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Dr. John Ortaldo, Laboratory of Experimental Immunology: On Target with the NCI

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Having the freedom to perform cellular and molecular research in cancer ... having good support ... working in a good facility: all of these attracted Dr. John Ortaldo, chief of the Laboratory of Experimental Immunology (LEI), to the National Institutes of Health in the early 1970s. "I knew that working at NIH would be a good thing," he said in a recent interview.

Another attractant was the Frederick terrain, similar to his home in Pennsylvania. In Maryland he would be able to pursue both his vocation—research, hunting for a cure for cancer; and in what little spare time he had, his avocation—hunting small game and fishing. When he's not hunting natural killer cells, Dr. Ortaldo relaxes with his children and grandchildren, shooting clay targets, fishing, and sometimes just shooting through the lens of a camera. "We have lots of fun with target shooting; several target ranges are within an easy drive of the Frederick area, and it's inexpensive," he said.

For several years, he and his youngest daughter have been participating in "couple shoots," male-female teams. They've done well shooting together, and he commented, "All the kids are good marksmen." Soon he may be able to teach them more of his skills when he "retires" in December.

We say "retires," because although he has been doing government research for more than 37 years, he will continue to work here one or two days a week and will also do some outside consulting. Dr. Ortaldo's dedication as a scientist perhaps echoes his avocation as a hunter and angler: Both require skill, patience, and an instinct for when and how to zero in on a target.

Focus on Natural Killer Cells

Since 1985, Dr. Ortaldo's skill in the hunt for a cure for cancer has led LEI in helping to define the role of natural killer (NK) cells and their activating receptors. "LEI was one of the first labs to show that NK cells make soluble factors, such as gamma interferon. Before that, no one even considered NK cells as doing much but killing other cells." It was with hunters' instincts that Dr. Ortaldo and his colleagues at LEI realized the NK cells are able to recognize pathogens and cancer cells, based on general, non-specific, pattern-type recognition.

Immunity works in one of two ways: either through environmental exposure such as an infection or through vaccination, which involves T and B cells, not NK cells, that have been "sensitized" to specific molecules on a particular pathogen. In contrast, NK cells and other cells in the "innate" system kill virus-infected cells, parasite-infected cells, and tumor cells without any sensitization.

"Part of how you generate immune cells is by secreting factors and communicating with adjacent cells within your spleen or lymph nodes. This is, in fact, why, when you get a virus infection, you get inflamed lymph nodes, a result of cell killing and secretion of soluble inflammatory factors. These inflammatory factors recruit and activate other cells at the site," he said.

With his hunter-researcher's skill and patience, Dr. Ortaldo led LEI's contributions to understanding NK cells. "Understanding the biology of the receptor system and the genetics of the regulation of novel NK receptors are both very important to understanding NK function," he said. Dr. Ortaldo and Dr. Howard Young have focused on the cytokines that NK cells make and how they regulate the immune system, through interferon production and through making other cytokines. "These soluble molecules are very important in the total picture of how the host responds to infection or cancer," Dr. Ortaldo said. Another achievement has been understanding the signaling of activating and inhibitory NK cell receptors. Until the early 1990s, no one realized that NK cells, found primarily in the blood, the liver, and the spleen, utilized unique receptor systems.

LEI's Dr. Steve Anderson has made important advances in the genetics of receptor expression, recently publishing a paper in Immunity on understanding the molecular mechanism of controlling expression, while Dr. Dan McVicar has zeroed in on NK cell receptor signaling. "LEI was one of the first groups in the world to really define how activating NK cell receptors work at the biochemical level, to identify the important intracellular molecules, including kinases, that regulate the positive and negative signals that are involved in regulation of NK cell function," Dr. Ortaldo said.

"Monoclonal antibodies enable us to detect NK cells as they express specific receptors and markers on their surface. Now we're studying how receptor expression is controlled, how receptors function and signal, what they signal cells to do, and how that impacts host immunity," Dr. Ortaldo said.

Part of LEI's Mission: Bring Together Different Types of Studies

Dr. Ortaldo recommends conferences as "the best place to establish collaborations because you hear somebody talk, you sit down with them after their presentation, start talking, and before you know it, you are collaborating." Videocasts are also a good source; recently, after hearing a videocast lecturer, Dr. Ortaldo invited the speaker to lecture here, and a collaboration has begun.

The LEI has many collaborators, both within and outside NCI, to help in the hunt to cure cancer. With justifiable pride, Dr. Ortaldo said, "The list is huge. There are lots of interactions with other labs, who are making unique mice, generating unique reagents, doing various studies that complement the work in the LEI."

With the hunter's inborn skill, Dr. Ortaldo often couples LEI's expertise, reagents, and extensive knowledge about the NK cells with others' expertise in different areas. "By collaborating with investigators who study ongoing models that you don't have, you can learn a lot more very quickly. One of my collaborators [Dr. R. Welsh, University of Massachusetts-Worchester] focuses on how the immune system regulates Cytomegalovirus and other mouse viruses, while I'm very interested in the role of NK cells during these infections. Howard Young has been interested in how NK cells might impact a system like Ebola; while we don't do that research here, we collaborate with investigators at USAMRIID to pursue these questions," he said.

"Steve Anderson, studying genetics of the NK cell receptor system; Dan McVicar, studying signal transduction of these innate-type receptors; Tom Sayers, exploring different models of immunotherapy, and others in the lab—all have many collaborators inside and outside NCI," Dr. Ortaldo pointed out.

"Good collaborators are better scientists in the long run because they can get more done with fewer resources, and we all have limited resources," he said.

NK Cells May Play a Role in Developing Immunity

Dr. Ortaldo and many other researchers believe that many people develop cancer but never know it because their bodies eliminate cancer cells as they form. In part, he has come to this theory because in the early 1970s, while finishing his PhD with Dr. Ron Herberman, George Washington University, Dr. Ortaldo and his colleagues discovered that what had been thought of as "noise" or "background" was actually natural cytotoxic cells present in normal individuals.

One of LEI's current projects suggests that NK cells are important helpers in developing specific immunities. Attempting to define how NK cells might be important in helping people to be immune to their own cancer, LEI researchers theorize that the presence of NK cells and their activity are critical in rejecting tumors. Through animal models, Dr. Robert Wiltrout, Director for the Center for Cancer Research, NCI and an investigator in the LEI, is studying renal carcinoma, while Dr. Ortaldo is studying the Lewis Lung Model, another mouse model. By manipulating NK cells, they hope to determine how NK cells in mice impact the development of immunity to cancer, and then to translate those findings into clinical trials.

"We're trying to understand the NK cell's function against cancer. We believe it is one of the innate cells that keep people from ever having cancer. In our study, we'll find out whether or not the mice develop immunity to cancer. We know NK cells can kill the cells, but is that the only thing they can do? Their ability to kill tumor cells is an important function, but it's not enough to keep people from getting cancer, because a lot of clinical studies done with NK cells that have been adoptively transferred into people show that the disease still progresses."

Dr. Ortaldo says that "Most people agree: if you really want to have a cure for cancer in people, you have to develop specific adaptive immunities. In treating renal and melanoma cancers, Dr. Stephen Rosenberg (Surgery Branch, NCI) has learned that you can get complete remission and cure by incorporating adoptive transfer of specific immune cells. However, it doesn't work all the time, and we don't understand why it doesn't always work. That's the big question: why do some people get cancer but not all?" Dr. Ortaldo said.

In a final observation, Dr. Ortaldo pointed out that in research, "You do experiments to learn; sometimes hypotheses are wrong. That information is useful, too. That's the wonder of doing research."

Dr. Ortaldo noted that he is grateful to the support of his research provided by Robin Winkler-Pickett, Anna Mason, Bill Bere, John Wine and by past postdoctoral fellows, visiting fellows, students and the rest of the LEI staff. 

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