The Little Yellow Engine that Could

Long considered more poisonous than precious, bilirubin starts to show its true colors as one of the human body's strongest defenders against oxidative assault.

By Mary Ann Ayd

If neurotransmitters is the first word that springs to mind when Solomon Snyder's name comes up, spotting the Lasker Award winner's moniker on a study of the pigment that causes jaundice could raise an eyebrow. But for the School of Medicine's director of neuroscience, the intellectual links between his career-beginning work on the molecular basis of psychiatric disorders and the latest studies emanating from his lab are all of a piece. According to Snyder, you can get from serotonin to bilirubin.

Two broad themes, he says, connect the dots in his 40-year fascination with neurotransmitters-the chemicals that allow the brain's 100 billion or so neurons to communicate with one another. The first motif is Snyder's repeated experience that fundamental, "untargeted" research on brain function often leads to practical results. The second is his aversion to preconceived notions about how the body is "supposed" to work.

Indeed, Snyder's free-association curiosity, inseparable from his voracious appetite for scientific findings not obviously in his field, has more than once turned neurotransmission dogma on its ear. A self-described "klutz" in the lab who relies on his postdocs and graduate students to figure out the nuts and bolts of experiments, Snyder is the consummate idea man. One study he came across, for example, showed that nitric oxide (NO) could relay messages to smooth muscle, causing it to relax and allowing blood vessels to dilate. Intrigued, he and M.D./Ph.D. student David Bredt went searching for NO in the brain and ended up shocking neuroscientists by demonstrating that the gas is-that's right-another neurotransmitter. And not just any old neurotransmitter, but one that regulates sexual behavior and initiates penile erection. Armed with these tidbits, Pfizer chemists transformed a discarded anti-angina drug into Viagra.

"The diversity of ways that neurotransmitters can act is startling," says Snyder. "The most seemingly bizarre signaling molecules may turn out to be as important for brain function and therapeutic intervention as the longest-known neurotransmitters."

Still-bilirubin?

Snyder's route to the molecule well known among physicians as a toxin evolved from his lab's work on nitric oxide. If one gas could be a neurotransmitter, they reasoned, might there not be others? It was their exploration of carbon monoxide that led, Rube Goldberg-style, to the conundrum of bilirubin.

Released in the breakdown of hemoglobin (the "red" in red blood cells), bilirubin is insoluble and must pass through the liver before it can be excreted. A small build-up results in the characteristic yellow tint of jaundice. At higher levels, bilirubin can produce brain damage or death in newborns. But if hemoglobin degradation stopped one step earlier, when water-soluble biliverdin is formed, the body could easily rid itself of the waste. "If all bilirubin does is become toxic in high amounts," says Snyder, "it doesn't make sense that animals would have developed its production at all. Why should mammals have evolved the energetically expensive, potentially toxic, and apparently unnecessary capacity to reduce biliverdin?"

Bilirubin has long been known-in the lab-as a potent antioxidant capable of disarming the highly reactive forms of oxygen known as free radicals that strip electrons from other molecules and cause practically all cellular damage. But, because cells contain so little bilirubin, it wasn't thought to contribute much to their protection. That is, until Snyder and postdoc Sylvain Dore set out to show that bilirubin the antioxidant is more than just a laboratory curiosity.

Four years ago, they reported finding that in mice engineered to lack bilirubin, brain cells suffered more oxidative damage than did brain cells in normal mice. Furthermore, adding even low amounts of bilirubin helped the cells survive. And in two sets of live mice caused to have strokes, animals unable to produce bilirubin had more brain damage. But what really caused Snyder to scratch his head was their discovery that bilirubin could consume free radicals at a ratio of 1:10,000.

Wondering what could be behind bilirubin's extraordinary disarmament ability, Snyder hit on the idea that perhaps it recycles itself. Late last year, he and M.D./Ph.D. student David Baranano offered evidence that bilirubin indeed is part of a catalytic cycle. "An oxidant reacts with bilirubin to make biliverdin, which is then converted back into bilirubin," says Snyder. "One oxidant down, 10,000 to go."

The researchers also showed that without biliverdin reductase, the enzyme that starts the cycle, human cancer cells and brain cells from rats experienced much more damage and cell death in response to an oxidant. And, compared with glutathione, a previously known antioxidant that consumes free radicals molecule for molecule, bilirubin appears to be the body's most potent antioxidant.

The next question is, Can bilirubin's newfound status be harnessed therapeutically? Noting that oxidative stress plays a big role in vascular disease, Snyder points to a number of "very elegant" epidemiological studies that tie elevated bilirubin levels to better alertness in newborns, and to less risk of heart disease and cancer in adults. But these findings, he says, were largely shrugged off-they just didn't jibe with what people thought they already knew about bilirubin. "Now," says Snyder, "they make sense.
"If you could get relatively small concentrations of bilirubin into the recycling machinery, it might be a very good way to ward off cellular damage from heart attack or stroke."

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