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Scientific giants of integrity; [ONT Edition] Eric Meslin . Toronto Star . Toronto, Ont.: Oct 5, 2005. pg. A.21

Abstract (Summary) Canadians James Till and Ernest McCulloch are more than just lab geniuses, The recent celebration of James Till and Ernest McCulloch's groundbreaking stem cell research in the early 1960s pays homage to two Canadian scientific giants, whose work went largely unnoticed by the general public until the pair were given a long overdue 2005 Lasker Award, North America's most coveted medical prize.

I quickly learned what many other students and colleagues of his had learned over the decades This was a person who oozed ethical integrity from every pore of his body. Not the simple- minded kind of integrity that we still foolishly assume will prepare our students for careers in science - where they must learn the proper rules and procedures of the scientific process, of authorship, or the ethics review committee process. No, Till oozed the real stuff the type of integrity that can't be learned in a book.

Canadians James Mill, above, and Ernest McCulloch, both from the University of Toronto, received the 2005 Lasker award for their groundbreaking work with stem cells. Canadians James Mill, above, and Ernest McCulloch, both from the University of Toronto, received the 2005 Lasker award for their groundbreaking work with stem cells.

Full Text (803 words)

Canadians James Till and Ernest McCulloch are more than just lab geniuses, The recent celebration of James Till and Ernest McCulloch's groundbreaking stem cell research in the early 1960s pays homage to two Canadian scientific giants, whose work went largely unnoticed by the general public until the pair were given a long overdue 2005 Lasker Award, North America's most coveted medical prize.

The news reports went out of their way to report on this achievement with typical Canadian hubris; had their work been carried out south of the border, McCulloch and Till might have already been awarded a Nobel prize.

Efforts also were made to compare their accomplishments to other, arguably more "famous" scientific duos, such as James Watson and Francis Crick who first explained the structure of DNA.

McCulloch is quoted in one story as saying that the pair did not "seek celebrity." This is reminiscent (with apologies to Shakespeare) of that wonderfully humbling line in Twelfth Night and paraphrased here - some scientists are born great, some achieve greatness, and others have greatness thrust upon them.

McCulloch and Till seem to have situated themselves squarely in the second category and for their accomplishments we Canadians are justifiably proud.

But something important is missing from this story. As it is with much of science, society tends to learn about the successes (e.g., sequencing the genome or finding a new planet) or, in rare cases, the failures (e.g., patient deaths in a clinical trial or a case of scientific misconduct).

But missing from the reports of the McCulloch/Till accomplishment was any sustained mention of the kind of scientists these men were and, more importantly, their approach to science and the pursuit of truth.

I have never met McCulloch, but I had the opportunity in the late 1980s and early 1990s as a new assistant professor at the University of Toronto, to work with Till. By this time, Till had long since left the lab to begin investigating, with Heather Sutherland, how to measure "quality of life" experiences with cancer patients.

As someone working in bioethics I had no prior knowledge of Till's work on stem cells, the most important of which occurred the year I was born.

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But I quickly learned what many other students and colleagues of his had learned over the decades This was a person who oozed ethical integrity from every pore of his body. Not the simple- minded kind of integrity that we still foolishly assume will prepare our students for careers in science - where they must learn the proper rules and procedures of the scientific process, of authorship, or the ethics review committee process. No, Till oozed the real stuff the type of integrity that can't be learned in a book.

If he were a subject of a moral philosopher's assessment, he might be described as a virtuous scientist, the type of researcher who can habitually be relied upon to do the right thing without being told what to do.

The "right thing" applied to all phases of his work, from the initial conception of an idea, to the meticulous description of an outline of the idea, to working out the problem to the solved, designing and conducting an experiment, analyzing the data, writing up the results, and submitting them to a journal for publication.

At each step, Till's integrity was on display. It may have been the smallest matter, such as the proper order of authorship, to the largest - the constructive criticism he would offer to help refine what you already thought was an exquisitely thought-through research question.

I was privileged to publish four academic papers with him and each paper was better than the one before. In those few years, I got a small taste of what many before, and many still, are learning from him.

These qualities of scientific rigour and ethical integrity make for a potent combination. Liberally sprinkled with an infectious laugh and sense of humour, there are few who can match Till's mentoring ability.

So while we celebrate the scientific accomplishments, let us not forget that truly good science also involves good scientists.

Sure, it would be nice to have more Canadians win Laskers and Nobels, but the true measure of Canadian greatness in science might also be measured by the number of students whose ethical integrity in science approaches that of people like Jim Till.

Eric M. Meslin, Ph.D., is director of the Indiana University Center for Bioethics, and assistant dean at the IU School of Medicine in Indianapolis.

[Illustration] Canadians James Mill, above, and Ernest McCulloch, both from the University of Toronto, received the 2005 Lasker award for their groundbreaking work with stem cells. Canadians James Mill, above, and Ernest McCulloch, both from the University of Toronto, received the 2005 Lasker award for their groundbreaking work with stem cells.

Indexing (document details) Author(s): Eric Meslin Section: Opinion Publication title: Toronto Star. Toronto, Ont.: Oct 5, 2005. pg. A.21 Source type: Newspaper ISSN: 03190781 ProQuest document ID: 906746951 Text Word Count 803 Document URL: http://proquest.umi.com.myaccess.library.utoronto.ca/pqdlink?did=906746951&sid=18&Fmt=3&c lientId=12520&RQT=309&VName=PQD

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RSC/2005 Centenary Medal Awarded to Co-winners of Lasker Award: Ernest A. McCulloch & James E. Till CCNMatthews Newswire . Toronto: Oct 27, 2005. pg. 1

Abstract (Summary) [Ernest A. McCulloch], FRSC, and [James E. Till], FRSC, of the Ontario Cancer Institute are the 2005 recipients of the Centenary Medal of the Royal Society of Canada celebrating the continued contributions their research has made to stem cell research. Co-winners of the 2005 Albert Lasker Award for Basic Research, Drs. McCulloch and Till are recognized for their revolutionary research in experimental haematology. Their most prominent discovery, that of hemopoietic stem cells in 1961, was rapidly followed by a classic set of papers describing their nature and the genetics that control these cells.

Full Text (287 words)

OTTAWA, ONTARIO--(CCNMatthews - Oct. 27, 2005) - Ernest A. McCulloch and James E. Till will be presented the 2005 Centenary Medal, one of the prestigious honours of the RSC: The Academies of Arts, Humanities and Sciences of Canada.

The Centenary Medal was created in 1982 to honour individuals and organizations who have made outstanding contributions to the object of the Society and to recognize links to international organizations. Those who received it during the centenary celebrations of the Society are listed in the Proceedings for 1982. Since then the medal has been awarded by decisions in Council, at irregular intervals, in recognition of exceptional achievements in scholarship and research.

Ernest A. McCulloch, FRSC, and James E. Till, FRSC, of the Ontario Cancer Institute are the 2005 recipients of the Centenary Medal of the Royal Society of Canada celebrating the continued contributions their research has made to stem cell research. Co-winners of the 2005 Albert Lasker Award for Basic Research, Drs. McCulloch and Till are recognized for their revolutionary research in experimental haematology. Their most prominent discovery, that of hemopoietic stem cells in 1961, was rapidly followed by a classic set of papers describing their nature and the genetics that control these cells. From this work they developed detailed studies of the nature of leukemia leading in turn to contributions on other forms of cancer and the care of those afflicted with the disease. Throughout, their scientific careers have been illuminated by unswerving efforts to serve the community and promote the highest ideals of health care.

The Centenary Medal will be presented to Drs. McCulloch and Till at a special event to be held in Toronto at a later date. Details regarding this event will be communicated shortly.

Indexing (document details) People: McCulloch, Ernest A, Till, James E Companies: Royal Society of Canada Publication title: CCNMatthews Newswire. Toronto: Oct 27, 2005. pg. 1 Source type: Wire Feed ProQuest document ID: 917496511 Text Word Count 287 Document URL: http://proquest.umi.com.myaccess.library.utoronto.ca/pqdweb?did=917496511&sid=1&Fmt=3&cli entId=12520&RQT=309&VName=PQD

Saul J. Sharkis* say for self-renewal potential. They also realized that Sidney Kimmel Comprehensive Cancer Center the nodules on the surface of the spleen—which they at Johns Hopkins called colony-forming units-spleen (CFU-S)—had vari- Johns Hopkins Medical Institutions able capacity for self-renewal, suggesting a functional Baltimore, Maryland 21231 heterogeneity within the population. This heterogeneity has led to the concept that not all stem cells are created equal, even though stem cells as a class are the This year, the recipients of the Lasker Award for Basic most primitive cells within a tissue and provide the or- Medical Research are Ernest A. McCulloch and James gan with a renewable source of differentiated progeny. E. Till. The landmark studies of McCulloch and Till in During the next decade, assays for more mature clono- the 1960s defined the hallmark properties of stem genic progenitor cells of bone marrow grown in vitro cells: the ability to self-renew and differentiate. were developed. A hierarchy was established and as these cells differentiated they were shown to lose the self-renewal potential characteristic of the earliest cells Not a week goes by that the scientific community or the in the stem cell compartment. The observed hetero- media fails to report on stem cells. The topic is being geneity also implied that regulation of clonal expansion discussed in the Congress of the United States as well may be stochastic. These basic tenets of stem cell biol- as in governmental bodies around the globe. The fund- ogy, namely, that the stem cell must demonstrate both ing of stem cell institutes by state governments and self-renewal and differentiation potential, have remained private benefactors is considered daily. How did we get both conceptually and practically the same even given there? The revolution began almost 50 years ago with the decades of additional research to understand how the fundamental studies of two Canadian scientists, Dr. stem cells maintain homeostasis of the organism. Ernest A. McCulloch and Dr. James E. Till. The pioneering work of McCulloch and Till now has been recog- Controversies in the Field nized by the Lasker Foundation, with their receipt of It was nearly 30 years after the discovery of CFU-S by the 2005 Lasker Award for Basic Medical Research. The McCulloch and Till that bone marrow hematopoietic landmark studies of McCulloch and Till in the 1960s stem cells (HSCs) were isolated successfully, enabling defined the hallmark properties of stem cells: the ability HSCs to be studied directly rather than through colony- to self-renew and differentiate. Working with mouse forming assays. Yet this delay did not deter McCulloch bone marrow cells, McCulloch and Till developed an and Till, their colleagues, and their students from con- assay to quantitate a class of early blood-forming pro- tinuing to establish the fundamental physiological roles genitor cells and to define the potential of these cells of HSCs and hematopoietic progenitor cells. They real- both to self-renew and to undergo extensive differentia- ized that the clonogenic assays, although quantitative, tion into many different blood cell types. Stem cells are did not directly measure the engraftment potential of very difficult to study due to their rarity (that is, 1 in the stem cell. The colony assay for CFU-S, although 10,000 bone marrow cells in the mouse). In addition, providing an observable window on the potential of their quiescent nature diminishes the ability to obtain a mouse HSCs in the short term (that is, 1 to 2 weeks complete stem cell phenotype or “footprint” to aid in post-transplant), did not establish the potential of these their identification and purification. cells for long-term engraftment. Other groups set out to identify the external factors that influenced the self- In the Beginning renewal and differentiation of HSCs. Identification of From 1960 to 1963, McCulloch and Till demonstrated new growth factors suggested extrinsic regulation that cells residing in the mouse bone marrow, upon rather than intrinsic control of stem cell properties. As transplantation to a heavily irradiated mouse recipient, scientists discovered these growth factors, they began migrate to the spleen and form discrete colonies (nod- to argue against the stochastic hypothesis of clonal ex- ules) (McCulloch and Till, 1960; Becker et al., 1963). pansion of stem cells. They developed an alternative Within the nodules, they identified donor cells belong- deterministic hypothesis: that HSC renewal and differ- ing to several hematopoietic lineages. They used ab- entiation were regulated by the external microenviron- normal chromosome marker studies to establish the ment. These two opposing arguments, heated at times, clonal nature of the nodules. The authors concluded have been at least partially reconciled by recognition that these nodules represented the progeny of single that the clonal expansion and regulated differentiation transplanted bone marrow cells based upon the direct of HSCs both contribute to long-term engraftment of linear relationship between the number of cells trans- donor HSCs in recipient bone marrow. However, each planted and the number of colonies observed. They hypothesis will be challenged over and over again, as demonstrated that the cells within the colony could they have been most recently with studies showing the give rise to additional colonies after serial transplanta- conversion of HSCs into cells of other tissues. tion into secondary recipient mice, the now classic as- Finally, a long-term reconstituting cell population containing CFU-S was isolated in 1988, described in *Correspondence: [email protected] the classical paper by Irving Weissman’s group (Span- Cell 818

grude et al., 1988). Now the long-term reconstituting the number of cord blood cells available for transplant cell could be studied directly. Through proof-of-prin- is limited. ciple experiments, scientists could examine the self- Let us fast forward to the late 1990s to look at addi- renewal and long-term reconstituting capacity of HSCs tional sources of stem cells. Human embryonic stem that heretofore were measurable only indirectly by the cell lines have been established in vitro. The ability to colony assay developed by McCulloch and Till decades grow pluripotent human embryonic stem cells in vitro earlier. Several different isolation technologies were de- might provide an inexhaustible source of stem cells for veloped for HSCs based on function and phenotype. therapeutic and research purposes. Early experiments Our group showed (Jones et al., 1990) that CFU-S, al- have shown that cell lines derived from human embryos though multipotent, did not copurify with the long-term may have both unlimited self-renewal capacity and dif- reconstituting cell. Then the hierarchy of HSCs was ex- ferentiation potential. The implications and promise for panded yet again: into early and later stem cells, com- therapy have become enormous. We are at the begin- mitted early and later progenitors, and fully differenti- ning of developing research approaches to use this ated cells. source of stem cells to benefit humanity, but the chal- One can reason that the earliest stem cell in develop- lenges are formidable. We should apply the same strin- ment is the zygote. Clearly the fertilized egg has a po- gent biological principles to characterize human and tential for differentiation (pluripotency) that far exceeds mouse embryonic stem cells that McCulloch and Till that of any adult tissue. Embryonic stem cell lines, both used to successfully characterize the HSCs of mouse mouse and human, exhibit both self-renewal and ex- bone marrow 45 years ago: Do they self-renew and dif- tensive differentiation capacity in vitro. However, one of ferentiate extensively as measured by serial transplan- the questions under great debate, both by scientists tation and long-term reconstitution? and by political groups worldwide, is the question of Many researchers continue to observe in animals that whether stem cells in the adult retain their capacity for bone marrow cells in general and in some cases a mar- self-renewal and pluripotency? These studies have led row population enriched for stem cells can repair many to the concept of stem cell plasticity. Once again the types of injured tissues. Thus, bone marrow cells ap- biological principles set forth by the studies of McCul- pear to be remarkably plastic, transforming into cells of loch and Till in the early 1960s prove relevant. These the liver, lung, and brain upon transplantation into in- early studies required transplantation of clonogenic jured recipients. Of particular note, in an animal model HSCs to obtain successful engraftment and rescue of of myocardial infarction (Orlic et al., 2001), the direct the irradiated mouse recipients. Studies in the 1960s injection into heart muscle of a stem cell enriched pop- and 1970s demonstrated functional repair of injured ulation from bone marrow or mobilized peripheral blood bone marrow by the stem cells. Parallel studies of pluri- HSCs resulted in an improvement in cardiac muscle potency today also need to demonstrate functional re- function. This has led to clinical trials in patients with pair of injured tissues (heart, lung, liver, etc.). Do the heart disease with early results showing some improve- injury signals (that is, the microenvironmental factors ment. Whether this is really plasticity remains a matter produced by the injury) directly regulate HSC differenti- of debate, but importantly, these studies have led to ation or is repair by HSCs a random event? This ques- the identification of cardiac stem cells that may be use- tion remains the subject of ongoing experiments by ful for therapy in the future. Scientists are now search- many different groups. ing for stem cell populations in many different tissues hoping that their isolation will lead to a therapeutic ap- Therapy: Then and Now proach for regenerative medicine. In the 1960s and 1970s, in the middle of a cold war and during a heightened nuclear threat, it was prudent for Cancer Stem Cells the military to consider the effects of ionizing radiation After establishing the basic tenets of stem cell biology, on soldiers. Research on treating lethal irradiation by McCulloch and Till turned their attention to leukemia. bone marrow transplantation was militarily justifiable and From the late 1970s until today, the Toronto group has sponsored. These sponsored basic research studies of been instrumental in comparing the properties of nor- McCulloch and Till were complemented by the initiation mal stem cells with those of malignant cells. They pre- of therapeutic intervention protocols at several medical dicted that in acute myelogenous leukemia the culprit institutions. Transplantation of bone marrow cells to was abnormal gene expression rather than a block in treat bone marrow failure caused by, for example, differentiation. They found that in myeloid cell lines self- aplastic anemia or hematological malignancy became renewal could be equated with immortality and sug- the treatment of choice for otherwise fatal diseases. gested that determination of differentiation in leukemia Additional sources of enriched HSCs were sought be- was promiscuous. This infidelity could be a result of cause within the bone marrow these stem cells are rare. genetic reprogramming similar to the plasticity that has Subsequently, both umbilical cord blood and mobilized most recently been observed with normal stem cells. peripheral blood were found to be enriched sources of As a result of these studies, the concept evolved that HSCs. These sources were tested for their ability to within a tumor there is a small population of initiating provide rapid and durable engraftment of bone marrow, cells that are now termed cancer stem cells. Currently, once again adhering to the criteria established by the this concept is under intense investigation. Solid tu- studies in animals of McCulloch and Till and their col- mors of tissues such as breast and lung are being ex- leagues in the 1960s. Umbilical cord blood contains amined to identify this rare cell type. It is hoped that more long-term engrafting HSCs than bone marrow, but removal of this initiating cell by selective destruction Essay 819

will lead to more efficacious therapies. Once again, characterization of the proliferative and differentiation capacities of these abnormal stem cells follows the biological properties outlined by those earlier pioneering studies of McCulloch and Till.

Concluding Remarks The importance of stem cell biology should not be un- derestimated given the potential for these cells to repair injured tissues, to become the target for destruction following malignant transformation, and to allow us to understand genetic and epigenetic changes during cellular proliferation and differentiation. Forty-five years ago, two basic scientists found nodules on the spleen of irradiated rodents transplanted with donor bone marrow. These nodules represented for the first time the clonal expansion of a stem cell. The cell itself would be difficult to capture, but McCulloch and Till developed an assay to study its behavior. When new students join my lab, I insist that they set up a spleen colony assay. The assay teaches techniques such as intravenous injection and sterile handling of bone marrow cells. It also shows reproducibly the clonal nature of stem cells as the students carry out the same cell dose-response curve for injected bone marrow cells that McCulloch and Till used to so elegantly show that the number of spleen colonies is directly proportional to the number of bone marrow cells injected. I can think of no more deserving a team for the Lasker award than that of Earnest McCulloch and James Till, whose revolutionary studies ignited the field of stem cell biology so many years ago.

References

Becker, A.J., McCulloch, E.A., and Till, J.E. (1963). Cytological dem- onstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197, 452–454. Jones, R.I., Wagner, J.E., Celano, P., Zicha, M.S., and Sharkis, S.J. (1990). Separation of pluripotent haematopoietic stem cells from spleen colony forming cells. Nature 347, 188–189. McCulloch, E.A., and Till, J.E. (1960). The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat. Res. 13, 115–125. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S.M., Li, B., Pickel, J., and McKay, R. (2001). Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705. Spangrude, G.J., Heimfeld, S., and Weissman, I.L. (1988). Purifica- tion and characterization of mouse hematopoietic stem cells. Sci- ence 241, 58–62. Document View http://proquest.umi.com.myaccess.library.utoronto.ca/pqdweb?index=13&...

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Six health-care leaders to be inducted into medical hall of fame Canadian Press NewsWire . Toronto: Apr 6, 2004.

Abstract (Summary) The other inductees are: the late Dr. Oswald Avery, who proved that genes are made of DNA, paving the way for future generations of molecular biologists; Dr. Maurice LeClair, former dean of medicine at the University of Sherbrooke and co-author (with Lalonde) of the influential 1974 publication A New Perspective on the Health of Canadians; and doctors Ernest McCulloch and James Till, pioneers in the field of stem cell research.

Full Text (223 words)

TORONTO (CP) - Six leading figures of the medical and health-care communities from the past and present will be inducted into the Canadian Medical Hall of Fame for 2004, the organization announced Tuesday.

The list includes the late Dr. John FitzGerald, the founder of Connaught Laboratories and the University of Toronto's school of hygiene, and Marc Lalonde, an influential health minister under former prime minister Pierre Trudeau.

"We are extremely proud to recognize these esteemed Canadians," said Murray Elston, chair of the hall of fame.

"Their achievements are laudable within the academic and scientific communities, but of equal importance, their work has made a significant impact on the health of individuals worldwide."

The other inductees are: the late Dr. Oswald Avery, who proved that genes are made of DNA, paving the way for future generations of molecular biologists; Dr. Maurice LeClair, former dean of medicine at the University of Sherbrooke and co-author (with Lalonde) of the influential 1974 publication A New Perspective on the Health of Canadians; and doctors Ernest McCulloch and James Till, pioneers in the field of stem cell research.

Inductees were selected from a field of more than 70 nominees by an independent committee of medical leaders.

Induction will take place at a ceremony in Ottawa on Sept. 30.

On the Net:

The Canadian Medical Hall of Fame website: www.cdnmedhall.org

Indexing (document details) Subjects: Social problems, Health Classification Codes 9172 Publication title: Canadian Press NewsWire. Toronto: Apr 6, 2004. Source type: Periodical ProQuest document ID: 620447321 Text Word Count 223 Document URL: http://proquest.umi.com.myaccess.library.utoronto.ca/pqdweb?did=620447321&sid=1&Fmt=3&cli entId=12520&RQT=309&VName=PQD

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Canadian duo dubbed fathers of stem cell research honoured with Lasker Award Ubelacker, Sheryl . Canadian Press NewsWire . Toronto: Sep 18, 2005.

Abstract (Summary) "I would not have any way of applying my science if they had not defined the stem cell for me," [Mick Bhatia] said. "My view of them is biased in a way because I would say they would be equal to a Banting and Best. The best way to describe it is that today they (Banting and Best) are [James Till] and [Ernest McCulloch]. For us in the field, that's really the apex."

"We had switched the focus from what might they look like to what can they do," said Till. "That was, I believe, our major contribution, to say: 'Forget it. Who cares whether they're purple or not. Let's focus on what they can do.'"

"We used the results to make a definition of stem cells," added McCulloch. "We said a stem cell had to have extensive growth potential - be able to grow through many cell-divisions - and secondly that it must be able to give rise to new stem cells - the process of self-renewal."

"I would not have any way of applying my science if they had not defined the stem cell for me," [Mick Bhatia] said. "My view of them is biased in a way because I would say they would be equal to a Banting and Best. The best way to describe it is that today they (Banting and Best) are [James Till] and [Ernest McCulloch]. For us in the field, that's really the apex."

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Full Text (1208 words)

TORONTO (CP) - On the surface, at least, they seem an unlikely duo: one the scion of a Toronto physician, educated at Ontario's tony Upper Canada College; the other the son of a Saskatchewan farmer, who attended his local public high school. One followed his father into medicine, the other veered sharply from his roots to become a biophysicist.

But what Dr. Ernest McCulloch and James Till share is a passionate devotion to science - and their serendipitous pairing led to a discovery that laid the foundation for what may be the most promising and ethically controversial area of international medical research today.

That discovery was recognizing the first stem cell, an entity that had been theorized about since the early 1900s, but never found until McCulloch and Till made the intellectual leap in the early 1960s while experimenting with bone marrow in laboratory mice.

Dubbed the fathers of stem cell research, the long-term colleagues will be honoured Friday in New York with the 2005 Lasker Award for basic medical research, sharing a prize of $50,000 US. The Laskers, referred to as "America's Nobels," have often been prescient: 70 of its winners have gone on to win Nobel prizes, 19 in the last 15 years.

The Lasker is the latest in a long list of honours for Till and McCulloch, including being named Officers of the Order of Canada and inductees into the Medical Hall of Fame. But true to their belief in scientific integrity, and in perhaps typically Canadian fashion, they steadfastly refuse to overstate their contribution to medical history.

"It's a surprise and a thrill," McCulloch, 79, said of the award during an interview with Till at Princess Margaret Hospital in Toronto, where they remain semi-retired senior scientists at the centre's Ontario Cancer Institute.

"I think it means that it justifies the work we did in the sense that for the people who supported our work, the fact that we were given the Lasker Award means that their money was well spent," he said of charitable donations and taxpayer dollars directed to research.

"After 40 years," added Till, the 74-year-old native of Lloydminster, Sask., "I think it means our work has stood the test of time reasonably well."

Mick Bhatia, director of stem cell biology at the University of Western Ontario, called their modest summation "an incredibly gross underestimation of what they've contributed."

"I would not have any way of applying my science if they had not defined the stem cell for me," Bhatia said. "My view of them is biased in a way because I would say they would be equal to a Banting and Best. The best way to describe it is that today they (Banting and Best) are Till and McCulloch. For us in the field, that's really the apex."

As with many great partnerships, their pairing came about more by accident than design.

McCulloch wanted to investigate how injected bone marrow would affect lab mice that had undergone lethal doses of radiation.

"And Dr. (Harold) Johns wasn't going to allow any mere physician to have anything to do with his radiation devices," McCulloch said of the Canadian who invented the Cobalt-60 radiation machine to treat cancer.

"He asked for volunteers to do the radiation of the mice, and Dr. Till volunteered. And once we began working together, it was no longer Dr. Till doing radiation and me doing bone marrow function. We were both doing everything and have been doing everything together really ever since, although in different ways."

During one experiment, they discovered lumps of cells scattered over the animals' spleens - the number of which exactly matched the number of marrow cells they had injected.

What was born from that eureka moment 45 years ago was a shift in emphasis from trying to "see" stem cells, which are rare

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(maybe one in 1,000 cells) and by microscope look much like any other cell.

As well, these progenitor cells would have to have the power differentiate, giving rise to offspring of varying functions, such as oxygen-carrying red cells and disease-fighting white cells in the blood.

"So that out of the work came a functional definition of stem cells that I think holds true today," McCulloch said in his self-effacing, measured style.

Dr. Connie Eaves, deputy director of the Terry Fox Laboratory at the B.C. Cancer Agency, said their work provided a test that allows scientists to pinpoint the elusive stem cell, which she likened to a seed planted in a garden, whose identity isn't known until it grows into a plant.

"There's no question that as a scientific pair who made a contribution to science, they are amongst the leaders in the biomedical field because they've made both conceptual breakthroughs and practical contributions that continue to form the basis of new developments."

Today, stem cells from blood, tissue and embryos are seen as the great hope of medicine, whether as the key to understanding how to defeat many cancers to regenerating disease-ravaged organs like hearts and livers and even parts of the brain.

"There's a lot of excitement about that possibility, but that's what it is, it's an area of hope and of possibility but not of established fact," said Till, ever the scientist.

Yet he is disappointed at the pace of stem cell research in the 45 years since he and McCulloch laid the groundwork. "My personal opinion is I thought we would have arrived here sooner."

"I'm not disappointed at all," countered McCulloch. "I've been delighted with what has happened."

That agreement to disagree without rancour is perhaps the secret to their potent partnership.

"Our combination of backgrounds and expertise gave us complementary perspectives," mused Till. "We had lots of discussions. We were convinced that when we disagreed that if we sat down and talked through the disagreement we would come up with an answer that was better than either's starting point of view.

"We were very open, very frank. Still are," he said. "But we were able all throughout to keep our personal and professional parts separate, no matter how much we might have disagreed professionally.

"That never threatened our personal regard and respect for each other," said Till, his eyes growing moist. "I'm getting emotional here."

The bond between the two men, based on a deep and abiding respect, is obvious as each relates what the other means to him.

"I'm perfectly convinced that I could tell Dr. Till anything and it was confidential and be entirely certain that it would not go further at all," said McCulloch, "and I think he feels the same way about me."

"I do," said Till. "And that trust to my knowledge has never been violated."

Indexing (document details) Subjects: Health, High tech industries, Awards & honors Classification Codes 9172 Author(s): Ubelacker, Sheryl Document types: News Publication title: Canadian Press NewsWire. Toronto: Sep 18, 2005.

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Canadian stem cell pioneers awarded top U.S. medical prize Tom Spears . CanWest News . Don Mills, Ont.: Sep 19, 2005. pg. 1

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OTTAWA - As the two Canadians who discovered stem cells are awarded the biggest medical prize in the United States, one of them cautioned that there's no guarantee that stem cells will ever meet the enormous hopes people have pinned on them.

Ernest McCulloch and James Till will receive the Lasker Award this week a prize that's often a first step toward a Nobel Prize.

The new cells they found in the early 1960s were stem cells, which are able to transform themselves into blood, bones, muscle or other materials our bodies need.

It's a huge honour, their colleagues say. Some say it's long overdue recognition for two men at the Ontario Cancer Institute who founded one of the hottest fields of modern medical science.

But as news of the award broke, Till cautioned that hard-headed science, not dreams, must define the role of stem cells in medicine.

If the huge research effort pays off, stems cells may become building materials that our bodies can use to repair damaged tissue such as heart muscle, bones or even brain cells, researchers believe.

"That's the hope. It requires a lot of things to be accomplished," Till said. "They (stem cells) have to have that potential. We don't know for sure they do. There have to be enough of them to make a difference. They have to be put in the right place (in a patient's body). And they have to be stimulated to do what one wants them to do. And all of these things are challenges, not accomplishments.

"This is a hope. These are not facts; these are dreams. At the moment the people in the field are just grappling with how to make at least some small parts of this dream a reality."

Will it ever work?

"If I had that kind of clairvoyance I'd be playing the stock market," he said. "That's a hope, and I hope their hope is right."

Still, the Canadian science world is celebrating the news of the Lasker win.

"Typically a scientist's findings are slowly disseminated. These guys started a brushfire," said Michael Rudnicki of the Ottawa Health Research Institute, one of Canada's leading stem cell researchers. He called them "heroes" who not only established the field, but brought up a younger generation of scientists.

Till reacted modestly, saying he thought the award was a good thing because it would inspire others in the field "particularly for stem cell research in Canada."

While McCulloch wasn't available for interviews, his partner added that "he's quite pleased that our early work is still recognized as science worth paying attention to."

Dr. Joseph Goldstein, a past Lasker winner who chaired this year's selection committee, had this to say:

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"Occasionally scientists take special note of an observation or interpret it in a novel way. These 'eureka moments' can profoundly alter the course of scientific progress.

"The Lasker Basic Research Award honours two individuals who uncovered the first stem cell, thus laying the groundwork for the entire field of stem cell biology."

Till said he and McCulloch succeeded because they went hunting for signs of what stem cells do, and not just what they look like.

Seventy past Lasker winners have gone on to win the Nobel Prize, including 19 in the past 15 years. There are several Laskers each year for different fields of medicine; Till and McCulloch won for "basic" science the principles underlying diagnosis and treatment of disease.

Some feel the recognition has been slow in coming. Another stem cell pioneer, Stanford's Irving Weissman, recently told the Canadian Stem Cell Network that the two men "should be on postage stamps."

The pair came from very different backgrounds; McCulloch was an internal medicine specialist, educated at a Toronto private school, who switched to research; Till was an Alberta farmboy educated at the University of Saskatchewan (for the $50 entrance scholarship) and Yale who planned to go back to farming if the wheels ever fell off his science career.

They joined forces at the Ontario Cancer Institute decades ago and, though semi-retired, have offices across the hall from each other at Toronto's Princess Margaret Hospital.

Ottawa Citizen

Credit: CanWest News Service; Ottawa Citizen

Indexing (document details) People: McCulloch, Ernest, Till, James Author(s): Tom Spears Document types: News Dateline: OTTAWA Publication title: CanWest News. Don Mills, Ont.: Sep 19, 2005. pg. 1 Source type: Wire Feed ProQuest document ID: 899125481 Text Word Count 701 Document URL: http://proquest.umi.com.myaccess.library.utoronto.ca/pqdweb?did=899125481&sid=1&Fmt=3&cli entId=12520&RQT=309&VName=PQD

2 of 2 8/9/2008 3:13 PM Canadian Medical Hall of Fame: Laureates http://www.cdnmedhall.org/laureates/?laur_id=61

Laureates

Dr. Ernest McCulloch

Inducted in 2004

Born: April 21, 1926, Toronto, Ontario Education: M.D. - University of Toronto, 1948

Ernest McCulloch received his MD in 1948 from the University of Toronto. Upon graduation, he began his education in research at the Lister Institute in London, England. In 1957 he joined the newly formed Ontario Cancer Institute where the majority of his research focused on normal blood-formation and leukemia. Together with his colleague, Dr. J.E. Till, Dr. McCulloch created the first quantitative, clonal method to identify stem cells and used this technique for pioneering studies on stem cells. In addition to providing detailed information about blood cell development, they established the concept of stem cells and set the framework in which stem cells are studied today. Their work gains a new freshness with the current interest in harnessing the developmental program of stem cells for therapeutic purposes.

In addition to his research career, Dr. McCulloch worked tirelessly on numerous provincial, national and international advisory committees and provided Copyright: Use of image must credit the leadership for the research division at the Ontario Cancer Institute, the Institute artist, Irma Coucill, and The Canadian of Medical Science at the University of Toronto and as President of the National Medical Hall of Fame in London, Ontario. Academy of Science of the Royal Society of Canada. He is a Fellow of the Royal Society of Canada and the Royal Society of London. In 1969 he was awarded the Gairdner Foundation International Award (with J.E. Till) and in 1988 he became an Officer of the Order of Canada.

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1 of 1 8/9/2008 3:18 PM Canadian Medical Hall of Fame: Laureates http://www.cdnmedhall.org/laureates/?laur_id=63

Laureates

Dr. James Edgar Till

Inducted in 2004

Born: August 25, 1931, Lloydminster, Saskatchewan Education: M.D. - Yale University, 1957

Upon completing his Ph.D. at Yale University in 1957, James Till relocated to Toronto and focused his studies on cell biology and the radiation sensitivity of mammalian cells. Resulting from this research was a 1961 original paper published in Radiation Research on the radiation sensitivity of normal mouse bone marrow cells. The publication, produced jointly with colleague Ernest A. McCulloch, was a ground-breaking paper in stem cell biology, because it established for the first time a quantitative method to study individual stem cells in adult bone marrow. Over the next decade, Till and McCulloch made many contributions to the understanding of normal and abnormal blood cell development. They also established the concept of stem cells and set the framework in which stem cells are studied today. This work continues to influence the research of investigators world-wide in many fields of study. Since the 1980s, Dr. Till’s sphere of research has expanded to include quality of life research, clinical and epidemiological studies, and research ethics. Currently, he Copyright: Use of image must credit the investigates decision making behaviours of cancer patients and those at high artist, Irma Coucill, and The Canadian risk of cancer, and the influence of the Internet as a source for information, Medical Hall of Fame in London, Ontario. support and advocacy.

Besides his research accomplishments, Dr. Till has served on many national and international committees and in numerous leadership positions, including ones at the Ontario Cancer Institute (now part of the University Health Network), the University of Toronto and the National Cancer Institute of Canada. In 1969, he was awarded the Gairdner Foundation International Award (with E.A. McCulloch) and in 1994 he became an Officer of the Order of Canada. He is a Fellow of the Royal Society of Canada and the Royal Society of London.

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1 of 1 8/9/2008 3:19 PM The Lasker Foundation - Basic Medical Research Award http://www.laskerfoundation.org/awards/2005_b_description.htm

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2005 Albert Lasker Winners Basic Medical Research Award Award Description

Albert Lasker Ernest McCulloch and James Till Basic Medical Research Award For ingenious experiments that first identified a stem cell — the blood-forming stem cell — which set the stage Awards Overview for all current research on adult and embryonic stem cells. Award Presentation Award Description The 2005 Albert Lasker Award for Basic Medical Research honors two scientists who first identified a stem cell, Jury Members which set the stage for all current research on adult and embryonic stem cells. By the turn of the 20th century, scientists were postulating the existence of self-renewing cells that could specialize for a wide variety of purposes. In a series of ingenious and elegant experiments 60 years later, Ernest McCulloch and James Till demonstrated Ernest McCulloch that such a type of cell in the blood-forming—or hematopoietic—system existed. They established the properties Acceptance Remarks of stem cells, which still hold true today. Furthermore, they lay the foundation for the isolation of stem cells and for Video Interview the detection of proteins that help these precursor cells develop and mature. Till and McCulloch's discoveries Article explained the basis of bone marrow transplantation, which prolongs the lives of patients with leukemia and other Key Publications cancers of the blood. Moreover, the team set a new standard of rigor for the field of hematology, transforming it from an observational science to a quantitative experimental discipline. James Till Acceptance Remarks In the late 1950s, McCulloch and Till, newly appointed scientists at the Ontario Cancer Institute in Toronto, began Video Interview to explore how ionizing radiation affects mammalian cells. This enterprise held great importance for several Article reasons. Scientists were trying to understand why and under what circumstances radiation therapy defeated Key Publications cancer. Furthermore, the Cold War was in full swing, so people wanted to devise strategies to save military personnel who might sustain whole-body irradiation from nuclear weapons. Finally, the technique of bone marrow transplantation was in its infancy; investigators knew that this treatment replenished the essential cells of the blood system and were eager to define the source of these cells.

Till and McCulloch worked out a system for measuring the radiation sensitivity of bone marrow cells. The researchers accomplished this feat by zapping mice with a dose that would kill the animals within 30 days if they did not receive a bone marrow transplant of fresh, undamaged cells. To obtain the donor material, the team divided bone marrow from unirradiated animals into portions, and exposed each to a different amount of radiation. The largest dose killed enough donor cells to obliterate their ability to rescue the mice; the smallest dose left much of it intact. The investigators knew how many unirradiated cells were needed to save the animals, so by counting the mouse survivors, they could infer the number of cells that had withstood a given amount of radiation.

Clumps or Clones? The scientists subsequently repeated the experiment but performed autopsies on the animals 10 days after transplantation. They noticed spleen nodules that contained dividing cells, some of which were specializing—or differentiating—into the three main types of blood cells: red cells, white cells, and platelets. The number of nodules was directly proportional to the number of live marrow cells the irradiated animals had received. The crucial entity was rare: About 10,000 marrow cells had to be injected for each nodule observed.

Aspects of the experiment and its results reminded the researchers of the test for live bacteria, which depends on the ability to reproduce. Scientists disperse bacteria on a Petri dish and each bacterium multiplies to form a colony. Counting colonies reveals the number of viable cells that were in the original sample. McCulloch and Till's experiment, however, didn't distinguish whether the spleen nodules originated from single cells that reproduced and differentiated, or came from clumps of multiple kinds of cells that then simply divided. The researchers wanted to find out whether all of the cells in a nodule—or colony, adopting the language of bacteriology—descended from a single cell (and thus represented a clone) or from multiple cells.

To accomplish this task, they needed cells that carried unique inheritable markers. They realized that irradiating cells would produce—at low frequency—exactly such markers in the form of visibly abnormal chromosomes. By dissecting spleen nodules into their constituent cells, Till and McCulloch could determine whether each cell from a given nodule contained the same rare chromosome. If so, the "colony-forming unit" must have been a single cell; if not, it must have been composed of multiple cells.

Andrew Becker, a graduate student working with McCulloch and Till, examined hundreds of cells from 42 nodules obtained from 36 animals. Most contained only normal cells but four contained cells with distinctive chromosomes. Almost all of the dividing cells in each of these nodules carried a unique chromosomal alteration. The colonies thus arose from a single cell.

Till and McCulloch next wanted to know whether the colony-forming cells could renew themselves, forming new colony-forming cells. To answer this question, they and their colleague Louis Siminovitch broke up spleen nodules into their cellular components. The scientists then injected irradiated mice such that each animal received most of the cells from a single colony. If the colony-forming cells could duplicate themselves, the second-round animals would develop nodules. They did, thus establishing that colony-forming cells can self renew.

Later, the team showed that the multiple cell types within a colony arose from a single cell. This experiment addressed a key question in hematology at the time—whether three separate types of precursor cells headed the

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lineages that produced red cells, white cells, and platelets, or whether a single common stem cell gave rise to all three lineages.

By the early 1970s, Till and McCulloch's experimental observations were clear-cut: They revealed that bone marrow transplantation owes its restorative powers to a single type of cell that not only can divide, but can differentiate into all three types of mature blood cells—red cells, white cells, and platelets. These features meant that the colony-forming cells represented a new class of progenitor cells—ones that could proliferate enough to repopulate the bone marrow of an entire animal, self-renew, and give rise to specialized cells that have limited life spans. This definition of a stem cell still holds true today.

From Stem to Stern This simplified diagram of hematopoiesis illustrates the two main properties of stem cells—self-renewal and differentiation—defined by Till and McCulloch. Each stem cell can either replace itself or can begin the path toward specialization, becoming a committed precursor cell. Precursor cells are converted to differentiated cells through the action of cytokines, some of which are shown. Some details of this scheme are still controversial.

Randomness and Genetic Programs A particular feature of the results struck the scientists, however. Although nearly all of the spleen nodules contained new colony-forming units, some had many and some had few or none.

They repeated the experiment with these second-round cells to find out whether the colonies would breed true: Would a nodule from a colony that had produced many nodules contain many colony-forming cells? The results they obtained indicated that the number of new colonies produced wasn't genetically programmed; instead it was random. Borrowing from the field of cosmic radiation, Till worked out a theory in which chance determined a stem cell's fate—whether it would begin to differentiate or instead divide to generate two new stem cells. Till tested this model of spleen-colony growth by computer simulation and the results agreed with the experimental observations. The theory remains strong today, more than four decades after its conception.

The researchers next homed in on molecules in the stem cells and the blood-forming environment that play crucial roles in stem-cell function. Elizabeth Russell and Seldon Bernstein, of the Jackson Laboratory in Bar Harbor, Maine, studied a particular strain of mouse that was anemic and exceptionally susceptible to radiation. The animals' anemia could be cured by injection of cells from mice that carried a regular version of the so-called "W" gene. McCulloch, Till, and Siminovitch showed that these genetically normal animals were donating colony-forming cells to their anemic siblings. Furthermore, they found that bone marrow from the anemic mice didn't form colonies when injected into genetically intact but irradiated mice. The anemic mice therefore carried a genetically encoded defect in their blood-forming stem cells.

A different strain of mouse—with flaws in the "Sl" gene—seemed very similar to the "W" mice, at least on the surface. These animals were also anemic and unusually radiation sensitive. So Till, McCulloch, and Siminovitch performed analogous experiments on them, expecting similar results. The results surprised them. Marrow from these mice behaved normally when injected into irradiated recipients. However, marrow from genetically normal mice didn't cure their anemia. These observations suggested that, rather than carrying defects in the stem cells themselves, the anemic "Sl" mice failed to support stem-cell growth. The results established the importance of the tissue environment in promoting normal stem cell duplication and specialization. Together, the work on "Sl" and "W" opened the door to the study of genetic regulation of stem-cell formation in mice, setting the stage for finding hematopoietic cytokines—proteins made by cells that affect the behavior of other cells—and their cellular receptors.

McCulloch and Till set a high standard for work on cell progenitors, and their findings strongly supported the

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hypothesis that cells with the capacity to self-renew, divide, and differentiate along many lineages existed and were available for rigorous analysis in adult animals. This finding paved the way for current attempts to physically isolate such cells, study their characteristics, and develop them for medical use. It also encouraged the pursuit of other types of stem cells, including embryonic stem cells. Like the stem cells they discovered, Till and McCulloch's work has differentiated and matured in many directions.

By Evelyn Strauss, Ph.D.

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