The financial markets are having a tough time understanding the combination of biotech companies Enzon and NPS Pharmaceuticals, perhaps because it doesn't follow the typical rationale for intra-biotech mergers. That is, it doesn't join competitors working with similar technologies or disease states. Rather, the companies have little overlap, an attraction they argue will result in a balanced, somewhat synergistic product portfolio. Still, they face the challenge of convincing divergent investor groups--earnings-oriented shareholders of Enzon and growth-chasing investors in NPS--that the resulting new company wo'n't be a hodge-podge of diverse technologies.

Microbial drug resistance is a real and growing problem, but drugmakers face disincentives: a plethora of products already on the market, the difficulty of differentiating drugs, and the habit of reserving truly new drugs for emergencies. Big Pharmas are backing out, creating opportunities for small companies who feel they can play successfully. But lack of interest from large partners means biotechs can't access the assets those firms hold, so many start-ups are pairing up with peers. Some firms are building businesses around an abundance of targets derived through genomics. But others are deliberately avoiding working with novel genetic code and instead studying whole cells and physiological changes in organisms. Many firms are addressing the lack of chemical diversity against targets. Some of these are pursuing diversity through natural products like marine microbes, insisting they'll fare better than earlier firms did, in part because of technological advances. Others are trying to create diversity synthetically, by taking structural approaches to understanding targets new and old, as well as compounds. Crystallography, in silico libraries, computational models and mass spectroscopy are key tools in iterative development processes that remain unproven in the anti-infectives field. Some firms are seeking to minimize the risks of novelty, by putting their efforts into developing new versions of antibiotics that worked well before resistance grew. No matter what technological approach start-ups take to developing antibiotics, all face similar challenges external to themselves-primarily in regulatory affairs and funding, but also in hunting Big Pharma partnerships.

Morgenthaler Ventures, biotech, medical device, and communications/computer technology investors since the mid-'80s, backed away from the biotech group in 1993. But the investment pendulum has now swung away from IT and toward health care. So the firm is back into biotech investing, and is also picking up the pace in devices.

There is tremendous value to be had in exploiting the pharmaceutical uses of natural products, but few companies built around natural-product platforms have enjoyed much success. To succeed, these companies shouldn't be focused on merely providing chemical diversity to the drug industry. Instead, they need to articulate how their libraries will allow them to close in, quickly and with a relatively low risk of failure, on specific drugs for specific diseases.