Tuesday, September 4, 2007

Is bigger better? The evolution of large-scale cancer research organizations

In the early summer of 1956, a newly graduated M.D. from the State University of New York Upstate College of Medicine at Syracuse, I found myself on the campus of Berkeley, California, as a post-doctoral fellow in the Department of Physiological Chemistry at the University of California School of Medicine. My two-year fellowship, which I was just beginning, shared my time between basic science on the Berkeley campus and medicine across the bay in San Francisco.

Shortly after my arrival my boss, Dr. David M. Greenberg, a celebrated biochemist and head of the department, informed me that he had arranged for me to attend the annual scientific meetings of the American Association for Cancer Research (AACR), to take place in Chicago.

That first meeting of the AACR to which I was exposed made an indelible impression on me. At the time, there were only several hundred members of the AACR worldwide, and it was difficult to gain elected membership.

At that meeting I was to hear the first presentation of Dr. Charles Heidelberger, who as a medical biochemist had had the brilliant idea of substituting a fluorine atom for a hydrogen atom on the 5-position of the nucleic acid base uracil--important to rapidly dividing cancer tissue--with the thought that this new molecule (drug) would 'gum up' cancer cells' ability to multiply, with the result of a true chemotherapeutic--anticancer--effect.

The new molecule was called 5-fluorouracil or 5-FU for short. Dr. Heidelberger synthesized this molecule himself, tested it on cancer-bearing animals himself and then tested it on humans himself. Of course, he had assistants and helpers in these endeavors, but it was his concepts alone that led to this scientific and medical breakthrough. Such was Dr. Heidelberger's erudition and creativity, that 5-FU has remained a mainstay in cancer chemotherapy--for colon cancer, ovarian cancer, breast cancer and many other cancers--for the last 50 years.

Dr. Heidelberger's published papers bore his name exclusively as the innovator of his therapy. At the time it was common in medical science to see published papers (studies) with one author alone--or perhaps two or three. Papers with single--or few--authors signified original research. They were the product usually of one person's brain. One person's creativity. Years later, in 1969, when I was elected to membership in the AACR, it was still part of the membership requirements that an applicant show original work by at least two different single-authored papers published in the peer-reviewed scientific literature relating to cancer, as well as have the written endorsements of several well-established senior investigators, known for their own original research. At that time single-authored papers--and scientific innovation in general--proceeded at a brisk pace, were actually common, especially in the cancer field.

Today, in the cancer journals--in the peer-reviewed medical literature as a whole--it is rare to see a single-authored paper. Or a paper with two authors, even three. Instead, in the most prestigious, leading journals it is common to see a paper with 20--25--even 30 authors! What? So many brains 'collaborating' on a single project? Is there a new idea here? Whose? Is there a Charles Heidelberger buried in these lists of investigators?

Concomitant with the multiple-authorship of published papers is the slowdown in cancer treatment innovation. No more brilliant innovations. No more wrenching from nature its deeply buried secrets. No more new directions. No more products of a single brain. One that has apprehended something no other brain has thought of.

Today we have the team effort. The team project. Perhaps not with the payoff that a briliant new idea can bring, but with an improvement--hopefully. A bettering of an understanding of science--and perhaps a more modest payoff therein.

And a lot of different authors get their names on a paper. You know--publish or perish? And a lot of different 'important' investigators get their names on many papers. How do you think department heads or their equivalents get their names on--publish--'100 papers' in a single year (yes, that happens--one investigator, reputedly, on 300 papers in one year)? If I were engaged in original research involving six different projects, I would find it a chore writing 6 different, adequate and complete papers for publication in one year--maybe 2 years. But some department heads and senior investigators simply tack their names on every paper sent out in their department for publication or by their junior investigators, justifying their doing so by reading through and commenting on their manuscripts before publication. In some departments a junior investigator would not dare send out a paper for publication without listing his/her boss as a co-author. (Guess who gets the money?)

But there is a reason for all this. A 'structure' which makes multiple-authored publications both possible and necessary.

In the mid-1950s, when I first attended the meetings of the AACR and heard the Heidelberger paper, as previously stated there were some 300-to-400 members of that organization. Today the membership is 24,000! No longer are the requirements for active membership proof of original research, but only 2 years' experience doing scientific work resulting in articles published in the peer-reviewed medical literature. Instead of the multiple, written letters of recommendation of several well-established, senior investigators, what is needed now are merely the signatures of "two nominators" on the membership application itself. And rather than scientists and clinicians only, active membership is now also open to 'administrators' and 'educators' in the cancer field. Also the application for membership must be accompanied by a fee, currently $255.

24,000. That's quite a bunch! With the diluted membership requirements one wonders whether all one has to do is appear in an open doorway of a basic research laboratory, and poof!--you're in--as long as you pay the fee. Of course, this is a simplification, but one wonders exactly how dilute the qualifications are today for becoming 1 of 24,000 cancer "experts."

And it is not the AACR alone whose ranks have swelled from earlier, more modest--but creatively vibrant--beginnings. It is the AACR's sister organization, the American Society of Clinical Oncology (ASCO), charged with investigating questions in clinical cancer medicine, whose ranks have become similarly enlarged (25,000 members at present).

The AACR and ASCO, as well as like research/clinical organizations worldwide, have become businesses. One look at their structure--their arms of research, clinical medicine, journal sponsorship, even foundations (to which members and readers of their journals are invited and exhorted to contribute monies, trusts, legacies, etc.)--and this aspect of their operations is readily apparent.

Have these hordes of researchers, these armies of researchers--the 20,000+ membership of these organizations--acted to dilute the 'brilliance quotient' when membership was in the several hundreds, composed of provably outstanding scientific minds whose 'track records' for original scientific thought--even as young investigators--was abundantly apparent?

When organizations numbered in the hundreds in membership, there were in general adequate funds available from cancer funding sources. If a "Manhattan Project" developed, requiring markedly additional funds, these materialized easily. But with research organizations numbering 20,000 or more in membership, a wholly different complexion developed.

Research salaries are paid by faculty or institution salaries or research grants, but whether grants or salaries, by far most of these funds derive from the U.S. National Cancer Institute, as appropriated directly from Congress in each budget year. This annual appropriation of the NCI budget by Congress in general limits the amount of cancer funds available each year.

Consider the funding dynamics of a cancer research organization of 20,000 members. Each member--researcher, administrator, educator--receives a salary, research project grant funds, travel allowances, in some cases institutional overhead, totaling well over $100,000 on average (in some instances of senior investigators, hundreds of thousands). That's a minimum of $2.4 billion annually. That doesn't even include the billions spent each year on institutional grants and contracts, cancer centers, large-scale studies and special multicentric (sometimes multinational) epidemiologic projects, NCI operations, and the like. The NCI budget as appropriated by Congress for 2007 only totals $4.75 billion--which is more than oversubscribed. Thus large-scale cancer research organizations contribute significantly to exhausting the reservoir of available cancer funds.

Organizations such as the AACR, in order to support a membership of 24,000, have had to grow from a small, mainly professional group to an immense, complex and powerful business enterprise--its business interests at times seemingly eclipsing its research operations. Frequently this organization importunes its membership--all 24,000 of them--to contact Congress in favor of more cancer appropriations--or for passage of certain legislation favorable to increased cancer funding. The leadership of these organizations stresses to Congress that they and their membership--all 24,000--speak with one voice: that the more cancer monies, the more new ideas to be explored. But many in these organizations do not believe as the "one voice" of its leadership. Because with each increase in the annual cancer (NCI) budget mandated by Congress, the reality is that a smaller percentage of approved research grants has been funded.

Is more better? Are cancer research organizations with membership in excess of 20,000 better equipped to deal with the complex problems in medicine today than in earlier times when membership was much smaller? On the positive side of this question, team efforts are definitely needed to solve the problem, for example, of the human genome and the genetic basis of disease, which can lead to many treatment advances and a new understanding of disease processes. On the other side, before the advent of large-scale research organizations, it was, for example, a few individual, brilliant, competing investigators--Watson, Krick, Franklin--who unraveled the double-helix structure of DNA and thus figured significantly in the important scientific and clinical benefits to result from this discovery. And working by himself, a lone researcher--Nobel prize winner Kary Mullis-- conceived of the polymerase chain reaction, which literally opened the door of the entire field of genetics to researchers, scientists, clinicians, pathologists and others the world over.

One cannot ignore the fact that in cancer medicine particularly, with the advent of large-scale organizations, important treatment advances have slowed considerably. One wonders: Are the armies of researchers in these organizations--who do not have to show proof of capacity for original research--creating funding or other shortages 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?

Is bigger better? Or is big brother somehow, invisibly, paradoxically, acting to smother--to exclude from opportunity--the most gifted of its ranks?