This year's Nobel Prize in Chemistry highlights how nature solved two complementary problems presented by the cell membrane. First, how does a cell let one type of ion through the lipid to the exclusion of others, and second, how does it permeate water without ions? These problems were attacked from the ground up, requiring a thorough understanding of physiology and biophysics. Both Rod MacKinnon of Rockefeller University and Peter Agre of Johns Hopkins School of Medicine were MDs who decided after their residencies that their hearts were in the basic sciences, and both focused their efforts like laser beams on their respective interests. Their discoveries have broad significance in biology and medicine. For life, some assembly is required. Primordial self-replication required concentration of molecular components, either on a surface or within a volume. In a sea of water and ions, the phospholipid bilayer was an effective self-assembling container, separating the organizing activity inside and stealing energy from its chaotic surroundings. But anyone who has spent time in a sealed plastic bag knows that it is not a viable environment; organization requires bringing in parts and discarding the useless and spent. Nature had only two potential solutions to exchange molecules without dilution: it either had to depend on uncharged, lipid-soluble, or lipid-enclosed molecules for its building blocks and castoffs, or it had to make gateways directly across the cell membrane. Given the sea's concentration of water (55 M), water's polar nature, and thus highly effective solubilization of Na+, Cl−, SO4−, Mg2+, Ca2+, and K+, there was never any real choice. Gateways were easier and faster than lipid vesicle exchange, and proteins provided the hydrophobic interfaces that enabled them to directly bridge the bilayer. Proteinaceous gateways are called channels, and channels selective for water or ions are ubiquitous in life. Moving ions from high dielectric water into a lipid bilayer requires a lot of energy, ranging from ∼60 kcal/mol for K+ to ∼330 kcal/mol for Ca2+. Water is not as difficult, although the ease depends on lipid fluidity and packing between lipids. Water activation energies range around 20 kcal/mol. Water and K+ channels lower these energies to ∼1/4 of their respective values and are at the same time selective. Remarkably, a K+ channel excludes other ions, even its alkali sibling, Na+, by a factor of >1000. Water channels block the nimble proton from tunneling through a column of water. Both accomplish this at rates bordering on free diffusion; K+ ions flow across cells at rates of 106–108 sec/channel, while water can flow at rates as high as 109 sec/channel. These channels cannot remain open holes—they must also be opened and closed (gated) by either stimuli or cellular control mechanisms. It is for a deep understanding of how proteins manage these feats that the Nobel Prize in Chemistry was awarded to MacKinnon and Agre. Standing on a 4-foot pipe, 100 feet above the tundra, young Rod MacKinnon must have wondered what it was like to be riding along an oil drop inside that pipe. Twenty-five years after that summer job working on the Alaskan pipeline, MacKinnon turned that problem inside out by finding out how ions go through a lipid pipe in the cell membrane. By this time he was working in much smaller dimensions, about 10−10 times smaller. Up to a third of the energy production of a cell is put to work in slowly pumping Na+ out of the cell and K+ into the cell via Na+-K+ ATPase transporters. Mammalian cells end up with roughly 140 mM K+, 30 mM Cl−, and 5–10 mM Na+ inside, and 140 mM Na+, 110 mM Cl−, and 4 mM K+ outside the cell. Ca2+ is even more actively excluded from the cytoplasm, resting at levels of ∼100 nM, ∼20,000 fold lower than its 2 mM extracellular concentration. Active separation of ions turns cells into batteries. Cells put this energy stored as separated charges to work, enabling them to sense and respond to external stimuli. By switching channels open and closed, the potential across the cell can be rapidly changed. Humans learned this trick of electrical switching a few billion years later, and put it to similar use, such as in sensing and responding to Cell editor emails. In the early 1950s, Alan Hodgkin and Andrew F. Huxley used K.S. Cole's method to clamp the cell voltage and measure the resulting current that flowed across the membrane. They proposed the sodium hypothesis, envisioning that individual channels in the cell membrane permeated Na+ ions while excluding K+ (Hodgkin and Huxley 1952aHodgkin A.L Huxley A.F The components of membrane conductance in the giant axon of Loligo.J. Physiol. 1952; 116 (a): 473-496PubMed Google Scholar, Hodgkin and Huxley 1952bHodgkin A.L Huxley A.F Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo.J. Physiol. 1952; 116 (b): 449-472PubMed Google Scholar, Hodgkin and Huxley 1952cHodgkin A.L Huxley A.F A quantitative description of membrane current and its application to conduction and excitation in nerve.J. Physiol. 1952; 117 (c): 500-544PubMed Google Scholar). Great advances were made by a generation of biophysicists that established the basic principles of channels such as selectivity, gating, and modulation (see Hille 2001Hille B Ion Channels of Excitable Membranes. 3rd ed. Sinauer Associates, Sunderland, MA2001Google Scholar). Two revolutions, the widespread application of molecular biology to identify genes and proteins and the use of Erwin Neher and Bert Sakmann's patch clamp technique (Hamill et al. 1981Hamill O.P Marty A Neher E Sakmann B Sigworth F.J Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.Pflugers Archiv - European J. Physiol. 1981; 391: 85-100Crossref PubMed Scopus (14897) Google Scholar, Neher and Sakmann 1976Neher E Sakmann B Single-channel currents recorded from membrane of denervated frog muscle fibres.Nature. 1976; 260: 799-802Crossref PubMed Scopus (1436) Google Scholar), allowed the next generation of scientists to identify and characterize hundreds of ion channels in cells of every type. An older but desperately needed technique for understanding ion channels was X-ray crystallography. But structural biology was making slow inroads into this field due to the difficulties of isolating and crystallizing multisubunit membrane proteins. Also, most X-ray crystallographers had their hands full playing with the thousands of other proteins being discovered. Brandeis assistant professor Chris Miller was purifying proteins and putting them into lipid bilayers for biophysical studies on channel permeation and block. The first undergraduate student to work in his lab was Rod MacKinnon. As an inspiration to undergraduates everywhere, Chris Miller tells the story of how he asked Rod to measure the pH of a solution and then left him to go into his adjacent office. After about 45 min he realized that “things were awfully quiet” and went to investigate. He found Rod “kind of frozen,” simply staring at a broken pH electrode; “Rod was stunned about breaking what he thought was a very expensive piece of equipment.” Miller told him, “No problem, just get another one from stores,” meaning the Brandeis stockroom, and left again to “think great biophysical thoughts.” Unaware of the stockroom, Rod spent the rest of the day going to department and hardware stores asking bewildered store clerks if they had any pH electrodes. (None did, and to this day, Chris Miller uses the same broken pH electrode in his work.) After an internal medicine residency in the mid-1980s, MacKinnon returned to his old undergraduate mentor at Brandeis (see photo, Figure 1) . There he thrived in the unique atmosphere of the Miller lab that is a mixture of basic biophysical inquiry and iconoclastic fun. Proceeding along the techniques in the lab, he used toxins as molecular rulers and mutagenesis of K+ channels to estimate the size of the extracellular vestibule leading into the pore. MacKinnon found a job as an Assistant Professor at nearby Harvard Medical School, and on his own and in collaboration with another Miller-ite, Gary Yellen, made numerous contributions to the understanding of K+ channel selectivity, toxin binding, and gating. But mutagenesis combined with electrophysiology could only take him up to the threshold of the selectivity filter; he could not look directly at the all-important interactions between the amino acids lining the pore and permeating ions without high-resolution structural data. This is the point at which MacKinnon made a remarkable move; the electrophysiologist mutated into a structural biologist. Moving to Rockefeller University allowed MacKinnon to devote all his time to research, and an appointment in the Howard Hughes Medical Institute gave him the resources to pursue full time crystallography. But with the move, only one graduate student reluctantly agreed to cast his lot in this highly risky proposition. Alice, MacKinnon's wife and a chemist, “felt sorry for him” and also joined the laboratory. Working harder than he had ever worked before, he dove into crystallizing his own proteins, with Brian Chait at Rockefeller joining in the collaboration to help with protein characterization. But purification and crystallization of membrane proteins was significantly more difficult than soluble cytoplasmic domains on which he had “practiced” (Morais-Cabral et al. 1998Morais-Cabral J.H Lee A Cohen S.L Chait B.T Li M Mackinnon R Crystal structure and functional analysis of the HERG potassium channel N terminus a eukaryotic PAS domain.Cell. 1998; 95: 649-655Abstract Full Text Full Text PDF PubMed Google Scholar). Nature grudgingly provided him with bacterial ion channels that functioned in much the same way as the eukaryotic proteins he had come to understand in depth. Over the next five years MacKinnon and colleagues crystallized several bacterial K+ channels, attacking selectivity, gating, and assembly questions (Doyle et al. 1998Doyle D.A Morais Cabral J Pfuetzner R.A Kuo A Gulbis J.M Cohen S.L Chait B.T MacKinnon R The structure of the potassium channel Molecular basis of K+ conduction and selectivity.Science. 1998; 280: 69-77Crossref PubMed Scopus (5468) Google Scholar, Gulbis et al. 1999Gulbis J.M Mann S MacKinnon R Structure of a voltage-dependent K+ channel beta subunit.Cell. 1999; 97: 943-952Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, Gulbis et al. 2000Gulbis J.M Zhou M Mann S MacKinnon R Structure of the cytoplasmic beta subunit-T1 assembly of voltage-dependent K+ channels.Science. 2000; 289: 123-127Crossref PubMed Scopus (279) Google Scholar, Jiang et al. 2002aJiang Y Lee A Chen J Cadene M Chait B.T MacKinnon R Crystal structure and mechanism of a calcium-gated potassium channel.Nature. 2002; 417 (a): 515-522Crossref PubMed Scopus (1172) Google Scholar, Jiang et al. 2002bJiang Y Lee A Chen J Cadene M Chait B.T MacKinnon R The open pore conformation of potassium channels.Nature. 2002; 417 (b): 523-526Crossref PubMed Scopus (1043) Google Scholar, Jiang and MacKinnon 2000Jiang Y MacKinnon R The barium site in a potassium channel by X-ray crystallography.J. Gen. Physiol. 2000; 115: 269-272Crossref PubMed Scopus (164) Google Scholar, Morais-Cabral et al. 2001Morais-Cabral J.H Zhou Y MacKinnon R Energetic optimization of ion conduction rate by the K+ selectivity filter.Nature. 2001; 414: 37-42Crossref PubMed Scopus (634) Google Scholar, Roux and MacKinnon 1999Roux B MacKinnon R The cavity and pore helices in the KcsA K+ channel electrostatic stabilization of monovalent cations.Science. 1999; 285: 100-102Crossref PubMed Scopus (382) Google Scholar, Zhou et al. 2001aZhou M Morais-Cabral J.H Mann S MacKinnon R Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.Nature. 2001; 411 (a): 657-661Crossref PubMed Scopus (474) Google Scholar, Zhou et al. 2001bZhou Y Morais-Cabral J.H Kaufman A MacKinnon R Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.Nature. 2001; 414 (b): 43-48Crossref PubMed Scopus (1609) Google Scholar). Along the way, he solved the fundamentally different structure of the bacterial Cl− putative channel (Dutzler et al. 2002Dutzler R Campbell E.B Cadene M Chait B.T MacKinnon R X-ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity.Nature. 2002; 415: 287-294Crossref PubMed Scopus (1300) Google Scholar, Dutzler et al. 2003Dutzler R Campbell E.B MacKinnon R Gating the selectivity filter in ClC chloride channels.Science. 2003; 300: 108-112Crossref PubMed Scopus (632) Google Scholar). The hardest of all was the 6TM voltage-gated K+ channel that MacKinnon had set his sights on from the beginning. This was accomplished in 2003 after a 6 year effort (Jiang et al. 2003Jiang Y Lee A Chen J Ruta V Cadene M Chait B.T MacKinnon R X-ray structure of a voltage-dependent K+ channel.Nature. 2003; 423: 33-41Crossref PubMed Scopus (1587) Google Scholar). Here, I will only summarize the major points of what the crystals provided on selectivity and voltage gating. MacKinnon's first major achievement was the structure of a bacterial two transmembrane-spanning (2TM) K+ channel (KcsA), first at 3.2 Å (Doyle et al. 1998Doyle D.A Morais Cabral J Pfuetzner R.A Kuo A Gulbis J.M Cohen S.L Chait B.T MacKinnon R The structure of the potassium channel Molecular basis of K+ conduction and selectivity.Science. 1998; 280: 69-77Crossref PubMed Scopus (5468) Google Scholar) and then at 2 Å resolution (Zhou et al. 2001bZhou Y Morais-Cabral J.H Kaufman A MacKinnon R Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.Nature. 2001; 414 (b): 43-48Crossref PubMed Scopus (1609) Google Scholar). The KcsA channel is a tetramer of two transmembrane-spanning α helices resembling a funnel (Figure 2) . To see how the structural features enable function, imagine you are a K+ ion darting randomly about the cytoplasm at 1 Å/pS. Here, your nearest ion neighbors are about 150 body lengths from your rather rotund shape. Two or three annoying water molecules are constantly flitting on and off your shoulders. In your random walk, you near the inner mouth of KcsA, where negatively charged amino acids attract a small crowd of fellow cations, like shoppers waiting for a department store sale opening. As the outer door formed by the base of the four S2 helices open, electrodiffusion pushes you into a 10 Å wide anteroom with 60–100 water chaperones to help minimize your electric personality. Your charged nature is further dampened by the electric field emanating from 8 helical dipoles 8 Å above you. There you wait for the gate to the elevator to open and allow you up and out of the cell. When the elevator gates open, you find that you are given very special treatment over the lowly Na+ ions. The carbonyl backbone oxygens lining the 12 Å long elevator shaft push the waters off your shoulders and lock you in their electrostatic grasp over a nanosecond. Your less portly Na+ siblings can't shed their waters, and diffuse away. Now you are in a queue, knocked forward by the unruly K+ ions behind you, all being pushed forward by a teravolt/cm field up the 12 Å shaft. You are handed from oxygen to oxygen 3–4 more times before you emerge and are joined by those pesky waters in your random walk. Your little excursion across the membrane took only a little longer than free diffusion, less than a microsecond. Gating of ion channels was next on the menu for MacKinnon and colleagues. By crystallizing channels that appear to be in open and closed configurations, they speculated that the base of the funnel could close by approximation of the cytoplasmic ends of the 4 S2 helices, one from each subunit. The pore lining helices are kinked by glycines halfway down their length, perhaps improving the seal of the gate. The voltage-gated 6TM channels were a holy grail; the mammalian channels had been studied in great detail by biophysicists with a mutagenic bent. Bacterial 6TM K+ channels have the architecture of voltage-gated K+ channels, but so far are functionally inactive when expressed in mammalian cells accessible to measurement. However, one functionally expressing 6TM voltage-gated Na+-selective bacterial channel, NaChBac, indicates that bacterial channels work essentially the same way (Ren et al. 2001Ren D Navarro B Xu H Yue L Shi Q Clapham D.E A prokaryotic voltage-gated sodium channel.Science. 2001; 294: 2372-2375Crossref PubMed Scopus (357) Google Scholar). 6TM channels have two “domains,” one (S1–S4) containing the S4 voltage sensor and a second (S5–S6) containing the 2TM pore and gate. Flexibility around the S4–S5 linker appears to make the whole protein difficult to crystallize. Although MacKinnon had crystallized the separate S1–S4 and the S5–S6 domains early on, the whole molecule had to be stabilized to achieve orderly crystals that diffracted to high resolution. Using Fab fragments of antibodies raised to the cytoplasmic facing S1–S4 segment, he was able to obtain this crystal structure. MacKinnon's structure showed that the S3 helix split, with its distal portion (S3b) forming a hairpin loop with S4 (Jiang et al. 2003Jiang Y Lee A Chen J Ruta V Cadene M Chait B.T MacKinnon R X-ray structure of a voltage-dependent K+ channel.Nature. 2003; 423: 33-41Crossref PubMed Scopus (1587) Google Scholar). MacKinnon proposed that the S3b–S4 “paddle” moves entirely through the bilayer, in turn pulling on the S5 helix to open the gate, upon depolarization. The location and movement of this paddle is the hottest area of debate in channel biophysics. Since crystals are static structures, more images and correlated studies will be needed to fully understand voltage gating. Growing up surrounded by Minnesota's 10,000 lakes of water, Peter Agre eventually became obsessed with how water gets in and out of cells (see photo, Figure 3) . Like MacKinnon, Agre put substantial time into training as a physician. After an education in chemistry at Augsburg College where his father was a professor, he obtained his MD at Johns Hopkins and did residency training at Case Western. Eventually he returned to Hopkins and worked with Vann Bennett on the role of spectrin in hereditary spherocytosis, a disorder of red blood cells. Based on a suggestion from Wendell Rosse (Hematology, Duke University School of Medicine) that the Rh antigen was an overlooked area, and encouraged by Bennett, Agre began to study this protein complex. With his colleagues, Agre purifed a ∼28 kDa polypeptide linked to the cytoskeleton within the Rh complex (Agre et al. 1987Agre P Saboori A.M Asimos A Smith B.L Purification and partial characterization of the Mr 30,000 integral membrane protein associated with the erythrocyte Rh(D) antigen.J. Biol. Chem. 1987; 262: 17497-17503Abstract Full Text PDF PubMed Google Scholar). Based upon its insolubility in the detergent, N-lauroylsarcosine, a simple purification system yielded large amounts of the protein. The 28 kDa protein (CHIP28) was abundant in red cells and renal proximal tubules (Denker et al. 1988Denker B.M Smith B.L Kuhajda F.P Agre P Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules.J. Biol. Chem. 1988; 263: 15634-15642Abstract Full Text PDF PubMed Google Scholar). Moreover, the 28 kDa protein behaved as a tetrameric integral membrane protein, another clue that it might be a transmembrane channel. Using the N-terminal sequence of the polypeptide, Agre and colleagues identified the CHIP28 cDNA from an erythroid cDNA library encoding a 269 amino acid protein (Preston and Agre 1991Preston G.M Agre P Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons member of an ancient channel family.Proc. Natl. Acad. Sci. USA. 1991; 88: 11110-11114Crossref PubMed Scopus (685) Google Scholar). The genetic database showed that the clone had homologs from prokaryotes to plants. When expressed in Xenopus laevis oocytes, the oocytes dramatically swelled when transferred to hypotonic buffer, and exploded in distilled water (Preston et al. 1992Preston G.M Carroll T.P Guggino W.B Agre P Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein.Science. 1992; 256: 385-387Crossref PubMed Scopus (1526) Google Scholar). The ooctye's swelling could be dramatically reduced by mercury-containing compounds. These facts riveted the attention of renal physiologists, since water is moved in large amounts in the kidney and mercurials had long been known to block water reabsorption. In fact, the physician/alchemist, Auroleus Phillipus Theostratus Bombastus von Hohenheim (aka Paracelsus) knew that mercurous chloride was an effective diuretic for treating edema in the 1500s (another dabbler in alchemy, Isaac Newton, may have taken too much!). Mercury turned out to be a useful tool in recognizing that the protein was a water channel. The oocyte explosion caused by the water channel, now called aquaporin-1, was the major turning point in Agre's scientific career. Agre and colleagues recognized that the aquaporin primary structure looked like an ion channel. They deduced that, in contrast to the one pore loop of K+ channels, aquaporins had two pore loops per 6TM subunit. Aquaporin permeability to water (109 H20/subunit/sec) and its exclusion of other molecules was confirmed by reconstituting purified protein into liposomes. By mutagenesis, organic mercurials were found to block water channels at a cysteine just proximal to the signature asparagine-proline-alanine (NPA) site in the pore loops of aquaporins aquaporins. This laid to rest any doubt that the aquaporin molecule itself was the water channel. Urea, glycerol, and even the tiny proton did not detectably permeate the channel (Zeidel et al. 1992Zeidel M.L Ambudkar S.V Smith B.L Agre P Reconstitution of functional water channels in liposomes containing purified red cell CHIP28 protein.Biochemistry. 1992; 31: 7436-7440Crossref PubMed Scopus (488) Google Scholar, Zeidel et al. 1994Zeidel M.L Nielsen S Smith B.L Ambudkar S.V Maunsbach A.B Agre P Ultrastructure, pharmacologic inhibition, and transport selectivity of aquaporin channel-forming integral protein in proteoliposomes.Biochemistry. 1994; 33: 1606-1615Crossref PubMed Scopus (170) Google Scholar). Using electron diffraction, Agre, Andreas Engel, and Yoshinori Fujiyoshi and their colleagues solved the structure of the human red blood cell aquaporin-1 channel to 3.8 Å resolution (Figure 4A; Murata et al. 2000Murata K Mitsuoka K Hirai T Walz T Agre P Heymann J.B Engel A Fujiyoshi Y Structural determinants of water permeation through aquaporin-1.Nature. 2000; 407: 599-605Crossref PubMed Scopus (1320) Google Scholar). In the middle of the pore, a cysteine's free sulfhydryl projects into the pore, providing the site where mercury binds and blocks water flow. Simultaneously, Stroud and colleagues solved the bacterial aquaporin GlpF structure to 2.1 Å resolution, enabling them to determine that the aquaporin pore is a 4 Å × 28 Å cylinder filled by a single column of water molecules (Fu et al. 2000Fu D Libson A Miercke L.J Weitzman C Nollert P Krucinski J Stroud R.M Structure of a glycerol-conducting channel and the basis for its selectivity.Science. 2000; 290: 481-486Crossref PubMed Scopus (835) Google Scholar). So what keeps ions out of its pore? Unlike the K+ channel's carbonyl oxygens that replace the K+ ion's waters of hydration, the water channel has three hydrophobic sides throughout most of its length. Aquaporin's ion dehydration energy barrier is too high for ions like K+ and Na+. But the most interesting point about aquaporin is its exclusion of protons. Free water readily enters the aquaporin channel and is stacked in a column from one end to the other. Much work on the unrelated bacterial gramicidin A channel had shown that it also sustains a column of water, but one that moves in a single file hydrogen-bonded chain, each water holding hands with the next (H of one water bonds with O of the adjacent water; Pomes and Roux 2002Pomes R Roux B Molecular mechanism of H+ conduction in the single-file water chain of the gramicidin channel.Biophys. J. 2002; 82: 2304-2316Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). In the gramicidin channel, protons (H+) can “move” faster than diffusion, effectively tunneling down a column of water molecules by inducing a cascade of hydrogen bond rearrangements like falling dominoes (hop-and-turn, or Grotthuss mechanism). This mechanism results in a remarkably fast relay of H+ and is called a proton wire. So why isn't aquaporin also a proton wire? Remember that the K+ channel 4 helical dipoles project their negative electrostatic fields into the cavity below the selectivity filter to stabilize K+. Aquaporin's two half helices (Figure 4B) are oriented in the opposite direction, projecting a positive electrostatic field onto a central water and constraining it. In addition, amido hydrogens from each of the asparagines tipping the half helices force the central water to be a hydrogen bond donor to its upstairs and downstairs H2O neighbors. Finally, the hydrophobic IFLV on the other side of the pore at this depth provides no alternative hydrogen bonds, isolating the water's own H bonds. The water molecules are forced to orient in opposite orientations in the two halves of the channel (de Groot and Grubmuller 2001de Groot B.L Grubmuller H Water permeation across biological membranes Mechanism and dynamics of aquaporin-1 and GlpF.Science. 2001; 294: 2353-2357Crossref PubMed Scopus (770) Google Scholar, Tajkhorshid et al. 2002Tajkhorshid E Nollert P Jensen M.O Miercke L.J O'Connell J Stroud R.M Schulten K Control of the selectivity of the aquaporin water channel family by global orientational tuning.Science. 2002; 296: 525-530Crossref PubMed Scopus (718) Google Scholar). Molecular dynamic simulations (www.nobel.se/chemistry/laureates/2003/animations.html) show that this prevents the central water molecule from reorienting to passage protons (Figure 4C). The hydrogen relay trick does not work because the proton wire is broken in the middle. One open question is the relative significance of the asparagines versus the helical dipole fields in constraining the central water, a question that might readily be resolved by mutagenesis of the key asparagines and examining proton/H2O transport of the mutant aquaporin. In KcsA, a sequence of 3–4 energy barriers must be crossed, consuming ∼10–15 kcal/mol. For aquaporin-1, only one 3 kcal hydrogen bond is broken, in agreement with the measured ∼3 kcal/mol activation energy (Zeidel et al. 1992Zeidel M.L Ambudkar S.V Smith B.L Agre P Reconstitution of functional water channels in liposomes containing purified red cell CHIP28 protein.Biochemistry. 1992; 31: 7436-7440Crossref PubMed Scopus (488) Google Scholar). The combination of high water concentration (55 M), low energy barrier, and doubled pore construction allows aquaporins to permeate water 10–100 times faster/protein than ion channels permeate ions. It is not surprising that water is constantly moving about between tissues in our waterlogged bodies. Ten aquaporin genes in mammals encode channels in kidney collecting ducts, lens, eye, brain, secretory glands, lung, and many other tissues. Various dysfunctions of these proteins may be involved in early onset cataracts, diabetes insipidus, Sjögren's syndrome, cystic fibrosis, and diarrheal diseases. The widely distributed aquaglyceroporins (AQP3, 7, 9) permeate water, glycerol, and other small uncharged solutes. Those present in hepatocytes and adipocytes may permeate glycerol during fasting. Irony and symmetry are nicely evident in the 2003 Nobel Prize. Two physicians won the Chemistry award. Their studies show us how ion channels provide surrogate waters for ions, and water channels provide surrogate hydrogens for water. I thank Rod MacKinnon, Chris Miller, Peter Agre, and Bob Stroud for valuable discussion, Robin Miller for Figure 1, Bertil Hille for Figure 2, and Andreas Engel for Figure 4B.