Nobel beginnings

A fledgling biochemist in a predicament

Paul Berg was in for a shock when he arrived at Western Reserve University in Cleveland. He had moved there from Pennsylvania with his wife, Millie, to start graduate school in 1948. Berg, now the Cahill Professor of Biochemistry Emeritus at Stanford and winner of the 1980 Nobel Prize in Chemistry, was raring to take a position in the school’s famous Department of Biochemistry. He soon realized, though, he had accepted a post in the Department of Clinical Biochemistry, a much smaller and less noteworthy program at the school, now known as Case Western Reserve. What happened next? Find out in this excerpt from the newly published A Biography of Paul Berg by Errol Friedberg (World Scientific Publishing Co., 2014).

Paul Berg in 1952 on graduation day at Western Reserve University in Cleveland, Where he got his doctoral degree. At his sides are professors Harland Wood (left) and Warwick Sakami.

When Berg first entered the premises that were to be his workplace for the foreseeable future he witnessed the harsh reality that his dream of working on metabolic studies using radiotracer technology may well become the nightmare of finding himself in the wrong department.

By the time he realized his grave error there was precious little Berg could do about the situation — few alternatives existed at that late stage of the game. Besides, Millie had already obtained a nursing position at one of the Western Reserve University hospitals. Even more dispiriting, soon after his arrival in the laboratory Berg learned that [the department’s chairman, Victor] Myers had assigned him the mundane task of measuring cholesterol levels in a cohort of postmortem human hearts to determine if there was any correlation with the cause of death. His brief career as a graduate student seemed poised to take a further nosedive when, about a month later, the aging Myers passed away, and the two remaining faculty members in the defunct department adopted Berg — reluctantly or otherwise!

As things turned out, Berg was far more fortunate than he might otherwise have been. Jack Leonards (who was immediately appointed interim chair of the department) and his colleague, Leonard Skeggs, were collaboratively working on the development of an artificial kidney for renal dialysis. Though this was a far cry from the metabolic labeling experiments being pursued in [biochemistry department chairman] Harland Wood’s laboratory just a floor away, Berg rationalized that work with the artificial kidney was nonetheless cutting-edge research in clinical chemistry. So without a word of complaint (at least to anyone within earshot) he rolled up his sleeves and got to work.

The notion of renal dialysis is credited to Dutch physician and engineer Wilhelm Kolff, who, having witnessed the demise of a 22-year-old man from renal failure, was inspired to invent the first functional kidney dialysis machine. Kolff fashioned a device from cellophane tubing wrapped around a cylinder that rested in a bath of cleansing fluid. Blood was tapped from an artery and, after being cleared of urea and other toxic metabolites, was returned to the venous circulation. Skeggs, who had impressive engineering skills in his own right, was convinced that with Leonards’ help he could improve on Kolff’s efforts.

Remarkably sanguine about a situation that might have prompted serious concern (perhaps even frank panic) in less determined individuals, Berg diligently set about his assigned duties, beginning with learning how to nephrectomize dogs. While assiduously reading the relevant literature, he noted that several putative but as yet unidentified urinary proteins were alleged to have been imbued with remarkable physiological assets. One was claimed to have anticoagulant properties, another to protect against gastric ulcers, and a third putative urinary protein had been suggested to reduce blood pressure. Their extremely low concentration coupled with the enormous salt content of urine had thus far discouraged the purification of these proteins for detailed study.

Here we witness the first of many instances in which Berg squarely faced a challenge in the laboratory — and contrived an innovative solution. The enterprising idea came to him that he might be able to exploit the dialyzer to reduce the amount of salt in the urine he routinely collected in huge jugs placed in the local men’s rooms, and then concentrate the dialyzed fluids by low temperature distillation to a manageable volume that he could test for biological activity. Berg located an old freezer with an intact and functional condenser and single-handedly fashioned a distillation apparatus with which he was able to effectively distill off much of the liquid and collect reasonably concentrated samples of urine to test for biological activity. “It was really a Rube Goldberg type of operation,” he laughingly recalled. “But in the end I was able to detect the anticoagulant factor, as well as an activity that suppressed ulcer formation in rats” — an impressively innovative start for a total novice in a research laboratory.

In the midst of these experiments Berg took graduate-level courses for credit in the “real” biochemistry department, including one that once again required oral presentation of relevant papers from the current literature. He elected to present a seminar on transmethylation, a biologically important chemical reaction in which a preformed methyl group is transferred intact from one compound to another, then a topic of considerable interest and controversy in biochemical circles.

'It was really a Rube Goldberg type operation. But in the end I was able to detect the anticoagulant factor ....’ 

Conventional dogma held that mammals were unable to synthesize methyl groups of methionine and choline de novo. They had to be supplied in the diet. But Berg uncovered hints in the literature that if one supplemented the diet of experimental animals with folic acid and vitamin B12, one could do away with the methionine requirement. Indeed, Warwick Sakami, a Japanese-born professor in the Department of Biochemistry well-versed in the use of radiolabeled substrates, had detected radioactive methyl groups in methionine and choline in the livers of rats previously injected with radioactive serine and later with radioactive formic acid.

Berg delivered a polished and thoroughly researched seminar that greatly impressed the assembled faculty. Buoyed by the enthusiastic reception to his presentation, Berg approached Sakami to express his interest in determining how 1-carbon compounds are converted to methyl groups in choline and methionine. Sakami was in turn becoming increasingly impressed with Berg’s keen intellect, his enthusiasm for biomedical research and his impressive knowledge of the topic at hand. Aware that the independent youngster had inadvertently landed in the essentially defunct Department of Clinical Biochemistry, Sakami asked Berg if he was interested in transferring to the Biochemistry Department proper as a graduate student, where he might undertake some of the experiments suggested in his seminar. Sakami sang the graduate student’s praises to department chairman Harland Wood, who enthusiastically reinforced Sakami’s overtures. Berg was beside himself with joy. When, in later years he published an account of these events for the prestigious Feodor Lynen Lecture delivered in 1977, Berg expressed his appreciation for the opportunity to launch his scientific career in the “real” Department of Biochemistry at Western Reserve.

“Although I only moved from one floor to the next, the change altered my life: I was brought into contact with people who loved and lived for biochemistry and thereby created an environment where the spark could be nurtured in others. Enzymology, intermediary metabolism and the trials of learning how to do a meaningful experiment occupied my waking hours.”

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