Basic Medical Research Award
To begin to explain what today's Basic Science Lasker Award winners, Ernest McCullough and James Till, accomplished, let me point out that the reason we are all enjoying this luncheon is that we have blood cellsred blood cells that carry oxygen around, white blood cells that protect us from germs and platelets that keep us from bleeding. We constantly produce these cells, and we make trillions of them every day.
Since the late 19th century we could recognize these different blood cells but we had no understanding as to how they were produced. To be sure, we knew that they came from inside of the bonesin the bone marrowand we could identify immature forms of them. But how they really were made was a mystery.
Thanks to McCullough and Till, we now know that these cells originate from bone marrow cells that we cannot readily see, called blood-forming (or "hematopoietic") stem cells. Groping about how to impart what this means, I was struck that no really appropriate analogies exist in our common experienceoak seeds make oak trees; carrot seeds turn into carrots; and when the seeds do their work, they're gone. The best I could do was to propose that stem cells are like the chefs in the kitchen who prepared the appetizer, the main course and the dessert for our lunch from their respective ingredients. I need to stretch the analogy by saying we aren't able to visualize the chefs in the kitchen, so all we see are appetizers, main courses and desserts in various stages of preparation, just as when we look in the bone marrow we see blood cells in development but not the stem cells that produced them. The absence of a more suitable comparison underscores the magnitude of McCullough's and Till's conceptual achievement.
A driving force behind McCullough's and Till's research was the realization that radiation from nuclear bombs and X-ray machines can kill blood-cell production. Researchers had shown that blood cell production in mice exposed to such radiation could be rescued by injections of bone marrow from healthy miceit's as if we radiated the Pierre Hotel kitchen and killed the chefs, yet still managed to have our full lunch by importing cooks from the Plaza Hotel. But what is doing the job of making blood cells in the bone marrow or the lunch in the kitchen?
Starting in the late 1950s, McCullough and Till systematically measured how many bone marrow cells were needed to restore blood cell production in radiated mice. These measurements enabled them to calculate that the number of cells in the donor bone marrow carrying out this rescue was very smalljust as in the kitchen, one chef can prepare a lot of meals. Even more importantly, they observed that the spleens of the radiated mice receiving replacement bone marrow contained small clumps of blood cells, which they called "colonies." Each colony contained red blood cells, white blood cells and platelets. This finding meant that something capable of making all blood cell types, a blood-forming stem cell, was trapped in the spleen. It's as if when we imported the Plaza kitchen to the Pierre, most of the chefs we brought in would work in the kitchen. But a few chefs got trapped in the Pierre Hotel elevators and went to work making appetizers, main courses and desserts there.
Now, if each chef in the elevator had a signature, like the food-coloring curlicues that adorn plates in gourmet restaurants, and we saw such distinct signatures on collections of appetizers, main courses and desserts, we could conclude that each set of lunches in the elevator was made by a particular chef. In a truly elegant experiment, McCullough and Till imparted distinct genetic signatures to blood-forming stem cells in donor bone marrow and documented that the blood cells in each spleen colony bore a particular genetic imprint, proving that diverse blood cells come from individual stem cells.
If, like carrot seeds, the chefs in the kitchen simply transformed themselves into our lunches, ceasing to be chefs, no lunches could be served here tomorrow. In the same fashion, if stem cells merely morphed into mature blood cells, blood cell production would cease. To sustain the output of blood cells, stem cells have to be capable of self-replication. McCullough and Till demonstrated this self-renewal potential of stem cells by repeatedly taking individual spleen colonies from one set of mice and injecting them into irradiated mice to generate new colonies.
With these elegant experiments and others performed over a decade, McCullough and Till established the reality of blood-forming stem cells, even though, like our invisible chefs, no one actually knew what they looked like. In recent years, the blood-forming stem cells have indeed been isolated. As anyone who reads newspapers knows, embryonic stem cells may allow us to regenerate damaged body parts. McCullough's and Till's work became the foundation of the most active field of hematology research, spawning like stem cells themselves, a vast effort that has defined how and in response to what stem cells divide and mature into specific blood cells. It has made into a quantitative science the technology of blood stem cell transplantation, a major medical procedure that sustains life when blood cell production fails. As a hematologist who treats patients with blood diseases, I am especially pleased to participate in the awarding of the Lasker Award to Ernest McCullough and James Till.