Aquaporin Water Channels: From Atomic Structure to Malaria
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Lindau Nobel Laureate Meetings272 / 340
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NobeliumChemistryChemistryWaterLecture/Conference
00:33
Ion channelOrlistatNobeliumHydroxybuttersäure <gamma->NobeliumWaterMoleculeWine tasting descriptorsBody weightAqueous solutionProtein biosynthesisSystemic therapyConcentrateNeotenyCell (biology)Lecture/Conference
01:07
Ion channelNobeliumMortality rateNeotenyLecture/Conference
01:32
NeotenyDyeingMagnesium hydroxideTopicityToxinPolymorphism (biology)Adenomatous polyposis coliGolgi apparatusMeeting/InterviewLecture/Conference
02:21
NobeliumCloningExtracellularPeptideHomologisierungFunctional groupTopicityAntigenProteinRadiation damageRed blood cellChemical plantGrade retentionMoleculeGeneHomologisierungMedicalizationReaktionsgleichungPeptide sequenceLipid bilayerProtein domainBiomolecular structureDiamantähnlicher KohlenstoffFumigationStimulus (physiology)Base (chemistry)Computer animationLecture/Conference
04:09
NobeliumBarrel (unit)FumigationData conversionProteinLecture/Conference
04:50
NobeliumData conversionProteinChemical plantDeterrence (legal)Ion channelMoleculeRed blood cellLecture/Conference
05:13
Cell membraneAquaporinIon channelNobeliumCell (biology)OsmosisBattery (electricity)Enzyme inhibitorFunctional groupSodium thiosulfateOcean currentSpeciesPhysiologyProtonationRNACell membraneWaterOsmosisChemistryThiolgruppeTransportBuffer solutionGezeitenküsteStop codonController (control theory)Nuclear porePondData conversionRed blood cellAquaporinQuecksilberchlorid <Quecksilber(II)-chlorid>Activation energyIon transporterFresh waterThermoformingTandem-ReaktionDeterrence (legal)Chemical plantExplosionProteinHomologisierungAreaSulfideHydro TasmaniaElektronentransferChemical structureFunctional groupMercury (element)SecretionAqua destillataActive siteCell (biology)Fatty acid methyl esterWursthülleFoodLaundry detergentMetabolic pathwayComputer animation
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ChemistryChemical structureCrystallographyCell membraneChemical structureThermoformingFatty acid methyl esterElektronentransferCell membraneFunctional groupWaterCrystallographyMemory-EffektProtein subunitMoleculeMolecular geometryMeeting/Interview
09:29
Chemical structureCell membraneCrystallographyChemistryCrystallographyMolecular geometryMoleculeCell membraneWaterSurface scienceChemical structureProtein subunitProtonationCross section (geometry)
10:09
NobeliumExtracellularElektrostatische WechselwirkungRestriction enzymeProtonationCross section (geometry)ChemistryWaterChemical structureExtracellularIon channelAquaporinBulk modulusResidue (chemistry)HydrogenProtein domainHydrogen bondMoleculeGemstoneDrainage basinThermoformingLibrary (computing)SolutionCell membraneMedical historyComputer animation
11:24
Active siteChemical structureEnzyme inhibitorNobeliumAquaporinAgeingCysteineAquaporinWaterFunctional groupMercury (element)GlycerinIon channelOrganische ChemiePhysiologyTransportSpeciesPathophysiologieChemical plantPilot experimentHematiteHomeopathyAngiotensin-converting enzymeMetabolic pathwayGemstoneResidue (chemistry)Infiltrationsanästhesie
12:57
HematiteAquaporinSekretionsvesikelCell (biology)Cell membraneMauveineOptical coherence tomographyFiltrationGenregulationPermeationChemistryWaterStratotypProteinAtomic orbitalActivity (UML)PhysiologyAreaComputer animation
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Cell (biology)ThylakoidCell membraneNobeliumConstitutive equationChemistryAntigenFunctional groupSurface scienceLocus (genetics)ChromosomeModifikation <Kristallographie>ThylakoidCell membraneModifikation <Kristallographie>Antibodies (film)FiltrationAntigenGenotypeDehydration reactionSeawaterGeneKlinische ChemiePathophysiologieCell (biology)Cross section (geometry)HematiteSurface sciencePermeationFunctional groupWaterProteinNanoparticleBiomolecular structureConcentratePhysiologyMemory-EffektMetabolic pathwayGenomeHydrateCapillary electrophoresisRock (geology)Active siteChain (unit)Computer animation
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Saline waterIon channelDNS-SyntheseHematiteHomologisierungProteinChemical structureOrganische ChemieWaterPharmaceutical drugSaline (medicine)Angelic acidSteam distillationSecretionTube (container)
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GenregulationGene expressionGrade retentionGenotypeSurface scienceCell (biology)Klinische ChemiePharmaceutical drugWaterActive siteGene expressionHematiteGrade retentionSurface waterSea levelFoodSeparator (milk)Blood vesselDehydration reactionOperonSeparation processCommon landAquaporinSekretionsvesikelPermeation
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Congenital disorderGeneGenotypeCongenital disorderComputer animation
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Capillary electrophoresisCell (biology)Base (chemistry)Cell membraneStratotypRadiation damageRiver sourceCapillary electrophoresisCell membraneTrauma (medicine)Separation processPerm (hairstyle)InfiltrationsanästhesieLead
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Metabolic pathwayList of causes of death by rateRiver sourceInfarktTrauma (medicine)Enzyme inhibitorGenotypeAnomalie <Medizin>Cell fusion
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TumorHeadacheWaterNobeliumDensityTrauma (medicine)ZellenradschleuseAcetoneCancer
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Cell membraneSetzen <Verfahrenstechnik>ChemistryPerspirationMarlPilocarpineWaterCell membranePerspirationPlant breedingSetzen <Verfahrenstechnik>Pilot experimentMedical historySurvival skillsIodineFunctional groupStarchDeathStress (mechanics)Human body temperature
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Nuclear poreGene expressionWoundAlanineLamb and muttonTransportGlycerinLysineMoleculeAquaporinResidue (chemistry)Separation processErdrutschNuclear porePhenylalanine
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NobeliumGene expressionMoleculePharmacySauerrahmFrench friesLecture/Conference
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NobeliumNobeliumChemistryAageHydrateNoble gasAgricultureLecture/Conference
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NobeliumCell (biology)AntigenActive siteGlycerinMetabolic pathwayPolymethylvinyletherChemistrySurvival skillsRed blood cellAgeingGlycerinExplosionGolgi apparatusOrganische ChemieCell (biology)Cell divisionParasitismLipideFeverProtein biosynthesisLeadRadiation damageTransportGene clusterSea levelTerrasse <Geologie>Base (chemistry)
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NobeliumMortality rateBase (chemistry)Abundance of the chemical elementsGesundheitsstörungNahtoderfahrungKlinische ChemieStream gaugeCommon landRadiation damageLecture/Conference
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AquaporinSolutionHemoglobinRadiation damageAquaporinTiermodellDeathController (control theory)Blind experimentCollectingRiver
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FarmerGesundheitsstörungStream bedArtemisininInsektengiftWursthülleAreaDeathNobeliumRecreational drug use
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MetabolismAquaporinGlycerinAdipose tissueUreaInsulinCatabolismChemistryArsenicKatalysatorgiftAmmonium dihydrogen phosphateAtom probeMetalTransportGlycerinLactitolSchwermetallFatSunscreenExplosionArsenicElimination reactionChemical plantSetzen <Verfahrenstechnik>Germanic peoplesAgeingButcherStem cellSurface roughnessLecture/Conference
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Chemical plantGesundheitsstörungIon channelAquaporinHomologisierungTiermodellGlycerinNitrateArsenateArsenicHyperthermiaChemical plantThin filmAquaporinStem cellWaterReducing agentErdrutschNobeliumWhitewaterMeeting/Interview
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Columbia RecordsNobeliumNobeliumLactitolIon channelElectronic cigaretteNobelpreis für ChemieKaliumkanalChemistryRiver sourceMeeting/InterviewLecture/Conference
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NobeliumMagmaRiver sourceBeerNecking (engineering)StratotypController (control theory)Lecture/Conference
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NobeliumColumbia RecordsBallistic traumaHope, ArkansasMeeting/Interview
Transcript: English(auto-generated)
00:15
The Lindau week is always my favorite week. Thank you, Countess Bettina, the Lindau Foundation,
00:22
and all the young scientists and my colleagues, the laureates. I'm going to talk about the biology of water. A little departure from chemistry, but probably part of the same realm of interest. Our bodies are primarily water.
00:42
Two-thirds of our body mass is water. It's the most abundant molecule in every tissue of our bodies. It was Albert San Giorgi, the Nobel laureate, who said, water is the solvent of life. But while we're made mostly of water, how does the water percolate within our systems? How can we synthesize cerebral spinal fluid, aqueous humor,
01:04
tears, sweat, saliva, concentrate on urine? It turns out that there is a plumbing system for cells, and that's what I'm going to describe. But I'm going to do so in the context of a discussion of young scientists, because young visitors here probably realize that the creativity that goes into the awards
01:23
that we older scientists are given credit for, the creativity occurred often in the very young parts of our career. So I'll introduce you to some young scientists. The first young scientist I'd like to introduce you is to me. I don't mean to scare you.
01:41
1970, when I left my home of Minnesota, I went to Johns Hopkins with the intention of becoming a global health specialist. But in those studies, things of great surprise appeared. Now, as a medical student working in a laboratory, the first topic we addressed was the problem of infectious diarrhea.
02:02
And I can assure you that if you're studying diarrhea, you can't expect this to enhance your social life. But we made progress. We identified the toxin that caused the E. coli variant of cholera. But we were stuck in terms of explaining how the fluid gets from the bloodstream into the gut mucosa.
02:21
So years later, when I started my own laboratory, it was actually on a different topic. We were studying the biology of the rhesus blood group antigen. I'm a blood specialist. We studied red cells. We identified some new proteins, including a protein which was quite surprising because it didn't stain with the typical stains.
02:41
No one had reported it before. So we cloned it out. And the deduced amino acid sequence had an interesting topology. As you can see, the lipid bilayer is spanned by this protein with three bilayer spanning domains and a repeat three more
03:00
in the opposite orientation. And when we watched the genetics database, there were some homologs already reported. And we thought, this will give us the function of this new molecule. A protein in the lens of eye, protein in the brains of Drosophila, protein in bacteria, and some genes in plant tissues.
03:22
But none of these had been biophysically solved. It was not clear what they did. So we were really stuck. We'd gone to a lot of trouble to purify, to clone, to express a new protein, but we didn't have a clue as to what it did. And this may illustrate an important part of our lives,
03:41
the work-life balance. This is discussed now in graduate schools and medical schools. It really wasn't 50 years ago. But how do you have a productive career as a scientist and at the same time have a family and a private life? And I think this is actually often very important. Now, my wife and I are blessed with four children.
04:02
They're grown now, they're your age. But when they're young, they're very, very cute. And on a basic scientist's salary, which is a relatively low salary, not impoverished at all, but not a big salary, every year we would spend our vacation in a tent.
04:20
We went camping at the national parks. And those who've been to the United States and have visited these parks realize how magnificent they are. We took the kids to Yellowstone, to Yosemite, Smoky Mountain National Parks. It was a wonderful time each year. And Mary, my wife, said, next year, let's ask the children which national park they prefer to go to.
04:41
And they all yelled Disney World. Well, yes, I can tell from your laughter, Disney World is not a national park, but we went to Disney World. And it's a long drive and a long drive back, about 1,500 kilometers. And we stopped in Chapel Hill, North Carolina on the way back.
05:00
And Mary and I had lived there before. We had friends, I had colleagues. And it was a conversation with John Parker at the University of North Carolina where he described this new protein present in red cells, also present in renal tubules, homologs and tissues of plants. But we thought it was a tetrameric, channel-like molecule,
05:21
but we had no clue what the specificity of the channel was. It was really that conversation on the way back from Disney World where it came to light that this might be the long-sought water channel, something physiologists had been searching for for a century to explain how it could have rapid osmosis in some tissues,
05:40
whereas in most tissues, the movement of water is relatively slow. So at John's suggestion, we teamed up with Bill Gugino. And I'll just give a little background. What John explained was that all cell membranes have a finite degree of fluid movement by simple diffusion, into the cell, out of the cell,
06:01
but specialized tissues such as renal tubules, secretory glands, and red cells apparently had high conductivity water channels, very specific for water. Allows water to enter and leave the cells, but it was not permeated by the proton
06:21
in the form of the hydronium ion, and the direction was created by the osmotic gradient. So it wasn't a pump or a transporter, it was a simple pore. Now in 1970, the year I was hitchhiking through Asia on my way to Johns Hopkins, Robert Macy at the University of California did a very interesting experiment.
06:41
He was looking at red cell water permeability, studying the membranes, and he went through the chemical cabinet and he discovered that mercuric chloride could stop water transport in red cell membranes. By washing the membranes free of the mercuric chloride and treating them with chemical reducing agents, he could restore water permeability.
07:00
He could turn it off and turn it on, and he deduced correctly that there must be an aqueous pore with a free sulfhydryl somewhere in the pore. And the measurements of the Arrhenius activation energy indicated that there were two distinct pathways, diffusion in all membranes, water channels in some membranes. So collaborating with Bill Gugino
07:21
in the physiology department at Johns Hopkins, we expressed this protein, we now know this as aquaporin-1, by injecting Xenopus laevis oocytes. Xenopus laevis is a species of amphibia, a frog living in South Africa, and their frog eggs have very low inherent water permeability.
07:43
In the springtime, probably even around now in the alpine areas here, amphibians will lay their eggs in freshwater ponds and they have such low water permeability that they don't swell. So the idea was we would have control oocytes injected with buffer alone,
08:00
test oocytes injected with complementary RNA from the new protein, and if the new protein encodes a water channel when they are transferred to distilled water, the test oocyte should explode. Exactly what happened. And this produced much jubilation in the laboratory. This is Greg Preston, the postdoc,
08:21
son of a carpenter from New Mexico. Very enthusiastic, very organized, and when he did the experiment, he was jubilant. I have to tell you the truth. I took this photograph of Greg three years after our first report was published. He was still celebrating. I think the reward of science is the discovery,
08:40
and then the applications lead to new discoveries. It's like a cascade of events when a new discovery is made. We were interested in the structure of this protein, the aquaporin-1. The famous architect Louis K. Sullivan has remembered for having said, form always follows function.
09:02
So we felt that if we could establish the structure of the protein, we'd have an understanding of how the water transfer occurred. And we teamed up with the laboratories of these two group leaders, Yoshinori Fujiyoshi from Kyoto in Japan, who developed the world's best electron microscope
09:21
for membrane crystallographic studies, and Andreas Engel from the Biocentrum at the University of Basel in Switzerland, an expert in membrane crystallography. And over a few years, we established the molecular structure of the aquaporin-1 molecule. And shown in the left panel from above,
09:42
you see a single subunit of a water channel, and you notice in the center, the aqueous pore, three angstroms in diameter, just big enough for water. And in the right panel, we have the structure when seen in cross-section. So the outer surface of the cell membrane is above,
10:02
the inner surface is below, and there's a single aqueous pore from top to bottom. Now, to move water without protons, there must be a very special structure. Of course, the chemistry of water is fascinating. H2O is predicted to be a gas,
10:21
and an atmosphere of water is a gas. In bulk solution, the hydrogen bonding between these water molecules causes it to form a fluid. So the channel exists of two structures, an extracellular domain and intracellular domain, where water is in bulk solution, separated by a small channel.
10:42
And we term this the hourglass structure. And if you look into this channel, you'll see residues which are shared amongst all members of the aquaporin family, which prevent movement of protons. Here's a fixed positive charge, a partial positive charge. Here's a shared motif where a single water molecule
11:02
is hydrogen bonded to two shared residues and isolated from the column of water for a billionth of a second. Perfect way of having pure water across a membrane. And this is work of David Cosineau, a talented graduate student who was in our laboratory, now a faculty member at Harvard.
11:21
So if you look at a cross-section of the channel at the very center, here with space-filling representation of a single water molecule, notice the tight fit. Here's the arginine, the positive charge, the histine, the partial positive charge. And here's the cysteine.
11:41
Cysteine reacts with mercurials. This is what Macy discovered. And the residue, this fold, as I mentioned, present in all members of the family, expressed in diverse species. Basically, every living organism has one or more aquaporins.
12:02
So the field got very excited. The renal transport physiologists were waiting for this. And together, our group and others cloned out a series of aquaporins for mammalian tissues and non-mammalian tissues, plants, microorganisms. So the repertoire now of all species
12:21
is hundreds of different aquaporin DNAs in the genetic database. But the human repertoire is made up of two subsets, those permeated by water, which we term classical aquaporins, those permeated by water plus glycerol, which we refer to as the aquaglyceroporins. And here's AQP1, our original discovery. And here are several others.
12:41
I'll tell you a little bit about each, the physiology and the pathophysiology. Also in this pileup are the two members of the family from the bacteria E. coli, AQPZ, a water channel, and GLIPF, a glycerol channel. So to establish the localization in kidney, we teamed up with Soren Nielsen
13:02
from the University of Aarhus in Denmark. Soren, at that time, was 29 years old. He just finished his medical and graduate studies and was hungry for a new project. And we've teamed up and worked together for the next 20 years. Soren, trained as Arvid Mansbach, is a superb microscopist.
13:22
And he localized with high resolution the presence of the aquaporin-1 protein in the renal nephron. Now I realize chemistry graduate students don't always learn about renal physiology, so I'll give a little background. An individual nephron has a glomerulus where filtration occurs the primary year and then passes through the proximal tubule
13:42
where water permeation is constitutively active. And this water permeation measurement is a compilation of a series of studies. Then the primary urine makes the bend and enters the ascending thin limb of the liver penalty where there's negligible water permeability and enters the collecting ducts
14:02
where regulated water permeability exists. So our aquaporin-1 protein in the proximal nephron is very abundant. And here's a cross-section of rat kidney. Here's an individual tubule. You notice the lumen is surrounded by a brush border intensely stained with the aquaporin-1 antibody as well as the lateral membranes and the basal membranes.
14:23
So our cartoon for explaining this is that water permeation enters the apical brush border. You can see these gold particles, immuno-gold staining, passes through the interstitium very efficiently. Our kidneys together will filter 200 liters of plasma every day and reabsorb 90%, 99%.
14:42
So moving through a single cell in the brush border epithelium that goes through the surface through aquaporin-1 and out through the outside through aquaporin-1, moving from primary urine back to the vascular space. Now, as a medical doctor, we're very interested in the pathophysiology.
15:01
And we were convinced that there would be inherited mutations which would be of clinical significance. And by localizing the aquaporin-1 gene in the human genome, we saw that it lay close to the coltan blood group antigens, a relatively obscure blood group antigen. And because coltan phenotypes had been defined,
15:23
we sequenced the protein and found a simple polymorphism explaining the difference, coltan A and coltan B. But in the whole world, there are a handful of individuals who have neither A or B. And those individuals had knockout mutations in the gene encoding aquaporin-1. We brought some of them to Johns Hopkins
15:41
for clinical phenotyping. What we found was that they were very normal. This is shown with permission, a retired school teacher from the south of France, surrounded by my colleagues at Johns Hopkins. And all normal individuals, when they're thirsted at night, will concentrate their urine to about 1,000 milliosmolar. That's the concentration of seawater.
16:00
But these null individuals, quite rare, can only concentrate a little bit, up to about 400 milliosmolar. Enough to get through the night, but clearly if they were thirsted longer than that, they would get into trouble with dehydration. Moreover, the protein is present in the vascular capillary endothelium, where water permeability is very important
16:20
at the time of birth. I'll just skip through this quickly. But this is a CT, high resolution CT, of the distal lung. Here's the bronchial, the air tubule, a surrounding venule. And here are the same structures from a normal individual and infused with physiological saline. Now the venule has become engorged,
16:43
has the wall of the breathing tubule. When we studied aquaporin-1 null individuals, their breathing tubules remained non-edematous, like this. They wouldn't move fluid into and out of the vascular space and lung easily.
17:00
Now at birth, our lungs turned from a secretory organ to an absorptive organ. This may explain the rarity of the phenotype because at birth, moving fluid out of the lungs is essential for that first breath of life. Another member of the family, referred to as aquaporin-2, is in the collecting ducts. And this is very important in clinical medicine.
17:23
Unlike aquaporin-1, which is constitutively present, aquaporin-2 resides in intracellular vesicles at basal state. This is a preparation from rat kidney. But when they issue preparations that are exposed to physiological levels of vasopressin,
17:41
the aquaporin-2 now relocalizes at the apical surface, moving from the intracellular site to the surface so water permeation can enter the cell and leave the cell through other aquaporins. And defects have been identified by Carl Van Oes and his team in Nijmegen. And the children that have mutations in aquaporin-2 have a severe nephrogenic diabetes insipidus.
18:02
They must drink at least 20 liters of water per day to avoid dehydration. And acquired defects are very common in clinical medicine. Overexpression in situations such as congestive heart failure leads to fluid retention. Underexpression in small children causes bed-wetting.
18:21
So you can see this is a very common problem in medicine. Another member of the family, and each of these is a distinct gene, aquaporin-0 studied by Masato Tsui when he was a postdoc. This accounts for congenital defects in the lens of small children who develop cataracts. It's rare for small children to develop cataracts,
18:42
but mutations in the AQP-0 gene have been found in several different families. Another member of the family, AQP-4, is expressed in a number of tissues, including brain. Now our capillaries in brain are very carefully managed because our cranium is fixed. If we should sustain a head injury,
19:02
the cranium could protect, but if it's a severe injury and brain damage occurs, swelling of some tissue will compress adjacent tissue, leading to permanent brain damage. And the localization of AQP-4 at the perivascular membrane in brain explains that. Now in a classic study undertaken by our colleagues
19:20
in Norway, led by Ole Petter Oderson, including his then-student, Mahmoud Amiri, a very talented young Iranian-born scientist whose scientific career began in a refugee camp in Pakistan. He was adopted by Norwegian social services, given an opportunity to obtain education,
19:42
and is now a leading European neuroscientist. And what Mahmoud discovered is that normal mice, when experiencing a defining brain injury, middle cerebral artery occlusion, reperfusion, the normal mice will sustain significant brain infarct and edema. Mutant mice, and the mutations can be
20:01
in a variety of molecules, including the AQP-4, are protected against the brain edema. The mutant mice suffer congenital seizures, so it's not a preferred phenotype, but it indicates if we could synthesize inhibitors to AQP-4, we would have a method for preventing and treating brain edema. And brain edema is often the final pathway
20:22
of the demise of patients who undergo head injury and stroke, stroke being the third leading cause of death in Western Europe and in the United States. Brain tumors also are accompanied by a lot of edema. This is an individual, otherwise healthy, developed headaches, and you can see
20:43
a large, non-malignant brain tumor, meningioma in the frontal lobe. This is examined by MRI. MRI is developed by Paul Lauterbur and Peter Mansfield, who shared the Nobel in 2003. But when weighted at the density of water, you see that the brain tumor is surrounded
21:00
by significant edema, and while the tumor can be removed, the edema remains. So this blasted brain edema is a huge clinical problem, and even after removal of the tumor, it took months for this to dissipate. Another member of the family, AQP-5 in secretory glands. The last membrane water crosses during the generation of sweat, saliva, and tears.
21:24
Now, in this very simple study undertaken by our friend Soren Nielsen and his team, he shows a wild-type mouse and an AQP-5 null mouse. And the mouse paws covered with starch and iodine, the animal's injected with pylocarpine,
21:41
so these blue dots represent amylase digesting starch reacting with the iodine, functional sweat glands. The null animal has normal-appearing sweat glands, but they're hypo-functional. Thus, the mouse is vulnerable to thermal stress. In 2003, Western Europe had, at that time,
22:01
the worst heat wave in recorded history, temperatures of about 40 degrees centigrade in Paris, 15,000 unexpected deaths of older individuals. So the ability to sweat made, in fact, the difference between survival and non-survival. Now, briefly, the aquaglyceroporins are very similar to the aquaporins.
22:22
This is a slide I borrowed from Bing Yap from the Lawrence Berkeley Laboratory, where he's aligned the pore-lining residues of the dark shading at aquaporin, the lighter shading at the glycerol transport molecule, and there's some subtle structural differences. Basically, the pore size of the water channel here is different.
22:41
This phenylalanine in the aquaglyceroporin is unrestrained, the small glycine here. So when this opens up, the glycerol pore is much larger. Now, I'd gotten fairly far in my career, had never, for one moment, thought about glycerol transport, but it's very important in maintenance of the integrity of skin.
23:01
And this got large interest from the beauty industry. Several years ago, the executives from the Christian Dior Laboratory wanted to visit me in my lab. Now, I don't know about your laboratories, but we're not often visited by Christian Dior. And I was suspicious that they had a commercial purpose, and they did, they wanted to give us
23:22
some resources for funding. Lots of strings attached, which we declined, but their chemists had identified some small molecules which lead to a subtle increase in the expression of aquaclyceroporin-3 in sun-exposed skin. Now, the beauty industry is not constrained by evidence proof.
23:42
The notion that if you use this very expensive skin cream, you'll look like this, that's for you to believe, maybe. But those of you who read French, this was the back of one of the French beauty magazines, see some pretty bold statements. Visible hydration, spectacular results. And what's this, the Nobel Prize in Chemistry?
24:01
I showed this to my mother. She was about 80 years old at the time, a farm girl, never gone to university. She saw that, and she smiled and said, Peter, I think you're finally doing something useful. Well, trust me, my mother is still giving me advice
24:22
at the age of 93. The aquaglyceroporins are also present in red cells. AQP3 is permeated by glycerol, and it turns out to be very important in the manifestations of malaria. The parasite will grow and divide with the synthesis of glycerol lipids
24:41
because of the glycerol uptake by the cell glycerol transporters, as well as the parasite's glycerol transporters. So a single parasite infecting a red cell can grow and divide to 32 daughter cells. That interrupts and infects 32 more cells. So in malaria, there's a massive development of parasites.
25:01
If you do the numbers, 32 times 32 is 1,000. So two cycles of 1,000 parasites, four cycles of a million, six cycles of a billion. These lead to horrific fevers and organ damage. I'll skip the details here because at this point in my career, I had an opportunity and I chose to make a switch
25:21
from a basic laboratory investigator to a program leader. I was asked to direct the Johns Hopkins Malaria Research Institute, and we're working in Africa. It's a wonderful opportunity. I will fly to West Africa tomorrow. Malaria exists in unfortunate abundance, tragic abundance in Africa,
25:40
and it's a disease mostly affecting small children. Now these children live in the villages surrounding one of our field stations to southern Zambia. They're protected, they're doing well. But here's a little fellow who was brought into the clinic near death in coma with cerebral malaria. His life was saved, but as you can see from the photograph, he has a disconjugate gaze
26:01
because the brain damage is permanent. He's blind for the rest of his life. So in addition to the half million or so deaths of malaria every year, there are many million children like this poor little boy who might survive but will never fully recover. It's a major, major problem for the world. And this basically shows the collections of brain edema
26:23
around the vascular space in a cerebral malaria model. Now, mosquitoes also have water channels. You may not think about it, but when a mosquito bites you, it's to take out blood. The blood is then used for the hemoglobin for egg synthesis, but the mosquito is actively moving fluids
26:41
around through aquaporins. And of course, mosquitoes transport malaria across borders. This is the Zambezi River separating Zambia and Zimbabwe, two former daughter colonies. Zambia has good malaria control. Zimbabwe's had some problems because of the political instability, and the mosquitoes bring it right back.
27:01
So here's some of our field workers in Zambia where they visit the countryside where the poorest people in the world are working as subsistence farmers. But by tracking the epidemic, treating, providing bed nets, the prevalence of the disease in many areas has declined remarkably.
27:20
This is our experience in Macha in southern Zambia. 15, 17 years ago, 1500 cases of 100 deaths. The introduction of the artemisinin, the miracle drug for which two of you won the Nobel Prize, brought it down substantially. The introduction of insecticide-treated bed nets has brought it on further, but it's still not zero.
27:40
It will come back if we relax our methods. I'll close by mentioning briefly glycerol transport. It's important in the movement of glycerol from fat to liver when we are starved. It's also, and this is the work of Jen Carver who is now at Duke. It also turns out to be a factor in heavy metal transport.
28:03
Arsenic transport freely occurs through the aquaglycera porins, and it is probably evolutionarily why we have these in our liver to excrete arsenic, which our progenitors may have been exposed to. So we excrete arsenic into the bile for elimination. And plants, plants also have aquaporins.
28:21
This is a photograph provided by Rolf Kaldenhof from the University of Wurzburg in Germany. Notice the wild-type Arabidopsis can maintain its stem turgor and foliage with a thin arborization of rootlets, whereas the experimental plants that had an 80% reduction in aquaporins in the rootlets
28:41
compensates by sending out more rootlets. When the drought comes, the animals can wander to the next waterhole, but the plants that remain behind are competing actively for water through the aquaporins. So just a summary slide to explain what I've mentioned. I'll just share a few points of what it's like to win the Nobel Prize.
29:02
If you're in the United States, there's a time difference so it's early in the morning, the phone rings. Pleasant voice on the other end, Swedish accent. This is an important telephone call for Professor Peter Agri from Stockholm. Is this Professor Agri? And I had a good idea who this would be. I said, I sure am.
29:21
And they explained that I would share the Nobel Prize in chemistry with Roderick MacKinnon, who also studied channels. He studied potassium channels. And I'm thinking while they're talking, you know, I was a terrible chemistry student in high school. When my teacher, Mr. Thornton, hears the news, he'll aspirate his morning corn flakes. This might be hazardous.
29:42
And then they told me that in a few minutes, like 10 minutes, there'll be a press conference. I should get ready for my day. I sprinted to the shower and my wife, Mary, always patient, always calm, called my mother back in Minnesota to give her the news. My mother was very surprised, but she kept her cool.
30:02
She said, Mary, tell Peter that's very nice, but don't let this go to his head. But as you can see, you can't control these celebrations. The local shopping center, where the price of high neck and beer is usually advertised, is now congratulating Dr. Agri. And I'd just like to point out that the implication
30:20
that I'm their best customer is a great exaggeration. So I'd like to give a little shout out, not only to the people in the lab and to the funding agencies, but to the team behind every scientist, friends and family. Keep us on track. Let us do what we're doing. And my challenge to the young people
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is that our careers are short. Looking back, there are a lot of interesting times, a lot of challenging times, but there are a lot of fun times. And I hope you all stick with science and have as much fun in your careers as I have had. Thank you so much.