Real World Medicine
By Maryann Brinley

lmost every biographical sketch of immunologist Gilla Kaplan, PhD, highlights the fact that she is a world-reknowned authority on the immune system’s response to virulent mycobacterial and other infections. Her investigations, which began more than 30 years ago, cover basic fundamental questions as well as new ways of treating HIV, TB and leprosy. In fact, Kaplan, head of the Mycobacterial Immunity and Pathogenesis Laboratory at UMDNJ - New Jersey Medical School’s Public Health Research Institute (PHRI) and a professor of medicine at the school, has long been supported by numerous grants from foundations as well as the National Institutes of Health (NIH)-National Institute of Allergy and Infectious Disease(NIAID). She also counts on the backing of the Bill and Melinda Gates Foundation for a newborn vaccination project in South Africa. “The vaccine project has been going on for seven years,” she explains. The Gates are “a couple who are truly committed to making a difference in the world” — a mission Kaplan understands intimately.

Looking at her lifetime of achievements, of course the emphasis is on the science. This is a researcher who has always been patient oriented and focused on disease. Yet, science and immunology are only part of her story. Again and again, the word “world” comes up, especially when you attempt to add up the miles and consider the countries she has experienced: South Africa, Brazil, India, Nepal, Bangladesh, Thailand, the Philippines, Ethiopia, Israel, and even Tromso, Norway, home to the northernmost university in the world, located above the Arctic Circle.

“My research has been taking me in three different directions recently, all of which are in South Africa,” she reports. A graduate of Hebrew University in Jerusalem, Israel, Kaplan earned her MS and PhD from the University of Tromso in Norway. She was an assistant and then an associate professor in the Laboratory of Cellular Physiologyand Immunology at Rockefeller University in New York City for 19 years before coming to PHRI in Newark in 2002. One of her leprosy research projects in Brazil lasted 17 years and another in India took seven years. For the past 11 years, she’s been training tuberculosis (TB) researchers in Cape Town, Johannesburg and Durban as well as studying the immune response to tuberculosis in patients there. “South Africa is a country with one of the most significant TB problems in the world.

“These international collaborations are difficult because we are often actually doing patient-based studies which carry risks. We arrive in these countries with a pre-approved protocol but have to get our work done in real time and in areas of the world that move very slowly.”

Though colleagues in these countries may have agreed in advance to the completion of a particular study in eight or 10 weeks, Kaplan admits, “We can cause ripples in those local waters. We come as their guests and collaborate with local physicians and scientists but it’s really hard work. There are always practical complications.”

What surprises Kaplan is that her team not only “completes the studies on time but also obtains results. Every once in a while, I am really amazed that we pull it off.”
Searching for drama in her international adventures, she can recall almost flying into the Phillipines during a political coup d’etat. “We had to wait in Hong Kong until the rebels left the airport in Cebu to land.” And she will never forget Nepal and the level of anxiety which greeted them. “I remember arriving there and how everyone was very anxious and nervous. There were four or five of us in the group and we were being viewed as foreign invaders. Yet, that study too eventually went very well.”

Kaplan’s worldwide patient-based projects began more than 20 years ago with her interest in leprosy or Hansen’s Disease, named after G.A. Hansen, a Norwegian who first observed the microorganism that causes leprosy in 1873. Caused by a bacillus known as Mycobacterium leprae (M. leprae), leprosy could only be studied directly in infected people because this agent would not grow in test tubes, in cultured cells or in the usual animal models. There are still approximately 600,000 new cases of leprosy each year, mostly in third world countries. “I have focused on immune system modulation,” she says. “We’ve been probing, perturbing, stimulating and suppressing the immune system as a way of re-setting it, to understand its complexity and how it contributes to disease.”

It was while studying the immune system of leprosy patients that Kaplan discovered one of thalidomide’s secrets. This is a drug which achieved worldwide notoriety in the early 1960s when it was linked to scores of birth defects in the children of mothers who had taken the sedative for morning sickness. International news reports and photos of deformed babies born without arms or legs shocked the public as well as the pharmaceutical industry. However, thalidomide could also reduce painful complications in people suffering from leprosy. So, in spite of it being considered dangerous, especially for pregnant women, thalidomide had also become the drug of choice for some aspects of leprosy treatment.

No one knew exactly why thalidomide worked in leprosy patients until Kaplan’s team at Rockefeller University, in 1991, showed that this pharmaceutical inhibited the production of tumor necrosis factor-alpha (TNF-a), a substance that stimulates the immune system. “Too much TNF-a can have a profound effect on the body not only in leprosy but in other diseases. Thalidomide modulates the immune system to reduce TNF-a production during infections. It is even being used to treat cancer now,” she explains. Independent of Kaplan’s breakthrough, Harvard researchers found that thalidomide belonged to a family of compounds which curb the growth of the blood vessels that feed tumors.

Overproduction of TNF-a has also been implicated in disorders such as sarcoidosis, multiple sclerosis and HIV/AIDS. “We did the actual research in my lab at the Rockefeller University,” she says. Now that thalidomide has moved into production at the Celgene Corporation in Summit, NJ, Kaplan, who is on the company’s board, has stepped away from this area of patient based-research and the ongoing clinical trials. “I keep abreast of what’s happening,” she says proudly. “You have to be very careful using thalidomide, but there are plenty of diseases for which it is beneficial.”

In the 1990s, Kaplan’s attention shifted to tuberculosis, a disease which elicits an immune response similar to leprosy. “People don’t realize that there is more TB in the world now than ever before.”

Her lab is especially interested in “the interaction between HIV and TB. Clearly, HIV is causing a massive exacerbation of disease progression and pathogenesis in TB.” Approximately 42 million people are HIV positive. One-third of the world’s population is infected with M. tuberculosis, the first disease shown to be caused by an infectious agent. Two million die from this disease each year. In both leprosy and TB, a strong immune response can be life-saving. Researchers want to know why some individuals can fight off the infection, control their body’s adverse reaction and limit the disease to a single site. There are many cases of people infected with the TB organism who never develop any sign of the disease itself.

“There shouldn’t be anything surprising about the workings of the immune system but overall, what was once thought to be simple is much more complicated than molecular biologists believed. We need to think of the immune response as a language,” she suggests. “This is a system that learns from its own experiences. Look at the 26 letters of the alphabet and then consider all the countless, possible, alphabetical combinations. In the same way, an individual’s immune response can be spelled so many different ways when being called upon to resist an onslaught from disease, injury, infection or inflammation.”

While the complexity of the immune system doesn’t surprise Kaplan, what does give her pause is the limited repertoire of immunologic mediators that drive this responses. “In this next century, we’ll all be talking about systems biology, or how well we can integrate our understanding of all the systems of the body. Maybe what will be most striking in the future about our ability to cope with disease, and protect the body itself, is how capable we are going to become at directing our immune systems. We won’t just be chopping out cancer,” Kaplan predicts, “We’ll be harnessing the body’s immune response to fight it.”