Idealism versus Reality: The Journey of a Parasitologist
C. C. Wang, Ph.D.
Professor of Chemistry and Pharmaceutical Chemistry
University of California, San Francisco
I was born in Beijing, China but have never had much chance to live
there during my life.
When I was a child, I followed my parents running around the countryside of Southern China trying to escape from the Japanese invasion. It was during those days that I became a victim of many dreadful infectious diseases, including vivax malaria, which placed me at the door of death several times. I was lucky to have survived them and eventually grew up in Taiwan and studied chemistry in my college years. I then had a chance to come to the States and received a Ph.D. in microbial biochemistry from UC Berkeley and went through postdoctoral training at Columbia and Princeton Universities majoring in biochemistry of Escherichia coli. I then decided that I must devote all I had learned to help the poor people in the world. Thus, without knowing anything about parasitology or the pharmaceutical industry in the West, I joined the Parasitology Division of Merck & Co. in Rahway, New Jersey in 1969.
I soon became rather disillusioned by my working environment, because all we were doing was screening drugs against the parasites infecting cattle, sheep, dog or even chicken. Thus, I started to organize a series of journal clubs, seminars and conference discussions with my colleagues in the Company under the title How can Merck contribute more to human health in the world?.
These activities went on vigorously for several months and aroused much attention within the Company. One afternoon, the President of the Company gave me a personal call and wanted to chat with me the next day. Sensing that my efforts might have finally made a dent, I spent a sleepless night and put on my best suit the next day to see our President.
The President was all smiles and said: C.C., I want you to know how much I appreciate your effort in starting the scientific discussions and dialogues among us. They are good for our research, our morale and our Company. Still full of smiles, the President sat back and continued: But, I want you to know also that the mission of our Company is not to do good around the world nor to discover scientific truth. Our main responsibility is to satisfy our stockholders. If by doing so we can also do some good, so much for the better.
During the ensuing years, I worked quietly with drug screens against coccidiosis in chickens with occasional opportunities to look into the biochemistry of this organism. I started to realize how fascinating the biology of these parasitic organisms is. Then, in the late 70s, my colleagues in the nematode parasite group discovered the potent nematocide, ivermectin, in their natural product screens. Our then new President Dr. Roy Vagelos was very progressive in his thinking and insisted that we must learn the mechanism of action of this new drug in order to improve our chance of finding additional new drugs in the future, even though FDA does not demand such knowledge. I was assigned this responsibility, and it was accepted with great reluctance.
The assignment turned out to be a total nightmare for me in the ensuing couple of years. Without any clue on how a macrolide, the structure of ivermectin, can kill a nematode, there was no possibility that one should not look into. After a very long list of tests and an equally long series of negative outcome, I became utterly desperate. I would go routinely to the local abattoir a couple times a week to collect the gigantic and smelly Ascaris, come back to the laboratory and soak them in ivermectin without knowing what to do other than staring at them with glassy eyes. Amazingly, a couple of weeks of such stupid act convinced me that the worms appeared to have a more stiff mid-section by the drug treatment, suggesting that ivermectin might work on the nervous system of Ascaris. This observation was quickly confirmed in Caenorhabditis elegans. Through collaborations with Alfredo Gorio at Rockefeller University using lobsters walking legs and Tony Stretton of the University of Wisconsin working with Ascaris we demonstrated that ivermectin acts by opening the chloride ion channels in these organisms, resulting in hyperpolarizing the muscle membranes in lobster and neuronal membranes in Ascaris. These invertebrates become thus immobilized by the drug action.
This episode provided me the biggest challenge in my research career and taught me many useful lessons. It also helped me in realizing some of my original idealism in helping the poor people. As we all know, the drug was subsequently donated by Merck in a noble gesture unprecedented in the history of pharmaceutical industry to the patients of river blindness in West Africa and Central America. The disease is now fully under control. Nowadays, I often secretively congratulate myself for being so lucky to be involved with the development of ivermectin, even though the involvement was such an infinitely small part of the entire effort.
In the early 80s, I was offered an opportunity to join the faculty rank of UCSF. I took it with some hesitation, because virtually no one was transferred from industrial to academic world in those days, particularly for someone with some 12 years in the industry. I went to UCSF without any research fund, equipment, personnel or even a viable project, but the move turned out to be one of the wisest decisions in my life. I love the free and fertile research environment in a university and the extensive interactions and communications in the academic world. Most of all, I do not have to engage in the endless drug screen any more, but to focus on the interesting biology of some of the human parasites I had always been longing to study. My initial focus was on the purine salvage enzymes in Giardia and Trichomonas in an effort to prove that new drugs could be found by selecting validated targets and designing specific inhibitors to them based on structure-function analysis. These projects went quite successfully over the years. I was then attracted by the fascinating mechanisms of translation initiation in Giardia and cell cycle regulation in African trypanosomes. I concentrate on these two subjects with the hope that they will turn into simple models for the biology of general and fundamental importance. Meanwhile, the unique simplicity in these models may also offer opportunities for anti-parasitic chemotherapy.
In recent years, there is an enhanced interest in translational research in the academic world. A close examination of it convinced me that it is the same boring and mindless drug screens I have suffered through as a young man. It may be an essential operation in pharmaceutical industries but utterly unsuitable for training graduate students and postdoctoral fellows. There is also a raised concern of global health among the universities, which is most admirable. But my 36 years of experience in this field has convinced me that global health is not a simple medical problem. It is more of an economical, political, social and cultural problem requiring far vision, commitment, compassion and devotion from powerful world leaders for long term help. The best we, the bench scientists, could contribute is to provide more insight into the unique basic biology of these parasitic pathogens so that it will be exploited for new drug discovery by pharmaceutical industries when the Third World turns into an attractive customer. High idealism can be accomplished only by very realistic and extremely patient approaches.