Using highly efficient clonal culture systems, Dr. Metcalf discovered the existence of a group of white cell regulatory hormones, the four colony-stimulating factors (CSFs) which regulate the formation of granulocytes and macrophages. Dr. Metcalf purified the CSFs, and, together with others, succeeded in isolating the genes for each CSF and mass-producing recombinant CSFs in bacteria, yeast, and mammalian cells.
Analysis of the actions of the CSFs revealed a new principle in biology: that the same regulator molecule can control cell division, differentiation commitment, and functional activity of mature progeny. This principle is proving to be true in regulator systems for other tissues.
The CSFs enhance the recovery of blood-forming cells after injury by drugs or irradiation and greatly increase resistance to potentially lethal infections. As a result of clinical trials conducted by Dr. Metcalf's group and others, clinicians are now using two of the CSFs extensively to treat patients with cancer and a wide range of diseases of blood cell formation. Consequently, treatment is simplified, more intensive chemotherapy is possible, and patients are able to leave the hospital much earlier.
In cloning and characterizing the leukemia inhibitory factor (LIF), with its remarkable range of actions, Dr. Metcalf introduced a new class of polyfunctional regulators. In addition to being an important new agent for the stimulation of platelet formation, LIF has facilitated work on gene manipulation in embryonic stem cells, and has been shown to be an important regulator of neurons and blastocyst implantation.
Dr. Metcalf demonstrated that myeloid leukemia can arise from perturbed CSF production, thus providing the first formal proof of the autocrine hypothesis of cancer induction by a known growth factor. He documented that these leukemias remain responsive to and dependent on normal regulators, thus extending to the leukemias the earlier concepts of tumor dependency of endocrine target tissues.
To Dr. Donald Metcalf, for identifying and purifying the specific white cell regulatory hormones, the colony-stimulating factors, two of which are used extensively to treat patients with cancer and diseases of blood cell formation, this 1993 Albert Lasker Clinical Medical Research Award is given.