December 2009

Retrospective: Mahlon Hoagland (1921–2009)

 

Mahlon Hoagland

Mahlon Hoagland, who contributed two seminal discoveries to the field of gene information flow, died on Sept. 18, 2009, at his home in Thetford, Vt., three weeks before his 88th birthday. Working in a group headed by Paul Zamecnik at the Massachusetts General Hospital, Mahlon revealed the enzymatic activation of amino acids at their carboxyl termini by the formation of acyl anhydrides with adenylate (1, 2) and co-discovered, with Zamecnik, transfer RNA (3, 4).

Mahlon was the son of a leading behavioral neurophysiologist. A career in either biology or medicine seemed ordained when he entered Harvard University in 1941, transferring from Williams College. At Harvard, he was deeply impressed by Louis Fieser’s organic chemistry course, recalling, “I was enthralled by his ability to breathe life into molecules” (5). When the war broke out, Harvard premedical students were fast-tracked. Mahlon was commissioned as a Navy midshipman and entered Harvard Medical School in 1943. Two years later, on a fateful morning at Boston’s Children’s Hospital, he contracted tuberculosis from a baby for whom he was caring. His infection progressed rapidly, and he ended up at Chelsea Naval Hospital, where he was discovered by a Harvard physician, Walter Burrage, who evacuated him to the Trudeau Institute in Lake Placid, N.Y., to “take the treatment,” the term used in that era to indicate fresh air and rest.

Returning to Harvard Medical School in 1947 to repeat his fourth year, Mahlon found that his initial interest in surgery remained strong. However, his promised appointment as a surgical resident at Massachusetts General Hospital was rescinded by the chief, who didn’t want a post-TB doctor rumbling around the wards. Mahlon applied for, and received, a surgical residency appointment at the Peter Bent Brigham Hospital but soon found that his tubercle infection had reactivated. Accordingly, he took a research post at Massachusetts General Hospital’s Huntington Laboratory, headed by the physician-toxicologist Joseph Aub. One of Aub’s many interests was beryllium toxicity, based on the problem of industrial exposure to the element (as beryllium oxide) in the phosphors used in the manufacture of fluorescent lamps. For the next three years, Mahlon worked on the induction of osteogenic sarcoma in animals exposed to beryllium as well as its effects on plant growth, becoming a recognized expert in this area of toxicology.

Although Mahlon was strongly influenced by Aub, it was another investigator he encountered in the group who made a deeper and more lasting impression on him— Paul Zamecnik. Zamecnik had joined Aub’s group in 1938 and had been directing a comprehensive program on the control of liver growth viewed as an issue of protein synthesis. By the time Mahlon had completed his beryllium projects, he had received an American Cancer Society fellowship and, on Zamecnik’s advice, joined Kaj Linderström-Lang at Copenhagen’s Carlsberg Laboratory. There, he was significantly influenced both by Linderström-Lang and Herman Kalckar. Mahlon then returned to Massachusetts General, where, again on the advice of Zamecnik, he did a stint in the laboratory of Fritz Lipmann.

Lipmann had written a prophetic review in 1941 on the energetics of ATP activation as a general mechanism in biological chemistry. Mahlon’s stint in the Lipmann lab exposed him to its gestalt and steered his attention to the possibility that covalent ATP activation might be involved in protein synthesis. This idea had not escaped Lipmann’s ever-fertile mind, and the two groups found themselves in “comfortable competition” a few floors apart. But Mahlon got it first.

In addition to his glittering training with the Copenhagen and Boston leaders in biochemical energetics, Mahlon had another great advantage— a cell-free system that the Zamecnik group had painstakingly developed, springing from an initial interest in protein turnover in normal liver and hepatomas and aided by key contributions by Philip Siekevitz, another member of the able team Zamecnik had assembled. The group also enjoyed a relatively unique trove: C14 amino acids from Robert Loftfield. Using a pyrophosphate exchange assay, Mahlon discovered amino acid activation (1, 2). Presciently, he and Zamecnik also observed that, once activated, the amino acid was not released from the catalytic activity (vide infra).

Only two years later, Mahlon found that the temporal and subcellular fraction pathways through which amino acids reached the ribosomes involved a “soluble” RNA (3, 4). This discovery was seeded by a puzzling result Zamecnik had obtained previously: that labeled amino acids became attached to a small amount of RNA in the system. Mahlon’s experiments defined the temporal and enzymatic attachment of activated amino acids to this soluble RNA and led to the important deduction that the enzymes responsible for activating the amino acids catalyzed their linkage to the RNA (these enzymes later to be defined as the aminoacyl tRNA synthetases). Previously, in 1956, Francis Crick had predicted, in a privately circulated document, the existence of an “adaptor” that would have to be involved in translating the DNA code into protein. Mahlon later wrote, admiringly, that he had had an image arise in his mind, that of him and Zamecnik “slashing and sweating our way through a dense jungle, rewarded at last by the vision of a beautiful temple, looking up to see Francis, on gossamer wings of theory, gleefully pointing it out to us!” (6).

Having made two monumental discoveries while he was a “senior” postdoctoral fellow, Mahlon was on the recruitment hot list. Harvard Medical School bacteriologist Bernard Davis had followed Mahlon’s career with increasing admiration and appointed him assistant professor in his department of microbiology. Mahlon undertook teaching for the first time, and, as he would recall later with a combination of humility and amusement, he was called into Davis’ office after every lecture for an intense post-mortem. He set up his lab, attracted fine students and postdocs, but increasingly disliked the landscape and moved to Dartmouth College as chair of biochemistry. There, he turned his research to the control of protein synthesis in regenerating liver and also led efforts to integrate basic research findings into the medical school curriculum. In 1970, Mahlon was recruited to take over the Worcester Foundation for Biomedical Research, which had been founded in 1943 by his father and Gregory Pincus. He promptly added a program in cell biology and won a core grant from the National Cancer Institute, making that institution the first NCI-designated cancer center in Massachusetts.

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