When I was taking a specialized Geochemistry course, "Crystal Chemistry", I realized that chemistry is mostly geometry. From a geochemical point of view, most of the crust of the earth is a gigantic oxygen crystal, with the oxygen atoms in or near a closest-packing arrangement, held together by covalent bonds with various metal ions.
In biology, the geometric view is even more relevant. For example, enzymes work either by making a lock-and-key attachment, or by making two or more such attachments and then shifting or bending the resulting complex so a different lock-and-key is facilitated. Most drugs that have been discovered, or engineered, are actually little geometric items that either promote or block a biochemical pathway in the body. A few are replacements for necessary molecules that are sometimes present in insufficient amounts, such as insulin, to treat Type I Diabetes.
Side effects of drugs result when the lock-and-key match is not perfect, and the matching part on the drug is also a partial match to a critical component of a different biochemical pathway. Side effects also occur when the waste-disposal systems of the body break down a drug molecule: some breakdown products have geometrical properties that interfere with other biochemical pathways.
In Ten Drugs: How Plants, Powders, and Pills have Shaped the History of Medicine, Thomas Hager discusses the discovery and development of ten families of medical molecules. The subtitle tells of three that could stand in for them all:
- Plants – The first chapter tells us the history of Opium, derived from the sap of a particular species of poppy. It also discusses how researchers learned to refine opium to extract morphine, the primary molecule in the mix. Morphine was the first opiate to be discovered; opiates are derived from opium.
- Powders – Heroin, prepared by chemically altering morphine, and opioids (not derived directly from opium or its components, but entirely synthetic) such as Fentanyl, bookend the discovery of painkilling medicines. Heroin came very early (1897), leading to many products, with varying amounts of pain-relieving properties, and all of them very addictive. Fentanyl came later (1959), and led to exceedingly powerful pain medications, which are also powerfully addictive.
- Pills – "The Pill" refers to birth control medication, which changed sexual politics in America and much of the world, and upended social systems in its wake. It also may have triggered the "Feel bad? There's a pill for that" ethos we live in.
In the ninth chapter we find the convoluted story of Statins, the drugs that lower blood cholesterol, which are taken in an attempt to reduce fatalities from heart attack and stroke. For the worst cases of extra-high cholesterol, lowering it does indeed help. But it is still now known if taking statin drugs will actually save (that is, lengthen) the life of the vast majority of those who take them because their blood cholesterol is slightly higher than a threshold such as 200 mg/dl. That value is a nice, round number that is near the center of a broad distribution: Some people with low or even very low cholesterol get heart attacks, and most people with moderately high cholesterol live long, healthy lives. 200 is a kind of break-over point, "because you have to draw the line somewhere."
Let's look for a moment at breakdown products. Morphine, its derivatives, and related opioids, work by stimulating the endorphin system, which blocks pain. This system works naturally to reduce pain, but goes into hyperdrive when opiates and opioids are present. These chemicals also produce a high, the "endorphin rush". Opiates and opioids are broken down to release a small molecule called THIQ. Some of the THIQ avoids further breakdown to re-attach to the endorphin receptors, but then it never is removed. This is at least part of the mechanism of opiate tolerance. It takes a larger dose of the drug to get results. Eventually, the brain can become saturated, and no amount of drug will have a sufficient effect. At this point, some drug addicts die from overdose, and the rest stop using it because they aren't getting a high any more. If someone claims to have used heroin heavily for more than twenty years, they are probably lying. By 20 years, saturation has occurred.
The last chapter of the book discusses monoclonal antibodies, which are a recent innovation (1986). They are as close to a "magic bullet" as we have so far been able to produce. I learned that medicines with names ending in "-mab" are produced this way. These are large molecules, so none of them yet work on problems in the brain or central nervous system, because they are too big to pass the blood-brain barrier. Perhaps that will change, maybe by a means of removing most of the molecule and purifying the "bullet" part.
Where can medicine go from here? Most modern drugs are produced for chronic problems. The low-hanging fruit exemplified by antibiotics seem to be mostly exhausted. The Baby Boom generation now in their 60's and 70's have lots of chronic issues, and drug companies love finding drugs for those. For a strep throat, you take a ten-day course of antibiotics, and you're done. For high blood pressure, you're on a lifelong prescription plan. Pay, pay, pay all the way to the grave. So most of what "Big Pharma" produces is to feed the Boomers' need for more comfort in their dotage. Will this change; will some remaining big problems (malaria, Ebola) be effectively dealt with? The author is guardedly hopeful. But if vaccination for malaria winds up costing $100,000, how much help can that be, when billions of people need the vaccine?
Are there larger and larger numbers of pills and potions in our future? Or will better preventive medicine arrive? I guess we need to stay tuned.
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