Proteins first, genes second
Courtesy Argonne National Laboratory.
More drugs, more genes, more quickly
POSTED 19 NOV 1998 By testing millions of new chemicals, we can identify new proteins and the genes that make them.
The glut of new genetic information from the Human Genome Project is an embarrassment of riches: We know the sequences of thousands of genes whose functions are totally obscure. As sequence data accumulates, traditional means of assigning functions to unknown genes seem painfully slow.
Mitchison, a professor of cell biology at Harvard Medical School, is promoting
This so-called chemical approach to genetics, now
getting under way at Harvard's Institute of Chemistry and Cell Biology,
reverses the traditional method of finding the role of genes. Mitchison,
The trick, Mitchison says, is to find chemicals that interfere with proteins (which is how most medicines work) and use resulting changes in the organism to understand the protein's role. The technique, if successful, would not only identify unknown proteins, but also candidate drugs that affect them. It may also get closer to the interesting question -- what the gene and its protein actually do.
Before we get to Mitchison's brand-
But how to find molecules that affect proteins?
Good question (even if we asked it ourselves). The
drug industry jealously guards its "libraries" of chemicals with drug
potential, which academics can't afford to duplicate. But Mitchison says
a new technique called split-
Even for the average 24/7 grad student, that's serious output. Here's how it works: Say we've got a chemical core that can link to other chemicals at locations "A," "B" and "C." If three different chemicals can link at "A," four at "B," and five at "C," the simple math that even Why Filers understand says the possibilities total 3 * 4 * 5 = 60. (Most chemical cores can actually bind many more chemicals, but our math anxiety means you'll have to suffer our half-witted example.)
To start, a lowly graduate student attaches the chemical
core to tiny plastic beads and exposes it to the various sub-
The new chemicals are then screened for activity in a soup of biochemicals. Those that are active (meaning they bind to a protein) may be tagged and used to isolate the protein. Then, by analyzing the protein's structure, scientists can predict what kind of gene sequence would produce it.
In a recent test run, the experimental technique
created more than 2 million different molecules, about one-
Makes drugs, too
Courtesy National Institutes of Health.
In chemical genetics, we identify proteins by finding something -- call it a candidate drug-- that affects it. Thus the process should be attractive to pharmaceutical companies, Mitchison says, because "by definition you already have a drug -- and that could cut two years off the drug discovery process."
Certainly, there's plenty of room for improvement in the drug discovery field. While most drugs work by affecting proteins, all of the estimated 600 active ingredients in human drugs affect roughly 300 proteins. Mitchison figures that leaves roughly 200,000 human proteins waiting for drugs that might affect them.
And among that list we can expect to find proteins that influence just about every disease you can name.
Confused enough already, or do you want to read up on this stuff?
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