NMR – From Physics to Biology and Medical Diagnosis
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Hypothetisches TeilchenBoatYearMeeting/Interview
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MeasurementIceFlugbahnKlemmverbindungLecture/Conference
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LiquidStomachNuclear magnetic resonanceAtomismField-effect transistorMeeting/Interview
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Nuclear magnetic resonanceEffects unitZeeman effectYearCartridge (firearms)Nuclear magnetic resonanceConcentratorTheodoliteEnergy levelHot workingGroup delay and phase delayComputer animation
02:06
Zeeman effectEffects unitNuclear magnetic resonanceNuclear powerSpin (physics)Local Interconnect NetworkAnomaly (physics)OpticsMaterialSpare partCrystal structureCartridge (firearms)YearMagnetizationEffects unitTheodoliteEnergy levelPaintBombAngeregter ZustandNew Year
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Local Interconnect NetworkYearHot workingMeeting/InterviewLecture/Conference
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Effects unitZeeman effectNuclear magnetic resonanceNuclear powerSpin (physics)Ring (jewellery)GlassMetreMagnetMagnetizationKickstandWeather frontUniverseMonthAudio frequencyNuclear magnetic resonanceSpin (physics)TheodoliteField strengthCartridge (firearms)FunkgerätHot workingRadarEnergy levelBloch, FelixYearFoot (unit)Ballpoint penTelephoneAngeregter ZustandGround (electricity)MeasurementScoutingPropeller (marine)SensorEngineMagnetostaticsPackaging and labelingApparent magnitudeBombStonewareString theory
06:21
HourBauxitbergbauMinuteCoherence (signal processing)Magnetic resonance imagingField-effect transistorMagnetizationInductanceRadioactive decayQuantumAlcohol proofSpantTesla-TransformatorPlane (tool)Thermodynamic equilibriumTransversalwelleSchubvektorsteuerungMeasurementMagnetMagnetic momentClassical mechanicsRelaxation (physics)Order and disorder (physics)YearRainFuel injectionStationeryRelative datingTransfer function
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MagnetismNuclear powerNuclear magnetic resonanceScale (map)MinuteFaraday cageCombined cycleParticle physicsCrystal structureCell (biology)Weather frontMeeting/Interview
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Crystal structureMaterialBending (metalworking)Combined cycleContactorTARGET2SeeschiffBottle
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Crystal structureMagnetic resonance imagingYearPhotographyScoutingYachtDomäne <Kristallographie>SeasonGunWeather frontVideoHot workingMeeting/Interview
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Nuclear magnetic resonanceWater vaporNuclear magnetic resonanceVideoLightHydrogen atomDesertionMeeting/Interview
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Hydrogen atomDigital electronicsCapacity factorRestkernMeeting/Interview
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Nuclear magnetic resonanceVideoFaraday cageOLEDNanotechnologyYearBill of materialsCrystal structureAngeregter ZustandScreen printingSpectroscopyAudio frequencyPlane (tool)Nuclear magnetic resonanceKickstandSensorMeeting/Interview
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Audio frequencyPerturbation theoryBasis (linear algebra)Nuclear magnetic resonanceSpectroscopyHot workingCogenerationOrder and disorder (physics)Spin (physics)Tape recorderNetztransformatorScoutingYearMagnetTypesettingMeeting/Interview
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Brownian motionNuclear magnetic resonanceBrown, RobertAtomismSensorNuclear magnetic resonanceYearPlant (control theory)Crystal structureFACTS (newspaper)Stock (firearms)Meeting/Interview
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Brown, RobertRegentropfenStock (firearms)Water vaporMicroscopeMeeting/Interview
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Brownian motionAmmunitionHot workingEinstein, AlbertWater vaporDirect currentAudio frequencyPlant (control theory)ParticleStagecoachAmateur radio repeaterMeeting/Interview
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Insect wingBrownian motionBauxitbergbauLiquidIrregular galaxySpare partAutomobileModel buildingCollisionYearFood storageSpare partElectric power distributionParticleLiquidNightFinger protocolAngle of attackPolradRotationHot workingNuclear magnetic resonanceMonthMarch (territory)JanuaryMeeting/Interview
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ViscosityRotationClothing sizesSpin (physics)Relaxation (physics)ParticleRelaxation (physics)SizingForceField-effect transistorViscositySpin (physics)Cartridge (firearms)March (territory)Electronic componentNuclear magnetic resonanceKey (engineering)SolidTransversalwelleMeeting/Interview
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Spare partField-effect transistorHydrogen atomMagnetic resonance imagingSaturdayWater vaporBrownian motionMeasuring instrumentMeeting/Interview
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Brownian motionTransmission lineBauxitbergbauAudio frequencyGemstoneDirect currentScale (map)RotationCrystallizationNatürliche RadioaktivitätMagnetic resonance imagingBeta particleCrystal structureYearCosmic distance ladderAtomismSpare partBallpoint penTemperatureOrder and disorder (physics)CryonicsElectronMeeting/Interview
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SolidCosmic distance ladderAmplitudeAtomismVisible spectrumConstraint (mathematics)Linear motorCogenerationMagnetic resonance imagingMagnetismHose couplingYearRing strainFoot (unit)MeasurementWeekForceTrainMeeting/Interview
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BauxitbergbauCrystal structureCosmic distance ladderYearCrystal structureDayLiberty shipVideotapeComputer animationMeeting/Interview
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PorcelainNuclear magnetic resonanceField-effect transistorMusical developmentBrickyardIceUniverseTARGET2Book coverMeeting/Interview
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MassField strengthEffects unitHot workingMassYearField strengthSpare partSignal (electrical engineering)Relative articulationBuick CenturyCell (biology)YachtRing strainPhotocopierRainStonewareComputer animationMeeting/Interview
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Plain bearingSpantYearDose (biochemistry)Quality (business)Cartridge (firearms)Finishing (textiles)Hose couplingUniverseField-effect transistorSpantStagecoachCosmic microwave background radiationHot workingRelative articulationMeeting/Interview
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Bird vocalizationBill of materialsMechanical fanYearEngineToolOLEDAlephMass spectrometryBook designDayUniverseGameGasStagecoachTurningTelephoneHot workingDecemberColorfulnessAlcohol proofBending (metalworking)PaperPhase (matter)Meeting/Interview
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BauxitbergbauHourLocal Interconnect NetworkGround stationSundialVideoVideoMeeting/Interview
Transcript: English(auto-generated)
00:14
everyone. I'm going to talk about NMR biology and medicine, so before lunch we will go
00:25
back down to earth. These are not elementary particles. You see here the king of Sweden, the queen of Sweden, my wife next to the king and myself. The question arises why was my
00:45
wife at some point standing next to the king of Sweden. Well the answer leads into my talk. It is that we achieved the possibility of determination of the complete structure of large
01:06
molecules of biological interest such as proteins which contain within one molecule hundreds to many
01:23
molecules where they really function in our bodies, for example in the blood, in the liver and in stomach liquid. The technique that we use is NMR nuclear magnetic resonance. I will
01:42
today in my talk concentrate on the contributions to this work that have been generated by physicists, about 40 physics graduate students in my group over a time span of 15 years. NMR is the
02:10
first observation of transitions between the Zeeman levels of in the simplest case spins of one
02:21
half. Now this has a history. In 1996 Peter Zeeman observed fine structure in the optical spectra of materials that he placed in a magnetic field and part of this fine structure
02:43
was referred to as anomalous Zeeman effect. 30 years later it was recognized that this anomalous Zeeman effect represented the energy splitting between the eigenstates of the nuclear
03:04
spins, in this case spin one half. The energy of these eigenstates is degenerate in the absence of a magnetic field and it is finite in the application of a magnetic field P0.
03:23
So we go back already 120 years with the story that leads to the applications that I will describe later in my talk and you'll see later on we will go back another 100 years
03:41
showing you how important it is to read the literature, to really use the possibility of standing on the shoulders of past heroes of science when pursuing your own work. It took a long
04:02
time until transitions between the Zeeman levels could be directly measured. The reason for this is that the energy splitting between the two levels in the case of spin one half is very small. It's
04:22
in the radio frequency range and until the Second World War there was no technology available that would have been able to detect such transitions. But the work of thousands and thousands of scientists and engineers, mostly in the United States but also in the other
04:44
countries involved in the war when developing radar technology developed these techniques and as soon as the World War was over some of these scientists returned to universities
05:01
and within months after the end of the Second War the first experiments in NMR were performed and you can see that the frequency of the transitions omega zero is proportional to the applied magnetic field. Felix Bloch in Stanford and Ed Purcell at Harvard obtained a Nobel
05:26
Prize in physics in 1952 for having performed the first NMR experiments. Now how do we perform NMR experiments today? We have quite big magnets. I'm standing here in front of a 900
05:43
megahertz magnet that produces a field that's about 500,000 times the strength of the earth's magnetic field and then we place our samples that's the solutions of biological macromolecules
06:03
in a small glass tube diameter typically five millimeters in the very center of this magnet and apply radio frequency fields onto the sample while it is subjected to the static magnetic
06:22
field. Now of course in these measurements we do not observe individual spins but we observe examples of spins that depends on the systems that we study but it's of the order of 10 to the 16 to 10 to the 19 spins and the magnetic moments of these spins add up to a macroscopic
06:49
magnetization indicated here by M and in the equilibrium situation this magnet is macroscopic magnetization is oriented along the externally applied field you can then and to describe
07:07
an experiment and the techniques that we use today for these experiments it is more convenient to use classical mechanics rather than quantum theory so we apply a second magnetic field
07:25
perpendicular to M and apply it for a time that's efficient to turn the magnetization vector out of its equilibrium situation by 90 degrees and you then use a coil in the plane in the
07:43
y prime x prime plane and you detect the magnetization that you have rotated into the xy plane and what you observe is what we call a free induction decay which shows a time frame a time decay which occurs typically over seconds to minutes and what this represents
08:07
of course is the decay of coherence of the magnetization vector in the xy plane perpendicular to the applied magnetic field this does not yet mean that we return to equilibrium
08:25
and so we have to use a second measurement and typically we then use a pulse length that turns the magnetization by 180 degrees and we measure the return to equilibrium
08:42
now it is clear that the transverse relaxation time that is the decay of the coherence in the xy plane must be shorter or equal to t1 and these basic considerations enable us to do quite a wide range of applications
09:05
which go from imaging human bodies to studying macromolecules or small molecules in solution and I would next want to spend a few minutes to tell you about the kind of
09:22
applications that are possible today and that are being pursued at an intense scale I show you here a combination of two molecules the light blue structure is a protein
09:42
that receives a drug molecule in our cells and the darkest structure in front is the drug molecule but this particular drug molecule was important in that it made organ transplantation possible in human
10:06
medicine and this happened in the 1980s it is only see it is the only molecule that also relates to the previous talks that were telling us about the estimated costs of future
10:23
experiments in particle physics this drug has so far sold for more than 40 billion dollars the drug has a structure and how do we now learn from our experiments about what to do
10:41
with this drug you see that there it is circular structure and it has chunks of materials that that stand out at the top and at the bottom now as soon as we have determined the structure of the complex I mean of the combination of this drug with its receptors we can study
11:04
the nature of the contact sites in the receptor we can then go back and tell the chemist where they might modify the structure both to improve the efficacy of the drug and possibly to get new patents for a new modified drug so that the whole thing becomes also
11:27
financially valuable so that is one approach and in my current work we are pursuing very similar experiments with a particular different line of receptor molecules these are
11:44
GPCRs besides running NMR spectra I have also played football and I wanted to play football for very many years so it is important to use magnetic resonance imaging which is based on the
12:04
same principles as the spectroscopy that lets us see the molecules and you see here images of my knees of my knees which were taken only like three years ago and since the knee looks good I can continue to play football and you see that this photo was taken by
12:27
Pete DeBatch in 2015 so that's the second very broadly used application of the NMR principle let me now go a little bit deeper into the basics of using the NMR principle for studying
12:50
large complex molecules in solution you will all recognize this molecule and it is water
13:02
that was first studied by Bock and also by Purcell and you get the single line because you can you only see the hydrogen atoms and because of the symmetry of the molecule you cannot distinguish between the hydrogen atoms when you look at biological macromolecules you have a rather
13:27
different situation you do not have just one kind of symmetry related nuclei that you can observe but you have typically hundreds to thousands and that yields spectra which show a lot of
13:44
overlap now we knew from working with a few well-separated lines what needed to be done and what could be done provided that we could resolve all the overlapping lines and this
14:00
problem was solved by the introduction of two-dimensional NMR experiments using a principle that has in that happened 40 years ago using principles that have since been applied in many different spectroscopic techniques which have higher energies and therefore present
14:27
increased technical difficulties for doing this sort of experiment you see we now have a two-dimensional frequency plane and we have a lot of lines that are well resolved by 1982 we
14:43
had cozy nosey sexy and foxy which enabled us to solve protein structures this is no dirty words I mean sexy stands for spinnaker correlated spectroscopy and so like and here is a simple
15:00
scheme which indicates to you what's behind these multi-dimensional spectroscopic techniques you see at the top a scheme where t2 represents the time that we are used to and by the time
15:21
that we get older with every second passing in order to get a two-dimensional frequency space we need to add an artificial second time axis and this is achieved by perturbation of the spin system you remember the classical description of the NMR experiments we use pulses that turn the
15:45
magnetization around so we use the first pulse perturb the system let it run for a certain let it evolve for a certain time and then indicate with the second second perturbation that we now
16:02
start to record data and of course if we vary the time t1 then we create an artificial second time dimension and from the time the two-dimensional time space we go into two dimensional frequencies based by Fourier transformation nowadays we use on a daily basis
16:25
four and five dimensional experiments and we have also developed six and seven dimensional experiments just expanding on this simple principle my colleague at CTH Richard Ernst was awarded the 1991 chemistry Nobel prize for his work on Fourier transform NMR and two
16:50
dimensional NMR this is one problem that had to be solved to obtain the spectral resolution that enables us to see individual atoms and just determine the structures at atomic
17:06
resolution now the second big problem that had to be addressed has to do with the fact that the molecules are under constant stochastic motion and this goes all the way back 200 years
17:23
to work by a British botanist Robert Brown he worked with plants with flowers and so he handled pollen like bees collect pollen he was collecting pollen
17:42
and he dropped pollen into a water beaker and curious as he was he looked at the mess and there's a microscope and to his big surprise he observed that the pollen weren't sitting on the water surface but they moved around in a stochastic way smaller pollen would change
18:07
direction at a higher frequency than larger pieces of pollen Brown published this in 1928 as an empirical observation and could not give an explanation he first checked that this didn't
18:25
represent life in the plant by repeating the experiment with inorganic particles which then also moved around understanding of this phenomenon came with work by Albert Einstein
18:44
which is less well known that the others of his efforts which he pursued in 1905. Einstein showed that the translational Brownian motion are due to stochastic distribution of collisions
19:06
with much smaller solvent molecules but more important for us here also showed in a second publication that if the collisions between the solvent molecules and the suspended
19:21
particles happened at angles that are not perpendicular to the surface of the particle then these collisions would induce rotational motion and Einstein published this work in the
19:41
Physique in 1905 in May and they took that was the work on the translational Brownian motion and it took him about eight months to realize that there were also rotational Brownian motions and that was published in January 1906. Now considering the relative importance that Einstein
20:05
has given to the different projects that he followed in 1905 it is interesting that in his lectures of the following years he spoke about the Brownian motion he didn't speak about relativity
20:22
theory or any of his other work so you see here an example he was invited by the on March 23 1907 they met in a restaurant there were exactly 20
20:42
scientists and non-scientific members of the society and Mr Einstein talks about the nature of motions of microscopically small parts part it should be particles which are suspended in liquid and when you read the text that follows then he very concisely describes what happens
21:07
in solutions where translational and rotational Brownian motion happens for us in NMR this this resulted in the Stokes-Einstein relation the Stokes-Einstein relation
21:27
showed that the key NMR parameters the translational the longitudinal and the transverse relaxation times t1 and t2 that I introduced at the beginning of my talk as well as the
21:45
nuclear overhauser effect are in a simple way related to the size of the dissolved particles now this means that when we perform NMR experiments with large particles in solutions
22:01
such as proteins or pieces of nucleic acids we are dealing with a widely different spin physics from what we would have either in small suspended particles or in solids and of course when you have largely different relaxation times for different components in a mixture
22:26
then you can use the difference in relaxation times as a filter and that is behind the application of the NMR principle for studies of human bodies all that has ever been seen in
22:41
imaging experiments so far are the protons the hydrogen atoms of the water and bones muscle tendons they can readily be filtered out they are not observable in the approach that is used
23:00
in using the NMR principle for imaging in medical diagnosis even here I just inquired in Lindau there are two MRI instruments available if you want to have parts of your body image before Saturday this is not all about Brownian motion when we want to study macromolecules
23:31
because us came out directly from Einstein's description of the Brownian motion
23:41
the translational as well as the rotational motions occur at frequencies I mean the change in direction occurs at frequencies of the order of 10 to the 10 per second and these are a periodic motions and you so you cannot take an image when you want to see
24:08
the structure you see when we get structure we have heard here about crystallographic structures you keep the molecules fixed in a crystal you lower the temperature and then you take an image
24:22
you have heard about cryo electron microscopy you fix the molecules in in a different way in a non-crystalline way but they are fixed in the low temperature and you can take an image here we are about six orders of magnitude away from the fastest judder that would enable us to
24:43
take a picture so that is not the way we can do the job in solution what we have to do is to search for scalar parameters which are measurable and which define the three-dimensional
25:02
structure and we ended up finding that the distances between atoms within these big molecules are the right choice you see when you have a distance between two particular atoms
25:21
it is the same in the upper left or the lower right part of this scheme and it also independent of the relative orientation of the two atoms and fortunately enough thank you fortunately enough in macromolecules i told you that the difference between physics from solids
25:48
or from small molecules the nuclear overhauser effect enables us to measure distances this is very early noe spectrum a two-dimensional noe spectrum it contains a couple of hundred peaks
26:05
each one measures the distance and whenever we you see the protein for those who are not in the field the molecules we are dealing with are linear chains and that's indicated at the top of this image now if we are able to determine the points along this linear chain
26:30
which are at the close distance as indicated by an nov peak then we form a loop as you can see in the upper right now if you form such a loop you will induce repulsive forces
26:48
because the chain contains quite a lot of atoms and so each measured nov constraint will generate between 10 and 1 to 200 constraints in total most of these are repulsive constraints
27:09
and so what we need to do is to get somehow from the distance space that is such generated which has n times 1 000 dimensions these days we typically have a distance space of
27:26
30 to 40 000 dimensionality using distance geometry principles and molecular dynamics minimizers we go back to the three dimensions in which the molecules are presented and i had very good
27:47
collaborations i mean graduate students in mathematical physics who solved this problem over a time span of about 10 years and then we get to structure and i tell you very briefly
28:02
what we do today we study g-protein coupled receptors in shanghai at the human institute of shanghai tech university here we are talking about the class of proteins in our bodies that are the most widely used target for drug development already now about 40 percent of all
28:28
prescription drugs target gpcs and so we have a nice cover to request funds for continuing with this research the questions that we want to ask want to investigate is that drug molecules
28:49
are obviously applied on the outside of the cell and the effect of the drug has to be felt inside the cell so signals have to go across the cell membrane over a distance of about
29:02
30 angstrom and we want to know how this happens in california and in zurich i work on sarcopenia sarcopenia is a newly accepted disease loss of muscle mass and strength in
29:23
advanced age and what the matter here is to improve the length of the health span during the lifespan we have so far within less than a century scientific work has resulted in a doubling of the lifespan the result is that too many years of
29:46
lifespan are lived under circumstances that cannot be considered as part of the health span and that's what we need to change sarcopenia has been defined and accepted
30:03
as a disease by the world health organization in 2016 osteoporosis which is of course related has been accepted in 1996 and between the two diseases the loss of quality of life in advanced
30:23
age is comparable to the loss of life of quality of life due to alzheimer's disease and so but we see possibilities to improve the situation with sarcopenia and osteoporosis
30:41
more rapidly than what appears to be the case for alzheimer's and of course my back background in teaching sports should come and play a role in our work on sarcopenia
31:01
i want to finish with a couple of general remarks for those of you of all ages who are here i found this very nice definition of how a research scientist should be made
31:21
research needs a bold and invigorating frame of mind which may be uncomfortable to others you won't make a career as in administration of universities if you adhere to this picture
31:41
i want to tell you a word about how nobel prices may be obtained so that you may obtain in this environment when i got the price in 2002 the other half of the price was shared between kuichi tanaka who at the time was 39 years old when he did the work that earned him
32:08
the nobel prize he was 22 years old he never studied beyond a bachelor's degree he published a single paper in his lifetime in english and he also had a patent to his credit
32:25
the very first patent that enabled to get macromolecules in the gas phase to perform mass spectrometry so 22 years old equipped with a bachelor's degree
32:44
and you see that's one of the first pictures of kuichi after he got the price the blue color indicates that he was still a lowly employee in this company that changed a few days late the second colleague who shared the other half of the price was john fenn
33:08
after a career in government business mostly in mostly in research institutes engineering institutes he joined yale university at the age of about 65 he discovered the result that gave
33:29
him the nobel prize at the age of 73 and he was 86 when he joined us in sweden so for all ages here you see there are possibilities to end up on stage in stockholm on december 10
33:48
but the most important thing of all is and now i'm talking to the young colleagues here that you have fun with your work you say fun this is another picture of the first protein
34:03
we solved and it looks quite nice to me and when you look a second time you see that it has the shape of switzerland you are now sitting right at the upper right corner there is the bottom there the algs go across and the colors of course indicate results that we obtained which
34:26
describe functionalities of the protein why do you need to have fun when you are in basic research you can fail it is typical that you fail and you have to try again
34:44
if you do not have fun in your work then you cannot fail then the time is lost but even if you fail the time is not lost if you had fun and satisfaction while you were doing your work
35:02
and i wish you luck along these lines thank you