Turned up to eleven: Fair and Balanced

Thursday, March 07, 2002


Vaccines and the future of molecular medicine
There was an interesting news tidbit in Nature about ongoing HIV vaccine trials at NIH that made me think about one of the central difficulties and challenges of modern medicine. For all of the advances in molecular biology, and their tremendous impact on med-tech and lifesaving treatments for all sorts of ailments, we are remarkably ignorant about many areas of disease, and we still rely on well tested but entirely empirical treatment and treatment development techniques.

First, a little history lesson (ugh!!), but trust me, it is interesting. Vaccination is a very old technology, dating back to the discovery of the cowpox virus as a vaccinating(derived from the latin root word for cow, incidentally) agent for smallpox. As an aside, the major reason for the allure of milkmaids, and probably the reason wealthy people used to bathe in milk, was the observation that milkmaids were less likely to get smallpox, a disease that has haunted man for at least two thousand years. This (eventually!) lead to the first vaccine, using concentrated cowpox virus as a protection against smallpox (it protected about 60% of people, if memory serves). Later, of course, this was improved upon. The first bacterial infection to be vaccinated against was, believe it or not, tuberculosis. The vaccine, named BCG (for Bacille Camille-Guerin) was made by a now well worn technique of serial passage on laboratory medium. The organism (they used a related bacterium to Mycobacterium tuberculosis, named Mycobacterium bovis) was grown for years on laboratory medium, and each time a colony was picked from an agar plate and streaked onto a new one, this represented a massive selection event, where only 1/1000 were permitted to survive. Over time, the selection pressure on the organisms to grow well on laboratory medium outweighed the preservation of virulence (ability to cause disease). The organisms that lose this ability are called attenuated.

This process is still used in creation of vaccines in more recent times, but has been supplemented by "subunit" vaccines, which use proteins from the surface of the invasive organism to create a response in the host's immune system. These vaccines are safer, because the patient population is never exposed to any infectious material, but often less effective in producing protective immunity. The reason that you need boosters for tetanus, for example, is that it is a "subunit" vaccine, specific to the tetanus toxin (produced by the bacterium Clostridium tetani). The subunit vaccine approach also allows for the idea of vaccinating against a disease such as Alzheimer's, which, as far as we know, is not caused by a microorganism. A vaccine that targeted the beta-amyloid plaque, which is thought by many to cause the disease, could conceivably be useful. Unfortunately, subunit vaccines are often terrible failures, and are much more expensive to develop, because molecular and biochemical techniques to make and purify the vaccine agent are more extensive than attenuated virus vaccines.

This brings us (more or less) to the present day, and the fundamental problem. For all of our technical prowess (and it is impressive), we have not gained the sort of basic understanding of the process of infection (bacterial or viral) that might allow us to improve our success rate. Drug discovery is expensive, in my opinion, not because curing disease is an intractable problem, and the law of diminishing returns has taken hold, as some would argue, but rather because we have exhausted the "shotgun" approach to medicine. By this I mean the approach that ignores the intricacy of the disease process, but rather fires a spray of medical treatment at the disease, with the hope that a few pellets hit the mark. This is, of course, in no way to denigrate the noble work of Medicinal Chemists, who have been a tremendous asset to the fight. We are, of course, attempting to solve these problems in labs across the country, but I fear that a pressure for applied research has lead many away from the basic studies that are necessary. I was watching the West Wing last night, and I thought it was one of the better ones (less preachly, treacly ultra-liberal stuff, more witty banter and personal relationship stuff), and a subplot had to do with the supercolliding superconductor (wait for the connection...). The senator who was blocking funding said "What is the application?" The response was "There is none." Later, that response was amended to "Discovery. The purpose is discovery." This, I think, the right response (the fact that the guy had non-Hodgkin's lymphoma, in my opinion, detracted from the story line). As they said, the great discoveries are often made serendipitously, by people looking to do something else. Only basic research can accomplish this.

As far as my view of molecular medicine goes, I think it has a bright future. Genomics and proteomics will be a tremendous help, but not the way most people think. We probably will never have "designer drugs" that are tailor made for each individual, unless there is a revolution in drug production technology. What these tools will do, though, is allow basic research to proceed down the path of understanding how our bodies work, in much greater detail, and much more thoroughly. At some point in the near future (maybe 10 years), a doctor will be able to draw a blood sample, purify the white blood cells, run them over a gene chip and a protein chip, and tell you exactly what is going on. Once a year, the doctor will draw samples from your blood, skin, and maybe a couple of very small biopsy sites, and give you a detailed rundown on your health. Our understanding of host-pathogen interactions will improve to the point that a new generation of drugs will fight bacterial disease not by killing all bacteria, but by directly stopping the etiologic (disease causing) agent. This will, incidentally, spill over into environmental science and ecology, where our growing understanding of complex interactions of species will allow humanity to preserve the environment, and ourselves, while maximizing the resources that we desperately need.

Whew! I think that is enough for now. (Simberg is to space as Orwin is to biology? Well, a guy can dream!)

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