17/12/05 The Times

The human guinea pigs

By Kerri Smith

Could animal testing become redundant? Some scientists believe technology has the answer

The high emotions that surround animal testing can often overshadow exciting developments that might ultimately end the need for it. A series of challenging and controversial TV programmes this week about testing drugs on animals, on More 4, included a drama documentary about the battle that develops between an animal rights activist and a laboratory biologist. Also this week, animal rights protesters clashed with police at the site of Oxford University’s proposed animal testing laboratory.

But amid all the strong emotion, one fact is often overlooked. Researchers are coming up with clever and safe ways to test products on human beings and their tissue. The motives are, of course, partly ethical. But this is not the only factor weighing on the decisions of some companies to limit animal trials.

harmagene, a Hertfordshire-based drug development business, is one such company. It was founded a decade ago by two research scientists frustrated by the way animal models sometimes failed to predict a drug’s effect on human beings. Pharmagene carries out tests on the safety and efficacy of new medicines on behalf of pharmaceutical giants using only human tissue samples.

All this, of course, applies to the earliest stages of researching a new drug. Animal experiments help scientists to understand the basic biological processes behind a drug’s action and to gauge toxicity. If there are no problems at this stage, a drug moves on to three stages of research on human beings, each one involving more patients than the last. The fact is that current law requires drugs to be tested for toxicity on animals before human testing begins. But the tantalising prospect remains that this could change if the innovative alternatives can prove their worth.

Pharmagene’s motivation for pursuing non-animal testing is overwhelmingly practical. As Bob Coleman, the company’s chief scientific officer, points out, even testing on two different types of animals — mice and guinea pigs, say — can give quite different results. “If two different species give you different answers to the same question about a drug’s action, how confident can you be that either one of them will be predictive of humans? ” harmagene says that it has reduced considerably the number of animals needed for testing by introducing tests on live tissue from every part of the human body. These samples are gleaned from surgical procedures, post-mortem examinations or transplant donors, with full consent from donor or relatives. Using them, Pharmagene says it’s possible to observe how and where drugs have their effects and to watch for toxic effects on cells. They can measure, for example, how a compound is metabolised by the liver, whether it causes inflammation, and how well it is absorbed by the gut.

If the results look bad, there’s no need for further testing and no animal involvement. If they look good, the results can yield clues as to what further tests are needed, whether animals are needed, and what species might be best suited. “No one test gives you all the answers,” says Coleman, “but our studies save wasting time and animal lives by testing a drug on animal species after animal species.”

Critics of animal testing, such as Europeans for Medical Progress, an organisation that campaigns for the modernisation of medical research, are eager to claim that replacing animal with human-based testing might yield better-quality results. Kathy Archibald, the director, says that the correlation between the side-effects that show up in animals and in humans is “pitifully small”.

Testing new products and theories on human beings rather than animals is not a new idea. Many of the great scientists of the past millennium used themselves as test-beds for their ideas, often neglecting health and safety for the advancement of science. And samples of human tissue or human cells grown in the lab have long formed a staple of the laboratory tool kit. There are several new takes on this.

One, reported at the British Pharmaceutical Conference in September, involves simulating flesh with a device known by its makers, the Hurel Corporation in America, as a “synthetic animal on a chip”. It is a microfluidic circuit, originally developed at Cornell University. Just 22mm wide, the microchip has etched into it a series of tiny chambers, each containing a sample of tissue from different parts of a human or animal body. The compartments are linked by microchannels through which a blood substitute flows.

“What we are trying to do is to mimic what goes on in the body on a micro scale,” says Leslie Benet, a professor of biopharmaceutical sciences at the University of California and chairman of the scientific advisory board at Hurel. The test drug is added to the blood substitute and circulates around the device. Its effects on the cells in each compartment can be measured by sensors in the chip and fed back for computer analysis. Professor Benet believes that such techniques could substantially reduce the need for animal experiments. A similar biosensor chip is being developed to measure the effect of new drugs on human DNA samples, too.

This kind of testing is arguably more sensitive than injecting drugs into rodents when scientists have only a hazy idea of the equivalent dosage required for humans. Although the method is still being validated, early studies with a cancer drug, tegafur, look promising. But the Hurel chip can’t yet claim to be as predictive as putting drugs into human bodies and seeing what happens. Enter microdosing.

Microdosing means giving human subjects a drug dose one-hundredth of what would be necessary for it to have an actual effect on the body and watching what the body does with it. With the aid of accelerator mass spectometry (AMS) — an incredibly sensitive measuring technique, which can pick up minute traces of a drug in the human body — the metabolic fate of a drug administered in trace doses can be followed. It may allow scientists to watch the metabolism of new drugs in the human body with no risk.

Early trial results are promising. A recent trial directed by Xceleron, a company set up by York University to take its research farther, assessed the effectiveness of the procedure with five different drugs and compared the results with full-dose human trials. “These were all molecules for which it was known that animal and test-tube models couldn’t predict results in humans,” says Professor Colin Garner, of Xceleron and formerly a professor of molecular epidemiology at York University, who led the study. With four out of the five molecules, the microdose showed “good predictivity” of the dose used at full pharmacological levels. For three of the drugs, the prediction was rated at 100 per cent.

The procedure has its critics, however. “The golden law of toxicity is that every substance is toxic in some dose,” says Simon Festing, a spokesman for the Research Defence Society, an organisation that aims to support researchers in promoting the facts about animal research. “This is true of water and salt as much as of new and controversial medicines. Almost no medicines that have toxic effects will show toxicity at low doses. Animals are hugely predictive of toxicity in humans. There is no conceivable alternative.”

If microdosing still remains on the drawing board of most pharmaceutical companies, it is because animal tests are still considered the optimal means of testing human drugs, by companies and legislators. Existing laws at least stress that reducing the number of animals used is a first priority. Many scientists have already begun to replace rodents and other mammals with creatures lower down the evolutionary scale, such as fish, and even bacteria, in the hope that this will engender less suffering.