00:00:00 So, Alfred Murski and I talked with one another about the question, what is a molecule of

00:00:26 ovalbumin-like, or a molecule of hemoglobin.

00:00:32 We asked, what happens when you boil an egg and the egg white becomes insoluble, or when

00:00:38 you heat blood and the hemoglobin in the blood becomes insoluble, too?

00:00:46 Or you can add acid or alkali chemicals, certain chemicals will denature proteins, change them

00:00:55 so that they no longer have the properties that they had, such as solubility in water.

00:01:02 The conclusion we reached was that the polypeptide chains in a protein, which would be far longer

00:01:11 if they were stretched out than the diameter of the molecule, are coiled back and forth,

00:01:17 and that they are coiled into a very well-defined structure, configuration, with the different

00:01:25 parts of the chain held together by hydrogen bonds.

00:01:29 The reason for our assuming that hydrogen bonds were important here is that reagents,

00:01:36 which we know react with hydrogen bond-forming substances, can act as denaturing agents for

00:01:45 proteins.

00:01:48 If I could stop you there, maybe, and get you—assume that our viewers don't even

00:01:54 know what a hydrogen bond is.

00:01:56 Could you explain in a little bit more detail how a polypeptide chain forms into the molecule?

00:02:06 The hydrogen bonds that we thought about in connection with proteins, native proteins,

00:02:14 which have a well-defined structure and well-defined properties, were discovered in 1920 in the

00:02:23 University of California by two young chemists there, Latimer and Rodebusch.

00:02:30 They had the idea that a hydrogen atom, which usually is attached just to one atom—in

00:02:39 water, you have two hydrogens attached to an oxygen atom, and in acetic acid, say, CH3COOH,

00:02:52 you have the hydrogen atom attached to one of the two oxygen atoms.

00:03:00 The properties of some of these substances, especially containing oxygen and nitrogen

00:03:08 atoms or fluorine, along with hydrogen atoms, were such as to indicate that something is

00:03:16 holding molecules together other than the usual forces that constitute the chemical

00:03:25 bond.

00:03:26 In the water molecule, it turned out that each oxygen atom forms two hydrogen bonds,

00:03:36 using its hydrogen atoms to two other oxygen atoms, and also two other oxygen atoms form

00:03:43 two hydrogen bonds to it, using their hydrogen atoms.

00:03:47 So the water molecules in ice are held together by these hydrogen bonds strongly enough so

00:03:55 that the melting point of ice is much higher than a chemist who didn't know about hydrogen

00:04:03 bonds and didn't know what the melting point was would have anticipated.

00:04:09 The molecules of acetic acid, the acid in vinegar, CH3COOH, turned out not to be CH3COOH

00:04:23 in the vapor phase or in solution in chloroform or some other solvent.

00:04:29 Instead, there are double molecules formed.

00:04:33 Two of these molecules come up, and the hydrogen atom attached to one oxygen atom hooks onto

00:04:40 another oxygen atom in the other molecule.

00:04:43 Similarly, the OH on that molecule hooks onto this oxygen atom.

00:04:49 So you get two hydrogen bonds between the two molecules of acetic acid.

00:04:55 In the course of time, during the years from 1920 to 1940, 1938, much had been learned

00:05:06 about the nature of the hydrogen bond.

00:05:09 Nitrogen, oxygen, and fluorine, when there's a hydrogen atom available, tend to hook on

00:05:17 to one hydrogen atom to form a bond between the two oxygen atoms, or nitrogen and oxygen.

00:05:31 We knew that in proteins, there are nitrogen atoms with a hydrogen attached, and there

00:05:38 are also oxygen atoms attached to carbon without a hydrogen attached.

00:05:44 We assumed, even before anything was known about the structure of these substances, that

00:05:51 you could form NHO hydrogen bonds.

00:05:56 So Mirsky and I said, in the globular proteins, such as ovalbumin or hemoglobin, the polypeptide

00:06:05 chain twists around, and one part, one group is held to another group in another part of

00:06:14 the chain by hydrogen bonds.

00:06:20 We said, in the presence of a denaturing agent, which could be heat or acid or alkali or some

00:06:27 substance, other than hydrogen, hydroxyl ion, the polypeptide chain unfolds from its native

00:06:38 conformation.

00:06:41 Then if you have these unfolded polypeptide chains, for example, if you put the hemoglobin

00:06:47 in alkali, it unfolds.

00:06:51 If you now add acid to bring it back to neutrality, the chains form hydrogen bonds with one another,

00:06:59 or within the chain, but often, one molecule forms hydrogen bonds with another molecule

00:07:06 and another and another, so that instead of a nice globular protein, you have a coagulant,

00:07:17 just a great mass of molecules all fastened to one another and tangled with one another,

00:07:23 held together by the hydrogen bonds.

00:07:26 That's the process of denaturation, unfolding the polypeptide chains.

00:07:33 Obviously, the next question was, just how do the polypeptide chains fold?

00:07:43 I began working on that problem.

00:07:46 Other people, too, began working on the problem.

00:07:49 One thing that you can do in those days was to take protein, for example, hair.

00:07:56 Take a hair and shoot a beam of X-rays at it, and the beam of X-rays gets scattered

00:08:02 off in certain directions preferentially, so if you have a photographic plate, you get

00:08:09 spots on it.

00:08:12 This is the way you study the structure of crystals with X-rays.

00:08:16 You take a crystal, pass a beam of X-rays through it, have the photographic plate, and

00:08:21 you get a very nice pattern of spots.

00:08:24 With the hair, you didn't get a very nice pattern.

00:08:27 You got a pattern, but it was pretty diffuse.

00:08:30 Nevertheless, it provided some information about the structure of hair.

00:08:37 Not enough to show how the polypeptide chains are folded, but enough to be sort of suggestive.

00:08:45 In 1937, I spent a good bit of the summer with models where I assumed that I knew what

00:08:53 the polypeptide chain looks like, except for the way in which it's folded.

00:08:58 I wanted to fold it to form the hydrogen bonds.

00:09:02 I didn't succeed.

00:09:04 The fact is, I thought that there was something about proteins that perhaps I didn't know.

00:09:12 By 1938, 1937, a method of making a more vigorous attack on determining the structure

00:09:22 of a protein had been discovered by a man named Patterson.

00:09:27 This was the first step toward direct methods of using X-ray diffraction to determine the

00:09:34 structure of crystals.

00:09:37 It was useful enough so that it became possible to determine the structure of amino acid crystals,

00:09:45 glycine, alanine, and other amino acids, and even simple peptides, glycylglycine or glycylalanine

00:09:55 or alanine, or a tripeptide.

00:10:02 In my laboratory in Pasadena, a number of my collaborators and students worked for several

00:10:10 years using X-ray diffraction and the Patterson technique to determine the structure of a

00:10:19 dozen amino acids and three or four simple peptides.

00:10:26 By 1948, it was evident, I realized, that my guess that there was something unusual

00:10:46 about amino acids and peptides was wrong.

00:10:52 We hadn't learned anything that we hadn't known back in 1937 from the study of other

00:11:00 simpler molecules.

00:11:02 The chemical bonds all had the same lengths, carbon-carbon bond length of 1 and 5,400 songstroms,

00:11:12 carbon-nitrogen 1 and 4,700 songstroms, carbon-oxygen 1.43.

00:11:19 If you form a double bond, it shortens down to 1.28.

00:11:25 The tetrahedral angle, these features showed up in the amino acid crystals and in the simple

00:11:34 peptides.

00:11:35 Nothing new.

00:11:36 What happened at that point?

00:11:39 At that point, 1948, eleven years after I had made my first effort to determine the

00:11:47 structure, the way in which polypeptide chains are folded, I decided one day to try again.

00:11:56 I was in Oxford that year as Eastman professor.

00:12:00 I remembered what the X-ray pattern of a hair looks like, this diffraction pattern, and

00:12:09 I thought, I'll see now if I can find how to fold a polypeptide chain so that it agrees

00:12:17 with this pattern and could be the structure of the hair.

00:12:24 The same structure, the same pattern is shown by fingernail, so hairs were growing laterally

00:12:29 across the fingernail.

00:12:30 In fact, that's essentially what it is.

00:12:36 Staple, too, gives pretty much the same pattern, so it's a common pattern for fibrous proteins.

00:12:46 Silk has a quite different pattern.

00:12:49 If you take a hair and treat it with a permanent wave solution, it becomes so flexible that

00:12:59 you can stretch it out to more than twice its original length.

00:13:03 Then, if you don't put on the fixer, what you do when you get a permanent wave, but

00:13:09 just keep it in this stretch position and take the X-ray photograph, it looks more like

00:13:15 a photograph of silk fiber than a photograph of an ordinary hair.

00:13:21 It's changed to a different way of arranging the polypeptide chains.

00:13:26 So far, I knew then that the polypeptide chain in ordinary hair must wiggle back and

00:13:34 forth.

00:13:35 Ordinary hair is said to be the protein alpha-keratin.

00:13:38 Keratin, spelled with a K, is the protein that makes up hair and horn and fingernail,

00:13:49 not muscle, but muscle has a similar structure.

00:13:55 I wanted to find some way of folding a polypeptide chain so that the residues were only a little

00:14:09 less than half the effective length in this direction that they would have if it were

00:14:15 stretched out.

00:14:17 Well, I succeeded.

00:14:20 It only took a couple of hours of work that day in March of 1948 for me to find the structure

00:14:30 called the alpha helix.

00:14:33 This alpha helix structure occurs not only in hair, horn, fingernail, and muscle.

00:14:40 The alpha keratin proteins and muscle, actin and myosin, actin and myosin, which are the

00:14:50 proteins in muscle, but also in hemoglobin.

00:14:56 In hemoglobin, you don't have an alpha helix that goes on and on and on.

00:15:02 You have a helix involving 20 or 30 amino acid residues, perhaps 7 or 8 turns, and then

00:15:10 it bends a corner and you have another helix.

00:15:14 In the hemoglobin molecule, there are about 32 of these segments of alpha helix.

00:15:21 In fact, hemoglobin contains four polypeptide chains, and each of these chains has a structure

00:15:30 involving about eight sequences, alpha helix sequences, using up about 85% of the amino

00:15:39 acid residues, and the others are involved in turning the corner.

00:15:43 How did you work out the structure?

00:15:47 Is this the story of the piece of paper?

00:15:50 Yes.

00:15:51 Yes, it's a well-known story.

00:15:53 Okay.

00:15:54 Yes.

00:15:55 If you could just tell it to the viewer who is—

00:15:57 In 1937, I had some simple molecular models, wooden balls.

00:16:04 A carbon atom was a black ball, like graphite, with holes bored in at tetrahedral angles,

00:16:12 and some rod sticks, which I could stick into these holes.

00:16:18 These are the bonds, and the nitrogen atom with three holes for its three, valence three,

00:16:26 and the hydrogen atom with just one hole for valence one.

00:16:30 I knew the dimensions, how long these sticks were to be to represent a carbon-carbon bond

00:16:36 and a carbon-nitrogen bond, so I tried building these models.

00:16:41 I built so many models by 1948 that I could sort of do it in my head, or just on a sheet

00:16:49 of paper.

00:16:50 So I took—here's a sheet of paper.

00:16:56 Okay.

00:16:57 Let me stop you right there for a second.

00:17:04 Fifteen thousand dollars, with which I made three 50-minute films.

00:17:11 What you were saying before we stopped was about, you built so many models, you could

00:17:17 in your head, or I could do them on a piece of paper.

00:17:20 So maybe if you could just pick it up at that point, I'd build something.

00:17:23 Yes.

00:17:24 Well, this day in March of 1948 in Oxford, I had a cold.

00:17:35 I was lying in bed for two or three days, and I read detective stories, light reading

00:17:41 for a while.

00:17:43 Then I got sort of bored with that.

00:17:45 So I said to my wife, bring me a sheet of paper, and I'm going to—I think I'll

00:17:50 work on that problem of how polypeptide chains are folded in proteins.

00:17:55 So she brought me a sheet of paper and a slide rule and a pencil, and I started working.

00:18:04 The sheet of paper that I had was ordinary eight, half by eleven, but I'll use this

00:18:12 sheet of paper, which you can see from a little distance.

00:18:22 I said, I'll draw a stretched out polypeptide chain, two dimensions roughly.

00:18:30 I don't need to make them accurate, these dimensions.

00:18:36 The polypeptide chain is CHR, R is for residue, which can be a hydrogen atom or a methyl group

00:18:46 or something like that.

00:18:48 Then I'll connect that to a carbon atom and connect that to a nitrogen atom.

00:19:01 This nitrogen atom has a hydrogen atom attached like that.

00:19:06 The carbon atom has an oxygen atom attached like that.

00:19:12 Then the nitrogen atom hooks on to another alpha carbon atom, they're called.

00:19:20 So I'll draw a line parallel to that one, CHR, and then just repeat that.

00:19:30 The carbon atom forms four bonds.

00:19:33 Carbon is quadrivalent.

00:19:35 Van't Hoff, in fact, said not only is it quadrivalent, as Kekulé had said and Franklin,

00:19:45 Englishman Franklin and German Kekulé, back about 1860.

00:19:51 Van't Hoff said the four bonds are pointed in tetrahedral directions,

00:19:57 109 and a half degrees apart, the tetrahedron.

00:20:03 Well, I'll draw that bond down there.

00:20:08 Here's C, O, N, H, C, H, R.

00:20:21 C, O, N, H, C, H, R, C, O, and so on.

00:20:43 Well, I could draw those and have the bond lengths just about right,

00:20:49 it's a certain scale, and the bond angles right, too.

00:20:55 And the very interesting thing about peptides is that this group of six atoms there,

00:21:05 the CN in the middle, the carbon, oxygen, hydrogen, carbon,

00:21:09 that group is a planar group.

00:21:13 And I knew that in 1937.

00:21:17 The theory that I'd been working on,

00:21:19 theory of chemical bonding and resonance,

00:21:22 required that this group be planar,

00:21:25 because there's some double bond character to the carbon-nitrogen bonds,

00:21:31 and double bonds introduce coplanarity.

00:21:37 So, there's a plane.

00:21:40 Here is a plane.

00:21:44 Here is a plane, and so on.

00:21:48 A succession of planar groups.

00:21:50 But this chain is pretty wobbly, wiggly,

00:21:55 because this carbon-nitrogen bond, you can rotate around it,

00:22:00 and you can rotate around this carbon-nitrogen bond,

00:22:04 and around this one.

00:22:06 So that by rotating around these,

00:22:10 the chain can assume a very large number of configurations.

00:22:15 Moreover, what's wrong about this plane,

00:22:19 the structure that I've put here,

00:22:22 is that the angle between these two bonds is 180 degrees.

00:22:28 But it ought to be 109.47 degrees.

00:22:35 The tetrahedral angle, not 180 degrees.

00:22:39 What's to be done next?

00:22:42 Well, I said, I don't know why I hadn't done this in 1937.

00:22:48 I don't think I got any smarter by 1948 than I was in 1937,

00:22:55 and I didn't really know anything new.

00:22:59 I said, suppose that all these residues

00:23:03 are equivalent to one another.

00:23:05 I know then that the structure that they have to assume

00:23:11 will be that of a helix.

00:23:14 There's a mathematical theorem that I have learned

00:23:20 that two equivalent asymmetric objects

00:23:27 are related to one another

00:23:29 by rotation around an axis and translation.

00:23:32 So I can make this angle the tetrahedral angle

00:23:37 by bending, by putting in a dihedral angle here.

00:23:45 If I make that angle right,

00:23:47 then these two bonds are no longer forming

00:23:51 a straight angle, 180 degrees,

00:23:53 but I can get them down to 109.5 degrees.

00:23:57 And with my assumption of equivalence of the residues,

00:24:03 then I have to make the same bend

00:24:09 with a parallel edge,

00:24:16 the same bend at the next,

00:24:19 and then the same bend at the next.

00:24:25 And if I've chosen the angle of slant right,

00:24:32 then this ought to come out

00:24:36 in such a way as to form a hydrogen bond.

00:24:41 Well, you see, I have a CO sticking down here

00:24:49 and an NH sticking up here.

00:24:53 I didn't finish that.

00:24:55 My angle isn't quite right.

00:24:58 I'd have to make a second trial.

00:25:02 But I found that by folding the paper,

00:25:07 and it took three or four efforts,

00:25:10 by folding the paper

00:25:12 in the right direction, like this,

00:25:15 then this fourth residue

00:25:17 had its nitrogen atom

00:25:19 just in the right position

00:25:22 to...

00:25:28 just in the right position

00:25:31 to permit its NH

00:25:35 to come up

00:25:37 and form that hydrogen bond.

00:25:41 Well, there's more to the story than that.

00:25:45 The other people

00:25:49 have been working on the same problem.

00:25:52 And in particular,

00:25:54 Professor Bragg,

00:25:56 Sir Lawrence Bragg,

00:25:58 and his associates,

00:26:00 Kendrew and Perutz,

00:26:03 who had been working on myoglobin and hemoglobin,

00:26:06 were trying to fold polypeptide chains,

00:26:09 and they hadn't succeeded

00:26:11 in finding the alpha helix.

00:26:13 But Max Perutz

00:26:16 thought of a way of checking

00:26:19 whether the alpha helix is present or not

00:26:22 by taking an X-ray photograph of a hair,

00:26:25 putting the hair at a different angle

00:26:27 from the conventional one,

00:26:29 not just straight up, but over.

00:26:31 So he very quickly was able to verify

00:26:34 that the alpha helix is present in the hair.

00:26:37 And...

00:26:41 Kendrew, John Kendrew,

00:26:43 doing his doctoral work

00:26:46 at Cambridge with Max Perutz,

00:26:49 determined the detailed structure

00:26:52 of a globular protein, myoglobin,

00:26:55 locating all of the atoms,

00:26:58 not very accurately,

00:27:01 but well enough so you could see

00:27:03 the polypeptide chain

00:27:05 and see the segments of alpha helix.

00:27:07 Max Perutz did a similar job

00:27:09 on hemoglobin

00:27:11 with each of the four subunits

00:27:13 of hemoglobin

00:27:15 having these eight segments

00:27:17 of alpha helix.

00:27:19 At the present time,

00:27:21 there may have been

00:27:23 300 or 500

00:27:25 globular proteins

00:27:27 that have had their detailed

00:27:29 molecular structure

00:27:32 locating all or most

00:27:34 of the atoms determined.

00:27:36 One of the other things

00:27:38 that we're going to do in the show

00:27:40 is relate how that

00:27:42 structure, on a very simple level,

00:27:45 relates to the function of a protein.

00:27:47 Could you talk a little bit

00:27:49 about that in terms of, say,

00:27:51 a hair or

00:27:53 an enzyme, globular protein?

00:27:55 How the structure determines

00:27:57 the function of macroproperties

00:27:59 of a protein molecule?

00:28:06 I had a student,

00:28:08 postdoctoral man,

00:28:10 working with me

00:28:12 in the 1930s.

00:28:14 He

00:28:18 went on

00:28:20 during the Second World War

00:28:22 to the Manhattan District

00:28:24 and discovered

00:28:26 an element, promethium.

00:28:28 He and two of his

00:28:30 assistants discovered

00:28:32 this missing element,

00:28:34 promethium.

00:28:36 With me, he

00:28:38 was working on

00:28:40 hemoglobin. He and I,

00:28:42 even before we

00:28:44 knew about the polypeptide

00:28:46 chains,

00:28:48 we didn't know

00:28:50 how they were folded

00:28:52 into the alpha helix,

00:28:54 were trying

00:28:56 to understand

00:28:58 why

00:29:00 iron atoms

00:29:02 attach oxygen

00:29:04 molecules to them.

00:29:06 I had found the explanation

00:29:08 of that. But also

00:29:10 we wanted to find

00:29:12 out why

00:29:14 the iron

00:29:16 atom

00:29:18 is in the

00:29:20 bi-positive state

00:29:22 that is, you can say it's

00:29:24 iron plus two.

00:29:26 Iron compounds can be either

00:29:28 almost all iron compounds

00:29:30 are either ferrous

00:29:32 salts, compounds

00:29:34 of iron with

00:29:36 valence of two,

00:29:40 oxidation number

00:29:42 plus two, or ferric salts.

00:29:44 For example, FeCl2,

00:29:46 ferrous chloride,

00:29:48 FeCl3,

00:29:50 ferric chloride.

00:29:52 There are many

00:29:54 thousands of iron salts

00:29:56 that are either ferrous or ferric.

00:29:58 The ferrous salts are very easily

00:30:00 oxidized. If you

00:30:02 take a ferrous

00:30:04 sulfate or ferrous chloride

00:30:06 solution, open to the

00:30:08 air, it begins

00:30:10 very quickly to change color.

00:30:12 This

00:30:14 means it's being oxidized

00:30:16 to the ferric state.

00:30:18 But hemoglobin

00:30:20 contains four iron

00:30:22 atoms in the ferrous state.

00:30:24 If you want

00:30:26 to put in an oxidizing

00:30:28 agent, it's easy enough to convert

00:30:30 the hemoglobin to

00:30:32 ferrihemoglobin

00:30:34 that contains ferric

00:30:36 iron atoms,

00:30:38 three plus rather than ferrous.

00:30:40 But this doesn't

00:30:42 happen in the blood, even though

00:30:44 it's hooking on the oxygen.

00:30:46 There's plenty of oxygen there

00:30:48 to oxidize it. It stays

00:30:50 in the ferrous form.

00:30:56 We studied the acid-base

00:30:58 properties of hemoglobin

00:31:00 and decided that

00:31:02 there was a certain

00:31:04 amino acid residue.

00:31:06 In fact, that there were two

00:31:08 residues

00:31:10 in the polypeptide chain

00:31:13 of the

00:31:15 same amino acid,

00:31:17 histidine.

00:31:19 Histidine has

00:31:21 its side chains up close

00:31:23 to the iron atom.

00:31:25 In fact, one of them

00:31:27 forms a regular chemical bond.

00:31:29 The nitrogen

00:31:31 atom in the

00:31:33 side chain ring, imidazole

00:31:35 ring of the

00:31:37 histidine

00:31:39 residue forms

00:31:41 a covalent bond to the iron atom.

00:31:43 The other one

00:31:45 does not. It's a little

00:31:47 farther away.

00:31:49 What it does is this.

00:31:51 It picks up a proton.

00:31:53 It's basic enough

00:31:55 so that it picks up a proton

00:31:57 and that

00:31:59 imidazole ion

00:32:01 with a positive charge

00:32:03 is right there close to the iron atom.

00:32:05 The result is

00:32:07 that

00:32:09 it tends to keep

00:32:11 the

00:32:13 iron atom

00:32:15 in the

00:32:17 ferrous state

00:32:19 instead of going to a ferric

00:32:21 state. If it went to ferric

00:32:23 state, iron would have

00:32:25 a charge 3+, having lost

00:32:27 an electron, and it would

00:32:29 be repelled by this

00:32:31 NH

00:32:33 group, the NH+,

00:32:35 the positively charged group of the

00:32:37 histidine side chain.

00:32:39 We assumed

00:32:41 that these

00:32:43 two histidines are in these positions

00:32:45 even though nobody

00:32:47 had yet determined how

00:32:49 the polypeptide chain

00:32:51 of globin wraps itself

00:32:53 around the iron atom

00:32:55 and the attached atoms

00:32:57 of the heme group.

00:32:59 That was done purely

00:33:01 by chemical arguments,

00:33:03 not x-ray diffraction.

00:33:05 When

00:33:07 the structure was finally

00:33:09 determined of myoglobin

00:33:11 and hemoglobin,

00:33:13 here you could see

00:33:15 that there were those histidine residues.

00:33:17 Kendrew and Perutz

00:33:19 located, identified

00:33:21 the residues in the polypeptide

00:33:23 chains, and there were

00:33:25 chemists, protein chemists, who were

00:33:27 using chemical methods

00:33:29 of sequencing, starting

00:33:31 with the free amino

00:33:33 end, what the first residue

00:33:35 is, the second, the third, the

00:33:37 fourth, fifth, and so on.

00:33:39 We

00:33:41 were able to interpret

00:33:43 some of the

00:33:45 properties of hemoglobin

00:33:47 even back in the

00:33:49 1930s, and now, of course,

00:33:51 a great deal can be

00:33:53 said about the structure of

00:33:55 hemoglobin.

00:33:57 In

00:33:59 1945,

00:34:01 I had an

00:34:03 idea about a disease.

00:34:05 The reason

00:34:07 that I had this idea

00:34:09 was that I had been working

00:34:11 on hemoglobin

00:34:13 for

00:34:15 10 or 12 years,

00:34:17 and also had been working

00:34:19 in the field of immunology,

00:34:21 studying the

00:34:23 interaction of antibodies

00:34:25 with antigens

00:34:27 and haptenic groups,

00:34:29 trying to learn why

00:34:31 an antibody

00:34:33 can

00:34:35 coagulate

00:34:37 suspension of bacterial

00:34:39 cells, learning about

00:34:41 the specificity of antibodies.

00:34:43 I heard

00:34:45 about the disease sickle cell

00:34:47 anemia, and

00:34:49 thinking

00:34:51 about it very quickly,

00:34:53 one fact

00:34:55 impressed itself on me.

00:34:58 The red

00:35:00 cells are twisted out of shape

00:35:02 in the patients with

00:35:04 this disease.

00:35:06 They look like a

00:35:08 crescent or a sickle, which is

00:35:10 where the disease got its name.

00:35:12 But in the

00:35:14 arterial blood, the red

00:35:16 cells go back to their normal

00:35:18 flattened spherical

00:35:20 shape. They're twisted out of shape

00:35:22 in the venous blood and not in the

00:35:24 arterial blood. So I said

00:35:26 to myself,

00:35:28 and in a few minutes to the

00:35:30 doctors that I was with,

00:35:32 the medical committee,

00:35:34 I said,

00:35:36 it must be

00:35:38 the hemoglobin molecules

00:35:40 that produce this change

00:35:42 in shape.

00:35:44 Suppose that a hemoglobin

00:35:46 molecule

00:35:48 manufactured by these patients

00:35:50 is different from a

00:35:52 normal hemoglobin molecule,

00:35:54 that it has a combining

00:35:56 region on one side

00:35:58 that is complementary to

00:36:00 a region on the other side.

00:36:02 So that just as an

00:36:04 antibody and an antigen will

00:36:06 clamp onto one another,

00:36:08 this hemoglobin molecule would

00:36:10 clamp onto another one,

00:36:12 and then a third and a fourth and a fifth,

00:36:14 and you'd get a big long chain of hemoglobin

00:36:16 molecules, and they would

00:36:18 line up side by side and make

00:36:20 a crystal,

00:36:22 light crystal that would grow

00:36:24 so long that it would be longer

00:36:26 than the diameter of the red cell

00:36:28 and would push the red cell

00:36:30 out of shape,

00:36:32 forming this

00:36:34 deformed structure.

00:36:36 And with

00:36:38 oxygen attached to the

00:36:40 hemoglobin, the oxygen

00:36:42 would be a sort of wart on the surface

00:36:44 that would keep the hemoglobin molecules

00:36:46 from clamping onto one another.

00:36:48 So in arterial blood,

00:36:50 you wouldn't get this

00:36:52 sickling of the red cells.

00:37:20 Okay, so we're ready.

00:37:24 You're interested

00:37:26 in the question

00:37:28 of

00:37:30 what young

00:37:32 people going into

00:37:34 chemistry might be

00:37:36 motivated by,

00:37:38 and what sort of a future

00:37:40 chemistry might have.

00:37:42 I suppose I can

00:37:44 go back to my

00:37:46 boyhood. I have a feeling

00:37:48 that after talking, being

00:37:50 with so many young

00:37:52 chemists and other scientists

00:37:54 over all of these years,

00:37:56 I have the feeling that

00:37:58 many of them had the same

00:38:00 motivations that I had.

00:38:02 So I'll talk about my

00:38:04 motivations.

00:38:06 I was

00:38:08 pretty curious about

00:38:10 the nature of the world when I was a

00:38:12 boy. I think that curiosity

00:38:14 played a big part in

00:38:16 my career. I just wanted to

00:38:18 understand things.

00:38:20 When I was 11 years old,

00:38:22 my father had died

00:38:24 when I was 9 years old.

00:38:26 My mother,

00:38:28 I guess I can say,

00:38:30 didn't understand me.

00:38:32 I think she had some difficulty

00:38:34 with my two sisters

00:38:36 a little younger than I

00:38:38 and more difficulty

00:38:40 with me. She didn't.

00:38:42 She just didn't understand

00:38:44 me.

00:38:46 I

00:38:48 didn't get along

00:38:50 especially well with

00:38:52 other boys.

00:38:54 I played baseball a little

00:38:56 and

00:38:58 other games, but not

00:39:00 very much.

00:39:02 It wasn't my

00:39:04 greatest

00:39:06 interest. I liked

00:39:08 reading especially.

00:39:11 When

00:39:13 I was 9,

00:39:15 there

00:39:17 was a letter in the

00:39:19 newspaper that my father

00:39:21 had written saying

00:39:23 that he had a son

00:39:25 8 years old, just

00:39:27 nearly 9, who

00:39:29 liked reading and he wanted to know

00:39:31 what sort of books

00:39:33 he should get me to read.

00:39:35 He said, don't say the Bible

00:39:37 and Darwin's Origin of Species

00:39:39 because he's already read them.

00:39:41 I

00:39:43 don't know.

00:39:45 I have that evidence that

00:39:47 at least I'd done some reading

00:39:49 in those books, but I can remember

00:39:51 I wanted to read.

00:39:53 I ran across

00:39:55 a book on insects

00:39:57 or some mention of insects

00:39:59 when I was 11.

00:40:01 I got a book out of the

00:40:03 Portland Library on insects

00:40:05 and I began collecting

00:40:07 insects. I made

00:40:09 quite a collection of

00:40:11 butterflies and beetles and other

00:40:13 insects when I

00:40:15 was 11.

00:40:17 My father had been a druggist

00:40:19 and a friend of his, another

00:40:21 druggist, was helpful

00:40:23 to me. When I

00:40:25 became interested in insects,

00:40:27 I told him I wanted to make a killing

00:40:29 bottle which I'd read about

00:40:31 so I needed some potassium cyanide,

00:40:33 an ounce of potassium cyanide.

00:40:35 He gave me an ounce

00:40:37 of potassium cyanide

00:40:39 and a quarter pound

00:40:41 plaster of Paris.

00:40:43 I went out on the back porch

00:40:45 because I knew that potassium cyanide

00:40:47 or HCN was

00:40:49 dangerous.

00:40:51 I mixed the plaster of Paris

00:40:53 with water and

00:40:55 poured the potassium cyanide crystals

00:40:57 into the bottom of a jar

00:40:59 and poured

00:41:01 the plaster

00:41:03 of Paris on top of it so

00:41:05 it solidified and I could put

00:41:07 the insects in the bottle and

00:41:09 that was it.

00:41:11 I did that for a year

00:41:13 and then I became interested in minerals.

00:41:15 I got a book on minerals

00:41:17 and copied tables

00:41:19 of properties and

00:41:21 I was very interested in properties

00:41:23 cleavage and color

00:41:25 and

00:41:27 other properties

00:41:29 of minerals. Later was

00:41:31 magnetic properties

00:41:33 of inorganic compounds

00:41:35 that I became interested in.

00:41:37 All along

00:41:39 chemistry

00:41:41 seemed to me to be a great subject.

00:41:43 I learned about it when I

00:41:45 was thirteen from another

00:41:47 boy my age who became

00:41:49 my best friend.

00:41:51 I went to college

00:41:53 when I was sixteen

00:41:55 to study chemical engineering.

00:41:57 I didn't know that there was

00:41:59 any profession for a chemist

00:42:01 except that of being a chemical engineer.

00:42:03 I got my

00:42:05 degree in chemical engineering

00:42:07 and

00:42:09 for one year between my

00:42:11 sophomore and junior years

00:42:13 I had a full-time

00:42:15 job teaching sophomores

00:42:17 at Oregon Agricultural College

00:42:19 quantitative analysis

00:42:21 the course I had taken the year

00:42:23 before. I liked

00:42:25 quantitative analysis

00:42:27 too.

00:42:29 In that year

00:42:31 when I was a full-time teacher

00:42:33 I learned about

00:42:35 the work of G.N. Lewis

00:42:37 on the electron theory

00:42:39 of the chemical bond.

00:42:41 A pair of electrons held jointly

00:42:43 by two atoms and

00:42:45 Irving Langer in 1919

00:42:47 wrote several very

00:42:49 interesting papers

00:42:51 going beyond

00:42:53 what Lewis had said.

00:42:55 From that

00:42:57 time on I wanted

00:42:59 to understand the chemical

00:43:01 bond.

00:43:03 The ideas about chemical bonding

00:43:05 were pretty primitive

00:43:07 hook-and-die sort of business

00:43:09 at that time.

00:43:11 There was very little

00:43:13 before 1914

00:43:15 when the Braggs

00:43:17 began their work, practically no

00:43:19 information about how close

00:43:21 together atoms are to one

00:43:24 another,

00:43:26 just what you could

00:43:28 determine, calculate

00:43:30 assuming some sort of structure

00:43:32 from a knowledge of Avogadro's

00:43:34 number, how many

00:43:36 molecules there are

00:43:38 in 16 grams,

00:43:40 how many atoms there are in 16

00:43:42 grams of oxygen,

00:43:44 or how many in 12 grams

00:43:46 of carbon, 12.

00:43:48 So

00:43:50 x-ray

00:43:52 diffraction

00:43:54 began

00:43:56 to yield results

00:43:58 that satisfied

00:44:00 some of my curiosity

00:44:02 about how atoms are attached to

00:44:04 one another. And as the years have

00:44:06 gone by, I've

00:44:08 become curious about

00:44:10 organic molecules

00:44:12 and about

00:44:14 biochemical molecules,

00:44:16 about the protein molecules in the human

00:44:18 body, and

00:44:20 about other aspects of the

00:44:22 world, too.

00:44:24 Especially now, I am

00:44:26 interested in how

00:44:28 metals interact

00:44:30 with one another.

00:44:32 So a professor

00:44:34 is in a fortunate position

00:44:36 of being able to work

00:44:38 to satisfy his curiosity

00:44:40 about the world.

00:44:42 And if he is fortunate

00:44:44 there is something new

00:44:46 about the universe, about the world

00:44:48 in which we live.

00:44:50 Here, Harlow Shapley,

00:44:52 the astronomer,

00:44:54 when he was around 30 years

00:44:56 old, I think, and working

00:44:58 at the Mount Wilson Observatory,

00:45:00 later he became professor of

00:45:02 astronomy at Harvard,

00:45:04 Harlow Shapley

00:45:06 studied

00:45:08 the

00:45:10 galaxy

00:45:12 that we are

00:45:14 in. This

00:45:16 arrangement of about a billion

00:45:18 suns, stars,

00:45:20 in a rather small

00:45:22 part of the whole

00:45:24 universe, and

00:45:26 with a sort of spiral

00:45:28 shape, he was able

00:45:30 to show that

00:45:32 Earth is not at

00:45:34 the center of the galaxy. Looking at

00:45:36 the Milky Way, which is

00:45:38 the stars in our galaxy,

00:45:40 you might think that we were pretty near

00:45:42 the center. He showed that we were

00:45:44 30 million,

00:45:46 let's see,

00:45:48 30,000 light years

00:45:50 away from the center of our

00:45:52 galaxy.

00:45:54 At the center of our

00:45:56 galaxy, there's

00:45:58 probably a heavy object

00:46:00 that has

00:46:02 hauled the stars by gravitation

00:46:04 into this galaxy.

00:46:06 I think he must have felt

00:46:08 tremendously

00:46:10 pleased with himself and happy

00:46:12 to have made that

00:46:14 discovery.

00:46:16 He made

00:46:18 another investigation

00:46:20 which probably

00:46:22 pleased him.

00:46:24 He decided,

00:46:26 he asked himself, how fast

00:46:28 does an ant

00:46:30 run?

00:46:32 He

00:46:34 saw in

00:46:36 Pasadena there, southern California,

00:46:38 a trail of ants going

00:46:40 from one place to another.

00:46:42 He timed the individual

00:46:44 ants to see how fast they

00:46:46 were going. They were going

00:46:48 faster in the heat

00:46:50 of the day than in the early morning

00:46:52 or in the evening.

00:46:54 Then he found a trail of ants

00:46:56 going across a corner of a room

00:46:58 in a house.

00:47:00 He started timing them

00:47:02 and building a fire

00:47:05 so as to bring the temperature

00:47:07 up higher and higher.

00:47:09 When he plotted the rate

00:47:11 at which the ants were running

00:47:13 against the reciprocal temperature,

00:47:15 he got a straight line.

00:47:17 He was able to determine

00:47:19 the

00:47:21 enthalpy

00:47:23 of activation,

00:47:25 the energy of activation

00:47:27 of the process that

00:47:29 makes the ants run.

00:47:31 I'm sure he was happy

00:47:33 to have determined

00:47:35 that a scientist

00:47:39 would devote

00:47:41 perhaps

00:47:43 to determining

00:47:45 the enthalpy of activation

00:47:47 of the biological process,

00:47:49 the rate-determining step

00:47:51 in the biological process.

00:47:53 Well, for years,

00:47:55 starting in

00:47:57 about 1919

00:47:59 when I took a course

00:48:01 in 1920,

00:48:03 when I took a course

00:48:05 in metallurgy,

00:48:07 metallography in Oregon

00:48:09 Agricultural College, I've been interested

00:48:11 in the metals.

00:48:13 I think one great problem

00:48:15 that young scientists,

00:48:17 young chemists might want to work on

00:48:19 is that of the nature

00:48:21 of compounds of metals

00:48:23 with one another.

00:48:25 Here, three-quarters

00:48:27 of the elements

00:48:29 are metals, and one-quarter

00:48:31 are non-metals.

00:48:33 A sixteenth

00:48:35 of the binary systems

00:48:37 are non-metal, non-metal systems.

00:48:39 And three-quarters squared

00:48:41 nine-sixteenths

00:48:43 are metal-metal systems

00:48:45 such as lithium and sodium

00:48:47 or lithium and magnesium

00:48:49 or iron and chromium,

00:48:51 these binary systems.

00:48:55 We understand organic

00:48:57 compounds very well.

00:48:59 Carbon atoms form these four

00:49:01 bonds directed

00:49:03 toward the corners of a regular

00:49:05 tetrahedron. This is a big

00:49:07 step toward understanding

00:49:09 any organic compound.

00:49:11 Inorganic compounds are a little

00:49:13 more complicated, but not

00:49:15 much more. We understand them

00:49:17 pretty well.

00:49:19 For example, potassium

00:49:21 hexachloroplatinate

00:49:23 contains

00:49:25 two potassium ions

00:49:27 and a platinum atom

00:49:29 with six chlorine atoms

00:49:31 out at the corners of a regular

00:49:33 octahedron.

00:49:35 It has these six chlorine atoms

00:49:37 attached in a well-defined

00:49:39 way, 2.32

00:49:41 angstroms from the platinum

00:49:43 to each of the six chlorine

00:49:45 and so on.

00:49:47 Metals—nobody understands

00:49:49 metals very well.

00:49:51 I've worked on trying to understand

00:49:53 metals and alloys

00:49:55 for—

00:49:57 I did my first experiments

00:49:59 on the X-ray

00:50:01 study of

00:50:03 intermetallic compounds in

00:50:05 1922.

00:50:07 That's been 66 years

00:50:09 ago. I still am

00:50:11 working on that same problem.

00:50:13 How do metal

00:50:15 atoms interact with one another?

00:50:17 Back in 1924,

00:50:19 I took some

00:50:21 mercury, put some mercury

00:50:23 in the dish,

00:50:25 a beaker, warmed it up,

00:50:27 and then took some potassium metal,

00:50:29 scraped the potassium oxide

00:50:31 off the surface,

00:50:33 and put it in, dissolved in the mercury,

00:50:35 warm mercury.

00:50:37 I was probably breathing

00:50:39 mercury vapor, you know.

00:50:41 I remember I didn't do it

00:50:43 in the hood. We weren't so

00:50:45 aware of toxicity problems.

00:50:47 I poured it

00:50:50 into a crystallizing dish,

00:50:52 and the next day when I came back,

00:50:54 here there were crystals,

00:50:56 half an inch on edge,

00:50:58 cubes with their corners

00:51:00 cut off. Cube octahedra.

00:51:02 Beautiful.

00:51:04 Of KHG-13,

00:51:06 one potassium

00:51:08 atom to 13 mercury.

00:51:10 Well, methane

00:51:12 is CH4.

00:51:14 Potassium

00:51:16 chloride is KCl.

00:51:18 Why

00:51:20 should this

00:51:22 mercury potassium

00:51:24 compound be KHG-13?

00:51:26 Well,

00:51:28 I think I understand that

00:51:30 now, but there are a lot of

00:51:32 these compounds with very

00:51:34 strange formulas.

00:51:36 In general, I don't understand

00:51:38 them and don't understand why they

00:51:40 have the properties that they have.

00:51:44 Here's a big

00:51:46 field for the future

00:51:48 that young chemists

00:51:50 who are curious about the world

00:51:52 can

00:51:54 contribute to our understanding

00:51:56 of the nature of the world

00:51:58 by making studies about

00:52:00 intermetallic compounds.

00:52:02 Can I get you to repeat that?

00:52:04 I think I may have been talking.

00:52:06 When you started your answer, I think I was talking.

00:52:08 Can I get you to go ahead and repeat that?

00:52:10 Here we have a great possibility

00:52:12 for young chemists,

00:52:14 young scientists

00:52:16 who are curious about

00:52:18 the nature of the world, who want to get

00:52:20 a better understanding. We have an

00:52:22 astonishing understanding

00:52:24 of the nature of the world

00:52:26 now compared with what we had

00:52:28 70 years ago when I began

00:52:30 the study of science.

00:52:32 But

00:52:34 we still don't understand

00:52:36 it well

00:52:38 enough.

00:52:40 Scientists are fortunate people.

00:52:42 Young

00:52:44 people, young men and women

00:52:46 who go into science, I think

00:52:48 are more fortunate

00:52:50 than their

00:52:52 compatriots

00:52:54 who don't know much

00:52:56 about science.

00:52:58 Every month, some

00:53:00 new discovery, often

00:53:02 an astonishing discovery,

00:53:04 is reported by

00:53:06 scientists.

00:53:08 Scientists can appreciate

00:53:10 these discoveries. They can

00:53:12 enjoy adding

00:53:14 to their understanding of the nature

00:53:16 of the world in a way that non-scientists

00:53:18 can't. The non-scientists

00:53:20 don't have the background

00:53:22 knowledge that enables them

00:53:24 to understand.

00:53:26 Only occasionally is there something

00:53:28 that comes along that a scientist

00:53:30 discovers that

00:53:32 everyone might

00:53:34 have an appreciation of.

00:53:36 I have a friend

00:53:38 named

00:53:44 let's see, what is his name?

00:53:46 Lewis.

00:53:48 Lewis and Walter up at Berkeley.

00:53:52 His father was a

00:53:54 well-known physician.

00:53:56 A friend

00:53:58 of mine

00:54:00 died some time ago.

00:54:04 Well, I'll think of his name.

00:54:06 Okay.

00:54:08 Lewis is

00:54:10 a physicist. He got a Nobel

00:54:12 Prize. He made

00:54:14 a liquid hydrogen bubble

00:54:16 chamber containing

00:54:18 all this liquid hydrogen and

00:54:20 studied nuclear reactions.

00:54:22 He did a lot of things.

00:54:24 His son, Walter, is a geologist.

00:54:26 His son, Walter,

00:54:28 came to him one day.

00:54:30 Here, I'm fabricating

00:54:32 this conversation. His son, Walter,

00:54:34 came to him one day and said,

00:54:36 You know, there's something strange

00:54:38 about the Cretaceous

00:54:40 and modern

00:54:42 sediments, eocene sediments,

00:54:44 say, that lie above it.

00:54:46 64 million years ago

00:54:48 was when the Cretaceous

00:54:50 ended.

00:54:52 All over

00:54:54 the world, you have these

00:54:56 layers of strata

00:54:58 full of bones,

00:55:00 fossils, full

00:55:03 of dinosaur bones.

00:55:05 Above, you have

00:55:07 layers

00:55:09 almost

00:55:11 free of bones,

00:55:13 of fossils.

00:55:15 It looks as though when the

00:55:17 Cretaceous period came to an end,

00:55:19 most animals

00:55:21 and plants became extinct.

00:55:23 All of the dinosaurs

00:55:25 died out at that time.

00:55:27 The great extinction occurred

00:55:29 64 million years ago.

00:55:31 Now, it's strange.

00:55:33 All over the world,

00:55:35 there's a layer

00:55:37 of clay

00:55:39 about

00:55:41 half an inch thick

00:55:43 between the Cretaceous rocks

00:55:45 and the other rocks,

00:55:47 the ones that have few

00:55:49 fossils in them.

00:55:51 Where can

00:55:53 that layer of clay have come from

00:55:55 all over the world?

00:55:57 One possibility

00:55:59 is that an

00:56:01 asteroid hit the earth

00:56:03 and vaporized

00:56:05 itself and a lot of

00:56:07 earth rock

00:56:09 and produced dust

00:56:11 in the sky,

00:56:13 which then gradually,

00:56:15 over a year's period, perhaps settled

00:56:17 down to earth, producing

00:56:19 this one-half-inch

00:56:21 layer of clay

00:56:23 all over the world.

00:56:25 The father,

00:56:27 Luis Alvarez,

00:56:29 Luis Alvarez,

00:56:31 I suppose, said to

00:56:33 Walter, there's a way that

00:56:35 we could check that asteroid

00:56:37 hypothesis.

00:56:39 These asteroids,

00:56:41 meteorites,

00:56:43 have a hundred times

00:56:45 as much iridium in them

00:56:47 as the terrestrial

00:56:49 rocks have. Probably

00:56:51 the terrestrial rocks' iridium

00:56:53 heavy, sank down

00:56:55 toward the core of the earth

00:56:57 when the earth was very hot and liquid.

00:56:59 If we just

00:57:01 analyze this clay

00:57:03 layer for iridium,

00:57:05 that will give us

00:57:07 the answer. They found ten times

00:57:09 as much iridium as

00:57:11 in earth rocks,

00:57:13 metal rocks.

00:57:15 Ten times, rather than a hundred times,

00:57:17 suggests that ten times

00:57:19 as much, nine times as much

00:57:21 earth rock was vaporized

00:57:23 along with the asteroid itself,

00:57:25 diluting it tenfold, you see.

00:57:27 The asteroid would have

00:57:29 been about

00:57:31 seven miles in diameter,

00:57:33 11 kilometers in diameter,

00:57:35 to have

00:57:37 produced the

00:57:39 amount of clay

00:57:41 that you have by counting

00:57:43 up a half-inch over the

00:57:45 surface of the earth.