For Lawrence Steinman, research into the role of an eye lens protein in the neurological disease multiple sclerosis (MS) drew a surprising link to a formative research experience more than 35 years earlier. The Stanford University neurologist's recent work establishes the protein αB-crystallin (CRYAB) as a central agent in controlling inflammation and programmed cell death in the brain (see page 474). It also tied in to a long-held fascination, kindled in his student days, in the visual system.

Crystallins are well known as the main refractive proteins in vertebrate eye lenses, where they contribute both physical and optical characteristics. In 1995, Dutch biologist Johannes van Noort and his colleagues discovered that CRYAB is also highly expressed — and highly immunogenic — in the brains of MS patients (J. M. van Noort et al. Nature 375, 798–801; 1995).

When Steinman read this work, he recalls, “My first thought was, 'What? This must have fallen off the shelf into the soup, because how could you have CRYAB in the brain?'”. Other researchers ran a handful of experiments investigating whether the lens protein contributes to the pathology of MS, but these were inconclusive. Steinman's own investigations into CRYAB's role in the disease didn't begin until 2001. The delay, he says, occurred for a very simple reason — it took him until then to think of the right set of experiments.

In 2001, his team showed that the gene for CRYAB tops the list of genes transcribed in the brains of people with MS, but not in healthy subjects or those with other neurological diseases. The researchers knocked out the gene encoding Cryab in mice, then induced the animals with a model of MS known as experimental autoimmune encephalomyelitis. “I didn't really know what to expect,” Steinman recalls, “but when I saw that the experimental disease was actually worse without Cryab, I made the operating hypothesis that CRYAB must be doing something that protects the brain in MS.” Steinman's team has since shown that CRYAB tones down many inflammatory pathways and helps prevent programmed cell death, both of which are involved in the autoimmune processes thought to underlie MS.

This discovery finally made sense of the 'eye' protein's presence in the brain. And although vision scientists knew that CRYAB could inhibit protein crosslinking, the full range of its roles in eye health — and as a possible therapeutic agent in diseases throughout the body — is just now coming to light. CRYAB may even have potential in vaccine development, given that some microbes, for example those that cause tuberculosis, have evolved crystallins of their own to short-circuit their hosts' immune responses.

Aside from the biological possibilities, Steinman relishes the personal connections that have arisen from this work. One is with van Noort, whose original 1995 study Steinman calls “one of the coolest experiments done in MS”. The two have become collaborators, with van Noort providing patient data for the current study.

Even sweeter, says Steinman, are the ties to his past. As a student at Harvard in 1970, he worked for Torsten Wiesel, who won a Nobel prize in 1981 for his research on the visual system. “Even though I went on to study brain diseases, I remained fascinated by visual science,” he says. “With crystallin, my early interest in vision has returned to intersect with my current work in a way that is ironic, strange and delightful.”