Not Ready for Human Consumption: Doing Preclinical Studies

By John Pezzullo

Before any proposed treatment can be tested on humans, there must be at least some reason to believe that the treatment might work and that it won’t put the subjects at undue risk. So every promising chemical compound or biological agent must undergo a series of tests to assemble this body of evidence before ever being given to a human subject.

These “before human” experiments are called preclinical studies, and they’re carried out in a progressive sequence:

  • Theoretical molecular studies (in silico): You can take a chemical structure suggested by molecular biologists, systematically generate thousands of similar molecules (varying a few atoms here and there), and run them through a program that tries to predict how well each variant may interact with a receptor (a molecule often in or on the body’s cells that plays a role in the development or progression of the target condition).

    This kind of theoretical investigation is sometimes called an in silico study (a term first used in 1989 to describe research conducted by computer simulation of biological molecules, cells, organs, or organisms; it means in silicon, referring to semiconductor computer circuits). These techniques are now routinely used to design new large-molecule drugs (like naturally occurring or artificially created proteins), for which the computer simulations tend to be quite reliable.

  • Chemical studies (in vitro): While computer simulations may suggest promising large molecules, you generally have to evaluate small-molecule drugs in the lab. These studies try to determine the physical, chemical, electrical, and other properties of the molecule.

    They’re called in vitro studies, meaning in glass, a reference to the tired old stereotype of the chemist in a white lab coat, pouring a colored liquid from one test tube to another. Don’t forget your goggles and wild hair.

  • Studies on cells and tissues (ex vivo): The next step in evaluating a candidate drug is to see how it actually affects living cells, tissues, and possibly even complete organs. This kind of study is sometimes called ex vivo, meaning out of the living, because the cells and tissues have been taken out of a living creature.

    The researchers are looking for changes in these cells and tissues that seem to be related, in some way, to the target condition.

  • Animal studies (in vivo): After studies show that a molecule undergoes chemical reactions and interacts the right way with the targeted receptor sites, you can evaluate the drug’s effect on complete living organisms to see what the drug actually does for them (how effective it is) and what it may do to them (how safe it is).

    These studies are called in vivo, meaning in the living, because they’re conducted on intact living creatures.

    In vivo studies tend to be more useful for small-molecule drugs than for large-molecule drugs. Animals and humans may react similarly to small molecules, but the actions of antibodies and proteins tend to be very different between species.