Profile of Jeffrey Ravetch

Jeffrey Ravetch's career path began with a focus on the smallest scale—individual molecules—then ramped up to studies in microbes, mice, and finally humans. For his work in immunological research, including contributions to unraveling the key mechanisms by which receptors for the invariant stem (Fc) region of antibodies operate, Ravetch was elected to the National Academy of Sciences in 2006.

In his inaugural article, Ravetch and colleagues identified a receptor for sialylated Fc that stimulates anti-inflammatory pathways (1). The receptor could potentially be a useful therapeutic for many autoimmune diseases, according to the study.

Ravetch, 57, is currently the Theresa and Eugene M. Lang professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at the Rockefeller University (New York, NY). He grew up in nearby Brooklyn, excited by scientific breakthroughs like the launch of Sputnik in the late 1950s and the subsequent space race. Books such as Paul de Kruif's Microbe Hunters (2) and biographies of Louis Pasteur and Albert Einstein fueled his imagination. “My heroes were scientists, not sports figures,” he says.

Clouds of Chlorine

Ravetch's parents were teachers in New York City public schools, and although neither taught science, they were able to provide their son with books, enrichment programs, and leftover lab equipment. “They let me do what I chose to in the basement. I had a little makeshift laboratory where I would dabble,” he says. “You'd get books at the library that would tell you about doing certain experiments and I'd make quite a mess, as you might imagine. I recall clouds of chlorine gas very distinctly when I discovered the power of laundry bleach.”

This self-directed learning foreshadowed Ravetch's academic career. From his initial basement work through high school, which offered little in terms of science education, Ravetch conducted his own experiments and pursued his own projects.

“[My high school] was a parochial school and didn't have any [science] facilities or teachers, so my education was basically things I could do on my own,” he says. He would go on to spend summer camps at Carnegie Mellon University (Pittsburgh, PA), work in a research lab on Long Island, and spend time in a marine research lab in Brooklyn in lieu of formal classwork during his youth.

Jeffrey Ravetch

After high school, Ravetch was admitted to Yale University (New Haven, CT) in the late 1960s. “When I went to Yale I was finally exposed to true science,” he says. “I was fortunate in being able to work in Don Crothers' lab as an undergraduate and that was how I became a scientist. I really owe Don for having the patience to let a complete neophyte into the lab and break things.” The Crothers group studied the physical biochemistry of nucleic acids, in particular, synthetic RNA duplexes.

“I got there in my freshman year and I just stayed. Nights, weekends, summers, it was really my first scientific home. I published my first paper when I was an undergraduate with Don” (3).

The Great Names

Sure that research was his destiny, Ravetch enrolled in Rockefeller's new M.D./Ph.D. program administered in tandem with Weill Cornell Medical College (New York, NY). As a molecular biophysics and biochemistry and English major, he thought the combined program was a good way to get grounded in biology, and its novelty attracted him.

“In those days Rockefeller had a curriculum with no courses, no exams—it reminded me of my early years being self-educated. You chose a laboratory, you chose a mentor, you decided what it was you wanted to study and designed a curriculum for yourself. The qualifier was, you had to find 3 faculty members who signed off to say you fulfilled their sense of requirements in their discipline,” he recalls. “I thought it was a great idea. I loved the idea that to qualify in genetics you sat in Norton Zinder's office for an hour and talked genetics. If he thought you knew enough, you were qualified. It was more of the same with Günter Blobel in cell biology. You had the opportunity—and you were required—to spend time with some of the great names in the field.”

Ravetch worked in Zinder and Peter Model's joint lab at Rockefeller, focusing on bacterial and phage genetics. DNA sequencing was a brand-new technique. “Through the rumor mill we heard it was a technique Wally Gilbert had developed,” he says. “I was sent up to Wally's lab to learn DNA sequencing—there was no other way to do it. I remember sitting in Allan Maxam's little cubicle and he showed me all of the reagents and gave me the protocols on hand-written pages that I Xeroxed. Then I brought the gels and DNA sequencing to Rockefeller and started teaching people how to do it here.”

One problem in the early days of sequencing was getting hold of restriction enzymes to manipulate DNA. “There were no companies selling these back then, and you had to make each enzyme yourself, so there was a black market in restriction enzymes,” he says. “You would make a few and then swap a few with a laboratory that had other ones,” Ravetch says.

After finishing his Ph.D. (in 1978) and M.D. (in 1979), Ravetch joined Phil Leder's lab at the National Institutes of Health (Bethesda, MD). Leder had just finished a remarkable series of studies on the genes that encode the light chain of Ig proteins and the rearrangements that generate antibody diversity. Ravetch arrived in time to study the heavy chains of immunoglobulins.

“There was a whole new world to figure out and we knew nothing about how the constant region could undergo this class switch recombination,” he says. “There were various postdoctoral researchers in all these labs around the world competing with each other. Each week we'd read each other's work in papers and Phil would go to a meeting and call us back and say, ‘Well, there's a lot of new information,’ which was the bad news, but we were still in the game and I think we did some interesting work from 1979 to 1982. It was an intense period of investigating this marvelously complex system of genes” (4, 5).

Into Fc Receptors

In 1982, Phil Leder accepted the chairmanship of the Department of Genetics at Harvard University (Cambridge, MA). “He dropped me off in New York on his way there,” Ravetch says. “I took my freezer box full of the genes I had cloned and reagents I had made, and started my own research group at the Sloan-Kettering Institute, across the street from Rockefeller. So I was close, but not quite home yet.”

Ravetch began research in two areas: the genetics of the malaria parasite, Plasmodium falciparum, and the constant, or Fc, portion of antibody molecules. The malaria research took off quickly and he was able to clone some of the first genes for P. falciparum, which revealed a genome that had undergone unique selection pressures, resulting in unusual chromosomes (6, 7).

At the same time Ravetch pursued the genes for an Fc receptor, a formidable cloning project due to the rarity of the mRNA for these proteins and a lack of enthusiasm from colleagues. “No one had any idea why there were Fc receptors,” he says. “The prevailing idea was that the Fc region stabilized the molecule and determined the half-life of the antibody, and all of the effector function was attributed to the complement cascade, so why would there even be Fc receptors? It made no biological sense. There wasn't much interest. Basically I had it to myself” (8).

Through the late 1980s and into the 1990s, Ravetch showed that some Fc receptors had important biological functions, and that our understanding of the interactions between antibodies, the complement system, and inflammation was not just incomplete, but flawed. With a few Fc receptors cloned, his next step was to use the new technology of transgenic mice to create Fc receptor knockout mice. The step from cells to animals changed Ravetch from a molecular biologist to a full-fledged immunologist.

The first knockout mice his group made were deficient in activating Fc receptors, which promote inflammation. To Ravetch's surprise, the mice could not respond to immune complexes of antibodies (9). The result meant that antibodies and complement were not interacting as previously thought, and that Fc receptors were essential to initiate the inflammatory response. Many people considered the results heretical, Ravetch says.

The next mouse line that they made had no inhibitory Fc receptor to calm inflammation (10). “When we made a mouse lacking the inhibitory receptor, we saw enhanced inflammation in a variety of inflammatory models, as you might expect,” he says. “But what we didn't expect was a spontaneous phenotype—meaning do nothing to the mice and they develop lupus (11). That really shocked us. ”

Ravetch's research led to a new paradigm in immunology. “It was one of the first examples of a balanced signaling system in an immunological system, where it had both activating and inhibitory properties,” he says. “It's kind of a common theme now in immunology. Many systems show this paradigm, but when we first came across it in the mid to late 1990s, it was somewhat unusual.”

The Significance of Sialylation

The next phase of Ravetch's career began when he came across intravenous Ig (IVIG), a therapy for autoimmune diseases. IVIG is approved by the Food and Drug Administration (FDA) for a small number of diseases but is also used for ≈85 autoimmune diseases. The drug consists of concentrated i.v. doses of IgG antibodies nearly a thousand times stronger than a normal treatment. This apparent overdose suppresses the immune system instead of activating it.

“No one had any idea why there were Fc receptors.”

To Ravetch, the body's immune response to the medication indicated that a small fraction of the IgGs were somehow different. Eventually, he found that, although all IgGs are glycosylated, a small fraction contain a sialic acid group added to the glycan sugars. He was able to isolate this fraction and found that the sialic acid converts the IgG Fc region from a proinflammatory molecule to an anti-inflammatory one (12). Such converted IgGs bind to a lectin on a regulatory cell population that subsequently stimulates an increase in expression of an inhibitory Fc receptor on effector cells, thus shutting down the inflammatory response (13).

In his inaugural article (1), Ravetch and colleagues identify the receptor for these sialylated Fc fragments, which is called SIGN-R1 in mice and DC-SIGN in humans. The receptor is unrelated to previously identified Fc receptors, and instead is a C-type lectin expressed on the surface of macrophages in the spleen of mice and on dendritic cells in humans. Without it, sialylated Fc fragments cannot suppress inflammation.

His results show that there is an unrecognized pathway that Fc molecules stimulate to suppress inflammation. The researchers suggest that regulatory cells release soluble factors that travel throughout the body, which up-regulate inhibitory Fc receptors on effector macrophages, calming inflammation.

Ravetch's studies have had practical results for monoclonal antibodies like herceptin and rituximab, which treat breast cancer and lymphoma, respectively. His work suggested that the Fc receptor seems to be key to their ability to shrink tumors (14).

“When I gave my first talk at an antibody therapeutic meeting in 2000 and showed data that a mouse deficient in activating Fc receptors could not modulate a tumor being treated with rituximab because it didn't have Fc receptors, the response was, ‘That's completely impossible. Rituximab works because it's modifying how this CD20 molecule is signaling.’ And none of that is true,” he says. “That's not how it works at all.”

Because of his work, scientists designing the next generation of antibody therapeutics now take into account Fc receptors and their glycosylation patterns, as well as binding epitopes of the Fab.

Ravetch is now developing a sialylated Fc portion to augment the efficacy of IVIG. He has a sample of a readily made experimental molecule, and has found clinical researchers willing to test it (15). The current stumbling block is the financing required to make significant quantities of the drug that meet the FDA's standards. Instead of working with a drug company, Ravetch and Rockefeller have teamed up with venture capitalists to raise the necessary funds.

Orchids in the Lab

Despite having begun his career in molecular biology, Ravetch has also tried his hand at genetics, immunology, and glycobiology, and he may venture into clinical trials with humans. “Our system has taken us through a lot of different areas,” he says, “and right now the push is to try understand what regulates glycosylation in vivo, what the structural implications are on the binding specificity, and what the signaling pathways are. If this is in fact what is going on, it should lead to an experiment in humans. I would very much like to take IVIG and make it 10 times more potent or make it as a recombinant. It's already worked in animal systems.”

Ravetch has won several awards for his research, including a National Institutes of Health MERIT Award, the Lee C. Howley, Sr. Award and the William B. Coley Award from the Cancer Research Institute. He is a member of the Institute of Medicine, and is a Fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science.

But Ravetch's life isn't totally consumed by science. Besides his love of poetry, which began when he was an undergraduate at Yale, he has devoted one corner of his lab to orchids, which he, his staff, and students grow for fun, relaxation, and competition. “The orchidarium is one of the places where people can sit and chat and have coffee,” he says. “It provides a welcome distraction. It's part of my philosophy—you should want to spend all your time in the lab, it should be the best place you know. It's all about having an envi-ronment where you look forward to coming to work and just enjoy sticking around.”