'Drugs behave differently in animals than they do in people'

VU's Wikswo part of team developing 'desktop humans' [From our Healthier magazine out now]

Pharmaceutical testing is a time-consuming, difficult and expensive process. Though work on human subjects is key, regulations require any new drug be tested on animals before being trialed in people. And this can be limiting.

Dr. John Wikswo understand the reality, As the director of the Vanderbilt Institute for Integrative Biosystems Research and Education points out, "Drugs behave differently in animals than they do in people."

Not surprisingly, drugs with results that look promising in cell cultures or in animal testing can fail in human testing, and that means the loss of millions, or even billions, of dollars in research.

Wikswo is part of a multi-institutional team working under a five-year $19 million grant from the federal Defense Threat Reduction Agency to develop a miniaturized "desktop human," interconnected modules that will act like a human body. In March, Wikswo announced that the liver module successfully responded to exposure to a toxic chemical in the same way as an actual human liver.

Ultimately, the goal is to connect the individual organ modules — researchers elsewhere are developing a heart, a kidney and lungs —  chemically in a fashion that mimics the way the organs are connected in the body, via a blood surrogate. The researchers hope the ''homo minutus," with its ability to simulate the complexity of human organs, will offer a more accurate way of screening new drugs for potency and potential side-effects than current methods.

Post reporter J.R. Lind talked recently with Wikswo about his research.

What is a "desktop human”? What would it look like? A computer? An android?

It will probably look like a tray, say 18 inches square, that will fit on the shelf of a small cell culture incubator the size of an under-counter refrigerator. The tray will be filled with modules. Each module will be an organ or a set of sensors. They will be connected by tubes and will have motors driving pumps and valves.

What advantages does this advance have over conventional methods, like animal or human testing, and over more advanced technologies, like organ-on-a-chip?

The problem with animal testing is that animals are not people. Drugs behave differently in animals than they do in people, and that makes it very difficult to determine whether the drug will be safe in humans and also have the desired effect.

Human tests are extremely expensive, take a long time, and cannot be conducted until many other studies have been done on cells in dishes and in animals. But those tests don't often predict what will happen in humans. Hence the desire for an alternative to cells in Petri dishes or animals.

In particular, you've been working on what is essentially a miniature liver and one of the key breakthroughs was getting size correct. Why not just recreate an actual-size liver or, conversely, why not create one that's just a few cells?

Human liver cells are extremely expensive and hard to get. Someday it will be possible to take a person's skin cells and convert them into liver cells, but that will also be very, very expensive. Hence one wants the miniature liver to be as small as possible, but not too small. A few cells will not act like an entire liver, and the small volumes of fluid associated with a few cells will make it hard to analyze what the cells are doing. We think we've found the correct size for the organs — one ten-thousandth of an adult human.

With different institutions working on different body parts, presumably one of the next steps will be hooking all of this stuff together. How close is that to happening?

Integration of organs is stating this summer. We anticipate having four organs running together in three years. There is a lot of testing to do. It is also important to have each organ the correct size relative to each other and to the universal culture media, like serum — salts, sugars, proteins, and other chemicals that are in blood.

The key thing that we are going after is to determine whether the liver, for example, might convert a drug into something that is toxic to another organ, say the heart. For this to work, the liver has to be big enough to produce enough toxin for the heart, and the fluid volume can't be so large as to dilute it so much that the heart wouldn't know that it's being fed a toxin.

Beyond pharmaceutical research, what other applications could this have?

This approach should have major applications to environmental toxicology. There are tens of thousands of chemicals in the marketplace that have never been tested for safety.

It will allow us to study human physiological regulation. We can record data from the system that can't be easily obtained from an intact human, and wouldn't be found in animal studies. The organs-on-chips should help eliminate animal experiments.

Finally, when these systems are working, they should be useful for studying human diseases — either rare ones for which there are few people to study, or infectious ones where studies on real humans is not possible.