Surface Physics and Immunology
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00:00
SemiconductorSuperconductivitySensorElectricityBoatFischer, ErnstYearMeasuring instrumentProtectionMeasurementMolekülmasseMinuteRutschungCartridge (firearms)Field-effect transistorShip classLightReaction (physics)SolidCooper (profession)Crystal structureAngeregter ZustandPhysicistCatadioptric systemLecture/ConferenceMeeting/Interview
02:46
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstHeatCartridge (firearms)RutschungMeasurementKette <Zugmittel>Angeregter ZustandHot workingString theoryRelative datingField-effect transistorVideoRemotely operated underwater vehicleLecture/ConferenceMeeting/Interview
05:06
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstKopfstützeMetalMicroscopeAtomhülleWater vaporCrystal structureLightBallpoint penRutschungRail transport operationsAngeregter ZustandField-effect transistorIncandescent light bulbVideoMorningFullingSunriseLecture/ConferenceMeeting/Interview
07:26
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstMicroscopeMeasuring instrumentPlane (tool)Refractive indexLightBrechungRutschungMetalBuick CenturyWavelengthAM-Herculis-SternMonochromatorHot workingAngle of attackAtomismChromatic aberrationGlory (optical phenomenon)Cut (gems)Hose couplingCartridge (firearms)Group delay and phase delayModel buildingLecture/ConferenceMeeting/Interview
09:45
SemiconductorSuperconductivitySensorElectricityBoatFischer, ErnstFire apparatusTypesettingBund Schweizer ArchitektenPhotometerWater vaporAngle of attackAlbumen printHot workingMeasurementPhysicistLightRutschungHomogeneous isotropic turbulenceVideoKickstandHydrogen atomFlightLecture/ConferenceMeeting/Interview
12:05
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstConcentratorWater vaporScale (map)FlashlightPhotographyMonorailFrictionRutschungMixing (process engineering)ViscosityCurrent densityEnergy levelLightPhysicistCartridge (firearms)Vega <Raumsonde>RegentropfenModel buildingFuse (electrical)AbsorbanceRemotely operated underwater vehicleDiffuser (automotive)Summer (George Winston album)Lecture/ConferenceMeeting/Interview
14:25
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstBund Schweizer ArchitektenCell (biology)RegentropfenAlbumen printSpare partPhysicistCogenerationConcentratorRutschungAlcohol proofVolkswagen GolfBuoyancyCoalMorningRulerAtmospheric pressureAbsorption (electromagnetic radiation)AbsorbanceLecture/ConferenceMeeting/Interview
16:45
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstField-effect transistorCellular manufacturingRutschungRulerAudio feedbackParticleMonopole antennaMagnetizationCell (biology)LeistungsanpassungFACTS (newspaper)JanuarySpare partAntiparticleLecture/ConferenceMeeting/Interview
19:05
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstField-effect transistorFlavour (particle physics)TurningRutschungSpare partDiaphragm (optics)MarsWhiteSunlightCorporal (liturgy)FoxLecture/ConferenceMeeting/Interview
21:25
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstPhysicistGround stationBund Schweizer ArchitektenField-effect transistorRutschungLaceCartridge (firearms)AntiparticleMarsShip classDayHourAngeregter ZustandLecture/ConferenceMeeting/Interview
23:44
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstDual in-line packageRutschungWind wavePlant (control theory)Bund Schweizer ArchitektenVolkswagen GolfWeightHollandSeasonFlightFoxLecture/ConferenceMeeting/Interview
26:04
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstVolkswagen GolfRoman calendarBund Schweizer ArchitektenWeekRutschungFuel injectionAbsorbanceBottleLightCardboard (paper product)Ground stationAnalog signalGentlemanThermalRoll formingLecture/ConferenceMeeting/Interview
28:24
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstRulerRutschungViseVolkswagen GolfReaction (physics)GentlemanUniverseDayMint-made errorsSummer (George Winston album)Field-effect transistorLecture/ConferenceMeeting/Interview
30:44
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstLaserPhysicistRutschungTongue and grooveParticleLaserGlassMetalWorkshopDrehmasseMicroscope slideHot workingFlightLightThin filmLecture/ConferenceMeeting/Interview
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SemiconductorSuperconductivitySensorElectricityBoatFischer, ErnstLightMetalParticleRutschungScale (map)AbsorbanceSizingSingle (music)Wind waveFunkgerätWavelengthGeokoronaStriking clockElectronElectron microscopeMicroformFlightMicro-g environmentRadarTape recorderProof testModel buildingOrder and disorder (physics)IceBook designLecture/ConferenceMeeting/Interview
35:24
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstThin filmDielectricBund Schweizer ArchitektenGeokoronaMetalCoatingOrder and disorder (physics)Volkswagen GolfWind waveGameRutschungPhotographyAbsorption (electromagnetic radiation)ParticleWavelengthScatteringFunkgerätScale (map)Dual in-line packageWeekYearElectricityCorporal (liturgy)FlightLecture/ConferenceMeeting/Interview
37:44
SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstWeekElektrische DoppelschichtYearCosmic microwave background radiationVolkswagen GolfRutschungDual in-line packageElectricityLecture/ConferenceMeeting/Interview
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SemiconductorSuperconductivityElectricitySensorBoatFischer, ErnstRoll formingBill of materialsRutschungPufferlagerRadioactive decayLightVolkswagen GolfStomachHochbahnAvalanche diodeTrade windLecture/ConferenceMeeting/Interview
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SemiconductorElectricitySensorBoatFischer, ErnstBund Schweizer ArchitektenPufferlagerMechanical engineeringDayAcoustic membraneRulerRegentropfenRutschungMechanicElectricityPlatingDishwasherFACTS (newspaper)EngineTrainDirect currentEnergy levelFoot (unit)LastLecture/ConferenceMeeting/Interview
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SemiconductorSuperconductivityData conversionVideoMaterialNanotechnologyElectric power distributionHot workingMeeting/InterviewComputer animation
Transcript: English(auto-generated)
00:22
As we all heard yesterday, every scientist is very excited about his own field. At the present time, I'm excited about biophysics. And I think that is the right field to be in. And I'm going to try to convince you that that's where the action is. Actually, I probably don't have to do that because even Professor Cooper is
00:41
in biophysics, as you saw. He dealt with a cat. So you see, we all get there sooner or later. What I'm interested in is protein molecules. And since I talked to a physics audience, I proposed first to tell you a little bit about protein so we all know what we are talking about.
01:01
Then I'm going to tell you how you can study protein absorbed on surfaces using an instrument called an ellipsometer. Then I'm going to tell you all I know about immunology. That takes five minutes, so that's quick. And after that, I'm going to show you how you can use this instrument to do immunology.
01:23
And finally, I'm going to show you how you can do everything what I'm talked about without using any instrument at all. So just to get started, if I could have the first slide. I can't read it, so I'm sure you can't. Can anybody get rid of that light in the corner?
01:45
Anyway, protein is a common name for a whole class of molecules which you have in your body. And for example, all the enzymes which catalyze reactions are protein molecules. And many of the hormones you have in your body
02:01
are also protein molecules. So you understand, it's a very important class of protein molecules. The molecular weight is very large. The molecular weight is typically 10 to the sixth. So if you are a solid state physicist and you deal with atoms, I see everybody is shading their eyes. Anybody can get rid of that light?
02:27
Now, the molecular weight is very large. So if you're interested in physics, of course, if you deal with copper or something, it's very simple. But if you want to find what the structure is of a protein molecule, it is very complicated because the molecular weight is so large.
02:41
Now, fortunately, protein is a polymer. That means that it's built up of smaller units called monomers. And in the particular case of protein, these smaller units are called amino acid. They are smaller molecules, and there are about 20 of those, 20 different kind of those.
03:00
And if I can have the next slide, the next slide shows what I got interested in. This is called a primary structure. And what is meant by that, if you have a protein molecule, it is made up of these monomers, and they are like pearls on a necklace. And the object of the primary structure is to find out which pearl is where
03:21
or which amino acid is where alongside the chain. And here, you see I've drawn two the same here, for example. And this is the object of the primary structure. And this is called a peptide chain because typically, a peptide chain have about 100 amino acids in it. And a complete protein molecule sometimes
03:42
consists of more than one peptide chain, maybe two or three or four, which are linked together. The first primary structure which was determined was for insulin, which, as I'm sure you all know, is a very important protein molecule. And this was done by Sanger. And this is a very small protein molecule,
04:00
have two chains, one is 21 and one is 30 amino acids in it. And this was a milestone in protein chemistry because now we realize that insulin is always the same. So insulin from you or from me or from somebody else is basically always the same molecule. And they didn't know that before.
04:20
Now, I'm interested in determining this primary structure. And I really haven't gotten very far along that line. And right now, I'm doing something else, which I'm going to talk to you about. Now, the next slide, next to Bilder. I'm getting better.
04:41
Now, if you have the protein in the body, it is not strung out as a pearls on a necklace. But it's curved up on itself. And this is the protein in its native or active state where it can do its work. Now, if you're very careful and heat up this protein, it may denature and string out like this.
05:02
Now, if you then cool the protein back again, it may refold and look like this thing of spaghetti. The interesting thing is that the active state of the protein molecule is given by the amino acid sequence here. Because if you recool it, it retakes the same shape
05:21
as it had before. You realize that's a very delicate operation. When you fry your egg in the morning, you denature the protein. But you know you can't get the egg back into the shell again because it's too cruel to do it that way. So you have to be very delicate to do it. And this is really so you understand
05:41
that the primary structure is the most important thing, in my opinion, but protein molecules. And I'm involved in making a microscope in which you can see this primary structure. And fortunately, I haven't gotten very far along that line. And I had to first learn how protein molecules behaved on metal surfaces.
06:01
And I started working on that particular problem. And that's how I got into immunology and going to give this talk I'm giving today. Now, if I could have the next slide, it shows a typical protein molecule, namely hemoglobin, which is this large blob here. And I compare that to a molecule of water so you see protein molecules are very large.
06:22
And for the rest of my talk, you can simply regard protein molecules as being a big ball of spaghetti because I'm not going to look in detail on these molecules. I'm just going to look at the general feature or structure of these molecules. And I'm going to look at them when they are at the metal surface.
06:40
First, when I got interested in this problem, I said, well, what you do then, you go to the literature and you look it up in the literature. But basically, since there are so few metal surfaces in the human body, nobody's interested in that problem. And so there are very little literature along these lines. So I had to look around then for some system, some method by which I could study protein molecules
07:02
on metal surfaces. And I came up with a well-known system and called an ellipsometer. And let me illustrate that principle for you, which is on the next slide. If you have a metal surface and if you shine light on a metal surface, the light is reflected.
07:21
Now, you all know that light have two directions. And if you shine light through a pair of Polaroid sunglasses, light will get polarized. Now, a plain polarized light is reflected from a metal surface. It basically reflected as elliptical light in general. Now, from the amount of ellipticity and from this angle here, you can tell two things
07:43
about the metal surface. You can tell what the index refraction is for the metal surface. But that is not what's going to interest us. What's going to interest us, if you absorb a layer on the metal surface, for example, a layer of oxide, or in our case, a layer of protein molecules, the ellipticity changes over here.
08:01
And from that, you can learn two things about this layer. You can learn what the index refraction is. And you can learn what the film thickness is. Well, the index refraction of protein is well known. It's approximately 1.5. And we're not going to be concerned with that. But what we're going to be concerned with is what the film thickness of the protein
08:21
is to absorb on the metal surface. And amazingly enough, even though we use visible light, you can get that film thickness to a fraction of an angstrom. So you realize that we are talking about average thicknesses, because you can actually tell if you do very delicate experimental work when you have less than a monolayer of atoms on the surface.
08:43
It's really a fantastic instrument. And I sort of jokingly call it the invention of the century. But it was actually invented in the last century, in 1880, by Drude. And it hasn't been used very much, because it's very difficult to get good, clean surfaces.
09:00
The next slide shows you an ellipsometer and how it looks like in all its glory. The instrument is about as complicated as a microscope. What you have, you have a light source. And you get lights of different wavelengths. Then you have a monochromatic filter. You get light of a single wavelength. Then you have your polarizer.
09:21
You get plane polarized light. Then you have something called a compensator, which changes the polarized light to elliptically polarized light. And if it's adjusted right, the elliptically polarized light comes off at plane polarized light. You see, light can go both ways. If it goes from here, it will reflect as elliptically polarized from here, as plane polarized.
09:41
Then you have an adder analyzer which cuts out all these light. And essentially, you get a zero reading over here. So what you do when you absorb something on the sample, you adjust this angle. And you adjust that angle. And you get a minimum reading on the photometer. And then the ellipsometer comes with a set of equations.
10:00
And from those equations, you can calculate what thickness you have on the sample here. Now, I'm going to cheat a little bit because I'm not interested in great accuracy. So what I'm going to do, I'm going to offset the angle here a little bit. And what that result in is that the current I read on the photometer will be approximately proportional
10:22
to the thickness of the layer I have on the surface here. And if you're not interested in angstrom, but units of 5 angstrom or so, that's perfectly good enough. The next slide shows you the apparatus. And as you can see, it is very simple.
10:41
What it is is simply a bucket in which you put salt water. This is water of the physiological solution. You don't have to use salt water. But everybody working in biology do. And if you don't do it, they get mad at me, you see, right? So you've got to do what other people do. Then you have a arrangement for stirring here.
11:01
You can stir it magnetically. And then you have a surface. This happened to be nickel. And what you want to do now, at time equal to 0, you want to drop some protein molecules into this bucket. And you will want to find whether they diffuse over and absorb on this surface. And this particular molecule I'm using
11:21
is known as bovine serum albumin. That is the most common protein molecule in the blood of a cow. And you should think of BSA molecule for a biologist the same as the hydrogen molecule for a physicist. If you don't understand the BSA molecule, you don't understand it. If you don't understand hydrogen,
11:41
you don't understand it, you see, right? The same kind of concept. Now what we want to do then, we want to find out whether these molecules will diffuse over and absorb on this surface. And this is all mounted in the ellipsometer. So while they diffuse over, light comes from here, hits the surface, is detected, and we
12:00
should be able to tell whether a molecule will absorb on nickel or not. On the next slide, it shows you the result. Here is time this way. This is 10 seconds. Here is photo current of this way, which is proportional with thickness. And here is the time where we drop the protein
12:21
molecule into the bucket, and we want to see what happened. Now I'll first explain these wiggles here, because physicists are always interested in wiggles. But in this particular case, I had to borrow an ellipsometer. And this ellipsometer was bothered by light from the ceiling and whatnot, so I had to work in the dark.
12:41
Now if you're going to drop protein in a bucket in the dark, you miss all the time. So you couldn't do that. So I had to have a flashlight in my left hand. And this is wiggles is due to my flashlight in the left hand. So you see, they are pearly experimental wiggles, nothing to do with the experiment. But as soon as you drop the protein in, what you find
13:01
is that the photo current increases, and then it levels off. And what that means is that protein molecules diffuse over, absorb on the surface, and you get a mono layer. Because if you've got two layers, why don't you get three layers or four layers, you see, right? So I claim you get a mono layer.
13:21
Biologists would tend to be nervous about that. But fortunately, as I said, the ellipsometer comes with equations. You can calculate this thickness, and the calculations comes out to be 30 angstrom, and which is approximately what the mono layer of boron serumaldium will be like. So we are pretty confident that that is true. Now the next slide shows you how
13:43
you can think about this experiment. You have here, when you drop the protein in the bucket, since you stir, the concentration will be uniform in the bucket almost instantaneously. I mean, it takes a fraction of a second, but we are not working on that time scale. So you have a uniform concentration
14:02
of the bucket, except close to the surface, because water is viscous. And if you stir, because of the friction of viscosity of water, you cannot mix water very well close to the surface, and you get left with this dead layer. So from here to the surface, the molecules simply have to diffuse.
14:21
And so we start out here, and you get this dead time, which you can calculate, where molecules diffuse from here and over to the surface. Then you get into this situation where you have approximately uniform linear drop of a concentration here, and then you get the linear relationship here on your curve. And then finally, when the surface
14:41
start getting covered over here, then of course, it has to level off, because the protein molecule will not absorb on top of themself. That they don't do that is one of the most important result from this experiment. At least that's what we're going to focus on now. And it would be a good idea here, I think, to try to illustrate the difference
15:02
between a biologist and a physicist. And if a biologist had done this experiment, he would have said, at 25 degree centigrade at one atmospheric pressure, if you drop buoyant serum albumin into a bucket, it will diffuse over and absorb on a nickel surface.
15:21
So basically, he'll say something like that. What a physicist would say is shown on the next slide. And you see, it's a fantastic generalization. In a physicist, I say protein absorbs on everything, even though I only tried BSA and nickel surfaces, you see, right? So in my interpretation is that the biologist would benefit
15:42
from being a little more brave, and physicists would benefit from being a little more humble. But for the part of this experiment, you should keep that rule in mind. It is basically true that protein will stick to everything. Every surface I've tried, it sticks to, but it will not stick on top of itself. You get stuck with this monolayer.
16:02
Now, we're going to extend the experiment, and the extension is shown in the next slide. What we're going to do now, I'm going to take these protein molecules, which comes from a cow, remember. We're going to take them out of the solution, start out with new fresh water, but we're going to leave the BSA molecules on the surface.
16:23
And now we're going to drop some rabbit serum into the bucket. Rabbit serum is blood from a rabbit, except you've taken the cells out. So there have no cells in there, and also some of the so-called clotting factors are out. But basically, rabbit serum contains literally maybe 100,000 different kind
16:42
of protein molecules. And what we're going to do now, we're going to ask the ilepsometer if any of these protein molecules, which you drop in here, will stick to those protein molecules that came from a cow. And amazingly enough, they don't.
17:01
And it's sort of like a miracle, but they do not stick. Matter of fact, I don't even have a slide about it, because when nothing happened, you can't really make a slide. You see, it doesn't look too good. So it does not stick. And for that reason, we can extend the rule. And the next slide shows the extended rule
17:21
that protein sticks to everything except itself and any other kind of protein. I have gotten in trouble many times because of this rule. So I ask you, please do not think about this as you do about Maxwell's equations, because there are many exceptions to these rules. And as far as I know, there are no exceptions to Maxwell's equations, except if Professor Dirac is correct,
17:44
or the implication of magnetic monopole is found, Maxwell's equation will be different. But these are just rule of thumb. But for this particular experiment, it pays to keep them in mind. And fortunately, again, there is one exception to this. And now I'm going to give you
18:00
my little course in immunology. And if I could have the next slide, here is I have written down some key words in immunology. The immunology system is your own defense against sicknesses. That's what it means. And the body has two ways of doing that. It does it with molecules, which is called humeral.
18:20
And it does it with cells, which is called cellular. And there are complicated feedbacks between those two systems, which basically are not understood, at least not by me. But what I'm going to talk about is the molecular system. And there are two words you have to learn. And I don't get them confused anymore. But I know in the beginning, it's
18:40
very easy to get them confused. First of all, if you put the foreign particle in somebody, it is called an antigen. The body then will respond, and it will make a particle, which is a protein particle called an antibody. Not to be confused with an anti-particle, but that is an antibody.
19:02
Now, the best way for me to learn about or understand things is to talk about examples. This is sort of an interesting part of my talk, because I have the choice now of talking about something innocent like chickenpox and something dangerous like syphilis. And sometimes it depends upon the age of the audience, which
19:21
I choose. But since this is a serious symposium, let me talk about chickenpox. When you get chickenpox as a child, the chickenpox is a virus. And a virus is foreign to your body. The virus is the antigen. The virus gets into your body,
19:40
and then the virus will start to multiply. At the same time, your body will recognize there's something there where it doesn't belong, and the body will start making antibodies. And these antibodies has many functions, but one of their main functions is to attach to the virus. When they attach themselves to the virus,
20:02
your white blood cells recognizes this object as being foreign, and they actually come in there and eat up the whole thing. And that's the truth. I see many doubting faces in the audience, and I told my mother this story, and she said that it's very nice.
20:20
She's from Norway. She said that's very nice, but it sounded like an Norwegian fairy tale. And in a sense, it does, but believe me, it is true. If you then get chickenpox again as an adult, as you know, you only get chickenpox once. If you get chickenpox again as an adult, you have these antibodies in your body.
20:41
And therefore, next time you get exposed to chickenpox virus, you get the virus in, the antibodies attach themselves right away, the white blood cells eat them up, and you don't get sick the second time. And that's really how we all can exist and be as healthy as we are. As I told you, I told my mother this story, and she was kind of doubtful. So I looked through the literature
21:02
to find out where this appeared first. And one of the first places I found was from George Bernard Shaw, which is shown on the next slide. As you know, he's not a scientist, or maybe he's a scientist, but he certainly is an author. And this was written in 1906 in a play called The Doctor's Dilemma, in 1906.
21:21
And he says here, there are two characters in the play, and one says to the other, apsanin. And apsanin actually is a name for antibody, which is still in use today. And one character says, apsanin is what you butter the deceased germs with to make your white blood corpuscles eat them. So you see, Bernard Shaw said exactly the same as I did,
21:42
and my mother has much greater respect for Bernard Shaw than she has for me. And now she believes it. Actually, there is another very interesting thing to me about this slide here, because these two characters go and talk to each other. And they come to the final. Here he says, one person says to the other, he says, gammon.
22:03
Now, when you talk to scientists, they just says garbage. They says terrific, you see, right? So I wasn't sure whether gammon meant nonsense or it meant terrific. So I had to go and look it up, and I looked it up in the dictionary. And in the dictionary, it says, gammon means nonsense. See, Bernard Shaw doctor's dilemma.
22:26
And you see, that's sort of an example of circular reasoning. And this circular reasoning, it actually used not that particular one, but it used in immunology, if I could have the next slide. Here is how a physicist view immunology in simple terms.
22:42
You have the foreign antigen. In our case, it's going to be BSA. And this is just a molecule that has certain sites on the molecule known as antigenic sites, will generally all be different. If you have a large virus, a virus is large as far as proteins go, a virus may have 1,000 sites.
23:03
But BSA, the molecule we are dealing with, always has five. So that's simple enough. The antibodies which the body makes, actually the body makes five classes of antibody, but the most common one is called IgG. And that always is divalent. It looks like a lobster with claws and divalent.
23:23
And each of the antigenic sites will provoke at least one antibody. So you see, if you put BSA into something, you'll get at least five different antibodies. And this is how the system is set up. Now, if you now are in the medical profession,
23:41
since these antibodies are very specific, they will attach themselves to this antigenic site on the BSA and to nothing else, or practically speaking, nothing else. Therefore, if I dealt with chickenpox, for example, and I wanted to know whether you had chickenpox, I could get a chickenpox virus, take it in my hand,
24:03
dip it in your blood, and if anything attaches to it, that means that you had chickenpox. Or I can do the opposite. I could take an antibody known for chickenpox and wave around in your blood, and if that attaches to something, it has to be a chickenpox virus.
24:20
So if you know one of these things, you can find the other one, because the chemical reactions are so amazingly specific. I mean, it really is stunning. And this is how the medical profession then used the system of immunology to find out what have ailed you in the past and presumably what's gonna happen to you in the future.
24:43
They are not as sophisticated at using wave functions yet for such things. Now, the next slide shows you where I will get my antibodies from. I drew this picture myself, so I thought I should label it so it wouldn't be any misunderstanding what it was.
25:03
It looks a little bit like a kangaroo, and the interesting thing is that all vertebrates, you know, people have, or anything that has a bone up the back, can have an immunology system, and only vertebrates have an immunology system.
25:22
And so you could use a kangaroo. If you can catch one, you can use a rabbit. For example, trees or plants do not, and in America, for example, all the chestnut trees have succumbed to a sickness. I don't know what it is, but all the chestnut trees are gone, and they will never grow up again, and there's no way they can cure themselves.
25:42
And we also have, where I live now, we have what we call the Dutch elm disease, which kills all the American elm trees. I don't know whether in Holland they have the American elm disease or not, but we have that, and there's no way these trees can cure themselves when they get sick. It may be that somebody will find a mutation,
26:02
but that will be a different tree. See, the tree itself will die. Now, possibly you can find a mutation that will be resistant to the sickness, but that would be a different tree. There's no way plants, insects, and what have you can cure themselves from diseases. Only vertebrates can do that, and that really is an amazing thing. Anyway, what happened now, let me go,
26:22
let me still have this slide. What happened now is that somebody, I don't do this myself, fortunately, somebody inject in the rabbit, bovine serum albumin, which you remember came from a cow. It definitely is foreign to the rabbit. It does not belong in the rabbit's blood. So what happened is the rabbit then
26:41
will form antibodies towards this foreign object, even though it is not a sickness. It doesn't have to be a sickness. Anything foreign in your blood, you will form antibodies to if the molecule is sufficiently large. And so two weeks later, somebody bleeds the rabbit because now the rabbit's serum will contain antibodies to BSA.
27:02
And now the rabbit presumably have produced antibodies, and then we can find out whether these antibodies exist in here or not. And I can buy these things from drug companies. These are standard things which you buy for $10 for a little bottle. It's a good business to be in, I think. This was my little course in immunology,
27:20
if I can get back, next slide. You remember now what we were going to do, we were going to use the, we're going to leave here on the surface, the bovine serum albumin, the protein from a cow. Now we're going to drop some rabbit serum in here, and I told you when you do that, none of the molecule in the rabbit serum
27:41
will go over and absorb on the surface. But this particular rabbit serum has antibodies in it because that rabbit has been subjected to BSA two weeks prior to we got the blood. And now we're going to see what happened, which is shown on the next slide. What happened now is that the,
28:01
immediately as you drop that rabbit serum in, the full current on the ellipsometer increases, which means that you start building up a thicker film. And this is time here, and this is the, see how the film increases. And after about approximately an hour, you have now a second layer, second molecular layer on that surface.
28:23
And this happens sort of immediately. And it's sort of a exciting slide to me, because when you look at this thing going on, what you're actually seeing is a chemical equation taking place, you know, chemical reaction taking place. And the way I view it is shown on the next slide. As you see here, here we have the surface with the antigen.
28:43
Here we have some antibody, which have attached themselves to the antigen, and starting building up the second layer. Here we have some antibody, but this is an antibody towards a different molecule and will not attach itself. And here we have some other protein molecules, and they will not attach themselves either. So out of this rabbit serum,
29:01
because of immunology, you select just as very small fraction of all the, see 100,000 different kind of molecules, which are there. And you can find out whether a rabbit has been subjected to BSA or not, or you can find out what kind of sicknesses is ahead, because it comes in the blood. So the next slide shows the final rule.
29:23
You see, I added on, I'm sure this is not proper English, but it goes over well in the region, I can tell you that, that the last rule is that any other protein accept its proper antibody or antigen, and antibody will stick to an antigen or vice versa, and a very specific reaction. Now the next slide shows some people
29:41
who had been in this area before, which I didn't know about, but I should have. Langmuir is a Nobel Prize winner, and he also worked for General Electric Company. And he was actually the first person who did immunology on a surface, but he dropped it right away. He was in and out in many fields, he was a very clever man.
30:00
But there is a person I'd like to speak a little bit about, he's Alexander Roten, and I think he is Swiss originally, he's been associated with the Rockefeller University. And he turned out, unbeknownst to me, when I did this experiment, that he had done a very similar experiment using the ellipsometer to detect immunological reactions.
30:20
Now unfortunately, and I don't say this, I want to detract from Professor Roten, and fortunately some of his experiments are really in error, at least in my judgment. But he certainly did this thing first, but because of some of the experiments in error, people have believed, I think, that the ellipsometer does not work, and this is not true.
30:41
The ellipsometer is just a great way of doing this kind of experiment, and I hope that I will be a better salesman for the ellipsometry method than Professor Roten has been. As I said, I work for General Electric Company, and we are a profit-making organization, at least sometimes. And we got very excited about this method
31:03
for using for practical immunology in hospitals. And so we tried to sell the medical profession on this method using ellipsometry to study, say, various kind of diseases you might have had. And we had several medical doctors looking at this, and while they were impressed,
31:22
they also thought the system was too complicated. And they probably were right, but in my, see, because as a typical physicist, I have now taken the ellipsometer, I had a laser as a light source. You don't need a laser as a light source, but you can have a plaque on your door saying, danger laser, and that looks very jazzy.
31:41
So I had that, and I had a, I shopped the laser light and locking amplifier. You know, physicists tend to make simple things very complicated, and I had done that as well, and so the medical profession thought it was nice, but it was too complicated. And in my dark moment, I had a feeling that almost everything is too complicated for the medical profession.
32:02
But that adjusted my dark. Actually, I'll probably break my leg now and I get in trouble. Actually, you should remember that the medical profession works on the most complicated thing of all, namely they work on us, and I'm really saying this with tongue in cheek. The problem is that they know as little about physics
32:21
as I know about medicine, that's where the problems are. Anyway, since it was clear to us that this was not such a good system for the medical profession, we looked around to find out whether we could make use of these rules, but on a simpler system. So we don't need this complicated piece of equipment. And we came up with one which is called the indium slide,
32:43
and I'll now demonstrate for you. The next slide shows an indium slide. What this is is simply a glass slide, it's a square glass slide, onto which I have deposited indium. Indium is a metal, and when you deposit indium on a slide like that, it goes down in little metal particles.
33:02
So it is not a continuous film of indium, but it's very small metal particles of indium. And what you're looking at actually is not a picture, but it's a real indium slide and mounted in one of these transparencies. You're not looking at a picture, you're looking at a real thing. And when the light in the thing hits the indium particles,
33:22
the light is scattered out, and therefore this looked darker than where you have no indium particles, because you do not scatter the light. And the next slide shows the electron micrograph. Oh, this is how the indium slide looks to your eye, and this is how it looks to an electron microscope. And you clearly see here you have small metal particles.
33:44
And I am jokingly saying that this proves that I have become a bona fide biologist, because you look carefully on this slide, you find out there's no scale on the slide. And I don't know if you've read biology books, but they absolutely never put scale on their electron micrographs, you see, right?
34:01
So this is my way of striking back. But I forgot, as I'm sure they do, not to keep things secret, but this metal particle is the order of wavelength of light. It's approximately 5,000 angstrom in size. Now, amazingly enough, when you stick such a slide in BSA,
34:21
and the next slide, please. When you stick such a slide in BSA, this slide will have been tipped in one end and put into BSA, the protein will absorb on the indium particles. I told you protein will absorb on anything which include indium particles. But the amazing thing is that this thin layer, which is like 30 angstrom thick,
34:41
you can actually see with your naked eye. And therefore, you shouldn't be surprised when the lopsometer can see things as a fraction of an angstrom when you can see, say, 20 angstrom or so with your naked eye. And it really is amazing. If you take a protein molecule and absorb on any other kind of surface, it will be there, but you can't see it.
35:01
Lipsometer could, but you cannot. You have to have these indium particles just to bring this protein molecule forward. Now, the next slide shows that there's always an explanation for anything, and it's also an explanation for this. And that is if you, this is done by Scharfman, and this was done with large metal spheres,
35:21
with single metal spheres, and he used radio waves onto these spheres for some purpose of radar, I think. And here is the scattering of radio waves from a naked sphere. And now if you put thin layers of dielectric coating on the sphere, you get a large amount of scattering when the sphere is the order or the wavelength of light.
35:42
And people ask me to explain this, and I really can't. I mean, the best way to explain it, let's say, is buried someplace in Maxwell's equations. You know, we gotta do, you know, spherical geometry and all these sorts of things, and it gets very complicated. And so the problem is complicated, but I mean, it's straightforward. All I do, I use metal spheres,
36:01
except they are much, much smaller than this, and I use thinner layers and everything else, but it scales with this problem pretty well. Okay, let me show you now how you can do immunology this way. This is shown on the next slide. Here, this is now real pictures. You see, it helped to take photography of it rather than doing it with your naked eye,
36:21
but here is an indium slide by itself. If you tip it over and put BSA on it, you see the BSA will absorb, and it becomes visible to you. Now, if you take this slide and dip it into a protein which does not contain antibodies, you see, this corner will have been in the solution twice, but it doesn't look any darker,
36:42
because you don't get any absorption here, because protein does not stick to any other protein, except when you deal with immunology particles. However, if you put one layer of BSA here, say, and over here, I put egg albumin, and which has nothing to do with BSA. Now, we dip this into rabbit serum, which contains antibodies to BSA,
37:02
and you see now the antibodies selectively go over and attach themselves over here. They do not attach them there, because antibodies are very specific. They only attach themselves where they are supposed to, and you see here, you can actually see this AA very well, and you can do immunology this way, and this hopefully is a simple method
37:22
by which you could do it. The next slide shows you how it actually looked. This is not a picture now. This is a real slide, and you clearly can see this corner here looks very much darker. What you're looking at here is something like 100 angstrom, compared to here, something like 50 angstrom, so you see it's a big difference.
37:42
I'll tell you some fun and games now. Since I worked, this is probably uncustomary for you to talk to people who work for corporations. Every year in General Electric Company, we have the opportunity to explain to our management what we have done that previous year, and as you can understand,
38:01
that's a week of high creativity on the scientists, and but this particular year, I had actually done something, and I'm gonna show you now for fun what I showed the management of General Electric Company. And on the next slide, I hope you can see this, I took a slide, and I carefully wrote, with a protein B as A, I wrote the letters B as A,
38:25
you see, right? And you can clearly see these letters standing up towards the background, and they're hopefully clearly visible up here. And now if you see, when you explain things to managers, you have to explain it such that they can understand it, or at least so they think they can understand it,
38:41
which is equivalent. And sometimes in General Electric Company, they are not too skilled dealing with protein molecules and things, so this is why for these slides. Now I take this slide and I dip it into rabbit serum, but this rabbit has never been exposed to B as A, so it does not have antibodies. And the next slide shows you what happened.
39:02
What you see here is that the rabbit serum, the protein in rabbit serum absorbs on the slide, and even though the letters B as A is still here, the background have become equally thick, and therefore you can't see the lettering anymore. They simply have disappeared. I mean, even though it says B as A there.
39:20
And I can prove it says B as A there, because if you take this slide, where it looks like that, and dip it into another solution, where the rabbit have had antibodies to B as A, what happened is shown in the next picture, is that the antibodies selectively find a correct spot and build up a double layer over the original letters.
39:40
And you again can see the layers, the letters B as A. You see, now you're looking at 100 angstrom letters on the background of 50 angstrom, and you can see that very well, or hopefully you can see it. You see, now you have a very simple method, and the medical profession, I think, is very delighted with that, because sometimes nurses and laboratories make mistakes,
40:02
but if you have imagination now, you can imagine that you're right what ails you on the slide. And you dip it into your blood, and then you just read it off, you see, right? Whatever is wrong with you. And hopefully that will work very well. I also proposed that they could put the bill
40:22
on the slide at the same time. And they liked that. Now, I've been talking here about B as A and the rabbit, and we have actually extended this system. We have looked at two practical systems, which I won't have time to go into. We have looked at hepatitis, which is a serious liver ailment,
40:42
and this is transmitted by blood transfusion from one person to the next. And this system works very well for that. And we also looked at the system by which you can detect cancer of the stomach, and the system is not quite satisfactory for that particular thing. And in immunology, what you have to do,
41:00
you have to detect very small quantities of molecules. And the best way, we were hoping that this should compete. There are many different ways of doing this, and we were hoping that this surface immunology should compete when they tag molecules radioactively. But by radioactively, they can detect things down to a nanogram or so per milliliter,
41:22
and we are a factor of 10 away from that. We do about 10 nanograms per milliliter, which is absolutely agonizing to me, but as I understand it now, it's a fundamental limit, and unless I get a very bright idea, I can't do anything about it. I was hoping it would replace radium unase, but it will not. And it's only good for a system
41:40
where you get down to about 10 nanograms or so, which is still pretty good, because it's a factor of 100 or so better than the other simple system which I know about. So I'm great optimistic about this system. But I won't tell you about that, because it gets a little too involved and too technical. What I'd like to tell you about is
42:00
the value of being ignorant, and that's always good, I think. And when I had done these kind of experiments first at General Electric Company, I gave a talk. And we have some, I'm not a protein chemist, but we have people there who are skilled in protein chemistry. And so they asked me, after they saw this and was in as good form as it is today,
42:21
they asked me, what kind of buffer do you use? And I said, buffer, buffer. I try to gain some time. And then I got the bright idea. And I said, what kind of buffer do you use, you see, And see, I'm a mechanical engineer. And in mechanical engineering, buffers
42:40
is something which keeps trains apart. But in protein chemistry and chemistry in general, buffers is something which keeps the pH of a solution constant. And I didn't know, but it's very important in protein chemistry to keep the pH of the solution constant. And so everybody uses buffers to do that. And so I asked him, and he said, he used phosphate buffer.
43:02
It's a very common thing to use in protein chemistry. So I said, fine, I'll use phosphate, and I'll do it all over again. And I'll show you it works. But to my amazement, when you put protein in phosphate buffer, nothing sticks to a surface. The rules have changed. Protein in phosphate buffer do not stick to surfaces at all.
43:22
You see, right, that's just absolutely amazing. So if I had been more knowledgeable at that time, I wouldn't have given this talk today, you see, right? Matter of fact, the last slide, can I have the last slide? I hope you see it. I put BSA here on the slide. But then I put, after that, I put two drops of phosphate buffer, pH 8 and pH 7 on the slide.
43:43
And then I washed it off. And you see, the phosphate buffer actually removes the protein from the slide. And I got this brilliant idea of making the general electric dishwashing detergent, and to take the eggs away from the plates we have in our dishwashers, you see, right? Little did I know that the dishwashing detergent,
44:02
everybody uses phosphate in their detergent. And it's a great pollutant. And they would love to find some way of getting rid of the phosphate. And I have no idea why phosphate take proteins off the surface. And I promised myself I one day will try to look at that. But I haven't had time yet. Maybe one of you would like to look at the biological problem that way.
44:23
Well, in conclusion, then, I like to say that the ilepsometer, I'm very excited about that. And I think it can tell you something about protein on surfaces, and probably also about membranes and surfaces. And I hope I get time to expand into that. Then we have this system of indium slides,
44:42
which is a practical system, since I basically work a large amount in applied physics. It's a practical system. And it shows you whatever you are dreaming out and trying to do, that it sometimes can lead to a result which may or may not have practical importance. Thank you.