Lloyd Old -- Two Steps Ahead
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I had an amiable conversation the other day with Lloyd J. Old, MD. Dr. Old is chairman of the Board of Directors of the international Ludwig Institute for Cancer Research. He is also the William E. Snee Chair of Cancer Immunology at Memorial Sloan-Kettering Cancer Center, director of the Scientific Advisory Council of the Cancer Research Institute, founding president of the Academy of Cancer Immunology, and a member of the National Academy of Sciences. In 2004, he received the prestigious Johns Hopkins University President's Medal.
Although admittedly few are as accomplished as Dr. Old, I often speak to leading cancer scientists. But what made this meeting particularly memorable was that Dr. Old and I (despite disparities in our respective positions) were once friendly colleagues at Memorial Sloan-Kettering Cancer Center (MSKCC), but had not spoken to each other for 30 years.
Dr. Old was one of my 'superiors' when I was at MSKCC in the mid-1970s. I vividly recall our conversations at that time. We did not speak often, but everything that he said to me then has resonated over the years. He was the first individual who helped me make sense of the field of complementary and alternative medicine (CAM). This changed my life and I am permanently grateful.
Lloyd Old has been associated with MSKCC for almost half a century. He came there in 1958 as research fellow and was regarded as a scientific prodigy. In science, as in music, many such young geniuses burn out after a brief sensation. But in the decades that followed he made a series of epochal discoveries that were to transform the field of cancer immunology. He was appointed MSKCC's associate director of research in 1973 (the year before I arrived). He was also vice president of Sloan-Kettering Institute during my three-and-a-half year tenure there. It is impossible to reconstruct for the reader how astonishing that appointment seemed at the time. In his book, The Painted Mouse, Joseph Hixson (a former MSKCC public affairs official) wrote that if Robert A. Good, MD, PhD, Sloan-Kettering's new president, had appointed Andrew Ivy, MD (co-inventor of the discredited cancer remedy, Krebiozen) to be his vice president it could not have been more controversial. And, indeed, in the 1970s, Lloyd Old was the actual driving force behind MSKCC's ill-fated program to submit controversial cancer remedies to serious scientific testing. It was because of his statesmanship and high scientific reputation that he managed to survive in a sometimes-daunting political climate.
Recently I received word through a mutual friend that Dr. Old had read my opinion piece on Herceptin in New Scientist (March 4, 2006) and was pleased with it. At his invitation, I therefore called and we spoke for half an hour in a most friendly way about a wide range of ideas - our past association, of course, but also his present work and future plans in the field of cancer immunotherapy. It is very odd how two individuals, separated by a 30-year silence, can pick up a relationship as if nothing had happened. I leave it to psychologists or philosophers to explain the essential tie that sometimes binds people despite vast changes in time and circumstances.
You have probably gathered by now that Dr. Old is one of my scientific heroes. The scope of his outstanding work is unprecedented in modern times. I am not just referring to its quantity, although he is the author of 570 PubMed-listed scientific papers. Prodigious though this output is, it does not represent a world record: that distinction is probably still held by our former colleague, the late Dr. Good, who wrote or co-authored over 1,500 papers. But, without in any way intending to belittle Dr. Good's achievements, I would suggest that Dr. Old's contributions have been even more far-reaching in the field of cancer and immunity.
As a medical student at the University of California, San Francisco, Dr. Old became fascinated with the idea that the immune system could be harnessed to treat cancer. This was certainly not a mainstream opinion at the time. Upon moving to New York, he took up his research position at MSKCC, but also became a young associate of Helen Coley Nauts, daughter of the pioneering Memorial Hospital immunotherapist, William B. Coley, MD. In the early 1970s, Dr. Old was appointed medical director of Ms. Nauts' Cancer Research Institute and guided that tiny organization to its present stature. It was Lloyd Old who, almost single-handedly, restored Dr. Coley's name and reputation through his famous Harvey Lecture of 1973 (Old 1973), in which he publicly declared Coley's work valid. He also argued persuasively in favor of Coley's hypotheses in many papers, and later in Scientific American articles (Old 1996).
In 1976, he engineered the removal of Dr. Coley's name from the American Cancer Society's list of "unproven methods" (the so-called quack list), along with those of several other early immunotherapists. This momentous achievement � the beginning of a new phase in which Coley would be properly hailed as the "father of cancer immunotherapy" � was celebrated at a black-tie banquet at the Pierre Hotel in 1976. (I had the pleasure of attending that banquet at Dr. Old's invitation.)
Here are some of his other outstanding discoveries:
In the late 1950s, he co-discovered the role of Bacille Calmette-Guerin (BCG) in the treatment of cancer (Old 1959). His publication on this topic in Nature, with Drs. D.A. Clarke and Baruj Benacerraf (who later won the 1980 Nobel Prize), is one of the foundation stones of cancer immunotherapy. BCG is now a standard treatment for some stages of bladder cancer and is used experimentally in the treatment of a number of other kinds of cancer, as well.
In 1961, he began his long-term association with Drs. Elizabeth A. Carswell and Elizabeth Stockert. In the following year, he also began his association with Edward A. (Ted) Boyse, which resulted in almost 100 PubMed-listed papers. (Around Sloan-Kettering, these three leading lights of immunotherapy were irreverently known as the "Good Old Boyse.") Similarly productive was his long-term association with Herbert F. Oettgen, MD, which resulted in around 100 papers. One of the extraordinary things about Dr. Old is the longevity and productivity of these collaborations. He is an excellent team leader, who manages to elicit the best effort from his closest collaborators. It is axiomatic that excellent people do not stick for over 40 years with someone who takes advantage of them!
What are some of his other major accomplishments?
Dr. Old and Dr. Boyse were responsible for the concept of differentiation antigens, or cell surface markers (Boyse 1969). These are large structural macromolecules that are associated with the differentiation of particular cell types. Many cells can be identified by their possession of a unique set of such antigens. This discovery led to the development of the important "CD" system for classifying cell surface antigens (Old 1969).
It was Dr. Old's search for these distinctive tumor antigens that led in particular to the discovery of the CD8 T cell antigen. This finding was central to the recognition of human immunodeficiency virus (HIV) and to the search for an effective treatment for AIDS. CD8 is a protein embedded into the cell surface of cytotoxic T lymphocytes, or killer T cells. Some CD8-marked cells can recognize and kill cancer cells. Old, along with Boyse and other colleagues discovered these cells in animals in the late 1960s (Old 1968).
This then led to one of the most momentous discoveries of 20th century biology, the p53 tumor suppressor gene. This is defined as a "cell cycle related transcription factor," which induces apoptosis (or programmed cell death) in response to damage to DNA or other forms of cell stress. A mutation in this tumor suppressor gene has been found in about half of all human cancers. Old's group discovered it in the late 1970s (DeLeo 1979). According to one theory, the utility of a scientific idea can be judged by the amount of productive research that it stimulates. From this perspective, Old and his colleagues clearly hit pay dirt: there are almost 40,000 articles in PubMed relating to the topic of p53, including 455 clinical trial articles.
Lloyd Old and his colleagues were also the first to demonstrate the link between the major histocompatibility complex (MHC), which is the most gene-dense region of the mammalian genome, and plays a pivotal role in the immune system and susceptibility to disease. This was shown in a paper on how cells resist virally-induced leukemia (Lilly 1965).
Lloyd Old's interest in non-specific immunity for cancer (an outgrowth of his early contact with the work of Dr. Coley) eventually gave rise to the discovery for which he is probably best known, tumor necrosis factor (TNF). Although TNF never became widely adopted as a cancer treatment, it has been extraordinarily productive as a research tool. There is a virtual TNF industry these days, with almost 75,000 research articles discussing this topic. In a typical month, 385 such articles are published - almost 20 on every working day of the year! In May 2000, I unofficially attended the 8th International TNF Congress in Trondheim, Norway. Researchers on TNF (as well as TNF-related apoptosis-inducing ligand or TRAIL) filled the cavernous, 1,000-year old Trondheim Cathedral for the opening ceremonies. Until then, I had tended to think of TNF ruefully as just a failed cancer therapy. But listening to the gathering sound of the organ in that imposing space, I had an epiphany and realized what a huge impact Lloyd Old's 1975 discovery of an "endotoxin-induced serum factor that causes necrosis of tumors" (Carswell 1975) had had on the world of science. In our conversation, Dr. Old reaffirmed to me his belief that TNF may yet play a role in effective cancer therapy.
These are clearly the landmarks of an extraordinary career. Yet some of Dr. Old's most provocative theories are those on which he is currently working. For instance, I have written often about the work of John Beard, DSc, who first proposed the trophoblastic theory of cancer in the early 1900s. Beard stated, in effect, that cancer was pregnancy in the wrong time and place. Dr. Old is one of the few prominent scientists who even seems to know about this work, much less to design intelligent experiments to test its accuracy. He seems determined to do for John Beard what he earlier did for William B. Coley, i.e., to restore his scientific reputation and make the world belatedly take note of his genius.
Old has identified a series of "cancer-testes" genes that are present in both cancer and in embryonic tissues and that are putatively trophoblastic in origin. He is concerned with the question of whether the expression of these genes in the cancer cell contributes to its malignant behavior.
He admits that discussion of this topic must be speculative, "but the finding that gametes, trophoblasts and cancers share a battery of antigens restricted to these cell types is an invitation to extend the search for other shared characteristics." (Old 2001). (Gametes, also called generative or sex cells, are specialized male or female cells with half the normal number of chromosomes. They merge with another cell of the opposite sex in the process of sexual reproduction, restoring the normal chromosome number.)
He continues:
"It was a similarity in the biological features of trophoblasts and cancer cells that prompted the Scottish embryologist John Beard at the turn of the last century to propose his trophoblastic theory of cancer. In his view, cancers arise from germ cells that stray or are arrested in their trek to the gonads. Under the influence of carcinogenic stimuli, such cells undergo a conversion to malignant trophoblastic cells. These malignant trophoblastic cells take on features of the resident cell types in different organs, but the resulting cancers, no matter their site of origin or how distinct they appear morphologically, are of trophoblastic origin." (ibid.)
Old notes that "Beard ascribed the invasive, destructive and metastatic features of cancer to functions normally displayed by trophoblastic cells, e.g., invasion of blood vessels, growth into the uterine wall, and spread beyond the uterus." This is an elegant restatement of the Beardian theory.
But Old is not a strict Beardian. You might perhaps call him a "neo-Beardian." He believes it more likely that normal cells devolve into trophoblast-like cancer cells, rather than that aberrant germ cells progress to trophoblastic-cancer cells, as Beard believed. In Old's words:
"From a contemporary perspective, Beard's idea that cancers are derived from arrested germ cells seems incompatible with our growing knowledge of serological and molecular markers that distinguish different pathways of normal differentiation and their preservation in cancer. Beard's insight that trophoblasts and cancer cells share common features is better explained by the induction of a gametogenic program in resident cancer cells, rather than the derivation of cancer from an aberrant germ cell" (Old 2001)
This is not the place to go into a long disputation on the strengths and weaknesses of strict Beardianism versus its neo-Beardian derivative. One could easily get lost in the details. However, here is Dr. Old's key conclusion:
"The end result, however, would be the same � selected features of cells undergoing gametogenesis and trophoblast development being imposed on transformed somatic cells." (ibid.)
"The end result would be the same." In other words, it is ultimately not very consequential whether normal cells devolve into trophoblastic cells, or stem cells progress to trophoblasts. The bottom line is that cancer is trophoblastic if not itself literally trophoblast. I believe Dr. Old's words are fundamentally important, and I hope to write about them in much greater detail in the future. Essentially, America's leading cancer immunologist has agreed Beard was right and cancer is trophoblastic in its very essence. Recognition of this single fact could unlock the secret of cancer, opening the way towards its ultimate control or even cure. Some people feel that this points to the role of various forms of pancreatic enzymes in cancer treatment - another topic about which I hope to write more in the near future.
Dr. Old was once involved in such experiments. At the present time he finds more fruitful the process of delineating a family of the trophoblast-related cell surface markers, called NY-ESO-1 and MAGE, that characterize these cells, with the goal of ultimately devising vaccines against them. Judging from his nearly 50 years of contributions, he will undoubtedly come up with findings that will be incredibly valuable for future research.
Cancer Politics
It is completely beyond me why Dr. Old--a former visiting professor at the Karolinska Institute in Sweden, with half a dozen epochal discoveries in medical science to his name--has not yet won a Nobel Prize. Few understand the secretive world of Nobel Prize politics. But the answer may lie in his extreme privacy. He certainly does not crave publicity. I remember well the difficulty I had in the 1970s in even getting an interview with him. He guarded this privacy jealously. When I was finally admitted to his tastefully furnished office, a portrait of another prodigy, Wolfgang Amadeus Mozart, on the wall, struck me as an appropriate icon. Perhaps it is the unconventional nature of Old's thinking that continues to put him a few steps ahead of the more conventional people who are responsible for making Nobel decisions. My late mentor, Albert Szent-Gyorgyi, MD, PhD, used to say that it was fine to be one step ahead of everyone else--just don't be two steps ahead. Old's championing of William B. Coley and John Beard certainly put him multiple steps ahead of his peers.
In any case, it is clear to me that Dr. Lloyd Old's work, like that of Otto Warburg and Linus Pauling, is worthy of not just one, but of several Nobel Prizes. When all is said and done, although he may not be granted this ultimate accolade, he will nevertheless have the gratitude of millions of cancer patients whose chances of surmounting the disease have been substantially enhanced by his nearly 50 years of innovative research.
Trophoblast Theory Again
In line with the trophoblastic thesis, this would include enhancing the immune system and using pancreatic enzymes. The trophoblastic thesis itself does not mention the role of vitamin B-17, which is a development of Krebs.
Linear Mode
