by Alan I. Packer

(Posted September 18, 1998 · Issue 38)

As the library budgets of research universities strain to keep up with journal subscription costs, as that pile of unread articles on your desk threatens to topple, and as new Nature and Cell spin-offs appear with regularity, isn't it a bit absurd to bemoan the loss of any one journal? Not necessarily . . .

A short note appeared in the December 12, 1997 issue of Science, informing readers that the Journal of NIH Research (JNR) would cease publication that month. The note cited a shortfall in advertising revenues as the cause of the shutdown, and quoted eminent researchers Bruce Alberts and Harold Varmus as saying they were sad to see it go, and . . . well, that was about it. After all, most would agree that the JNR editorial staff put out a fine product, but could anyone working in or around the biomedical sciences these days possibly be desperate for something new to read?

No, it will take some work to convince you that the disappearance of the JNR is a major loss. According to the note in Science, the JNR was owned by the Medical Economics Company of Montvale, New Jersey, and was sent every month at no cost to about 35,000 recipients of National Institute of Health (NIH) grants. A typical issue would begin with an editorial, followed by several pages of analysis on new research findings; occasionally a longer Focus section would back up these analyses, taking an in-depth look at an emerging area in biomedicine. There would also be excellent behind-the-scenes coverage of the fate of NIH and National Science Foundation budgets on Capitol Hill, news of the NIH itself, articles on legal issues related to biomedicine, and an attractive closing page entitled Evolutions, which summarized a field in eye-catching color cartoons.

All of this was well done. Still, it must be said none of this is irreplaceable given the comprehensive science, news, and political coverage found in the "front of the book" sections of Science and Nature. The real gem in the JNR turns out to have been the monthly section called Landmarks. Each issue, this section reprinted a classic paper along with a brief introduction, an interview with one or more of the paper's authors, and a commentary by a scientist whose work has been influenced by the paper. At a time when a comprehensive review article can survey an entire field and not reference a single paper published more than five years ago, it was a pleasure to read papers that spawned whole areas of research.

Some examples, then. Is there a more apt credo for the scientific age in which we find ourselves than the first sentence of Oswald Avery, Colin MacLeod, and Maclyn McCarty's 1944 paper on the identification of DNA as the genetic material? "Biologists have long attempted by chemical means to induce in higher organisms predictable and specific changes which thereafter could be transmitted in series as hereditary characters."

Looking for something that still generates controversy? How about John Gurdon's 1966 demonstration that nuclei from adult frog intestinal cells could support development when injected into an enucleated egg? The road to "Dolly" and "Cumulina" began, at least conceptually, over thirty years ago.

Again and again in these papers, one sees abstract and mysterious problems yield to clear thought and clever experimentation. In a phrase, theories are replaced by molecules. Avery and colleagues replace the "transforming principle" with the macromolecule deoxyribonucleic acid. Vernon Ingram, in his 1957 paper on sickle cell hemoglobin, reveals that the difference between normal and sickle hemoglobin is due to a single amino acid substitution. After all the speculation on the nature of the genetic code, Marshall Nirenberg and Heinrich Matthaei describe in their 1963 paper a cell-free system that can generate polyphenylalanine from polyuridylic acid. Seymour Benzer is bold enough in 1967 to suggest, and go on to demonstrate, that a genetic approach to the ultimate mystery of animal behavior is plausible: "Complex as it is, much of the vast network of cellular functions has been successfully dissected, on a microscopic scale, by the use of mutants in which one element is altered at a time. A similar approach may be fruitful in tackling the complex structures and events underlying behavior. . . ."

The introduction to Benzer's paper, "Behavioral Mutants of Drosophila Isolated by Countercurrent Distribution," is also worth reading for its reminder of the intellectual courage he exhibited. Benzer began his career as a physicist working on semiconductors, then switched to the fine structure of bacteriophage genes, the protein-coding problem, and finally he established the genetics of neurobiology and behavior in the fruit fly - an area of intense research to this day. Benzer's work also demonstrates how many of these classic papers are in the same intellectual lineage. One can see his screen of mutagenized Drosophila in search of behavioral mutants as an important precursor to Christiane Nusslein-Volhard and Eric Wieschaus's 1979-1980 screen of Drosophila embryos for developmental mutants. Many of the genes identified in these studies - period, sine oculis, wingless, gooseberry, hedgehog, and engrailed, to name a few - are now as familiar to developmental geneticists as old friends.

Another interesting connection began in 1965, when Henry Harris and John Watkins demonstrated how scientists could use inactivated Sendai virus to fuse together many different kinds of cells. They used the technique in 1969 to show how the malignant phenotype of a cell could be suppressed by fusion with a normal cell, thereby demonstrating the existence of what we now refer to as "tumor suppressor" genes. Six years later, Georges Kohler and Cesar Milstein used the same technique to fuse myeloma cells and B lymphocytes as the first step to generating monoclonal antibodies; these reagents are just now entering the clinic as a treatment for cancer, which was Henry Harris's concern all along.

What else can one learn from the commentaries on these papers? For one thing, the times certainly have changed. Many of the scientists invited to comment on these landmark studies take note of the leisurely pace of the research in these classic papers. Some doubt the riskier propositions would have been funded today. Perhaps most strikingly, many of the potentially lucrative discoveries were not patented by their makers, notably Kohler and Milstein's work on monoclonal antibodies, Louis Sokoloff's pioneering work in functional brain imaging ultimately used in positron emission tomography (PET), and Jon Gordon and Frank Ruddle's work with transgenic mice.

Lest the reader think this is all interesting but essentially old news, it is important to note that many of the classic papers still generate controversy. For instance, Gerhard Opelz has just this year published a paper confirming his 1974 study (with Paul Terasaki) that preoperative whole blood transfusions improve the outcomes of kidney transplants. He comments, "This kind of research has to be continued. It is really very unsatisfactory, I have to say, after all these years not yet to know why this happens."

All told, this series of papers in the Landmarks section of the JNR provides a glimpse of how groundbreaking science is actually done. The brilliant insights, the hard work, and the lucky breaks are all outlined here in the text and in the interviews. The interviews and commentaries in particular provide an antidote to the restrictive nature of the scientific paper, which Peter Medawar once called "a fraud in the sense that it does give a totally misleading narrative of the processes of thought that go into the making of scientific discoveries."

One can imagine all sorts of additional educational uses for Landmarks, and they should be explored. Most pleasing of all, however, might be the opportunity to sit down with one of the issues on a Saturday morning, when the phone has stopped ringing and it's quiet enough to hear the equipment humming in the lab. Given an hour or so, one could reread (or read) one of these articles and still learn a thing or two. One might even derive a little inspiration from the exercise, and there ought to be a place in the literature, somewhere, for something like that.

Andrzej Krauze is an illustrator, poster maker, cartoonist, and painter who illustrates regularly for HMS Beagle, The Guardian, The Sunday Telegraph, Bookseller, and New Statesman.

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Endlinks

Electronic Scholarly Publication - another source for classical research papers, with an emphasis on genetics.

History of Science Society - an organization for amateurs and professionals interested in the history of science. Members have access to the History of Science and Technology Database.

WWW Virtual Library: History of Science, Technology, and Medicine - a well-organized guide to online information, papers, conferences, and exhibits. Maintained by the Australian Science Archives Project.

Access Excellence Classic Collection - a series of historical overviews on topics ranging from vision to radioactivity. Written primarily for students.