Saturday, July 02, 2005

The Interface of Physics, Chemistry, and Biology

Probably the greatest discoveries of the 21st century will occur at the interfaces between traditional disciplines.  Those who are considering a research-oriented career would do well to consider what kind of problems they want to work on, then obtain an education that readies them to attack those problems.  This differs from the old-fashioned approach.  Traditionally, one would decide which discipline applied most directly to the problems of interest, then studied that discipline.  

There is a nice illustration of this in the June 23, 2005 NEJM: How Ebola Virus Infects Cells. (Subscription required for full text.)  Scientists have known for years that there is a complex mechanism that permits viruses to enter cells and infect them, bypassing the usual defenses.  The mechanisms vary for different viruses.  This is a matter of great interest, for obvious reasons.  We would like very much to be able to stop viruses from entering human cells.

In How Ebola Virus Infects Cells, Dr. Kawaoka describes the precise mechanism for breaching the cell membrane, as outlined in a recent paper by Chandran et al. 1:
Chandran et al. propose a third triggering mechanism (Figure 1). They discovered that proteolysis by two endosomal cysteine proteases, cathepsin B and cathepsin L (which are active in a low-pH range), renders a conformational change in the surface glycoprotein of Ebola virus. They showed that glycoprotein-mediated infection is substantially reduced in cells lacking these proteases; that cathepsin B and cathepsin L can individually cleave Ebola virus GP1 to yield an approximately 18-kD N-terminal fragment, which is further digested by cathepsin B; that the extent of viral infectivity mediated by glycoprotein is correlated with the efficiency of the production of the 18-kD fragment; and that selective inhibitors of cathepsin B and of both cathepsin B and cathepsin L block viral infection in cultured cells (Figure 1). Their model therefore predicts that after the internalization of Ebola virus into the endosomes of cells, the C terminus of the viral GP1 is removed by cathepsin B, cathepsin L, or both in the endosome, leaving the 18-kD N-terminal fragment. Subsequent digestion of this fragment by cathepsin B initiates membrane fusion by GP2, the still-intact fusion domain of the glycoprotein molecule.
In order to understand this, one must understand the physics of hydrophobic/lipophilic interactions, the nature of the conformational changes in protein folding, and the effects of pH upon enzyme activity.  One also must have a good understanding of the types of bioactive molecules present at the site of entry.  This means that one must have a grasp of physics, chemistry, and molecular biology in order to understand virology.  

Many well-informed persons are worried about the potential health impact of climate change.  Some of the more predicable ones should not be too difficult to control:
Dengue, schistosomiasis, and Rift Valley fever are only three examples of major human diseases that can be expected to be influenced by global climate change. There are experimental vaccines for dengue and Rift Valley fever, and drugs for treatment of schistosomiasis. We can combat all three diseases with environmental sanitation and health education. In spite of these measures, we have not been successful in controlling them and we can expect local and world changes in temperature and rainfall to make their control more difficult.

Fortunately, the changes will happen gradually and if we act now, we have time to learn more about the epidemiology and ecology of the vector-borne and zoonotic diseases. We also have time to devise better control and prevention strategies. These studies will require interdisciplinary research. The trend today in graduate education and in university and government research is to specialization, and in infectious diseases the trend is to specialization at the molecular level. This trend is laudable to a point; many of our solutions will require understanding at the molecular level. However, this particular problem will also require training in more general and interdisciplinary fields including field ecology, general medicine, epidemiology, forestry and botany, entomology, climatology, and zoology to name a few.
The mechanisms are explained in that article, and in this one:
But it won't be a gradually warming world that triggers future health crises, says Patz, a scientist based at the UW-Madison Center for Sustainability and the Global Environment. It will be a dramatic increase in severe weather events - major storms, heat waves, flooding - triggered by a shifting global climate that will wreak most of the human health havoc.

"Averages don't kill people - it is the extremes," Patz explains.

The issue, Patz says, is how are we going to adapt? If we don't do something to mitigate the potential human health effects of climate change, the world, beginning at the local and regional level, will begin to experience climate-related catastrophe. [...]

Strong El Nino events, for example, tend to trigger heavier rainfall in the American southwest, setting the stage for rodent population booms and increased risk of exposure to hanta virus, a sometimes deadly disease transmitted through rodent urine and droppings.
There will be some advance warning for some of these problems, and some are problems that we have some capacity to combat.  Some will come with no warning, and there may be some for which we have no effective defense.  

It is interesting to speculate about what effects this will have on the economy.  Specifically, will it be feasible to continue the trend of globalization, if any given cargo container could bring the next epidemic to our shores?  Of course, any of you could speculate about that as well as I.

1 Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science (in press). (Available at http://www.sciencemag.org

Topics: science, medicine, armchair musings
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