Primer: Drug Discovery

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not.  So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

There are a few ways to approach the general idea of drug discovery, but I’m going to try and tackle it from the historical treatment first, and maybe revisit it in a future Primer.  I am part of the Division of Medicinal and Natural Products Chemistry at the University of Iowa, and the two components of it, Medicinal Chemistry, and Natural Products, are both integral to the idea of developing new drugs.  Medicinal Chemistry is just as it sounds: the study of designing and synthesizing new drugs, using principles of chemistry, pharmacology and biology.  The idea of Natural Products, however, is a bit more interesting in that, just as it sounds, it studies chemical compounds “developed” in other organisms that may be useful as drugs.

The oldest records tend to cite the ancient Chinese, the Hindus and the Mayans as cultures that employed various products as medicinal agents.  Emperor Shen Nung, in 2735 BC, compiled what could be considered as the first pharmacopeia, including antimalarial drug ch’ang shang, and also ma huang, from which ephedrine was isolated.  Ipecacuanha root was used in Brazil for treatment of dysentery and diarrhea, as it contained emetine.  South American Indians chewed coca leaves (containing cocaine) and used mushrooms (containing tryptamine) as hallucinagens.  Many different examples of drug use in ancient, and more modern cultures, can be pointed to as early forerunners of today’s drug industry.

However, it was the 19th and 20th centuries that really kick-started the trend, as this is when modern chemical and biological techniques started to take hold.  It was in the 19th century when pharmacognosy, the science that deals with medicinal products of plant, animal, or mineral origin, was replaced by physiological chemistry.  Because of this shift, products like morphine, emetine, quinine, caffeine and colchicine were all isolated from the plants that produced them, allowing for much purer, and more effective, products to be produced.  Advances in organic chemistry at the time really helped with the isolation, so these discoveries wouldn’t have been possible previously.

In today’s world, there are a few ways you can go and discover a new drug:

  1. Random screening of plant compounds
  2. Selection of groups of organisms by Family or Genus (i.e. if you know one plant that makes a compound, look for more compounds in a related plant)
  3. Chemotaxonomic approach investigating secondary metabolites (i.e. Drug A functions in your body, then is metabolized in your liver to Drug B, which also happens to be functional)
  4. Collection of species selected by databases
  5. Selection by an ethnomedical approach

I think the latter two are the most interesting, especially with a historic perspective.  With the latter, we’re talking about going into cultures (a la the movie “Medicine Man“) and learning about the plants that they use to cure certain ailments, then getting samples of those plants and figuring out what makes them effective.  It has been estimated that of 122 drugs of this type used worldwide from 94 different species, 72% can be traced back to ethnic groups that used them for generations.

The discovery of new drugs of this type is actually somewhat worrisome as these cultures die out or become integrated into what we’d consider “modern society.”  These old “medicine men” and “shamans” die before imparting their knowledge to a new generation and these kinds of treatments are lost.

The collection of species and formation of databases is interesting, and only more useful in recent history due to the advent of computers that can actually store and access all the information.  With this process, we’re talking about going into a rain forest, for example, and collecting every plant and insect species you can find, then running various genetic and proteomic screens on the cells of each plant and insect to see whether they produce anything interesting or respond to anything.  This process can involve thousands of species across a single square mile in a rain forest, necessitating a great deal of storage space for the samples themselves, but also computing power to allow other researchers the ability to search for information on that given species.

An example of a “screen” that one could carry out would be to grow bacteria around your plant or insect samples.  If you ever heard the story of penicillin, you’ll know that Alexander Fleming (1928) noticed that his culture of Staphlococcus bacteria stopped growing around some bread mold that had found its way into the culture.  From that bread mold, penicillin, was developed as our first antibiotic.  The same kind of principle can be applied here: mix your samples together and “see what happens.”  If anything interesting happens, you then continue investigating that sample until you isolate the compound that is doing that interesting thing.

The isolation of that “interesting compound” can be very tricky, however.  In many cases, a particular anticancer agent or antibacterial agent may be housed inside the cells of our plant species.  Getting that compound out may be difficult, as it could be associated with the plant so tightly that you have to employ a variety of separation techniques.  And even after you apply those techniques, what you are left with may be nonfunctional, as the compound may require the action of that plant itself to work properly (i.e. the compound you want may still need other components to work).  Even after you isolate the compound you want, in order to make it a viable drug, you have to be able to synthesize it, or something like it, chemically in a lab setting.  Preferably, on a massive scale so you can sell it relatively cheaply as a drug to the masses.  These processes can be daunting and costly.

So basically, it can be fascinating to discover new drugs, especially ones that were actually “discovered” thousands of years ago by cultures that have long since died out.  However, you may find that “discovering” the drug may be the easy part – mass producing the drug could be the most challenging aspect of the ordeal.

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