"Stand Up to Cancer"

About a year ago a blog was published on MedTruth, "Is Bigger Better?" describing the evolution of large-scale cancer research organizations, i.e., in excess of 20,000 members, whose growth was associated with a considerable slowing of important advances in cancer, with a "gobbling up" of cancer research funds appropriated by Congress to the annual budgets of the National Cancer Institute (NCI) and from other sources, and with a possible, paradoxical lessening of opportunity for the truly gifted, for young investigators whose ideas may be "outside" current cancer concepts--whose scientific thinking may harbor the truly great discoveries to come. The blog asks: Is bigger better? Or is big brother somehow, invisibly, paradoxically acting to smother--to exclude from opportunity--the most gifted of its ranks?

On Friday evening, September 5, 2008, all three major television networks--NBC, ABC, CBS--simultaneously telecast a live, star-studded, hour-long, commercial-free telethon, "Stand Up to Cancer," in Los Angeles, attended by thousands of people and dignitaries, aimed at raising large amounts of money for cancer research. Present were celebrities from the entertainment world, such as Jennifer Aniston, Halle Berry, Keanu Reeves, Jack Black, Patrick Swayze, Billy Crystal and others, presidential nominees John McCain and Barack Obama, and network news anchors Katie Couric, Charles Gibson and Brian Williams, who acted as emcees. People and business organizations were urged by these celebrities to call in their donations, while other stars from the entertainment industry--America Ferrera, Christine Ricci, Neil Patrick Harris, Kirsten Dunst--answered phones. Other stars, Jennifer Garner, Forest Whitaker, and again Halle Berry, read personal accounts from patients battling cancer, while cancer "survivors" Elizabeth Edwards (wife of former presidential candidate John Edwards, now battling recurrent breast cancer) and Lance Armstrong recited U.S. and global cancer statistics. This was an unprecedented effort to raise funds for cancer research in order to break the existing bottleneck to effective cancer treatments.

According to an ABC News update on Thursday, September 11, 2008, the "Stand Up to Cancer" telethon raised "one-hundred million plus" dollars. This seems like an enormous amount of money raised by this most significant and monumental effort. Will it increase the amount of cancer research funds by 100 percent? By 50 percent? By 10 percent? How significant was this fund raising effort by this distinguished, if not spectacular, gathering of celebrities, cancer research advocates, scientists, news anchors, even the two 2008 major presidential nominees--speaking for the necessity to raise more funds for cancer research, exhorting the nation's private resources, individuals and industry, to come together in a convincing demonstration of the need and willingness of the public to sponsor more effective cancer therapy. "100 million+" is a lot of money. But is it?

The cancer research budget for the National Cancer Institute (NCI)--part of the federal government--as allocated by Congress for fiscal 2008, i.e., currently, is $4.8 billion. This is 48X the funds raised by Stand Up to Cancer (SU2C). But there are other sources of federal cancer research dollars, as well as sources from the private-sector, such as the American Cancer Society (ACS); according to its Annual Report the ACS allocated $146 million to cancer research in 2007 (about the same for 2008). Thus the total available federal and private-sector cancer research funds are at least $5.0 billion annually, and the additional funds raised by this extraordinary gathering of dignitaries, celebrities, scientists, presidential nominees, news anchors, cancer advocates--$100 million--represents only 2 percent of available, annual cancer research funds. Will this make a significant inroad against cancer?

These additional funds raised by SU2C are to be relegated largely to translational cancer research. Translational cancer research seeks to convert ("translate") scientific "discoveries" that have been accumulating at the laboratory level--which have to date not resulted in any clear-cut clinical advances--to actual, new, near-term therapies that will significantly benefit cancer patients. However, it must be borne in mind that critics of this type of cancer research have alleged that many of these discoveries--made by the armies of members (20,000+) in large-scale cancer research organizations are artifactual--i.e., not real--in nature, and the reason they cannot be "translated" into effective cancer treatments is because they are intrinsically faulty.

The American Association for Cancer Research (AACR)--one of the large-scale cancer research organizations referred to in Is Bigger Better?--has been selected by the Scientific Advisory Committee of SU2C to administer these new funds. The AACR is a private organization made up of scientists, clinicians, educators and administrators. Many in its membership (currently 24,000) are at the heart of all--and the leadership of many--cancer research organizations, cancer programs and cancer centers in this country and the world over. This organization over the years sponsors annual scientific symposia, has raised funds for myriad cancer colloquia and causes, maintains official liaison and interacts with the NCI, ACS and other important cancer groups, is the sponsor and publisher of well known cancer journals, has inaugurated its own charitable foundation--but has never been the actual controller of the type of funds raised by SU2C. If all $100 million go to the AACR, it will represent a windfall for this organization, the magnitude of which it has historically never known.

On September 9, 2008, the AACR issued an Internet advisory stating it will participate in "selecting the most promising research projects" for funding (from the new SU2C funds), that the new funds would enable the "best and brightest" investigators from leading institutions around the world--usually senior investigators--"to work together." What follows is a series of words and phrases--"collaborative efforts," "Dream Teams...of top investigators who have never worked together," "team-approach, rather than competition"--ominously reminiscent of a Communist manifesto, such as would send author and philosopher Ayn Rand (who championed the individual as the "supreme" value of society) spinning in her grave (her portrait graces the 1999 U.S. first-class postage stamp). I am reminded of the get-together of pianist Arthur Rubenstein, cellist Gregor Piatigorsky and violinist Jascha Heifetz, regarded as among the greatest living musicians of their time or of any time--for a recording session. The trios to be recorded by these outstanding musicians--because of their brilliance--would be so great as to be "transcendental." But they weren't transcendental. They were a flop. Because each artist was a "virtuoso" in his own right, each had different "takes"--which did not mesh--on the trios recorded.

In its advisory the AACR emphasized the value of a "team-oriented" apporach, implying that true achievement is more likely to be the results of "collective," i.e., "collaborative," efforts. Nothing could be further from the truth. Historically true achievement--especially in science and medicine--was/is the result of one person. One mind. One brain.

August Kekule in 1865 (rumored the result of a reverie, based on his 25 years of prior work) discovered the ring structure of benzene--which was responsible for the phenomenal growth of organic chemistry, biochemistry, the pharmaceutical industry, medicine, modern chemistry-dependent industry, the production of many commercial household and industrial products, etc. Enrico Fermi, capitalizing on the work of Meitner and Hahn before him, was the developer of the first atomic reactor, which led to both nuclear weapons and the modern nuclear industry--yielding electric power in countries all over the globe, nuclear medicine, and other fissionable-based industrial and medical products. Frederick Banting, working at first in his garage and then at the University of Toronto, isolated and purified--and was thus the discoverer of--insulin, which revolutionized modern medicine (and medical theory) and remains the treatment regimen for millions of people all over the world with diabetes mellitus. Alexander Fleming, working alone and publishing a paper in 1929 showing the killing effect of a strange substance leaching from a penicillium mold in an agar plate--inaugurated the antibiotic era which has saved the lives of millions of people the world over annually. Jonas Salk, publishing the results of his work in the Pittsburgh (Pennsylvania) newspapers because of his distrust for the medical journals and their medical sponsors, was the innovator of the first polio vaccine, which was administered to the children all over the cities and rural areas of America--with the exception of Boston (Massachusetts)--in early 1955. (The doctors of Boston--then considered the "mecca of U. S. medicine"--refused to have the children of Boston immunized with a vaccine they deemed "dangerous.") Later that same year, 1955, Boston suffered the worst polio epidemic ever recorded in the U.S.) The Salk vaccine, followed by the subsequently developed and competitive Sabin vaccine, virtually eliminated poliomyelitis from the face of the earth. In 1957 Dr. Charles Heidelberger developed the anticancer drug 5-FU (5-fluorouracil). Working alone, Heidelberger, a medical biochemist, conceived the idea of substituting a fluorine atom for a hydrogen atom on the nucleic acid base uracil--important to rapidly dividing cancer tissue--with the thought that this new molecule would inhibit cancer cells' ability to multiply and would thus result in a true anticancer effect. Dr. Heidelberger synthesized the molecule 5-FU himself, tested it on cancer-bearing animals himself, then tested it on humans himself. Such was Heidelberger's erudition and creativity, that this work not only advanced chemotherapy signficantly but that 5-FU has remained a mainstay in cancer therapy for over 50 years, used today--by itself and in conjunction with other chemotherapy agents--in a spectrum of human cancer. James Watson, Francis Krick, Rosalind Franklin and Maurice Wilkins, working alone and on both sides of the Atlantic in the 1950s, unlocked the mystery of the double-helix structure of DNA, making possible the first scientific inquiries into the genetic code--and genomes--of various species, including humans, and thus figuring significantly in the important scientific and medical gains to result from this signal discovery. Watson, Krick and Wilkins all received the 1962 Nobel Prize for this work. Franklin unfortunately died (of ovarian cancer) in 1958 and was thus ineligible to be included in this prize, since Nobel Prizes are not awarded posthumously. Biochemist Kary Mullis, working by himself, conceived and developed the polymerase chain reaction (PCR), allowing the amplification of specific DNA sequences, literally opening the door of the entire field of genetics to researchers, scientists, clinicians, pathologists, forensic investigators and others the world over--for which Mullis received the Nobel Prize in 1993. The PCR made possible entry of the science of genetics--and the science of medicine itsef--into the modern era. Luc Montagnier and Robert Gallo, working alone and again on each side of the Atlantic--Montagnier at the Pasteur Institute in Paris, France, and Gallo at the National Cancer Institute in Bethesda, Maryland--were the co-discoverers in 1983 and 1984 of HIV, the presumptive viral cause of AIDS. While Montagnier is generally credited with priority in this discovery, Gallo is regarded as establishing the science which led to this virus' identification and scientific 'portrait.' The discovery and identification of HIV continues to have far-reaching effects on the treatment of millions of AIDS patients worldwide and research on the development of retroviral vaccines in general. Albert Einstein. A German-born theoretical physicist, Einstein is perhaps the ultimate example of an individual working by himself to achieve an extraordinary scientific discovery. Employed as an examiner in a Swiss patent office, personally out of touch with the physics community, in 1905 he published a paper in the German journal, Annals of Physics (Annals der Physik) on the "Special Theory of Relativity," in which he speculated that small amounts of matter could release vast amounts of energy, according to his accompanying equation, E = mc2 . Einstein's monumental discovery changed not only the world of physics and mathematics but has had lasting and unabating ramifications on the worlds of social, scientific, political, ethical--and even religious--thinking and institutions, and continues to have effects on the current world of particle physics (cf. CERN's "Large Hadron Collider").

As many of you know, I , myself, may have reason to understand the contribution that single investigators, working alone, have made to the march of science, because of my discovery of the biochemical (i.e., thermodynamic) mechanism of cancer cachexia, the weight loss and debilitation seen in late-stage cancer, which accounts for 73 percent of all cancer deaths. But I would like to relate an incident which occurred long before then, which was to acquaint me with the importance of but a single individual to the progress of medicine.

Just having received my M.D. degree as a 26-year-old in May 1956, I found myself, two months later, as a post-doctoral research fellow in the Department of Physiological Chemistry at the University of California School of Medicine at Berkeley, as a result of winning a U.S. Public Health Service Post-Doctoral Research Fellowship. In this department where I spent half-time (the other half was spent across the bay in San Francisco, in clinical medicine) my immediate milieu was a sea of Ph.D.s and graduate students who did not exactly appreciate an M.D. in their bailiwick. M.D.s are in general considered a waste of time--and sometimes not too bright--in a basic science department, since most would go on to practice clinical medicine. My boss, and department chairman, renowned biochemist David M. Greenberg, however, was very kindly and encouraged me in scientific directions he thought would be most helpful. In my experimental work I needed a key biochemical, essential to energy metabolism in cancer and normal cells, glyceraldehyde-3-phosphate, G3P for short. The only trouble was none was commercially available. Fine biochemical companies advertised they would custom synthesize it in gram quantities at $800 per gram (a very large sum at that time), but would not guarantee its biological activity. Frustrated, I apprenticed myself to a famed sugar-phosphate biochemist (professor) on the Berkeley campus, who himself had synthesized G3P by a complicated multi-step organic synthesis, including a hydrogenation over palladium, which (if done wrong) might "blow up" the wing of the building in which the hydrogenation apparatus was located. I tried this 10-step organic synthesis, each step starting out with large amounts of material and ending with much smaller amounts. The "synthesis" took me over a month, and when I was finished I ended up with gram quantities of useless "crud." I was sure I could not obtain G3P by this method--no matter who synthesized it. But I thought about the situation. And suddenly it occurred to me that I could start out with a chemical "skeleton" of G3P and in a single, one-step inorganic synthesis--if it worked--I could open up an epoxy bond with common sodium dihydrogen phosphate (NaH2PO4) and obtain more, 100 percent pure, 100 percent biologically active G3P overnight than had ever been seen before. And that's the way it turned out. The sugar-phosphate chemist (full professor) under whom I apprenticed myself for a short time, was not happy to hear of this achievement. But my department chairman, Dr. Greenberg, was and encouraged me to make application for a U.S. patent on it after obtaining the University of California's consent for me to do so and the concurrence of the Surgeon General of the United States. In a short time the price of G3P tumbled from $800 per gram with no guarantee of biological stability or activity to under $20 per gram with full guarantee of biological stability and activity. (And in a few years I did receive a U.S. patent on this process.) In the intervening 50 years since then and now this very same material has sponsored countless research projects, opening a door to the investigation of energy metabolism that had been previously shut tight. And teaching me--even at a young age--about those who would control the politics and purse-strings of biomedical research.

Returning to the AACR advisory on its plans for the SU2C funds, not only is this advisory inaccurate and incorrect, implying that true scientific achievement would be more likely the result of "collaborative" efforts of scientists "working together," rather than the individual efforts of scientists working by themselves, but the advisory stresses the team-approach to be of potentially greater value "than competition." But competition is the heart of creativity. And scientists in competiton with one another have frequently cracked the code of discovery. In the above list of those who were innovators of great discoveries, Salk and Sabin were in competition with one another, each turning out to make great, individual contributions, one an oral vaccine, the other an injectable. Watson, Krick, Franklin and Wilkins were all competitors, racing to see who would be first to decode the mysterious structure of DNA. Gallo and Montagnier contended vigorously with one another, even instituting lawsuits to determine who was truly the discoverer of HIV.

After extolling the "collaborative" approach of the "best and brightest" scientists from "leading institutions" around the world "working together," the AACR advisory also states the following: "A portion of the [SU2C] funds raised will also support innovative, high-risk, high-impact, research grants, many of which will fund talented young investigators who are driving cutting-edge research"--i.e., individual investigators. Are these the truly gifted, young investigators that the MedTruth blog, "Is Bigger Better?" spoke of, those "whose ideas may be 'outside' current cancer concepts--whose scientific thinking may harbor the truly great discoveries to come?" Who magically cannot seem to have their grant applications approved or funded?

"A portion" of the funds going to these "talented young investigators" reminds me of an incident that occurred in the early 1990s. My wife and I were at the annual scientific meetings of the AACR, at which I was to give a paper on the second day of the 4-day meeting. Usually, on the first evening of the conference the AACR holds a "Mixer," open to all registrants of the meetings, the purpose of which is to have the newly elected members--and the newer members in general, including its younger attendees--meet the senior members of the AACR. That was the case in 1957--when I was young attendee at my first AACR conference; at the Mixer I personally met such well known and accomplished scientists as Charles Heidelberger, Sidney Weinhouse, Dean Burk, George Weber and others. But--strangely--at the Mixer in the early 1990s, there were no senior scientists to be seen. The Mixer took place in a very spacious hall, in which there were hundreds of young and unfamiliar-looking individuals milling about--but none of the AACR officers or its more prominent members I had come to know. And in contrast to earlier years when the hall contained all types of refreshment and drinks, at the present Mixer there were only a few stations containing potato chips, and a corner cash-bar where one could purchase cold drinks. But my wife is a "coffee-holic," and she expressed to me, "There's not even a hot cup of coffee here." After saying hello to some old friends we left for the hotel lobby. But our elevator "inadvertently" left us off in a sub-basement. We were about to re-enter the elevator when my wife said, "Wait. I smell coffee!" We found ourselves walking down a corridor full of overhead pipes in the direction from which the smell of coffee was coming. And suddenly trays of hot food appeared from kitchens to the right side of the corridor being wheeled across the hallway to a very large banquet room to the left side of the corridor. Echelons of waiters, all carrying hot foods on enormous trays above their heads were entering this banquet room. And it was obvious the smell of coffee was emanating from this room. My wife and I peeked into this room---filled with large white linen-covered tables, around each of which were ten people, many of whom were in formal attire. About 200 people were seated around these tables. But--suddenly--I recognized one of the faces--then another--then another--and then many! It was a banquet for the "senior" members of the AACR. The mystery was solved. While the younger and newer members of this organization were milling about upstairs at the Mixer, imbibing potato chips and cold beer, my wife and I had stumbled onto an exclusive gathering (unlisted in the Program) for the AACR's senior membership. Later I learned that the AACR itself had paid (from its general funds) for this gastronomic feast.

As alluded to previously, even at a young age my research projects had placed me in a position of an early understanding of the politics and funding of biomedical research. And as illustrated by the above incident of the AACR banquet for its senior membership, the AACR knows how to take care of its own. Over the years I have become acquainted with the words and language--with the catch-phrases and code-expressions--large-scale cancer research organizations use in communications with each other and in their dispatches and communiques to the public. The AACR states "a portion" of the SU2C funds will go to "young investigators"--the very people who find it so difficult to get grants for their ideas. But the advisory doesn't specify how much--how much of the $100 million will go to these frequently gifted individuals. But let us now look at the initial emphasis and predominant verbiage of this advisory. The phrases "most promising research projects," "collaborative efforts," "best and brightest," "leading institutions," "working together," "interdisciplinary and multi-institutional Dream Teams" do not speak of "young investigators" working alone, but of the 'ol' boys' (and girls') network, the senior makeup of large-scale cancer research projects, institutions and organizations who have always received the lion's share of cancer research funds. One can be sure that the predominant (SU2C) funds will go to these well connected, in this case "inter-connected," scientists--as they always have--the very ones who have sponsored the scores of discoveries at the laboratory level waiting to be "translated" to new treatments. The words "a portion" appear in this advisory almost as an afterthought, and clearly imply a minority of the SU2C funds. Even so, the language used indicates that this slim "portion" will support high-risk, high-impact research grants, "many of which"--but not all--"will fund young investigators."

I have an alternative proposal for the AACR. One that holds real hope for progress in the cancer research world--for new discoveries. For new treatments. For new benefits for cancer patients urgently waiting. Let's use these funds--exclusively--for our "talented young investigators." Let's get young investigators--not the older, more "established" scientists, some of whom may in reality be hard-pressed to recognize new ideas--to sit on the peer-review committees. Let's use the $100 million to take all those grant applications from our younger people--that have not been approved, or approved but not funded--and take a second look.

The Stand Up 2 Cancer funds raised could indeed have high impact, not funding collaborative-type research--where the whole is hoped greater than the sum of its parts--but going exclusively to those who are willing to work alone and test the new ideas which have germinated in their young minds.