Discovery and design of medically useful molecules - from bench to bedside

When I started my graduate training back in the mid-1960s, not much was known about the three-dimensional structure of proteins. One of the questions being asked then was: “If two proteins have the same function, would they have the same (or very similar) structures?” At that time, the structures of only two proteins, whale myoglobin and horse hemoglobin, had been determined and they were found to have very similar tertiary structures. Both are from mammals. But hemoglobin was known to be present also in many invertebrates, in some bacteria, and even in some plants. Do those non-mammalian hemoglobins have structures that are similar to those of the mammalian proteins, seeing they are all capable of binding oxygen reversibly? For my thesis, I worked on the structure of the hemoglobin of a marine worm. To make a long story short, the structure of that marine worm hemoglobin turned out to be very similar to those of the mammalian hemoglobins. It was a nice result.

Soon after I came home from graduate school, I was introduced by my father to a friend — a fellow physician — who inquired about my thesis work. Very proudly, I told him that I had determined the structure of an invertebrate hemoglobin and showed that it had a structure very similar to that of mammalian hemoglobins. I was taken aback by his next question: “Is it useful for blood transfusion?” I could not respond.

It was a legitimate question that my father’s friend had asked. Indeed, what good is basic knowledge if it doesn’t have a useful application?

Scientists seek to understand the workings of nature, the secrets of the universe, the mysteries of the unknown. We seek to understand life itself and the relationships among all things living and not. “For what purpose?”, we are asked. “To gain knowledge” is our standard response. “And what for is the knowledge?” “The knowledge will be used for the good of mankind” is how we usually justify what we do. “When?”

When, indeed. To the sick who could benefit from the knowledge that we gain, to the agencies that fund our research projects, to the taxpayers whose money we are spending, the answer that they want to hear is “Now!” I agree.

In the years since graduate school, I worked on a number of proteins, but mostly on antibodies. I contributed to the knowledge of the basic structure of antibodies and to the application of that knowledge to the development of therapeutic antibodies. (I refer the reader to the article that I co-authored with my daughter, Cecilia, which appeared in this column on Nov. 18, 2010.) These days, I am applying the knowledge that I had gained over those years of working with proteins to the design of possible vaccines against a variety of diseases. I would like to believe that I am translating what I have learned in the laboratory into something that has medical use.

The application of discoveries generated through basic research to the development of drugs and procedures useful for medical therapy is usually described as “bench to bedside.” Obviously, this is what I’m trying to do. But to my knowledge, none of the antibodies which I have helped develop for therapy has made it to the clinic. And my vaccine work still has a long way to go. So, my dream of contributing to human health remains unfulfilled.

There are a number of examples of research work that have truly gone from bench to bedside.

The first and probably the most famous example is the development of penicillin. It was serendipitous — an accident. Alexander Fleming was culturing bacteria in a petri dish when it became contaminated by a mold, later identified as Penicillium notatum. He noticed that the mold was somehow inhibiting the growth of the bacteria around it. He concluded that the mold was secreting a substance that was killing the bacteria. He named the substance penicillin. Eventually, penicillin was purified and its structure determined, allowing for chemical synthesis and the development of more efficacious variants. To this day, the penicillins are still the most widely used antibiotic (although more and more bacteria are becoming resistant to them).

Another is the result of the seminal work done by our very own Baldomero (Toto) Olivera and Lourdes (Luly) Cruz. Toto, Luly and colleagues have studied the many components of the venom that conus shells use to paralyze and kill their prey. The work on a particular conus peptide, done primarily by Michael McIntosh who was a young student in Toto’s lab then and now a psychiatrist and a professor, has led to the development of a molecule, ziconotide (marketed under the trade name Prialt), that is now being used to treat severe chronic pain.

Yet another is the rational design of a neuraminidase inhibitor that is used against influenza. To gain entry into a target cell, influenza virus has a molecule, hemagglutinin, which binds to sialic acid on the surface of the cell. Once inside the host cell, the virus reproduces itself and the nascent virus particles exit to infect other cells. But those nascent viruses also have hemagglutinins on their surface and those molecules bind to the sialic acid of the cell that they had just exited. To free themselves from attachment to the host cell, the viruses have neuraminidase, an enzyme that cleaves the sialic acid connection. The detailed structure of neuraminidase was determined, as well as the way it binds sialic acid. By carefully studying the binding site of neuraminidase, molecules that mimic sialic acid and which could act as inhibitors of the enzyme were developed. One, zanamivir (trade name Relenza), has proven to be effective in the treatment and prophylaxis of influenza.

Many other examples could be mentioned, but they are too numerous to discuss in this space. And there will be more examples in the years to come.

I hope that someday my life’s work could be cited as one of those examples. Then, I will be able to say that I have recognized and heeded the implications of the question posed by my father’s friend 43 years ago.

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Eduardo A. Padlan is an adjunct professor at the Marine Science Institute, UP Diliman, and is a corresponding member of the NAST. He can be reached at [email protected]. He has no direct personal or commercial interest in any of the products mentioned in this article.