Christopher Miller has an uncanny ability to find things he isn't looking for.
From a dull high school physics teacher he discovered a love of science. As a graduate student setting out to validate his mentor's unconventional views, he submitted a Ph.D. thesis supporting the prevailing paradigm about cell membranes. And as an independent scientist, he keeps coming across new proteins while searching for others.
Following the unexpected has served Miller well. For the past 30 years, Miller has been lucky enough to pursue research that still engages him. He investigates how ions, or charged atoms, move across membranes that surround cells. Ionic motion forms the basis of many of life's processes, including nerve impulse generation, muscle contraction, hormone regulation, and blood pressure control.
Miller examines at the molecular level how certain proteins in cell membranes, called ion channels, select particular ions for entry or exit and how the channels create ionic currents, the basis of cellular electricity. Ions are water-soluble and so need watery protein pores to pass through the cell membrane, a fatty, nonaqueous substance.
While many biologists research channels in cells to understand their physiologic function, Miller, a biophysicist, prefers a simpler approach. He developed a method of isolating ion channels from cells and placing them in defined, artificial membrane systems to study their intrinsic properties. "I love these proteins not for what they do, but for what they are," said Miller.
A passion for research and quantitative analyses of the natural world began for Miller in high school because of the Cold War. His high school physics teacher was a "droner." But the new, resolutely hands-on physics curriculum, which had been introduced in the 1960s into American schools after Sputnik, captured Miller's imagination. He majored in physics at Swarthmore College.
As a senior, a biophysics course offered him weekly visits to scientists in the Philadelphia area. At one session, he met his future mentor, Gilbert Ling. Ling's radical ideas challenging the very existence of cell membranes appealed to Miller in that authority-questioning milieu of the '60s. With time, though, Miller's graduate research in muscle physiology convinced him that Ling's ideas were wrong. Ling felt betrayed by Miller's "defection," yet allowed him to obtain his Ph.D., which a departmental committee without Ling approved. While such an experience might have soured others for science, Miller recalls his grad-school years as an enlivening time that produced a healthy distrust of personal attachment to theories.
As a postdoctoral fellow, he would have to employ that skepticism toward his own findings. Miller had sought out his new adviser Ephraim Racker because he had developed a method to study membrane-bound enzymes separately in artificial membranes called liposomes. Liposomes are microscopic spherical shells composed of a fatty outer layer with an aqueous center.
Miller, though, was interested in employing another synthetic membrane system, called a planar lipid bilayer, to study membrane proteins, and, one day, ion channels. A planar lipid bilayer places a flat membrane in a tiny hole situated in a plastic partition between two aqueous solutions. Electrical current is detected whenever an ion-conducting protein is incorporated into the bilayer.
Miller became excited by ion channels in the late 1970s because a new technique called the patch-clamp method enabled scientists to study the electrophysiology of these proteins—one at a time—in nerve cells. The patch-clamp method, which won its inventors the 1991 Nobel Prize in Physiology or Medicine, employs a thin glass pipette drawn out to an open tip that seals to a tiny area of the cell membrane. It allows measurement of current through single ion channels in many cell types.
Miller hoped ultimately to use the bilayer technique as an alternative to the patch clamp to study single ion channels, but removed from the cell's complexity. His first task in Racker's laboratory, however, was to study a calcium ATPase "pump" protein from rabbit muscle. Pumps, unlike channels, require energy to move ions, and this calcium ATPase pump had been long known to be a key component controlling the triggering of muscle contraction. Instead, Miller found a potassium channel.
Concerned that he had discovered an artifact, he decided to use his system to isolate a familiar protein: the acetylcholine receptor channel. This was a well-characterized channel in the Torpedo ray electroplax organ, which the fish employs to electrocute its dinner. This time, though, Miller found a chloride ion channel, the first ever characterized. Chloride channels are now known to reside in almost every cell in the body.
For the past three decades, Miller has elucidated numerous facets of potassium and chloride channel behavior. He also has mentored many students, including Roderick MacKinnon (now an HHMI investigator), who won the 2003 Nobel in Chemistry for later work on potassium channels.
These days, chloride channels are the main focus of Miller's research. Although early work viewed all these proteins as channels, Miller recently demonstrated, to his complete surprise, that this molecular family contains chloride pumps as well. Additional research has revealed the human genome has nine such genes: five code for pumps, and four for channels. They all regulate the amount of chloride in the cell, but pumps use energy to do so.
Miller is hot on the trail to determine what distinguishes the chloride pumps from the channels, given their structural similarity. Given his track record, who knows where the research will lead him?