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Whitehead finds answer to old puzzle

It is not often that a Whitehead Institute discovery has an immediate effect on a patient's life, let alone someone who has won the Olympic gold medal three times. But it can happen, as a recent discovery in Professor Harvey Lodish's lab shows.

Dr. Lodish is a member of the Whitehead Institute and professor of biology at MIT. The lab's recent discovery (Cell, March 10, 1995) of an off-switch that shuts off red blood cell production has actually solved a 30-year-old medical mystery.

The mystery first surfaced during the 1964 Winter Olympics when a Finnish cross-country skier won three gold medals. His extraordinary success was, in true Olympic tradition, surrounded by controversy. Some accused the skier, Eero Maentryanta, of blood doping--adding red blood cells before the race to increase his oxygen level and stamina. Tests showed that he had 15 percent more red blood cells than normal, yet there was absolutely no evidence of blood doping.

Today, Professor Lodish and his associates-Ursula Klingmuller of Whitehead, Benjamin Neel of Beth Israel Hospital, and Lewis Cantley of Harvard Medical School-and their colleagues in Finland know exactly why the Finnish athlete had more stamina than his competitors. He and other members of his family have a genetic mutation that bestows a higher-than-normal level of red blood cells. A receptor for a growth hormone on some of their bone marrow progenitor cells-the cells responsible for replenishing the supply of red blood cells in the body-lacks the key "off" switch.

The hormone receptor affected by the Finnish mutation, the erythropoietin (Epo) receptor, was first isolated and cloned in the Lodish laboratory in 1989. Erythropoietin, a kidney-derived hormone, stimulates the growth and maturation of red blood cells. When the oxygen level in the blood drops (as in a normal person who rapidly ascends a high mountain), the kidneys release Epo. Epo binds to receptors on bone marrow progenitor cells, causing them to divide and then to differentiate into red blood cells. Once the number of red blood cells reaches the desired level, Epo release stops. But how the production of red blood cells is shut off to regulate the number of red cells in the bloodstream remained a mystery.

In 1993, a group of Finnish researchers led by Dr. Albert de la Chapelle at the University of Helsinki identified the mutation that affected the Finnish Olympic skier and his family-the mutation chops off 70 amino acids at one end of their Epo receptor molecules.

Recently, Professor Lodish and his associates deciphered the exact mechanism by which this mutation brings about the clinical picture seen in the Finnish family. They found that in normal cases, the Epo receptor itself sends two signals to the inside of the cell-one activates proteins that turn on red-cell specific genes and the other deactivates them. When Epo binds to the receptor, there is a burst of activity of growth-related messages. The signals are then turned down a few minutes later by the receptor's deactivating signals. The mutant receptors in the Finnish athlete and many of his relatives generate the activation signal normally but lack the deactivating signal. Even low levels of Epo causes their red cell progenitors to grow and divide. This finding by the Lodish group has solved the mystery of the Finnish athlete's extraordinary success, closing one loop in the Epo receptor story.

A version of this article appeared in MIT Tech Talk on May 17, 1995.

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