Genetics professor studies proteins, wins big prizes

With his greying, Provost Salovey-like moustache, round tortoise glasses and small stature, Arthur Horwich does not fit the mold of a world-famous scientist.

Between conversations about the Chicago Bears and spirited impersonations in a faux-German accent, however, Horwich, Eugene Higgins Professor of Genetics at the Yale School of Medicine, quickly lends support to the old adage “appearances aren’t everything.”

First came the Hans Neurath Award. Then the Gairdner International Award. The Wiley Prize in Biomedical Science and the 2008 Rosenstiel Award quickly followed.

Most recently, Dr. Horwich was awarded the Louisa Gross Horwitz Prize by Columbia University and elected to Institute of Medicine. In a press release, Columbia’s Dr. David Hirsch lauded the prolific Yale scientist.

“The knowledge [Horwich and collaborators] have given us about the structures of protein folding and DNA has laid the foundation for extraordinarily important fields of study that have and continue to lead to new scientific and disease breakthroughs,” he said.

And with several prestigious awards under his belt, some speculate the Nobel Prize may in his future. The numbers, at least, are on his side. Since the Horwitz Prize was created in 1967, over half of its recipients have gone on to win the Nobel in chemistry or medicine.

a stroke of genius, luck

Like many scientific breakthroughs, the one responsible for Horwich’s eventual celebrity was an accident.

Prior to Horwich’s seminal work in the late 1980s, protein-folding theory was dominated by the work of the late Christian Anfinsen, Nobel Laureate in chemistry. Anfinsen suggested that all the information a protein needed to fold into its three-dimensional form was contained in its primary structure, the linear chain of amino acids out of which it is composed.

Many scientists interpreted this to mean that proteins could fold into their native shape spontaneously from a linear form. Other scientists suspected that intermediate steps existed between a protein’s unfolded structure and its final configuration — but did not fully understand them.

In 1987, through a bit of serendipity, Horwich set out on a research odyssey — one that continues to this day — that would show the folding process was much more complex than previously imagined.

Laughing, he started: “Way back, way back … we sort of accidentally stumbled across a mutant — a yeast mutant.”

This mutant, he said, contained irregularly folded proteins. But his lab could not explain just why.

“It was 11 o’clock at night, and we were just sitting around after a long day of work, throwing around ideas,” Horwich said.

It was then that he made the critical insight — that there might be a type of machine that actually folds proteins in cells.

the german connection

“At first we had trouble believing this was real,” Horwich said, his eyes wide. “It seemed almost heretical.”

But the experimental method did not fail him and his talented team of lab members. After a year of work and paper-publishing, they began a collaboration with Dr. Ulrich Hartl, director of the Department of Cellular Biochemistry at the Max Planck Institute of Biochemistry, whose interest was piqued by this novel idea.

After collaborating for several years, the duo eventually concluded that there was, in fact, a protein-based machine that assists in folding other proteins. Using emerging genetic sequencing tools, the scientists were able to pinpoint the protein’s identity as Hsp60 — the yeast counterpart of the already-identified bacterial protein GroEL, which wrongly had been thought to be integral to protein assembly, as opposed to folding.

Due to their suspected role in aiding protein formation, these proteins retained the name — “chaperonins” — that had been given them by Dr. John Ellis, a scientist at the University of Warwick, England, several years earlier.

The fluid interior of a cell is rich in salts and other compounds that make it difficult for a chain of amino acids — the building blocks of a proteins — to coil. Combined with the relatively high temperatures at which many organisms thrive, protein folding would be near impossible in the absence of chaperonins, Horwich said.

Incorrectly folded proteins are drawn into the chaperonin complex by hydrophobic interactions and are then released into a sequestered chamber, where conditions allow the protein to reach its natural, lowest energy state.

And with that, the “one sequence, one structure” tenet of protein chemistry was clarified at the molecular level, Horwich explained.

“The final step in the transfer [of information] from DNA to functional protein is the protein folding itself,” he said.

“hunting” diseases

Building on this wealth of mechanistic knowledge, the focus of the lab has begun to move towards the implications of protein misfolding in disease, said Dr. Wayne Fenton, a researcher at Horwich’s lab.

“I think we’ll continue to be interested in the mechanisms underlying this problem, however,” Fenton notes. “But after all, [Horwich] is a physician, and he still wants to address a problem that directly affects patients.”

At this point, the lab has identified several possible links to certain protein-dependent diseases such as Alzheimer’s, cystic fibrosis and amyotrophic lateral sclerosis.

Current efforts in looking at ALS through the lens of protein misfolding are proving most fruitful, Fenton explained.

But will these developments be enough to propel him to a certain ceremony in Sweden next year?

When asked about the possibility of a Nobel for Horwich, Fenton replied candidly: “Handicapping the Nobel committees’ decisions is a losing proposition, so I won’t even speculate.”

As for Horwich himself? With a shrug, he flatly responded, “We’re just going to go to work and do the best we can.”

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