“Collaboration” is now a commonplace buzzword, used across the spectrum of society—in business, in education, in social ties, and in science. Indeed, Dr. John Niederhuber, Acting Director for the National Cancer Institute, strongly encourages collaborations with various intra- and extramural entities.
One such collaboration is a bonding between chemists (if you’ll pardon the pun) and biologists. According to Dr. Victor Marquez, director of the Laboratory of Medicinal Chemistry, “As chemists, we like to find out where our expertise can be applied to understand, at the molecular level, the biological processes that our biologist colleagues are studying. Most of the time, it involves making an analog of a natural component of the system, changing a little bit the atoms and the configuration of things. We chemists create the stuff that we study!”
Originally from Venezuela, Dr. Marquez in 1971 did postdoctoral work in NCI-Bethesda and returned in 1975 as a visiting scientist, taking a leave of absence from the family pharmaceutical business. “The idea was to come here for a couple of years, but a couple of years have become almost 30 now,” Dr. Marquez said.
“I never thought I would come here,” he said, his voice still a bit bemused at the unexpected turns his life has taken. “Most people that come here are fleeing because of bad things that happened. I was perfectly safe there, but I didn’t feel like I could stay there, at a university or any other institute, because it’s very politicized, and also I would be doing too much teaching and not as much research, so I wanted to come here.”
In 1987, Dr. Marquez received tenure and was granted a “green” card. Four years later, he became a U.S. citizen. During this time, he worked with nucleosides, adding protein kinase C agonists and inhibitors in 1990.
“With research, there’s a lot of serendipity.”
Dr. Marquez believes that “with research, there’s a lot of serendipity.” For example, when he first came to work at NCI in the Laboratory of Pharmacology and Experimental Therapeutics, biologists in his lab were studying nucleosides. Collaboration began almost immediately: Although he’d never thought of working with nucleosides, the biologists offered him a challenge that piqued his interest. The structure he developed then has strong similarities to an important chemical compound we all carry in our bodies: nicotinamide adenine dinucleotide (NAD).
Dr. Marquez still receives requests from other researchers for samples of the compound, since it is such a stable analog of NAD. “They use it to bind to enzymes that bind to this NAD because they know it’s not going to be destroyed. And just very recently, in 2005, a paper came out in Nature from a group that had used my NAD analog to look at an enzyme,” he said.
One of the most exciting compounds Dr. Marquez and his colleagues have developed was N-methanocarbathymidine. “At that time, I was not interested in developing a drug, I was just interested in the concept” of sugar flexibility, Dr. Marquez said.
He built molecules that would freeze this flexibility in different forms. “It’s almost like when you bake a cake: if you don’t use the right amount of ingredients, your cake will be too hard or too soft. This sugar has the right flexibility and the right rigidity to do all the stuff that DNA needs to do with it,” Dr. Marquez explained.
Building the molecules with different forms of flexibility was “almost like taking snapshots of something that is in motion,” he said. “You make a sugar that ‘freezes’ the molecule in a certain conformation.” As Dr. Marquez and his lab, in a collaboration with Dr. Shizuku Sei, now head of the Viral Vector Toxicology Section, Applied/Developmental Research Support Directorate, explored the preferred binding conformation for particular enzymes, they learned that one of these compounds had very good antiviral activity. Ultimately, the compound was found to be very potent against Kaposi’s sarcoma. The compound has been licensed, and its pharmacology is being studied, with the aim of taking it to the clinic.
“This compound also has very good activity against orthopox viruses [smallpox, among others], and so would be a first emergency measure to a terrorist attack. Researchers are trying to make this compound in large quantities to store for protection against potential bioterrorism attacks that use the smallpox virus,” Dr. Marquez said.
In another collaboration concerning a new antiviral agent, Dr. Marquez and his colleagues again made a serendipitous finding that started with the modification of a natural product, neplanocin A, to see how it could influence the agent’s biological activity. Dr. Marquez and his researchers designed a nucleoside analog called 3-deazaneplanocin A. Now, the Department of Viral Therapeutics, U.S. Army Medical Research Institute for Infectious Diseases, uses this compound as one of its most potent compounds against Ebola virus.
Dr. Marquez often goes over data with the postdocs and “tests” it with 3-D models. Then, in another collaboration, he may have the U.S. Naval Research Laboratory’s X-Ray Crystallography Laboratory test that data in another way. “When we run all the experiments, we know what we think we have, but when you get an X-ray structure, that is the final proof. It is very rewarding because you are doing these things out of the logic of the reactions of the chemistry, and you never see it; and when the crystallographer sends you the pictures, you say, ‘Aha!’ And sometimes we are wrong. We tell them this is what we have, and the crystallographer says, ‘That’s not what you have, you have something else.’”
For example, when Dr. Marquez was developing the fluorine compound with sulfur and fluorine in the same molecule, he thought the fluorine would be in an “up” position. “When we got the X-ray structures, the fluorine was down, and it turns out that when you have oxygen, the reaction goes in one way, but when you have sulfur, there is a ‘double inversion’ mechanism—which caused the fluorine to go down. I learned something from that. It opened a new window on what could happen.”
Collaborations an Important Part of Research
Dr. Marquez noted that chemists do not live in isolation. These collaborations mentioned earlier are an important part of their work. “We make molecules when we think there is a biological concept that we can apply as chemists to solve a problem. That makes us very interconnected with the rest of the biological community, because we can make a lot of things that other people can use,” Dr. Marquez said, reflecting on the many kinds of interactions he has had over the years with other researchers.
These collaborations range from the first compound he discovered in 1980, Zebularine, to his most recent collaboration in a search for a compound to treat prostate cancer. While in many instances, he and his colleagues have seen results from their research almost immediately, in other cases, tangible results have taken years. For example, while Zebularine, about which a paper was published in 1980, had very mild antitumor activity, it was another 20 years before Dr. Marquez determined how and when it would be active, and now the compound is being considered for “a therapeutic application in treating cancer,” he said.
Most recently, Dr. Marquez has been collaborating with Dr. Peter Blumberg in Bethesda on compounds that are strong protein kinase agonists that could serve, among other things, to treat prostate cancer. Drs. Blumberg and Marquez have focused on understanding the signal transduction of diacyglycerols and searching for chemical alternatives to replace it.
“Discovery Is What Brings Cures”
Dr. Marquez commented that basic and applied research must be balanced—neither too much of one or the other. “Give enough freedom to the scientists to discover new things, because discovery is what brings cures. If we all keep doing the same thing, just making better aspirin is not going to cure a disease. We need to find something completely different, something that we’ve not thought of before. Having the freedom to look where we wanted to led to our new antiviral agents. One has to have the freedom to look where nobody else is looking.”
Many great scientists seem to have the same philosophy that Dr. Marquez expressed. Just recently, Nobel Prize Laureate Dr. Avram Hershko, speaking at NCI-Frederick, commented that he started his own research in an area that no one else thought was very interesting—research that eventually led to a Nobel Prize in Chemistry in 2004.
“I love unexpected results; that’s the beauty of research. Recently, we were trying to make a seven-member ring, but something went wrong and we got a six- member ring. Now, understanding why we got the six and not the seven is opening up other possibilities for us to do things we did not think of before. So, unexpected results, as long as you can explain them, are very much welcome,” he said, laughing.
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“Collaboration” is now a commonplace buzzword, used across the spectrum of society—in business, in education, in social ties, and in science. Indeed, Dr. John Niederhuber, Acting Director for the National Cancer Institute, strongly encourages collaborations with various intra- and extramural entities. 
Dr. Marquez still receives requests from other researchers for samples of the compound, since it is such a stable analog of NAD. “They use it to bind to enzymes that bind to this NAD because they know it’s not going to be destroyed. And just very recently, in 2005, a paper came out in Nature from a group that had used my NAD analog to look at an enzyme,” he said.