Albert Lasker
Basic Medical Research Award

Award Presentation by H. Robert Horvitz

The cell is the fundamental unit of life. Our bodies are made up of cells, about 10 trillion cells, and these cells are of many types: skin cells, blood cells, muscle cells, nerve cells and so on. These cell types are strikingly different from each other, yet the genes they carry are, in almost all cases, identical. How can this be? The answer is that the expression of genes is controlled, so that some genes are expressed in some cells and other genes are expressed in other cells. The consequent difference in gene expression is what makes cells differ. Abnormalities in gene expression are responsible for many diseases, for example, many cancers. How gene expression is controlled is one of the fundamental and most important problems in biology.

Many biologists believed this problem had essentially been solved years ago, with the finding that specific proteins can bind to genes and turn them on or off, causing different genes to be expressed at different times and in different cells. Extensive research by a vast number of scientists has led to the identification and analysis of such proteins and has revealed how these proteins work and how abnormalities in the functions of these proteins can cause disease. However, these scientists missed a process that controls the expression of many and possibly of most of our genes. Today we honor the discoveries of three scientists who discovered this process and who have revolutionized our thinking about gene regulation: Victor Ambros, David Baulcombe and Gary Ruvkun.

These three scientists are very different. Ambros, who began his professional career studying the virus that causes polio, is quiet, unassuming and deeply thoughtful. Ruvkun, by contrast, is a bit flamboyant, and his active research interests include fat metabolism, aging, the origin of life and the search for life on Mars. Baulcombe is a British botanist whose curiosity and perseverance have led him to make discoveries so general that they have impacted the field of human medicine. What discoveries have brought these three together today, and what led them to these discoveries?

The answer to the second question is easy: tomatoes, tobacco and worms. More specifically, Ambros and Ruvkun studied a microscopic roundworm, and Baulcombe studied cells isolated from plants, notably tomato and tobacco. The work of Ambros and Ruvkun I know well, as both began their studies of worms as postdoctoral researchers in my laboratory, where they focused on the problem of how genes control the development of a worm about 1/25th of an inch long. Ambros and Ruvkun were interested in genes that control the timing of specific developmental events, such as when particular cells become skin cells or nerve cells. Ambros and Ruvkun studied two genes called lin-4 and lin-14. Simplifying a bit, lin-14 causes animals to be at a young developmental stage; as an animal develops lin-4 turns off lin-14, allowing the animal to mature to a later stage. How does lin-4 turn off lin-14? Ambros and Ruvkun together began molecular studies of lin-14, and then in their own laboratories analyzed the molecular biology of lin-4 and lin-14 in detail. Ruvkun found that the lin-14 gene encodes a standard gene product, a protein, and he identified the precise site in the lin-14 gene at which lin-4 acts. Ambros found that lin-4 encodes a gene product unlike any that had ever been seen before — a tiny RNA, only about 22 nucleotides in length. This tiny lin-4 RNA was later named a "microRNA," and it was the first microRNA to be discovered.

Soon after these findings, in June of 1992, Ambros and Ruvkun exchanged gene sequences and simultaneously discovered that the lin-4 microRNA sequence is complementary to a set of seven sequences located at the site in the lin-14 gene at which lin-4 regulates lin-14 (in the 3' UTR of the lin-14 mRNA, for the experts). This and other findings led them to establish that lin-4 turns off lin-14 by direct RNA-RNA base-pair binding, like the base-pair binding between the two strands of the DNA double helix discovered by James Watson and Francis Crick.

In 1993 Ambros and Ruvkun reported their discovery of this first microRNA and of how this microRNA acts to control gene expression. This discovery did not set the biomedical world on fire. Rather, one might say that hardly anyone noticed, which, I think, is typical of major but totally unanticipated breakthroughs.

What did cause the scientific world to become excited about tiny RNAs? The answer is a set of subsequent observations by Baulcombe and Ruvkun. First, in a completely independent line of study, Baulcombe had been examining the ways in which plants can defend themselves against viruses. Plants can silence the genes of invading viruses and similarly can silence other genes introduced into their cells. In a landmark paper in 1999, Baulcombe analyzed cells from tomatoes and tobacco and found that whenever such gene silencing occurred the cells synthesized a tiny RNA of about the same length as the lin-4 microRNA and complementary in sequence to the silenced gene. Soon thereafter Ruvkun discovered a second C. elegans microRNA, called let-7, which also controls developmental timing. Then, strikingly, Ruvkun identified microRNAs essentially identical to let-7 in a wide variety of animal species, including mosquitoes, pufferfish, chickens, cows and humans. Together, these findings of Baulcombe and Ruvkun revealed that tiny RNAs are not an oddity of a microscopic worm but rather are found extremely broadly and mostly likely universally among members of the plant and animal kingdoms. Subsequent studies performed in part by Baulcombe and Ruvkun took this principal of universality one step further, establishing that the generation and basic mechanism of action of these tiny RNAs are conserved in plants and worms.

At this point, I'd like to put the discoveries being recognized today into a broader context. This work involved absolutely basic research, focused on fundamental questions concerning the biology of worms and plants. When this work began, neither the generality nor the application of the potential findings was at all clear. Worms and plants were not popular organisms of study. None of these three researchers targeted any human disease. Nonetheless, their studies established mechanisms that appear to be universal among both plants and animals, and their findings might well help provide the basis for the understanding and treatment of a broad variety of human diseases.

I think there are two messages here. First, basic research, i.e. discovery-based research, can lead not only to interesting findings — an obviously important aim in and of itself — but also to insights relevant to disease and humanity that would be very difficult to reach by directly targeting a specific disease for study. Basic research is the driver of biomedical knowledge. Second, companies in the private sector cannot finance the broad and exploratory basic research that is needed to drive scientific knowledge, since one can never guess where basic research might lead and hence one cannot define a robust "business plan" around truly basic research. Basic research must be supported primarily by governments, as governments can fund discovery-based efforts with confidence that they will benefit humanity without knowing ahead of time precisely how they will do so.

In this context, I want to convey my deep concern about the future of government-funded basic science in this country. Federal funding for science in general and for biomedical science in particular is in dire straits. For example, in inflation-adjusted dollars the annual budget of the National Institutes of Health, the primary supporter of biomedical research in the U.S., has dropped 13% since 2003. The consequence is that many lines of important research have been stopped, and many researchers — particularly the young researchers who should be the leaders of tomorrow — are being driven from the field. Many of you here today are leaders in your communities. I ask you, with your contacts in the worlds of science, business, journalism and government, to do what you can to ensure that basic scientific research is supported by the federal government as it should be. Otherwise, discoveries like those we are honoring today will become distant memories rather than models for what we hope to achieve in the future.

Finally, I'd like to finish by thanking and congratulating our winners of the 2008 Lasker Basic Medical Research Award. The discovery of the importance of tiny RNAs in biology was a monumental feat, requiring intuition, insight, courage and dedication. To quote one of our prize winners, Gary Ruvkun, "Tiny RNA genes may be the biological equivalent of dark matter — all around us but almost escaping attention." Thanks to the three of you, tiny RNAs have no longer escaped attention. Congratulations, Victor Ambros, David Baulcombe and Gary Ruvkun.