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or Chi-Huey Wong, Ph.D., Ernest W. Hahn Professor and Chair in Chemistry, The Skaggs Institute for Chemical Biology and the Department of Chemistry, carbohydrates are the best-kept secret in the cellular world.

A significant portion of Wong's research life has been spent trying to understand the role of sugars with the added goal of developing small molecules to affect their function. In the cellular world, sugars are responsible for jump-starting some of the most destructive human diseases. Cancer, virus and bacterial cells all have unique sugar structures called receptors on their surfaces; until recently, very few people knew what they did or even why they were there in the first place.

"If you look at the important discoveries in the past 40 years," Wong says, "most have been about proteins and not much about sugars. But understanding what sugars do is one of the reasons I got into the field of chemistry."

These cell surface sugar receptors interact with host cells. Basically, viral and bacterial cells are like uninvited guests. During infections, even metastatic cancers, these cells spread throughout the body, searching for a place to light. When they land on the surface of a host cell, they immediately try to insinuate their way inside -- and the host cell always recognizes its sugar receptors first. Take the influenza virus, for example. Once it attaches itself to the host cell, the sugar receptors open a doorway to the interior of the cell. The doorway opens through sialic acid, a compound found on the surface of host cells. The sugar receptor binds to the surface of the host, the virus emits an enzyme that removes the sialic acid and, in the process, allows the viral RNA to enter the cell and replicate. The result is that patients get sick or cancer spreads.

Wong's goal is as simple and straightforward as the sugar receptor process is complex and mysterious: "The more we understand about the way sugar receptors work, the better chance we have to develop a new strategy of therapy."

STRATEGIES FOR COMPLEX PROBLEMS

Wong is a great believer in the power of simplicity, and he likes simple plans. "You start with a highly complex system like sugars that is very difficult to understand. But once you understand it, you can come up with simple strategies to solve these complex problems. That is something we are very interested in doing."

And there are a lot of scientists interested in doing it. Compared to other labs at TSRI, his laboratory is quite large. "The nature of our research requires a lot of effort," Wong says. "So, I have a big group, usually around 35 people. Without them, I could not do the work. I really owe them a great deal."

The names of his colleagues, both past and present, are posted on the lab's Web site -- as Wong groupies, a title he reacts to with amusement. "One of my lab people came up with that name," he says. "But I'm pretty close to my group and deeply involved in our research. Basically, I'm overwhelmed by research but in a good way. Because of the way TSRI works, we have been able to focus most of our efforts on research. I teach one graduate course, but that's very light, so I have been able to concentrate on the research."

Of course, research is not all that he concentrates on. This spring he took a week to tour the Princeton University campus with his son, one of the places that had offered an invitation to visit. His son is interested in science but is also an accomplished violinist, winning an international music competition in California and performing in Europe as well. In the Wong family, art and science run together, almost neck and neck.

A SINGULAR DEDICATION TO SCIENCE

His daughter graduated from Harvard last year with a degree in fine arts -- she is a painter. His wife, a former high school teacher, is now a freelance artist. Wong is no stranger to the arts himself.

"As a child in Taiwan I was interested in art," he says, "but I also realized that it was not an easy career. So I had to be more realistic growing up -- I studied science." The study of science led Wong from Taiwan to doctoral studies at MIT, to postdoctoral work at Harvard, to a professorship at Texas A&M, and finally to The Scripps Research Institute. All along the way, he pursued science in a singular, straightforward fashion, and continues to do so in much the same way today. He knew what he wanted then, he knows what he wants now.

"As a graduate student, I chose a lab right away," he says. "No second thoughts. Perhaps it was because I had some research experience in Taiwan after I got my masters degree. I spent five years as an instructor and was very involved in research. That period of time helped me define my interest in chemistry. After that, I knew that I wanted to do research."

When it came down to doing research on sugar molecules, the first thing Wong and his lab team knew they had to do was develop a method for synthesizing sugar molecules on a large scale. As he puts it, this is very, very difficult. Sugars play multifunctional roles in the body, and the problem that Wong was most interested in -- the receptor role -- was the most difficult of all. These complex sugars exist in minute amounts, making them even more difficult to isolate, characterize, or synthesize.

To put that difficulty in perspective, Wong points out that the human body contains nine monosaccharides or building blocks to assemble all the various carbohydrate structures, called polysaccharides. "But the number of possible polysaccharides is enormous," he says. "Each monosaccharide building block has about four functional groups for linkage. The number of combinations of the nine monosaccharides that form a tetramer -- a polymer consisting of four molecules -- is more than 15 million."

The upshot of this enormous complexity was that no one could quite figure out a way to actually create enough carbohydrate molecules to study. What they needed was a new technology. What Wong did was put that new technology on his personal computer, developing a program for creating a broad range of oligosaccharides in a singular operation.

The program is called Optimer. You can create a library of oligosaccharides one-by-one or you can synthesize a specific one; the choice is yours. "It's very fast and very simple," Wong says. "If you need to create a sugar structure, you enter the sequence into the computer, and the building block for making the sugar structure immediately appears on the screen. A few minutes later, after mixing the building blocks in sequence, the structure you want is produced."

Once Wong and his colleagues get their hands on these new sugar structures, they set about trying to find things that stop them from working. In theory, it's similar to other work being done on cancer vaccines. "Take the cancer cell sugar receptor," he says. "To create a vaccine, we can attach this unique sugar receptor to a carrier protein and inject this joined compound into the body. The immune system produces an antibody that recognizes the sugar receptor. When these new antibodies discover a cancer cell with the same sugar receptor, the antibodies block the receptor, and prevent the cancer cells from attaching to an endothelial or host cell. As a result, you stop the cancer."

The goal is the same in developing a new drug therapy, but with a slight variation. Rather than tricking the body into producing an antibody, Wong hopes to design small molecules that will activate the immune system to produce weapons to kill cancer cells, or that will inhibit the formation of the sugar receptors -- in other words, small molecules that will wreck the machinery that produces the sugars in the first place.

"This is how pharmaceuticals are often developed," he says. "You need a small molecule for a specific target that will inhibit its function. Various cells have unique sugars but some cancer cells share the same structures, especially metastatic cancer cells. But to proliferate, the metastatic cancer cell still has to attach itself to the host cell, and that attachment is often through the sugar receptors. You can design a very small molecule that mimics the cancer cell surface receptors, so they both have to compete for the host cell attachment -- but the small molecule wins. It's a tough thing to do but that's what makes chemistry so interesting."

The mechanics are essentially the same for the lab's other research focus, developing small molecules that don't fall victim to drug resistance. Eventually, all chronic diseases like cancer or HIV develop resistance to treatment. Their cells mutate and the inhibiting factors no longer work against the new viral design. But they still have to get through the sialic acid on the surface of the host cell, Wong insists, no matter how much they mutate.

In the case of HIV, he and his colleagues looked at the drug resistant mutations -- more than 100 of them -- and found a common trend. Most therapies disable the virus by latching onto a protease (an enzyme that works as a catalyst) that the virus needs to multiply, but HIV's ability to mutate rapidly renders these protease inhibitors ineffective within as few as five weeks. The most successful treatment tries to get around that by overwhelming HIV with two or three in combination therapy, but even this approach fails eventually.

Wong now thinks he knows how HIV adapts so quickly to these treatments. HIV proteases apparently change structure so that the inhibitors no longer bind tightly. "We have studied the mutation pattern of HIV protease from patients who take these drugs, and found that the enzyme often rejects the drug by reducing the size of one of the drug binding sites," he says.

In fact, these mutations look just like feline protease in FIV, another virus Wong and his colleagues have studied. They looked at the corresponding binding site on HIV protease inhibitors, and found that most of them have chemical structures that were too large to interact with the shrunken areas in drug-resistant proteases. With that in mind, they redesigned the drugs, giving them a smaller chemical group at the critical binding site that increased their effectiveness against both HIV protease and its drug-resistant mutants. So, no matter how much mutation occurs, the drug will always find a way to bind to the protease and kill the virus.

THE FIRST BI-FUNCTIONAL ANTIBIOTICS

"More important," Wong says, "there were no resistant mutants detected in treated cell culture after one year. The redesigned drug may last longer as drug resistance is lowered."

In research published this spring, Wong and his colleagues have developed new small-molecule inhibitors to target bacterial RNA. These inhibitors bind to the bacterial RNA, blocking the protein production machinery. They also block the enzymes that cause drug resistance. These new molecules represent something of a medical breakthrough. They are the first bi-functional antibiotics, stopping the spread of bacteria and reducing its ability to develop resistance to drugs -- all at the same time.

A simple plan, indeed.