Albert Lasker
Basic Medical Research Award

Award Presentation by Denis Baylor

It's a pleasure to introduce the winners of this year's Albert Lasker Basic Medical Research Award: Clay Armstrong, Bertil Hille, and Roderick MacKinnon. Clay, Bertil and Rod have made outstanding discoveries about some of the most important molecules in living cells: ion channels. Ion channels are specialized protein molecules in cell membranes. They generate electrical signals in nerve cells and muscle fibers, produce the cardiac rhythm, and instruct glands to secrete. An individual channel molecule is an on/off switch that controls the flow of ions across the membrane. When switched on, it allows a specific type of ion—Na, K, or Cl—to cross the membrane. These ion movements produce small electrical currents that change the membrane voltage and transmit information from one place to another.

An ion channel is a remarkable molecular machine. Typically it sorts ions one at a time, yet allows the preferred species to pass through at a rate of a million per second, far higher than the speed at which the best enzymes can process their substrates. One of several types of signal can activate channels. Some switched on by the membrane voltage itself have a voltage sensitivity tenfold higher than that of the logic gates in a spanking new computer. Wonderful as they are, channels do not always work properly, and malfunctions produce an expanding list of diseases that includes epilepsy, cardiac arrythmias, and cystic fibrosis.

Before Clay, Bertil and Rod's work, physiologists knew that ion channels are important, but what channels actually are and how they work were only understood at the level of the formalisms that Hodgkin and Huxley had enunciated two decades earlier. Hodgkin and Huxley's work, which earned the Nobel Prize in 1963, had revealed that separate pathways allow ions of different types to cross the membrane, and that, for certain neuronal channels, the voltage across the membrane determines whether ions are allowed to pass or not. It was not clear how ions pass through channels, how channels achieve their remarkable selectivity for ions, nor how the voltage across the membrane instructs the channel to allow ion flow or to block it. The complete molecular structure of a channel? Forget it! This of course was before our awardees came on the scene.

Clay Armstrong, from the University of Pennsylvania, performed ingenious physiological experiments that gave a radically new physical picture of what a channel is and how it works. He opened the study of channel topology and the dynamics of the different parts of the channel molecule. He demonstrated that a potassium channel contains a water-filled hole through the membrane, with enlarged vestibules at each end. Near the cytoplasmic side of the channel there is a "gate" that closes to prevent the passage of ions or opens to allow ions through. By measuring a tiny electrical current generated by conformational transitions that cause the pore to open, he showed that the membrane voltage controls the sodium channel's gate by moving charged pieces of the channel itself. Inspired experiment and inference led him to propose that sodium channels become inactivated (temporarily unable to open) when a tethered ball attached to the channel becomes stuck in the open pore. Many thought this bold mechanical picture too simple (or plain wrong) until Aldrich and his colleagues confirmed it years later by mutational analysis in potassium channels. Clay continues to make new discoveries about how channels work, most recently showing that the presence of ions in the channel's pore influences how its gates operate. Rivals in the field describe him as having an uncanny depth of insight.

Bertil Hille, from the University of Washington, provided a physical mechanism for ion selectivity. He did so by characterizing the gauntlet an ion must run as it traverses the channel's pore. The approach was beautifully direct: find the size of the hole in a sodium channel by trying a variety of ions and determining the largest that can squeeze through. The bottleneck he measured would allow a sodium ion to pass only after it had shed all but a few of the water molecules that normally surround it. Loss of the waters was energetically compensated by negatively charged carboxyl oxygen atoms in the pore wall. This picture explained how a sodium channel effectively allows only sodium ions to pass, yet lets these "chosen" ions through at a very high rate. Bertil extended the analysis to potassium channels and showed that they achieve selectivity in a more subtle way, stripping potassium ions of water and allowing multiple ions to dwell in the pore at one time. Electrical repulsion among the ions allows them to traverse the pore at very high rates even though they interact strongly with the pore walls. More recently, Bertil discovered that some channels are regulated directly by interactions with G-proteins, ubiquitous signaling molecules of the cell interior. He continues distinguished investigations on fundamental mechanisms of cell signaling. Bertil's book, Ionic Channels of Excitable Membranes, is prized by students and senior scientists alike for its depth and clarity.

Rod MacKinnon, at The Rockefeller University, did the unthinkable: He crystallized a potassium channel and determined its entire molecular structure by X-ray diffraction. Earlier he had used physiology and molecular biology to demonstrate that a potassium channel consists of four subunits and to identify the amino acids that line the channel's outer vestibule and pore. The next logical step was to visualize the complete structure of a potassium channel. Doing so required him to test countless crystallization conditions, construct many mutants, and in his off hours learn X-ray crystallography. He did all these things in short order, finding a beautiful structure built from four subunits that come together to make an inverted teepee spanning the membrane. The form and makeup of the pore provide a firm structural basis for the high potassium selectivity and ion transport rates in these channels. Indeed, as Hille, Hodgkin and others had inferred, multiple potassium ions reside in the pore. Now the channel that Rod crystallized was from the bacterium Streptomyces lividans. In a beautiful sequel to the structural work, Rod showed that the bacterial channel can be blocked by a scorpion toxin that blocks potassium channels in higher organisms. This indicates that the structure of the potassium channel's mouth was conserved as higher organisms evolved. Rod is extending this work to other channels, and we eagerly await his next structure.

In closing, it is clear that Clay, Bertil and Rod's fundamental insights into these key molecules will become ever more important in understanding and conquering human disease.