Discovering New Drugs

Two billion times this year you (and your fellow Americans) will go to the doctor and the doctor will write up a prescription. You'll take that illegible slip to a store. There, a pharmacist will funnel pills from a big jar into a little vial, slap on a label, and hand you a bill. You might not even wait till you get home before taking a dose. And soon your sinus headache or sore shoulder or hacking cough or black mood will quit bothering you and you can get on with the business of living.

Who made those excellent pills, and how?

pills

Thirty years ago, who was a scientist sitting at a lab bench pouring liquids from one beaker into another. "You know," said James Gardner, "distillation. Bunsen burners." Gardner, a vice president at Pfizer Inc, gave the second in this year's Frontiers of Science lectures at Penn State (which Pfizer sponsors) on "How Drug Development Works."

How, he explained, was then like negotiating a maze: "You went down a corridor, making progress, until you hit a wall. Then you bounced off and started down another corridor. Sometimes you got somewhere, sometimes not." Since the 1960s, as the pharmaceutical industry and its federal watchdog, the FDA, have grown, that maze has become more like a high-money brand of the boardgame "Chutes and Ladders".

"Based on an insight," Gardner said, "a chemist will come up with a compound that could have an effect on a disease. It could block some reaction, or act as a decoy."

Roll the dice and start the game: Test it on tissue samples or bacteria to see if it really works. Then come trials in animals, in healthy people, in patients. There are lots of chutes to failure and not many ladders to success: Is it safe? What's the proper dose? Does it have side effects? How long does it linger? Can we scale it up—make lots of it economically? Has someone beat us to it? Will the FDA approve it?

Most of those chutes send you right back to Start.

"The norm is to fail," said Gardner. "Of 5,000 compounds evaluated, only six will enter human trials. Only one comes out at the bottom as a drug. It could take 12 to 24 years. It could cost $500 million."

The rules are about to change. With the Human Genome Project and new computerized automation, drug development will be less chancy in the 21st century—and more likely to cure a disease instead of just masking its symptoms.

Luck and the Little Blue Pill

From penicillin to Viagra, luck's had a lot to do with drug discovery.

Alexander Fleming was studying staphylococcus bacteria in 1928 when penicillium mold (then used only to ripen Roquefort and other cheeses) got into his Petri dishes and ruined his experiment.

In the late 1990s, researchers at Pfizer were doing clinical tests in V.A. hospitals on a drug effective against the chest pain of angina. "And we found we couldn't get the pills back from the vets," Gardner said. "Then doctors started finding pills missing from the hospital cabinets. Very quickly we learned the reason." The drug is now known as Viagra, or "the little blue pill," and is prescribed for impotence. "Impotence affects older men, men with spinal cord injuries, coronary artery disease, hypertension, diabetes, depression, prostate cancer . . . It was a surprisingly unpublicized, untalked about, and untreated disease until Viagra was introduced a year ago. Since then, doctors have written millions of prescriptions."

Pfizer's scientists hadn't meant to start a sexual revolution. "We were looking for a drug that would dilate coronary arteries," Gardner explained. "More blood, more oxygen, less angina—better lifestyle." They'd found a substance in the blood, cGMP, that caused arteries to dilate. "Investigating this molecule," Gardner said, "we discovered an enzyme, PDE5, that broke it down." With PDE5 around, cGMP was destroyed and arteries shrank thin and blood-poor; without it they opened up. "So we thought, let's see what we can do to stop the action of this enzyme." PDE5 was, they found, "an amoeba of an enzyme. It wraps itself around the molecule, locks on at several binding sites, then destroys it." They decided to design a decoy, a molecule PDE5 could snugly lock onto—and then find itself caught.

"We worked with the idea on the computer," Gardner said. "It took about four years before we found a molecule that allowed PDE5 to lock on, but that the enzyme couldn't destroy. We tried well over 1,000 compounds before we found Viagra."

Then, after the clinical tests showed its usefulness for something sexier than angina, "we had more work to do to make it very specific, so dilation occurs only in that one part of the anatomy."

So far, Viagra looks to be one of the 3 out of 10 drugs that, on average, will actually pay back its own R&D costs.

Robot Chemists

Luck may always be needed. But in other ways, how drugs are discovered is changing fast.

In the mid-'40s, following the success of penicillin, which Pfizer manufactured, the company wanted another antibiotic. "For over four years, we asked people—our salesmen, our friends—to send us plastic bags of dirt," Gardner said. Pounds of dirt, over 135,000 samples from all parts of the world, arrived parcel post. "We isolated the compound that had the most effect on the contents of a Petri dish. Terramycin came from dirt."

The technology's a little different now. Although they may still look for active compounds in dirt (or rainforest plants or deep-sea creatures), scientists now use silicon chips instead of Petri dishes to look for an effect: "We lay down strata of bioreactive materials to create 144 æwells' on a chip. Each responds in a different way. We customize the chip to tell us what we want to know, and read the response with a scanner."

Synthesizing new compounds to attack a known target like PDE5 is even more high-tech. "Instead of a chemist creating them one at a time, we have machines that break down chemicals into their components and randomly shuffle the deck to make a bunch of things we never knew about. These new compounds are made in dark, unlighted factories by robots, 24 hours a day. Then we run them through another machine, and in one pass we know what the compound is and whether it has the characteristics we're screening for."

One Drug Fits All?

Bigger changes will come from the Human Genome Project and its offshoots. "Genomics research—that's where the insights will come from," Gardner said. Which genes code for which proteins? Which genes are active in a normal cell that aren't working when the cell is diseased (or vice versa). Which mutations to a gene contribute to disease, and how? These are the sorts of questions genomics researchers are asking. With the answers, said Gardner, "We'll be able to create tests, identify new drug targets, and customize treatment. Before, we got to the proteins and the enzymes often by happenstance. It was relatively crude. Genomics will give us a better understanding of where a disease comes from."

Simple tests for certain single-gene diseases are already in use. Other tests might tell which version of a virus a patient has, or what proteins a patient's cells are producing. Knowing the genetic code, the instructions for how these proteins are made, gives drug developers more clues to how to block—or enhance—their action.

"Today we have about 500 targets that we're creating drugs to impact," said Gardner. "The promise of genomics is an exponential jump in the number of targets, and thus in the number of insights.

And best, genomics will help even old drugs work better. "There are genetic polymorphisms, genetic differences from one person to another, that can have an effect on how an individual responds to a certain drug," Gardner said. "If you understand those polymorphisms, you can tailor the drug to cause fewer side effects and to work better. You can screen potential patients and say who should use the drug and who should not.

"It won't be one drug fits all' anymore."

James R. Gardner, Ph.D., is vice president of investor relations for Pfizer Inc. He graduated from West Point with a B.S. degree in engineering. His early career includes eleven years of military and government service in such positions as staff assistant with the attorney general of the United States and assistant professor at the U.S. Military Academy. He holds both M.P.A. and Ph.D. degrees from Princeton University.

Last Updated May 01, 1999