You, in a dish: cultured human cells could put lab animals out of work for chemical and drug testing

Science News,  April 5, 2008  by Patrick Barry

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At 8 o'clock on a March morning last year, doctors at Northwick Park Hospital in London began injecting six healthy men with an experimental arthritis drug. It was the drug's first safety trial in humans, and it had passed all the necessary tests on mice and monkeys with no indication of danger.

Once inside each man's bloodstream, the drug bound strongly to the "seek and destroy" cells of the immune system, the T cells. As a result, these attack cells became hyperactive and began leaving the blood vessels and entering tissues--something T cells normally do only at the site of an infection. The T cells proceeded to attack and kill healthy cells of vital organs such as the heart, liver, kidneys, and lungs.

Within an hour, the men were vomiting and writhing in excruciating pain as their immune systems began attacking their bodies from the inside out. All six nearly died, and they still suffer from lingering health impairments.

Clearly, the animal tests had missed something.

As invaluable as mice have been for medical research, differences do exist between human and mouse biology. Sometimes, these differences generate misleading test results. In the case above, for example, the drug bound to a receptor molecule on the human T cells more tightly than it did to the mouse version of that receptor. The drug also activated a kind of T cell that the lab mice lacked.

A better way to find out how a drug will affect human cells, some scientists say, is simply to test it on human cells. That's now becoming a practical option.

Over the past few years, scientists have developed sophisticated ways to screen drugs and other compounds on lab-grown cells from various human organs. Coupled with the burgeoning knowledge of cells' inner workings that comes from genomics, proteomics, and other "-omics," these screening techniques offer a way to test compounds on human biology long before they're tested on actual humans.

These screens could aid pharmaceutical development by identifying promising candidates and weeding out compounds earlier if they don't work in humans (even though they may work in mice). Many scientists think that in the wake of genomics, such screens are the next logical step.

"Everybody in the industry thinks this is the right way to go," says Aled M. Edwards of the Ontario Cancer Institute in Canada, who has no connections with companies offering such screening services. "I know that pharmaceutical companies are doing this."

And drug companies aren't the only ones. The Environmental Protection Agency and the National Institutes of Health are launching a joint program to test potentially toxic industrial chemicals on human cell cultures instead of on animals, the agencies announced in February during a meeting in Boston of the American Association for the Advancement of Science, as well as in the Feb. 15 Science (SN: 2/23/08, p. 117).

Sparing animals from serving as guinea pigs and improving the accuracy of test results are both reasons for the growing interest in these screening techniques, but the pharmaceutical industry has another reason as well. Money.

PLAYING THE NUMBERS The cost of developing new drugs has been steadily increasing for decades, yet the number of new drugs that make it to market each year has remained essentially constant. As a result, the average development cost for each new, approved drug exceeds $800 million, by some estimates.

"Plenty of drugs are going into the pipeline--it's just that too many are dropping out," says Janice M. Reichert of the Tufts Center for the Study of Drug Development in Boston. Many drugs make it through the gauntlet of laboratory and animal tests successfully, only to fail during human trials. Some drugs simply prove to be ineffective in people; others turn out to be unsafe or to have unacceptable side effects.

Recruiting people to serve as subjects and running clinical trials can cost tens of millions of dollars. So when a drug fails near the end of trials, the financial loss can be enormous.

In a sense, this rising dropout rate is a consequence of the genetics revolution. In the 1970s, pharmaceutical companies adopted shotgun tactics for screening thousands of chemicals using high-throughput chemistry. The search focused on compounds that hit the same protein targets as did existing, proven drugs. Researchers tested any matching compounds on animals in the hope that the drug was more effective and had fewer side effects than the old drug, often with great success.

The rise of human genetics yielded a windfall of novel biological targets for treating diseases, and companies applied the same shotgun techniques to find drugs for these new targets. The effects of these drugs, however, were less predictable because no previous drugs bound to the same targets. Scientists relied on animal tests to show that a drug worked and to reveal dangerous side effects, but differences between animal and human biology meant that some effects of the new drugs were inevitably missed.