Watching Bacteria Eat

FROM H. PYLORI TO COOKING, SANS NOBEL

With encouragement from Krebs, Kornberg completed his undergraduate degree in chemistry in 1949 and he then continued on at Sheffield to do his thesis work with Bob Davies, where he almost discovered Helicobacter pylori. Davies was studying gastric physiology and asked Kornberg to explore the nature and function of gastric urease, an enzyme that breaks down urea in the stomach. Using radiolabeled compounds, some of which he'd synthesized himself, Kornberg confirmed that urease was present in the stomach - and only in the stomach. "That was good," he says. "But before I wrote my thesis, it struck me that conceivably the enzyme might not be there all the time."

So he asked a bacteriologist friend to lend him some of those "newfangled antibiotics." When he fed the compounds to his cats, the urease activity disappeared. "So I thought, hah! It must be due to bacteria" - an idea that was at the time so preposterous that his friend declared it "nonsense" until he saw the bugs under a microscope with his own two eyes. Last year, Australian researchers received a Nobel Prize for isolating those bacteria and showing that they were involved in ulcers.

Although the work didn't earn Kornberg science's top honor - "I merely made an observation and that's not quite enough for a Nobel Prize" - it did get him a postdoctoral fellowship from the Commonwealth Fund. "The chairman of the interview board was the Right Honorable Lord Adrian, president of the Royal Society, Nobel laureate, and the world's most distinguished physiologist," says Kornberg. When asked if he wasn't disappointed to have contributed so little to an understanding of gastric physiology, Kornberg replied, "I am of course disappointed that I haven't put a new fact into the textbooks, but I derive some consolation from the thought that at least I've taken one out."

During that two-year fellowship, from 1953 to 1955, Kornberg worked with biochemist Efraim Racker and with Melvin Calvin of photosynthesis fame. He also traveled around the United States, as Commonwealth Fellows were required to write an essay about some aspect of American life not connected with their work. Kornberg's topic was regional cooking. "I ate my way across 41 states," he says.

WHAT DO BACTERIA EAT AND BURN?

Kornberg then returned to Krebs' lab in Oxford, where he set out to study how the liver breaks down proline. "I started doing experiments and thought, let me check the library and see what's new. First thing I saw was a paper answering, totally, what I was about to do," he says. So he needed another project. "Then I remembered a conversation I'd had with Racker over tea." The Krebs cycle, Racker mused, takes in compounds containing two carbons and burns them completely, producing carbon dioxide and water. Yet many bacteria subsist on a diet of two-carbon compounds. If they burn those molecules for energy, Racker wondered, how can they also use them to generate the building blocks for macromolecules such as proteins?

"It was a central question in biochemistry, and a conundrum," says Antonio Romano, who spent a sabbatical year working with Kornberg in the late '60s. "How could the Krebs cycle keep on spinning and producing energy, yet at the same time intermediates are being removed to make amino acids? You can't have your cake and eat it, too. So how was this possible?"

Kornberg didn't know, and neither did Krebs. So, using techniques he'd picked up in Calvin's lab for tracing the fates of metabolic intermediates, Kornberg attempted to find out. But he quickly hit a snag. "I remember coming home and telling my wife that I'd been doing experiments feeding radioactive acetate to bacteria, knowing the Krebs cycle will burn it, but that there has to be another pathway to allow the bacteria to use acetate to make cellular materials. But when I look at the radioactive products, all I see is the Krebs cycle. She looked at me and said, 'How can you see a Krebs cycle?' And I thought, that's it! This is a paradox. Things get burned by the Krebs cycle yet all I see is the Krebs cycle. So maybe it's not the Krebs cycle I see but merely compounds that are normally involved in the Krebs cycle. Maybe they do something else."

That train of logic led Kornberg to discover the glyoxylate cycle, a metabolic bypass that allows bacteria, fungi, and fatty seedlings to synthesize cellular materials from Krebs cycle intermediates while avoiding the loss of carbon as carbon dioxide along the way.

Kornberg credits Krebs with promoting his discovery: His former mentor insisted that they coauthor a Nature review on the work soon after Kornberg had done his preliminary write-up. "So this article was published with 'Kornberg and Krebs' and it immediately rang bells everywhere," he says. "This was simply because Krebs had joined me. If I had done it on my own, who would have taken any notice?"

SOLUBLE AND WITTY

Even so, half the battle in science is coming up with a workable problem in the first place. "As Medawar always said, 'Science is the art of the soluble.' And Hans has a nose for what is soluble given the technology of the moment," says John Ashworth, a former graduate student, now chair of the board of Barts and the London NHS Trust. "He has always been able to spot those areas where you could ask fundamental questions using relatively simple techniques which were often devised by other people in other systems for other things. That's what I always thought was his great strength."

"Hans knows his biochemistry and has contributed greatly to our understanding of sugar metabolism in bacteria. He's one of the few people in the world who has discovered a metabolic cycle," says Harlyn Halvorson, a former director of the Marine Biological Laboratory, who spent many summers working and teaching with Kornberg in Woods Hole, a town Kornberg describes as being "the ideal place in which to spend an English summer."

It's that kind of humor that marks Kornberg's character for many. "He's amazingly witty," says Ashworth. "Like many people who learn English relatively late - I don't think he learned until he was 10 or 12 - he has an absolute fascination with the language and is the source of more excruciating puns than anyone else I know." Take, for example, Kornberg's description of his move to the University of Leicester, where he was appointed the first chair in biochemistry in 1960. Kornberg was given a beautiful lab and everything he needed - except for the front door key. After coming through the bathroom window (long before the Beatles song made that a popular refrain), Kornberg told the vice chancellor that he "took possession of the department and emerged flush with success."

STILL AT THE BENCH

From Leicester, Kornberg moved to Cambridge, where he took up studying how bacteria import fructose - a project that occupies him to this day. In his lab at Boston University, Kornberg patiently disables one type of sugar transporter after another and watches to see how Escherichia coli get around the problem. "The way I do it is probably unintelligent design," says Kornberg. "But nevertheless it's evolution in action. Pure Darwinism."

Kornberg also teaches a core course in the University Professor Program. "He's really marvelous," says Collins. "Very charming and enthusiastic and engaged. He's living history and he knows everybody, so he can share those stories to bring alive what could otherwise be some pretty dry science."

But his real passion remains the bench work. "It's just astonishing that at his age and stage of life he remains as enthusiastic an investigator as he is, and as caring a mentor as he continues to be," says Howard Hiatt of Harvard Medical School, another longtime friend and colleague.

"Unless he's off receiving some honor or title in Europe, he's always in the lab, always at the bench," says Chris Lourenco, Kornberg's current research assistant. "We work together, side by side. The science is great and we just have a good time." That's something that Ashworth remembers well. "Science was fun in Hans' lab," he says. "It was serious, you had to do it right, but you also had a very good time."

And retirement hasn't stopped him. "I think his vocation is also his avocation," says Halvorson. "His hobby is doing science. He enjoys it and I can't imagine him not doing it." Referring to the old-fashioned tradition of the independent investigator getting science done with his own two hands, Kornberg says, "I started off as a little man working by himself at the bench, and I intend to be carried out of here feet forward as a little man working by himself at the bench. Because that's where the fun is." khopkin@the-scientist.com