Horwich shared the mutant strain, called mif4, and heard back from an excited Hartl two weeks later. “He said, ‘you’re absolutely right,’” remembers Horwich. “His work suggested that whatever was going wrong with this mutant, it had something to do with polypeptide chain folding inside the mitochondrial matrix.”

The mutation carried by this strain, it turned out, was in a gene that encodes a mitochondrial protein whose production is amped up when cells overheat—one of the class of protein machines thought to help refold proteins under stressful conditions. For that reason it had been dubbed heat shock protein 60, or Hsp60. Versions of this protein are found in nearly every cell of every organism in the world. The surprising thing was that Hsp60, in Horwich’s mutant yeast, appeared necessary for protein folding under normal conditions.

The notion that Hsp60 could be necessary for protein folding provided “enormous focus” for the group, according to Wayne Fenton, a senior member of Horwich’s lab. The researchers probed a related protein found in bacteria, called GroEL, from every angle possible to understand how it worked. “If we didn’t have the tools or the skills to answer the question we needed to answer, then we figured someone else did and we found a collaborator,” says Fenton. “Usually they would teach us a thing or two, and we’d say, ‘hey, this isn’t so hard,’ and then start doing it ourselves. Art and I share that point of view.”

A biochemist by training, Fenton was a research scientist in the Rosenberg lab at Yale when Horwich joined as a postdoc. He ran his own lab for a time but lacked patience for the administrative duties that came along with being a principal investigator. When Horwich established his own lab, sights set on OTC, Fenton joined up and has been working at Horwich’s side ever since. Both avid sailors, the two men are friends as well as colleagues.

In the 1980s and early ’90s, Horwich, Fenton, Cheng, and a growing group of collaborators focused their attention on GroEL. In a painstaking three-year effort with Yale crystallographer Paul Sigler, who died in 2000, the group elucidated GroEL’s molecular structure by x-ray crystallography. Working with Helen Saibil at Birkbeck College in London, the team captured further details of the machine in various states via electron microscopy.

Snapped together in the cell with a protein cap called GroES, the GroEL complex is shaped like a hollow bullet whose tip pops on and off to chauffeur in unfolded proteins and close them off from the cellular environment. Safely inside, the proteins fold on their own, as Anfinsen predicted. But without GroEL, the proteins clump together before they have a chance to fold, and the cell dies. The scientists named the complex a chaperonin and placed it in a class of proteins—called chaperones—believed to assist other proteins in their tasks.

“From the time of Anfinsen we thought that proteins fold and that’s all there is to it,” says Richard Lifton, an HHMI investigator and Horwich’s department head at Yale. “Art’s work completely overturned that paradigm because actually, no, if you didn’t have these chaperonin machines, the proteins would come crashing down.”

Anfinsen’s principles, Horwich hastens to point out, were alive and well throughout these experiments. Horwich’s belief has always been that chaperonins facilitate a process that happens quite naturally by creating a sheltered “changing room” for proteins much like Anfinsen’s test tube.

An Obligation to Evolve

Horwich and his collaborators still study GroEL—most recently using electron microscopy with Saibil and collaborators in California to capture images of proteins moving through the machine—but with the larger mystery of its structure and function solved, the ALS work now occupies most of his time.

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