As part of Brandeis University's 50th anniversary celebration, there were many events that focused on remembering the University's past. However, on 17 October 1998, Dr. Gregory Petsko, Professor of Biochemistry and Director of the Brandeis' Rosenstiel Basic Medical Sciences Research Center, offered his audience a view through the keyhole of the door to the future. Inspired by Petsko's unique ability to capture students' attention when he lectured in my General Chemistry class last year, I was looking forward to hearing him speak that day. A Glimpse Through the Keyhole to the Future
by Betty Chan"There's a door over here and a door over there. I want you to design a key that will open this door, but not that door. If you open this door, you can save 50 million people. However, if you open this door, but by some chance you open that door as well, 100 million people will die. You can ask me one question." This is how Professor Petsko began his lecture entitled "Doorway to the 21st Century: How Biomedical Research Will Change Your Life and the Lives of Your Children" -- with a puzzle for the audience, just as he always did when he gave our General Chemistry lectures. The audience's questions reflected its consideration of the serious and heavy implications behind opening any door. Petsko answered, "What I do is describe the locks that the keys fit into."
Professor Petsko, who specializes in X-ray crystallographic analysis of proteins and enzymes and in molecular pharmacodynamics, continued to expand on this key-lock theme with examples of some of the work he has done at Brandeis along with his colleagues Professor Dagmar Ringe, who was my General Chemistry professor, and both their graduate and undergraduate students. Their work consists of crystallizing proteins of interest and taking X-rays of the crystals. These X-rays, along with computer-aided design and mathematical modeling, provide three-dimensional models of the proteins. These protein models are important factors in finding the solutions to the key-lock puzzles.
The proteins that Petsko and his team are interested in are usually the causes of some of the most lethal diseases. The venom of sea snakes was used as the first example in Petsko's lecture. According to him, there was no antidote in 1979. Using colored slides, Petsko presented the audience a three dimensional model of the poison. At first glance, there is a slender piece jutting out from the rest of the structure. Petsko explained that it is this key-like piece that blocks electrical signals between nerves and muscles, leading to death. This key-lock puzzle was solved by using this key-like piece to make antibiotics. The entire poison would have been too lethal for that purpose.
Although not as deadly, osteoporosis is a serious condition for many people. A molecule has been found to reverse the effects. In other words, "you get your bone back," Petsko said. A three-dimensional model of this molecule shows a hook-like extension. It is this piece that can fit into a lock found in natural biological processes of humans and reverse the deterioration of bone. Currently, this molecule is offered only as injections. Petsko and his team are working on finding an oral drug that can make the same hook-like extensions.
Professor Petsko applied the key-lock strategy to one of the symptoms of juvenile diabetes -- blindness. He explained that the high concentration of glucose present in the blood induces a protein found in the eyes to produce toxins, which leads to blindness. Again, a three-dimensional model of this eye protein was made. Once they knew what the protein looked like, a structure of a key could be generated. An eye wash was made to prevent the protein from binding to glucose. It was a perfect fit, another key-lock puzzle solved.
After acknowledging all these successes in finding the perfect keys to fit the locks, Professor Petsko turned to discuss the future. He pointed out that people are living longer today. Yet, there are severe consequences. "Cancer and Alzheimer's didn't come up until we started living longer," he said. One of the goals for the 21st century would be to find cures for such ailments.
"One of the things that has to change in the 21st century is that we have to do a better job of killing microbes," Professor Petsko told the audience. There is no doubt that the word "microbes" conjures up fears, more so today than in the last few decades. Viruses and bacteria that were once thought to be wiped out are reappearing as different strains. Drug-resistant strains of malaria have been detected. "If drug-resistant bacteria beat the last antidote, we're back in the 1890s and 1910s," Petsko said.
Most of the graves in Massachusetts are clustered by year. The clusters consist of mostly children, and they reflect the diphtheria epidemic. Back then, diphtheria was highly fatal for anyone under the age of 20. Today, it is no longer a major concern in developed countries, but in the former Soviet Union, diphtheria outbreaks have been recorded. The pathogenic bacteria rely on metal ions, especially iron, to become virulent. The liver responds by filtering the iron out of the blood. The bacteria then respond to the shortage of iron by switching on the production of a toxin. The toxin attacks cells; the bacteria can then retrieve iron from dead tissue. Petsko explained that a frightening small dosage of this toxin is enough to kill a person. The lethal dose of the diphtheria toxin is only 18 times that of the Botulinus toxin. By comparison, the lethal dose of cyanide is 330 million times as much as for the Botulinus toxin.
Currently, Professor Ringe is working with the protein that triggers the diphtheria toxin production. X-ray crystallography was used to reveal the structure of the protein. Although drugs to prevent toxin production have not yet been found, Petsko is concerned about the outcomes. "Today's antibiotics actually strengthen resistant strains of bacteria. When they kill normal strains while leaving resistant strains unaffected, they're essentially selecting for the resistant strain's survival," Petsko later said. A key has yet to be made for this lock.
The AIDS virus is another example of the need to combat microbes in the 21st century. The protein of interest is involved in replicating the virus. The drug protease inhibitor blocks that lock. However, the key is too expensive to make. A cheaper drug to open the same lock has yet to be made. Professor Petsko is optimistic. He told the audience, "There will always be a need for new drugs, but it's a mistake to think we can never win against bacteria."
Another goal for the 21st century is speedier development and access of new drugs. Today, it takes 9-13 years to develop a drug and to have the Food and Drug Administration approve it. On one hand, the tedious and long process ensures that there are no lethal side effects. "We want to be sure that by opening this one door we don't open up any others," Petsko said. However, there are consequences, especially where children are involved. Because they are most susceptible to diseases, time is an important factor. "If you work on diseases that kill children, 13 years just doesn't cut it," Petsko said.
This glimpse through the keyhole to the future brought confidence, hopes, and concerns from the audience. Some of the questions directed to Professor Petsko after his lecture reflected the audience's concern about the serious implications behind the door. "It's all the same story as we delve deeper and deeper into research and development. Our ultimate goal and motivation is doing something to improve the human condition," Petsko said. However, as the process of promoting humankind becomes more and more personal, bioethical questions are raised. These issues were addressed to Petsko, who responded, "My credentials as a scientist don't give me the right to preach on morals and values. I can give you information, not my opinion, but information on the subject so that you can make your own decisions." Petsko also stressed that better communication between scientists and the public was necessary for making progress.
At one point, Petsko was asked what his inspirations and motivations were in being a research scientist. His answer was very honest and would have an impact on me for a long time. "Oftentimes as we take two steps forward, it's followed by one and a half steps backward. It is this challenge that makes his job worthwhile," Petsko told the audience. "People say that science will dehumanize man. That is a statement that I believe to be tragically false. ... What we do is beautiful. I'm not a fan of 20th century art, but in some ways I believe that scientists are among the last great artists. We uncover things for you to see. That's the other great motivational force."
(Editor's Note: Betty Chan is a sophomore at Brandeis University.)
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