Albert Lasker Award
for Special Achievement in Medical Science

Award Presentation by Eric Kandel

Eric Kandel

For the past 50 years—the past half-century—out of which emerged the coherent molecular-based biology that we now enjoy, the scientific community has been fortunate in having been served brilliantly by several truly outstanding leaders. Each of these combined scientific creativity with a broad vision and a commitment to biology as a whole. James Darnell, whom we honor today with a Lasker Special Achievement Award, is one of these great leaders. More than anyone else, Jim helped redirect molecular biology from its origins in the study of genes in bacteria and bacterial viruses to a focus on the larger picture, the genes in the cells of higher organisms. Moreover, he led by example, by making not one but two fundamental contributions. One, in the 1960s he discovered that, in mammalian cells, messenger RNA, which carries the message from the DNA template on how to make proteins, is processed from a larger to a smaller functional form. Two, in the 1980s he discovered how signals outside the cell lead to the turning on of genes inside the cell.

Let me begin with Darnell's background and scientific contributions.

Jim Darnell was born in September of 1930 in Columbus, Mississippi and did his undergraduate work at home at the University of Mississippi before going on to take his medical training at Washington University in St. Louis. The great biologist, Salvatore Luria, who later recruited him to MIT, said of Jim's origins, "He is the best thing to come out of Mississippi since William Faulkner."

Like Faulkner, Jim proved remarkably creative. At the beginning of his career in the mid-1950s, the major experimental system being used in molecular biology was the bacterium E. coli. But Darnell realized while he was still in Harry Eagles' lab at the NIH that biology was becoming sufficiently mature to take on the much more difficult study of more complex cells—mammalian cells—and the viruses that inhabit them. Jim's work was pivotal in moving the focus of modern biology from bacterial to animal cells. He was among the first to appreciate that the cells from higher animals could be cultured and studied much like simple bacterial cells. Much as Max Delbrück and Luria had earlier used viruses that inhabit bacteria to creatively probe genetic mechanisms in bacteria, Darnell now sought to use animal viruses to define the mechanisms whereby mammalian cells make proteins.

Unlike the situation in bacteria, little was known in 1961 about how information encoded in the template DNA in higher animal cells was transferred to proteins. In bacterial cells, the idea was first entertained that the amino acids, the building blocks of protein, were lined up directly on the template of DNA, an idea that was soon dismissed. Next, some thought that the ribosomes, the multimolecular machinery that synthesizes the proteins might serve as the template carrier of the information from the DNA in the nucleus to the cytoplasm. This idea was also soon rejected. Finally, in 1961, Sidney Brenner and François Jacob discovered a special short-lived species of RNA in bacteria, which they called "messenger RNA," which delivered information from the DNA template to the ribosomes. Darnell therefore spent the year 1961 with Jacob in Paris. When Darnell returned to the United States to join the faculty at MIT, he set out to find the equivalent "messenger" in animal cells and to determine the rules that control its production. In a series of papers in the early 1960s, Darnell helped establish the first link in animal cells between RNA, the protein synthesis machinery, and its final products.

His overreaching ideas were forged through a detailed analysis of another kind of RNA, called ribosomal RNA, an RNA that actually forms part of the ribosomes, the machinery where the proteins of the cells are synthesized. Here, Jim made the remarkable discovery that the size of the ribosomal RNA molecule "shortened" during its journey from the nucleus, where it was made, to the cytoplasm, where it was used. This provided the first clear evidence that information in the genome is copied into an RNA precursor that is "processed" to a smaller, functional product.

Darnell now honed in on messenger RNA. In 1971 he solidified the fundamental principle that for messenger RNA as well, there is a large precursor and small product, by finding that the larger precursor RNA population in the nucleus and the messenger RNA population in the cytoplasm shared a common signature: They both had the same tail.

In focusing on the precise relationship of the genome template to the initial RNA copy, Darnell turned to a human-specific adenovirus, a virus that causes cold symptoms, and wrote prophetically, "the adenovirus system offers many advantages as a model for the study of possible processing of nuclear RNA into mRNA because viral sequences can be specifically identified by DNA-RNA hybridization." By using a single gene of adenovirus, the late gene, Darnell was able to show that here again the large primary transcript is processed into its smaller final form within a few minutes of its synthesis.

These fundamental studies, in a set of papers that stand as models of scientific rigor and transparency, set the stage for one of the major discoveries in modern biology: the discovery that the genes of higher organisms differ dramatically from bacterial and viral genes in having interruptions in their instructions for what protein to make. Thus, genes of higher organisms are not continuous like those of bacteria but are split into pieces consisting of protein coding and non-coding regions. The processing of the larger RNA precursors into the smaller messengers involves the removal of these non-coding regions, by a mechanism called splicing. The coding regions are then stitched together to obtain the final instructions for protein synthesis. The discovery of splicing was made by two groups, one led by Phil Sharp at MIT and the other by Richard Roberts at Cold Spring Harbor, using the same adenovirus RNA pioneered by Jim Darnell. Both Sharp and Roberts have emphasized repeatedly that they would not have carried out their experiments were it not for the adenovirus system and the framework of thinking about mRNA processing developed in Darnell's earlier work. The Sharp-Roberts experiments, in turn, provided us with a radically new understanding of the discontinuous organization of genes in higher organisms and therefore in our genome—a radical departure of what we had learned as dogma from bacterial geneticists. So Jim was right to get us to insist that studying elementary process in higher organisms would introduce new principles.

In the 1980s, Darnell opened up and largely elucidated, on his own, a second field of biology. In studying the response of cells to viruses, he discovered a new mechanism for a cell's reaction to events outside the cell. This mechanism does not use diffusible small signaling molecules inside the cell; instead the signal is carried directly from the membrane, where events on the outside are perceived, to the nucleus by a protein that directly activates genes.

Darnell approached this problem by studying the interferon response pathways. The interferons are hormones that are released following viral infection and which produce proteins that make cells resistant to viral infection. In studying the interferon response, Darnell discovered a new class of proteins that can serve as transcription factors, or gene activators, that link events at the cell surface directly to the turning on of genes. To emphasize their dual role, Darnell called these factors STATs (for Signal Transducers and Activators of Transcription).

Darnell discovered that in the uninfected, unstimulated normal cell, these transcription factors were tethered to receptors for interferon at the cell membrane. Upon binding interferon, this receptor pairs with proteins called JAK kinases, identified by George Stark and Ian Kerr, which activate the STATs. The activated STAT transcription factors then pair with each other and move into the nucleus, where they turn on genes.

Since each type of interferon turns on different genes, Darnell next asked: how is this specificity achieved? He discovered that the STATs constitute a family of proteins and that different interferons recruit different STATs to mediate their actions. Thus, Darnell's work provided an elegant solution to how the different interferon protein sensors at the cell surface can lead directly to the selective turning on of genes and of a unique cellular response. Indeed, after Darnell's discovery of the actions of interferons, many other important factors involved in a myriad of biological processes were found to act through this general pathway (including the interleukins IL-2, IL-4, IL-6, granulocyte macrophage colony-stimulating factor, erythropoietin, growth hormone, prolactin and leptin).

What is so remarkable about Darnell's career is that he has combined this sustained high level of scholarship and influence on biology with an extraordinary sense of pedagogy and academic leadership.

In 1986 Darnell co-authored, with Harvey Lodish and David Baltimore, the first edition of Molecular Cell Biology. Together with Molecular Biology of the Cell, by Alberts, Raff and their colleagues, the Darnell textbook helped define for many undergraduate and graduate students the modern molecular cell biology that we know and love. These two textbooks have been extremely influential. They have not only documented the remarkable unification that biology has achieved on the molecular level, but they also illustrated the power, generality, and elegance of biological principles that have emerged in the last 50 years, a power that now places biology on the same level of pedagogy as physics and chemistry.

Finally, Darnell has trained in his lab a cadre of major scientists, including David Baltimore, currently President of Caltech, and a number of superb molecular biologists: Sheldon Penman, Jonathan Warner, Ron Evans, Joe Nevins, Ed Ziff, and Jeff Friedman, and indirectly, by example, his talented son Robert Darnell. His interest in helping start young scientists on the path to an independent career led to his efforts to restructure Rockefeller University. Darnell realized early on that the future of Rockefeller University would be dependent on its ability to attract and develop a strong, young faculty. This had been hampered by an outdated system where junior faculty were typically not independent but were recruited from within the labs of full professors. By systematically and tactfully guiding changes in this system, Darnell made it possible in 1990 to initiate and guide the long-term effort of building a new faculty.

Darnell's has been a remarkable career of lifetime achievement in science, pedagogy, national, and university leadership—a career that has made, and continues to make, a great impact on modern biology, on the students that he has trained, on the institutions to which he has belonged and to the national enterprise which he helped lead.