By Cynthia Robbins-Roth

BioWorld Today columnist

The evening news recently was full of statistics apparently showing that breast cancer incidence dropped significantly after women fled hormone replacement therapy (HRT) in the wake of a large U.S. study showing higher-than-expected risk from the treatment.

Women between the ages of 50-69 showed an 11 percent drop in the disease in 2003, with hormone-dependent tumors decreasing at a rate twice that of non-dependent tumors. That is a key observation, because 70 percent of all breast cancers are hormone-dependent.

The study authors cautioned that the results need to be repeated in other populations and followed in coming years. Just because those two things look directly connected doesn't mean they really are. But it sure looks suspicious.

It might even explain the big burst of breast cancer cases that plagued Marin County, near San Francisco. Environmental contamination, pulses from electrical transformers, excessive exposure to chlorine in hot tubs . . . theories ran rampant.

Could it be that the highly educated, upper-middle class population was more prone to treat menopausal symptoms than surrounding communities?

It may be years before this finally is thrashed out. But there is a big take-home message for our industry to be considered right now.

You Can't Out-think Mother Nature

Our industry's bursts of innovation are based on the belief that using technology to understand disease at the cellular and molecular levels lets us design better drugs than ever before. "Better" in this case is defined as more targeted, more selective in action, aimed at just the right site in the body to treat the disease and not cause nasty side effects like typical drugs.

But sometimes the need to simplify in vivo systems to apply that technology leads us too far away from the complex reality of what happens in a living, breathing person. Those beautiful protein networks and enzymatic cascades generated by experiments can't describe the full story.

We find our wonderful new drugs, designed with care and intelligence, still have wildly unexpected effects when put back into those real-world patients with their uncontrolled genetic backgrounds - so unlike the C57 BL/6, the classic inbred mouse strain admired for its consistent genome that it stars in many preclinical studies.

Recent years have seen the launch - to much hullabaloo - of targeted treatments, followed by a growing din of unexpected patient problems.

Merck, Pfizer and others focused on creating more selective anti-inflammatory drugs, aiming at the COX-2 enzyme in hopes of avoiding the nasty GI bleeding that made chronic use of existing drugs dangerous. They instead ended up with increased risk of heart attack and stroke.

Lilly's antipsychotic, Zyprexa, and its relatives from other companies, were designed to act on several neurotransmitter receptors to treat schizophrenia and bipolar disease. The FDA information noted that nobody actually understands how inhibiting those receptors treats these diseases.

What also is not understood is how those drugs cause serious weight gain (up to 60 pounds within months) and diabetes.

New treatments for Parkinson's-induced compulsive gambling and sexual behavior in some patients. Even Rituxan, the wonderful targeted cancer monoclonal antibody sold by Genentech, Biogen Idec and Roche, required warning labeling when some patients developed the same rare brain infection seen in some multiple sclerosis patients taking Biogen's Tysabri.

Maybe Mother Nature Really Does Know Best!

There is a growing understanding, especially in immunology and tissue regeneration, that getting more specific actually might make things worse. Instead of trying to figure out how to use biotech's purified interferons and interleukins to fight cancer and inflammation - and generating fevers and pulmonary edema - less-specific treatments sometimes can provide that generalized kick in the pants that sets the body's own indefinable processes to work more effectively.

Stem cells and growth factors pose a similar challenge. Biotech firms have spent years trying to get the various growth factors or stem cell subpopulations to drive specific healing processes in wounds, spinal cord injuries and degenerative brain diseases.

Companies like Aldagen are finding that putting a more diverse cell population (in its case, sharing the ALDH marker but little else) in the right place in vivo may just let the complicated cascade of local factors sort out the correct task.

So what does this have to do with HRT and breast cancer?

Maybe we were trying to cure something that is not in fact a disease, and found ourselves acting against the body changes that millions of years of evolution put in place. Maybe as women leave the child-bearing years, those who turned down the fertility-related hormones survived longer because those hormone-responsive tissues were given a chance to go quiescent. There are all kinds of other entertaining theories about how the hormonal changes modify brain activity and emotional behavior in useful and interesting ways that had a survival advantage for the community.

Bottom line: Maybe technology is not always the best answer. Just when we think we are solving a problem, we can be creating another. To improve the odds of commercial success, we need to beef up the influence of biologists and pharmacologists on drug discovery and design to bring Mother Nature back into the equation.

Robbins-Roth, Ph.D., founding partner of BioVenture Consultants, can be reached at info@bioventureconsultants.com. Her opinions do not necessarily reflect those of BioWorld Today.

BioWorld Today  January 2, 2007