Chance, Mischance, and Persistence

As an intramural science showcase, the National Institutes of Health Research Festival on the Bethesda campus is dominated each year by reports on cutting edge biomedical research. But at one mini-symposium during the 15th festival last month, several NIH researchers described innovations that have already reached the marketplace, and the challenges surmounted along the way. The session was conceived as "sort of a greatest hits package," says Steven Ferguson, deputy director of the NIH division of technology development and transfer. The division organized a similar symposium last year and expects to make it a fixture of future festivals. The examples to choose from are plentiful: more than 1,200 license agreements for commercialization of NIH inventions have been signed since 1993, generating two-thirds of all federal government royalty income. Two of the presenters this year-Robert S. Balaban of the National Heart, Lung, and Blood Institute (NHLBI) and Hynda K. Kleinman of the National Institute of Dental and Craniofacial Research (NIDCR)-emphasized the roles played in their discoveries by chance and mischance. Balaban, chief of the lab of cardiac energetics in NHLBI, described a moment of revelation that arose from an unexpected experimental result. In the 1980s, he and colleagues were using magnetic resonance imaging (MRI) to examine urea in the kidney. They were imaging the medulla, but spectroscopy indicated the urea was in the cortex. This contradiction was resolved when they realized that they were not looking at urea or metabolites, but at the tissue's macromolecular structure. Balaban explained that tissue water molecules were coupling with lipids at specific sites in the macromolecular matrix and were being held together long enough that when they diffused out, an effect was detectable in the water. "MRI is basically looking at life's matrix. That is, it amplifies the properties of water," he pointed out. "By the experiment not working, we found an underlying principle that gave us a better understanding of the process." It also spurred the researchers to wonder if they could image tissues by amplifying the water signal. Using a technique called saturation transfer, they irradiated tissue samples to scramble the protons in a spectrum that moved them into water, where they generated a signal. The researchers then swept the irradiation frequency and plotted the amplitude to measure the saturation transfer spectrum. By making use of this proton exchange between water and tissue molecules, their technique provides much-improved images and informational content from MRI.1 "It tells us not just about the chemistry of the lipids but also their dynamics and motions," Balaban said. A button for this "magnetization transfer" capability is now standard on MRI equipment. Kleinman, chief of the cell biology section in NIDCR's craniofacial developmental biology and regeneration branch, recalled that both the first patent application in 1985 for her team's invention and the first paper describing it were rejected. Yet, the product that eventually emerged, a reconstituted basement membrane complex called Matrigel, has since been used in thousands of published experiments. Currently licensed to two companies, Matrigel has numerous uses. For example, it promotes cell differentiation in vitro and is a substratum for tumor invasion activity. In vivo, it can increase the take of either tumor cell growth or transplant tissue. The rejection of the initial patent application was for lack of usefulness, she said. It was resubmitted and accepted in 1989. Both Cell and the Journal of Cell Biology rejected the first paper describing Matrigel. By the time it was published in Biochemistry, another paper from Kleinman and colleagues already had appeared in the Journal of Cell Biology that demonstrated the complex's ability to stimulate cell differentiation. The Biochemistry paper has since been cited more than 850 times.2 Serendipity had a hand in the first company contact Kleinman made for the product. It arose from a conference at which her postdoc was "hanging around a booth because the attendant was cute," and overheard several people ask about Matrigel. Recently, her group faced new challenges following a discovery about a small polypeptide called thymosin beta4 that is known to be important in immune function. The researchers filed a provisional patent in 1998 concerning the peptide's angiogenic properties. But they were told that such agents are too common; greater "physiological significance" had to be demonstrated. Back at the lab, they discovered that thymosin beta4 is a potent healing factor, especially for corneal epithelial cells.3 They re-filed the patent in January. "We think this is going to be a very important material for eye disease," she declared. In three words, Kleinman summarized a key lesson from her experiences: "Don't give up." Steve Bunk (sbunk@the-scientist.com)is a contributing editor for The Scientist. References 1. S.D. Wolff, R.S. Balaban, "Magnetization transfer contrast (MTC) and tissue water proton relaxation in vivo," Magnetic Resonance in Medicine, 10:135-44, 1989. 2. H.K. Kleinman et al., "Basement-membrane complexes with biological activity," Biochemistry, 25:312-8, 1986. 3.K.M. Malinda et al., "Thymosin beta4 accelerates wound healing," Journal of Investigative Dermatology, 113:364-8, 1999.

Chance, Mischance, and Persistence

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