, the Axel laboratory has been interested in how the brain, which consists largely of neurons, is capable of representing the richness of the external world through the use of its senses. The properties of a scene or an odor need to be internally represented in the brain to allow an individual to sense and discriminate aspects of the environment. Odors, for example, allow organisms to choose foods and their mates. In the late 1980s, Dr. Linda B. Buck, a postdoctoral student in the laboratory, initiated studies that identified the genes responsible for the recognition of odors in the nose. Remarkably, she and Dr. Axel found not just one gene but 1,000 genes, approximately 5 percent of the genome, encoding the molecules that sense odors in the environment. But the research didnít stop at identifying the genes. The genes allowed the laboratory to ask the more difficult question as to how odors are represented in the brain. By using the genes, they were able to demonstrate that different odors result in the activation of different patterns of neurons in the brain. Dr. Axel now is studying how the brain first deconstructs the odor in lower brain centers and then reconstructs the "percept" of an odor in the higher brain centers. Dr. Axel believes this deconstruction and reconstruction is the method the brain uses to understand the sensation of sound, hearing, and vision, too.

On the day of the Nobel announcement, however, he was in San Francisco, away from his beloved Gotham. He was telephoned at 2:45 a.m. ó 5:45 a.m. New York time ó from someone identifying himself as the chairman of the Nobel Prize committee. Skeptic that he is, Dr. Axel thought the call was a joke being played on him by a friend. He asked the caller to hold while he checked the Internet for verification. First he checked Yahoo, and the news of the award was there. But, Dr. Axel thought his friend might have "gotten" to Yahoo. He then checked the official Nobel Prize web site. The press release there convinced him he had won. He made a cup of coffee to stay awake and savor the moment. He also hugged Dr. Cornelia Bargmann, a neuroscientist who studies nervous system architecture and behavior in the nematode (and olfaction). Dr. Axel was in California helping her move to New York City for her new job at Rockefeller University. "It was a good week," Dr. Axel says. "I won the Nobel and the woman I love came to New York with me." He plans on donating his half of the $1.3 million proceeds of the Nobel Prize to charity.
Graduate students and fellows, those individuals whom Dr. Axel says the Nobel Prize honored, yearn to come to his laboratory because of his track record, charismatic personality, originality, and resources to pursue significant but risky scientific questions. Ben Shykind, who began in the Axel laboratory as a Columbia undergraduate and returned in 1996 after obtaining his Ph.D., says Dr. Axel has a saying: "Before you know, you must imagine." Such an attitude is risky in science, but Dr. Shykind says Dr. Axel has an "uncanny ability to be right, is open to any cool ideas, and has the resources to undertake pursuing them." Dr. Axel also is known for being extremely challenging intellectually because he has an uncanny ability to see the flaws in data and logic. Stories abound of Dr. Axel sitting in the back row of a scientific seminar, talking to the person sitting next to him, rumpling newspapers, and then raising his hand when the speaker is finished to ask the definitive and often crushing question about the data.
At one of several events held at P&S to honor him for winning the Nobel, approximately 1,800 people showed up. Dr. Axelís response to the outpouring of affection: "Either my reputation of being difficult isnít true at all or people appreciate the fact that I am difficult and demanding." As all the speakers of the event that day indicated, itís the latter, and they marveled how he keeps pushing himself, his students, his fellows, Columbia University, and the boundaries of science.

NOBEL PRIZE PHOTO: © THE NOBEL FOUNDATION 2004. PHOTO: HANS MEHLIN
NOBEL DIPLOMA: © THE NOBEL FOUNDATION 2004. CALLIGRAPHER: SUSAN DUVNńS

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