The Molecular Architect: A Profile of Julius Rebek, Jr.

As a boy, Julius Rebek, Jr. was sure that he wanted to be an architect. Perhaps if circumstances had been slightly different, the now-celebrated chemist would have distinguished himself in that career, too.

“I look at a molecule and I can see myself walking around on its surface, so I know something about its shape and its size and, say, its acid and base sites, its positive and negative sites,” says Rebek, professor and director of the Skaggs Institute for Chemical Biology at The Scripps Research Institute. “I think most practicing organic chemists can do that. Maybe it comes especially easily to me.”

Other aspects of his life have not been so easy. An early influence was the Red Army, which swept into Rebek’s native Hungary in October 1944. He was six months old. His parents fled with him, on foot, across the border, and Rebek spent the rest of his infancy and early childhood in a “displaced persons” camp in Austria. His father, determined to make a new life in America, passed up opportunities for Canada and Australia before an American sponsor finally appeared in 1949—a farmer in the prairie state of Kansas.

It was hardly the end of the rainbow. “Our sponsor was a man who thought he was getting indentured servants,” Rebek remembers. His father, who had been a lawyer back in Hungary, was put to work as a laborer, under conditions so difficult that the Church World Service, which had arranged the sponsorship, relocated them after six months. Rebek and his family ended up living in a working-class neighborhood of Topeka. His father earned money for the family as a gravedigger and then a school janitor, and moonlighted as a house painter. “In the summers, my brother and I would paint houses with him,” Rebek remembers with a chuckle. “And you know what? I’m still a really good painter. Most of the places I’ve lived, I’ve done the interior painting.”

Building a Career in Chemistry

He glided through high school. A former teacher, years later, would remark on how easy everything seemed for the Hungarian kid. By his senior year, Rebek was taking courses at Topeka’s Washburn University, where he later enrolled as a college freshman before transferring to the University of Kansas.

There, he remained still set on becoming an architect, until one day in organic chemistry lab, the professor stopped by his bench, noted his talent, and invited him to join the lab for the summer. “It meant that I would be working in an air-conditioned lab rather than out painting houses, so I jumped at the chance,” Rebek says. “And that’s how I became a chemist.”

He was awarded his doctorate at the Massachusetts Institute of Technology (MIT) in 1970, joined the University of California, Los Angeles, as an assistant professor, and soon invented what later became a widely-used process—the “three-phase test”—for detecting elusive intermediate compounds in chemical reactions. He moved to the University of Pittsburgh in 1976 and soon became a full professor as his lab produced a steady output of novel and useful molecules. Some were nanoscale, rotor-like “machines” that helped inspire the field of nanotechnology. Others were molecules that could specifically recognize and trap target compounds by wrapping partly around them—and, he quips, “it was this work in molecular recognition that finally earned me professional recognition.”

He returned to MIT in 1989 and almost immediately made the news for an achievement that grew out of his molecular recognition work. Some of the novel molecules produced in his lab were designed to envelop their targets by self-assembling, piece by piece, into a larger wraparound structure. Tinkering with these self-assembling structures, Rebek realized that he might be able to craft a molecule that not only self-assembles from its constituent parts, but also self-replicates using its own structure as a self-complementary template—like DNA or RNA, but with far simpler chemistry.

In 1990, he reported the development of amino adenosine triacid ester, the first artificial, self-replicating molecule. “I just wanted to know if I could do it,” he remembers—but his achievement was hailed by evolutionary theorists such as Richard Dawkins, who saw it as a nice example of how self-replicating structures might have arisen on the early Earth.

Accommodating Hosts and Guests

Rebek joined Scripps Research in 1996 as director of its newly established Skaggs Institute for Chemical Biology. By this time, his lab had become the pioneer producer of self-assembling cavitands—capsule-shaped molecules for recognizing, grabbing, and effectively trapping other molecules. Most cavitands left one end of the “host” structure open for the “guest” molecule to enter, but Rebek, as usual, took the concept further. “It became a challenge to me to completely surround the guest molecule,” he says.

He did that by fashioning a self-complementary, quasi-hemispheric molecule, a yin to its own yang, that resembled either half of a tennis ball cut along its seams. With hydrogen bonding sites along its “seam” edges, it could come together with other copies of itself in solution. Meanwhile, its interior structures could be designed to grab and capture a particular guest molecule, so that the self-assembling “tennis ball” would come together completely around this guest molecule, long enough to be useful.

It was and still is a broad, enabling technique with applications in drug delivery, chemical sensor design, and even basic chemistry. “The behavior of a molecule in such a small space is very different than it is out in bulk solution; you can see things there that you can’t see any other way,” Rebek says. “In fact, naturally occurring protein catalysts and receptors do exactly the same thing; they bind molecules in really small spaces.” 

Thanks in large part to Rebek, cavitand chemistry is now an active and growing field comprising roughly 20 research groups around the world. The Rebek lab continues to be in the forefront; one of its recent creations is an optically switchable cavitand that opens up its cavity when hit by ultraviolet light, enabling light-based control of host-guest reactions. Another, described last year, is an “ouroborand” structure that normally swallows its tail—like the mythical serpent Ouroboros—but spits it out in the presence of certain metals, a feature useful in controlling reactions or making metal sensors.

New Directions in Nano-Architecture

Rebek also has recently been applying his lab’s broad expertise in nano-architecture to the creation, for the Department of Defense, of molecules that detect and simultaneously neutralize a large class of chemical warfare agents. The recent inventions that have emerged from this effort might soon lead to the development of simple fluorescence-based badge detectors and even quick-acting antidotes. “This is now a big part of my lab’s work, and I love the idea of turning the basic techniques we’ve developed into real-world, practical applications,” he says.

At age 67, Rebek has trained 50 PhD students and some 200 postdocs, and has accumulated a long list of awards, two recent ones being the Nichols Medal from the American Chemistry Society, and an honorary doctorate from the University of Bonn. He is a fellow of the Royal Society of Chemistry and a member of the National Academy of Sciences.

And he still thinks of himself as architect, of a kind. “The Chinese philosopher Lao Tse noted that the value of structures is chiefly in the spaces they enclose,” he says, “and that’s often how I think when I make these capsules, just as an architect would try to imagine the space in a living room or the height of the ceiling.”

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