NEW YORK As its name implies, the Strategic Plan for Research of Weill Medical College of Cornell takes the big picture. And there could hardly be three more important diseases for the plan to attack than AIDS, tuberculosis and malaria, each of which kills millions worldwide every year. The precise and complex ways in which each of these pathogens does its dirty work are the respective specialties of the three most recent faculty recruits in the Department of Microbiology and Immunology: Dr. John P. Moore, Dr. Luis Quadri and Dr. Thomas J. Templeton.
AIDS, TB and malaria have been identified by Dr. Carl Nathan, chair of the department, as "persistent diseases" that are chronic and defy easy defeat through vaccines, drugs or public health strategies. They were logical research focuses for a portion of the new faculty the college was seeking to recruit under its strategic plan.
AIDS is caused by a virus, TB by a bacterium and malaria by a protozoan. In their newly renovated offices and laboratories of the Medical College's Whitney Pavilion, the three recruits can talk about these microbes and their biochemistry with the intensity of a long-term obsession.
For Moore, an English-born scientist who holds the title of professor of microbiology and immunology, AIDS has been a subject of research since 1988. In 1992 he joined the Aaron Diamond AIDS Research Center, and he comes to Weill Cornell from a joint appointment at the center and The Rockefeller University. The author of more than a hundred scientific papers, he is one of the leading AIDS researchers in the world.
When he is asked how optimistic or pessimistic he is about AIDS, Moore answered: "It's such a huge question. The answer has to be specific to so many angles. In the United States, antiviral therapy results in control of HIV infection in 70 or 80 percent of the people who take it. So it's a treatable, if not a curable, infection. Outside of the States and Europe, unfortunately, is where the major problem is. Eighty or 90 percent of HIV infections are in Africa or Asia. And their health-care budgets cannot afford the price of therapies. That's not a scientific issue; that's a political issue."
Moore's lab is one of many working on a vaccine that might blunt the rapidly growing international spread of HIV/AIDS. He is interested in the proteins of the virus's envelope that allow it to attach to the host's cells, to fuse to cells and to get inside them, where they wreak their destruction. "If we can raise effective antibodies against the envelope proteins, that could stop the virus from getting into the cell," he said. "So we're trying to design versions of the envelope proteins that we hope will be good immunogens -- will give a good immune response. The present generation of proteins are not very good; we're trying to develop better proteins. These are in animal trials. If they work, well, that's great. If they don't work, well, it's back to the drawing board to take advantage of what we've learned from the first go-around."
Moore does his vaccine work in collaboration with other institutions and companies. "We go with the professionals. They know how to handle the animals, and we produce the immunogens. We send them materials, they do the experiments and they send us blood samples to analyze to see how the vaccine worked."
Moore said: "Components of any effective AIDS vaccine are going to have to stimulate both cellular immunity and antibody-mediated immunity. We have collaborations with groups trying to make immunogens that will make cellular responses, and we're trying to make the antibody-mediated responses."
He goes on to say that all the investment in an AIDS vaccine may bear fruit in five or seven years.
"We will have, I think, a vaccine that will give at least some degree of control over HIV sometime in this decade," he said. When told that sounds rather optimistic, he said, "People were saying 10 years ago we'd have an AIDS vaccine in three years' time. Making predictions is a mug's game in certain respects. Realistically, we're not going to succeed in the next couple of years. But the framework is in place to succeed in the longer haul."
Besides a vaccine, Moore is working on new drugs to treat HIV. Some of these are aimed at a main receptor protein of the virus, known as CCR5, which helps the virus fuse to and enter cells.
Quadri, an Argentine-born assistant professor, is interested in certain kinds of enzymes known as non-ribosomal peptide synthetases and polyketide synthases. These are important because they assemble hundreds of compounds with useful pharmacological activities, and they also are involved in producing molecules that act as virulence factors during bacterial infection.
"These enzymes have good and bad sides," he said. "The good part is that they are involved in the production of several compounds that are very useful for us. On the other hand, these very same enzymes are involved in the biosynthesis of compounds that help a pathogenic bacterium like Mycobacterium tuberculosis to infect the host. ... We are looking into the relevance of several polyketide synthases for the virulence of Mycobacterium tuberculosis. Once we have established how relevant they are, we will try to determine what the products of these enzymes look like, and what do they do when the bacteria infect the host."
He continued: "We are also working on several peptide synthetases, to understand how they work -- to try not only to come out with drugs that will eliminate the activity of these enzymes but also to fundamentally understand their molecular mechanisms." Some of these enzymes are very big and multifunctional, he said. For example, he said, cyclosporin A synthetase has more than 15,000 amino acids.
"We are also interested in combinatorial biochemistry," he said. "For example, can we make chimeric enzymes -- fuse two different enzymes from different pathways and get a new product?" He spoke with gratitude of the support he has received from Weill Cornell and of his lab on the seventh floor of the Whitney Pavilion, which has the advantage of windows open to daylight. "When you work the 12-hour days of an assistant professor," he said, "you are grateful to have windows."
Templeton, also an assistant professor of microbiology and immunology, is from Montana and never imagined that he would be working and living in New York City. But the research environment here is ideal, he said, and his interest in pursuing malaria research brought him here. He can discourse on his specialty with enthusiasm and clarity.
Malaria is a parasite that enters the body via syringe -- the puncture of a mosquito's proboscis. "Within a matter of minutes, the parasite is cleared from the circulation, entering liver cells," he said, "and so it escapes the immune system's immediate surveillance. After about a week of replication within liver cells, a new parasite form is released and enters red blood cells, initiating the blood-borne stage of disease. Cycles of replication within red blood cells, followed by waves of lysis and reinfection of new cells, amplify the infection and as a result cause the pathology of the disease in non-immune individuals. Since ancient times, malaria has been known and diagnosed by a cycle of fevers. You get a peak of fever, then a few hours later chills, and then 48 hours or so later you get fevers again.
"Malaria is lethal when the immune system does not check parasite growth," Templeton continued, "and parasites become so abundant in the blood system that you have a shortage of red blood cells and become anemic. In endemic countries, this largely occurs in children, or in adults who don't have prior immunity. Also, the parasite can 'hide out' in the venules of deep tissues. The parasite is cleared by the spleen, and to avoid clearance by the spleen, it becomes 'sticky' so that it adheres to the walls of the blood vessels in deep tissues, within organs like the brain and lungs. The venules within the brain can become so clogged with parasites that patients lose oxygen flow and go into a coma -- termed cerebral malaria -- often resulting in death. Again, this happens mostly to children. It's mostly children under the age of 6, mostly in sub-Saharan Africa -- between 1 million and 2 million a year. Thus malaria can be considered a childhood disease of tragic proportions in undeveloped countries."
Templeton is interested in the parasite "from an academic and intellectual standpoint as well as a foundation of basic research for vaccine development," he said. "I'm interested in how the parasite recognizes the host, reacts to the host and the proteins that the parasite presents on its surface as a means of interfacing with the host. Anything on the surface of the parasite is exposed to the host's immune system and is, therefore, by definition, a candidate for a component of a vaccine. ... In fact, to date, there's no effective vaccine for any protozoan organism. Only for viruses and bacteria."
He added: "Right now, malaria definitely has the upper hand. It rapidly becomes resistant to drugs and is transmitted by the mosquito with efficiency. Adequate health care and economic development do not exist in countries where malaria is endemic. But, now, with the renewed interest in malaria research, I think that in the next five to 10 years we will have significant direction and promise for a vaccine."
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