cc  >> Welcome to Wednesday Nite  @ the Lab at UW Madison.  Thank you for joining us.  Tonight, we have a speaker who  really, I don't think needs, at  least based on the audience  here, needs much of an  introduction.  But I'm happy to introduce Dave  Nelson from the Department of  Biochemistry.  Dr. Nelson graduated from St.  Olaf with a bachelor's degree in  chemistry and biology, and then  he continued on to Stanford  Medical University where he  received his PhD in  biochemistry.  And if that's not impressive  enough, he went on to do his  postdoc at Harvard Medical  School in biochemistry.  And he's been here as a  professor since 1971 in the  Department of Biochemistry.  He actually mentioned the 1971  so I thought I'd emphasize that  he's been here for a few years,  a handful.  And many students will recognize  him. 

 He is most certainly one of the  most popular professors and well  known in biochemistry, and they  actually use his book,  "The Principles of  Biochemistry," in his class.  So without further ado, I'd like  to introduce Dr. Dave Nelson.  (applause)  >> Dave Nelson: Thanks.  And thank you all for coming  tonight.  If we were to step outside the  building to the sidewalk and  grab the next 10 people that  came by and ask them what they  could tell us about biology,  chances are that they would tell  us two things that they knew for  sure.  One is that ATP is important,  and the other is that DNA is  important.  Beyond that, we're probably  asking more than is reasonable  to ask the man on the street or  the woman on the street.  But DNA has become so central a  part of our culture that we see  it around us all the time.  I have here, for example, a set  of slides that show the many  ways in which DNA is  represented.  Artistically sometimes, and  sometimes with the effort to  make a scientific point. 

 People even build their houses  with spiral staircases and their  bike racks with spirals.  And there are now remarkably  expensive, remarkably beautiful  efforts to put on the video  screen the things that go on in  the cell like pictures of DNA  here.  This is a picture that won  somebody the Nobel Prize not so  long ago.  Here's a place that clearly is  designed in the same role, same  general picture as DNA.  Here's a piece of art that's  DNA.  We watch CSI and we know that  DNA is the stuff that they  sequence to nab the bad guys.  I teach a group of high school  kids at West High School who use  computers to generate images  like these that help them  understand what DNA is like and  what it's for.  Some people go the whole route  when they want to show how much  they care about DNA.  Many of these images are  generated now with a computer   and 50 years ago you would not  have been able to come close to  showing what these molecules are  like.  So one of the things I want to  do tonight is to talk to you  about the period of history  during which DNA was first found  and then found to be interesting  and then found to be very  interesting and then the modern  era in which it was found to be  absolutely central to biology. 

 (laughter)  In joke.  It's even become the modern fig  leaf.  So the story of DNA actually  begins a long time back, a time  when the scientists that worked  on it had very, very few tools  with which to dissect this  molecule.  And in fact the early chemistry  of this is kind of a remarkable  story of a young man who had  earned a medical degree.  Here he is, Friedrich Miescher.  He was deaf and he was,  therefore, unable to hear the  heart sounds and the other  sounds that a physician then  needed to be able to hear.  And he decided, therefore,  to go into research.  And he went to work with a man,  Hoppe-Seyler, who was already at  this time a famous chemist and  became much more famous.  He eventually published his own  journal, and as far as I know  it's still published to this  day, a hundred years later, with  his name on it.  But Friedrich Miescher was the  one who first, in this  laboratory in --, looked to see  what some of the materials were  in cells that were on surgical  bandages. 

 The boss in this lab,  Hoppe-Seyler, was interested in  any kind of human cells, and he  knew that bandages, in those  days where there were no  antibiotics, were always covered  with pus, and pus was full of  human cells.  And so he said, Miescher, you go  look and tell us what that stuff  is made out of.  Miescher began to fractionate  the material that he got from  surgical bandages.  And he found, among those things  that were present, some things  that everybody already knew  about.  He found proteins, for example.  He found carbohydrates.  He found some small molecules  that he couldn't identify, but  he recognized that they were  small anyway.  And then he found unidentified  stuff which, of course, will  eventually turn out to be DNA.  This was stuff that he  recognized didn't have the usual  properties of the other  molecules that people studied at  that time.  It was pretty easy to tell if  something was a protein. 

 It had a certain solubility in  water and it wasn't soluble in  alcohol, for example.  But his stuff didn't fit any of  the rules and, therefore,  attracted serious interest over  several years.  And he found in the course of  examining this that not only  were all of the usual elements  present, carbon and hydrogen and  nitrogen an oxygen, but there  was also phosphorous present.  And this was the first clue that  this stuff was different from  what had been previously  isolated from cellular material.  He characterized this material  as well as one could in 1874.  The chemical tools that were  available then were very  primitive, and it wasn't easy  for a chemist to identify  anything that came from a crude  mixture.  But he did find that there was  something interesting and  remarkable about the material  that he isolated from bandages.  He reported this to his boss.  And Hoppe-Seyler was so  surprised and interested in it  that before he would let his  student publish any of this, he  went into the lab himself and  redid these experiments, which I  can't tell you how unusual this  is for a professor.  Albert Kossel, who was also a  student of Hoppe-Seyler and he  who won the Nobel Prize in 1910  for his work on nucleic acids,  found that the building blocks  from which this stuff that  Miescher had discovered was  built were simple chemical  compounds. 

 Simple chemical compounds where  the structures looked like these  simple things with a dozen or  about that many atoms in them.  And this was, therefore, the  step towards trying to define  what the material was.  But at this time nobody had any  idea that it might be equated  with the genes.  So there was not the kind of  frantic interest in this that  there would have been if this  had already been known to be  genes.  One of Kossel's students was  actually a person here from  Wisconsin who had gotten his  degree here and then had gone,  as most American biochemists  did, to Europe to kind of finish  his education.  He had worked with Kossel.  That was EB Hart, who actually  was a very famous nutritionist  at this university during the  early period of the 20th  century.  Hart was the one who actually  carried out the so-called single  grain experiment that led to the  discovery of vitamins here.  And he also discovered, among  other things, that copper cured  a kind of anemia that was  actually quite common here.  He found that iodized salt cured  goiters, the thickening of the  thyroid gland in people who grew  up away from the sea where there  wasn't very much iodine in their  food. 

 And he also came back from  Europe with his interest in  phosphorous that he obtained  from Hoppe-Seyler's laboratory.  His is another story we'll tell  another time.  Kossel got tired, I guess, of  extracting material from  surgical bandages.  But he was interested in this  material, and he discovered, he  actually spent time in Basel.  And in Basel there was a river,  a place where salmon migrated  in.  And so salmon eggs were easy to  get at and so were salmon sperm.  And he discovered that salmon  sperm were really made of this  material.  By this time people were  beginning to suspect that the  material had something to do  with the nucleus of the cell,  which of course we now know is  where the genes are.  And it became, over the years,  called nucleic acid, partly  because it was from the nucleus,  nucleic, partly because it had  the properties of an acid,  behaved like that kind of a  chemical species.  And we still, today, call these  things nucleic acids. 

 Here was a young scientist who  worked at the Rockefeller  Institute during the first 30  years or 40 years, I guess, of  the 20th century.  He was a wonderful scientist who  did beautiful experiments and  set his field back 20 or 25  years.  His was one of those stories of  somebody who barked up the wrong  tree and who was so good that  people assumed that he must know  what he was doing.  At this time the nucleic acids  had become a sufficient interest  so that people like Levine here  wanted to know exactly what  their chemical structure might  be.  And at that time at the  Rockefeller Institute in New  York there was a collection of  very good chemists who had the  equipment and the know-how to  really tackle a tough problem  like this.  So he and a group of people  around him tackled the problem  of determining what this nucleic  acid was made out of.  He knew from Kossel's work that  the building blocks were these  nice simple small molecules  called bases.  And he identified what those  bases were.  And he found that the nucleic  acid had four different kinds of  them, and he could separate  those four different kinds.  And he drew the conclusion that  this material must, therefore,  be a simple structure. 

 I don't show you very many  chemical structures here, but  this is a simple structure in  which each of these is one unit  and there are just four of them.  One of the each of the four  kinds of bases that are present  in this material.  When he postulated this it made  a lot of sense.  When he chemically looked at  this material there was about  equal amount of each of the four  things.  But the problem here was that  this compound was so simple,  chemically, that it couldn't  possibly be a gene.  It's not complex enough to  convey the information that a  gene had to have to tell a cell  how to make something.  And so this is the mistake that  I said set the field back for a  long time.  Levine was famous and nobody  questioned the validity of his  work.  But it turned out that Levine  had been victimized by a  property of nucleic acids, of  DNA in particular, that he  couldn't have known about and we  now still get victimized by  every so often.  DNA is a huge molecule. 

 It is long and very, very thin.  And like anything that's long  and very, very thin, it's  fragile.  So if you shear it, it breaks.  And if you shear it a lot, it  breaks into very small pieces.  And worst than that, it's very  susceptible to being broken down  by enzymes that are present in  your fingers and all around us.  So what had happened to him is  that he'd taken this nucleic  acid, had started to work with  it in the laboratory, and while  he worked with it, it broke down  into simpler and simpler pieces  until finally he had something  so simple that it couldn't be a  gene.  And that was too bad because it  turned out that it is a gene.  One of the experiments that he  did was a very interesting one  that one has to wonder about in  retrospect, but he didn't, at  that time, have the ability to  order from a biochemical supply  house a purified reagent that  would do this or that to DNA.  But he knew that when dogs ate  DNA, it broke down.  And it broke down into these  four pieces that he wanted to  examine. 

 What it was in the dogs that did  the breaking down he didn't  know.  So he just took the short method  of creating a dog with two  fistulas, a fistula is an  opening from the outside so you  can actually reach from the  outside into the inside  of the dog.  One of them was in the stomach  and the other was a little  further down in the intestine.  He would put DNA in the stomach  and take it out in the  intestine, and in the mean time  the dog's digestive processes  broke it down and gave him the  chemical pieces that he needed  to work with.  Well in any case, Levine  eventually, very near the end of  his life, realized that he had  been had by these properties of  DNA, and he recanted but it was  too late.  So many people had spent so many  years chasing the will o' the  wisp.  When I started graduate school,  I was as green as one can be in  a place like that.  And I remember nervously walking  into the first laboratory that I  was going to work in and finding  a person there who was clearly  older than I was and presumably  more experienced doing something  that even I knew was foolish.  He was pipetting something from  the beaker, and he had the  pipette in his mouth backwards.  He was sucking on the wrong end  of the pipette. 

 (laughter)  And I looked at him  and I thought, man, if this guy  doesn't know that much then I'm  better off than I thought.  Well, it turns out that he knew  what he was doing.  He was pipetting DNA.  And a pipette is a long, thin  glass thing that has a very  small hole in one end and a big  hole in the other end.  And if you pull DNA solutions  through that small hole, that  shears it into smaller and  smaller pieces and so you're not  looking at the real stuff  anymore.  So he had to use the pipette  with the big hole and prevent  damage to the DNA.  And so one learns these things  as he goes along.  In retrospect some of these  things seem so very simple but  in prospect they're not always.  I recently reread the book  "Arrowsmith," a Sinclair Lewis  novel from the 1930s, I guess.  And it clearly is written about  the Rockefeller Institute and  about this period and about  these people, and it's  interesting comment on the way  they operated there. 

 There are quite a few ballerina  or fancy, very conceited types  at that place for a while.  Well, the next part of the story  is what happened to make people  start realizing that DNA was a  gene, was the stuff of genes.  In Britain, Frederick Griffith  who was, up until this time,  completely obscure and seems to  have become completely obscure  after this time, but for one  year, one glorious year, he did  an experiment that gave the clue  that DNA was really the stuff of  genes.  He was doing experiments with  the bacteria that caused  pneumonia, pneumococcus, and he  found that there were two kinds  of pneumococci, one that was  harmless to humans and one that  caused pneumonia and was  anything but harmless, it was a  bad one.  And they looked slightly  different.  In the laboratory you could  plate them out on the surface  and you could tell which was  which kind.  And what he was trying to figure  out was what made one  pneumococcus a serious pathogen  that could cause disease and  death and the other one  harmless.  And he did this experiment, part  of which made a lot of sense at  the time and one part of which  was surprising, in retrospect,  surprising he did it, but in any  case, he did this experiment.  He had two different kinds of  bacteria.  One he called the rough strain,  the rough kind of bacteria. 

 And that was the non-virulent  kind.  It doesn't hurt mice or people.  And then he had the other kind,  which he called smooth because  it looked smooth in the  laboratory on a plate, and that  one was very virulent and when  injected into a mouse, killed  the mouse every time.  The first rough strain could be  injected into a mouse with no  damage at all.  If he took the smooth strain  that would normally kill the  mouse and first kill the  bacteria by heating it, and then  injected it into the mouse, that  was fine.  The mouse was happy and lived.  But if he took those killed, bad  bacteria and injected them  together with some live, good  bacteria into the mouse, the  prediction was that the mouse  should be fine.  The dead bacteria aren't going  to hurt them, the live bacteria  are the good kind that don't  hurt them.  But it turns out that this  mixture of dead, bad bacteria  and living good ones killed the  mice.  And his conclusion, correct  conclusion, was that somehow or  other something had moved from  the bad, lethal bacteria, which  were dead, into the living, good  bacteria, which had made them  bad. 

 There had been a transformation  of one kind of bacterium into  another.  And that transformation wasn't  just for a little while, those  bacteria turned out to be bad  forever.  They had been transformed  permanently into something whose  progeny would also be bad.  That is, they had been  genetically transformed.  Now people look at this  experiment and they say, gee,  something has passed from one of  these bacteria, the dead one, to  the other one, and that  something must carry heredity,  must be a gene.  And so the race was on.  Griffith himself didn't  participate.  I don't think he was as  interested in this question as  he was in the disease pneumonia  itself.  But others, including Oswald  Avery at the Rockefeller  Institute, became very  interested in this.  He actually recruited two young  colleagues, MacLeod for a while  and McCarty after that, and  during the period from late  1928-'29 until the 1940s, this  laboratory concentrated on what  was going on during this process  in which a bad bacteria passed a  gene to a good one. 

 The transformation.  There's a marvelous book, I  think I'll show you a picture of  it later, about this period and  about this man Oswald Avery.  He was apparently a quiet and  completely unassuming,  completely dedicated person, who  just went straight to his lab  and worked, then went straight  to his bed and slept, then went  straight to his work.  And over those many years that  he studied this problem, he  became the world's authority on  the bacteria that caused  pneumonia.  But that's not what he cared  about now.  What he really cared about was  what it is that causes a good  bacterium to be transformed into  a bad one, a virulent one.  And the approach to this was to  take dead, bad bacteria, break  them up and extract from them  anything you could get out of  them, and then add that back to  the living, good bacteria to see  if it would transform them.  When he found that it did, then  he took that material and he  tried to further fractionate it  to see what was in that material  that was causing this.  And little by little he was able  to throw away the side fractions  that didn't have this property  of transforming and get a more  and more and more pure sample of  something that still had the  ability to genetically transform  the bacteria.  As he purified and purified,  what he found was that the  material had less and less sugar  in it, less and less  carbohydrate I should say, and  importantly it had less and less  protein until finally he got to  the point where the material  that would transform bacteria,  the stuff that seemed to be  conveying genetic information,  had no detectable protein and no  detectable polysaccharide,  carbohydrate. 

 And he was forced, therefore, to  the conclusion that the gene  must be the other stuff, mainly  the nucleic acid.  By this time, the kinds of  nucleic acid that were found in  plants and animals and yeast had  been studied enough so that we  were now clear that what he was  studying was a kind of nucleic  acid called dioxynucleic acid.  Which, of course, is now DNA and  the stuff of genes.  Well, it was with these two that  he did this work, and he  eventually got to the point  where he had the courage to  publicly proclaim that he had  done this, but he was very slow  and quiet about it and didn't  make a big splash.  And consequently, I suppose,  didn't get the credit that he  might have deserved otherwise.  There's a marvelous book here.  Rene Dubos is the author of the  book.  He himself won the Nobel Prize  in medicine.  He was a colleague of Avery's at  the Rockefeller Institute.  And the book, "The Professor,  the Institute, and DNA,"  is a great read. 

 It's not a heavy scientific read  but it's a very interesting  story of the time and about the  way science was done in those  times.  So these are pictures from the  laboratory of, on the left, the  rough, and the right the smooth  bacteria.  This way of spreading them out  on the surface allowed him to  recognize which was which.  And it was that transformation  of one into the other that he  finally attributed to this DNA.  Here is a letter that he typed  to his brother, and I'm sure you  can't read it but I'll try.  "If we are right, and of course  that is not yet proven, then it  means that nucleic acid,"  misspelled like a good  scientist, "are not merely  structurally important,"  misspelled like a good  scientist, "but functionally  active substances in determining  the biochemical activities and  specific characteristics of  cells and that by means of a  known chemical substance it's  possible to induce predictable  and hereditary changes cells."  So this is his modest way of  saying, we have discovered the  stuff of genes.  This paper, even though it  wasn't published with a great  flourish, attracted the  attention of a lot of people.  One of whom eventually became a  faculty member here, and I'll  tell you about him in just a few  moments.  But it didn't actually convince  the whole scientific public that  he was right.  There is the argument that you  can hardly ever get away from  that even though you purified  away most of the protein,  there's still a little bit in  there, and it's the protein  that's the gene. 

 You have a contamination of a  protein that you can't detect.  So it actually took a second  experiment by a different group  several years later to really  convince the world that this  stuff was DNA.  Here's the paper itself.  It surely should have been and  probably still, I could say it  was one of the 10 or so most  important scientific papers  published in the 20th century.  But here are the two who did the  clincher experiment.  They were Americans Al Hershey  and Martha Chase.  They were CalTech at this time.  Chase was a student, Hershey was  the prof.  But this time, biochemists in  this country, and abroad as  well, had begun studying a model  organism, a real simple creature  that did certain things  exceptionally well, and one of  them was to make DNA.  The creature was a virus that  infected bacteria, a so-called  phage. 

 And it had the interesting  property that it injected genes  into the bacterium, and the  genes then took over the  metabolism of the bacterium.  So the question with this simple  virus was, what does it inject?  Does it inject protein or does  it inject DNA?  If it's DNA, then we'll go along  with the conclusion that DNA is  the stuff of genes.  So by this time, which was  somewhat after the Second World  War and after the large national  laboratories had developed the  capacity because of the  Manhattan Project for the bomb,  they developed the capacity to  make radioactive isotopes which  were, for the first time in  1950, available to the  scientists who were going to use  them in their experiments.  And that allowed them to do an  experiment in which they took  this virus, here it is, it looks  like a little spider.  It's got a head full of what we  now know to be the genes.  And it sidles up to a bacterium,  squirts in the genes, and then  if you shear the bacterium, you  can get the virus to leave the  rest of it, and now you can ask,  what went in?  The way they ask what went in is  that they made two kinds of this  bacteriophage, one in which the  protein parts, the red parts  here, were all radioactively  labeled.  And the nucleic acid parts were  not radioactive.  And then they had the opposite  situation where they had a  bacteriophage where the protein  was not radioactive but the DNA  was.  And they did separately this  experiment where they let the  phage inject its DNA or inject  whatever it was going to inject  into the cell.  And then they separated the  phage from the cell and asked  what got in. 

 And the answer was very clear  that the radioactive protein  didn't get in and, therefore,  couldn't be the gene and the  radioactive DNA did get in  and, therefore, was the gene.  And so we had our answer and it  was a kind of spectacular  experiment that convinced  everybody, and from then on  there was no going back.  Now, I said that several people  had been inspired by and  interested in the experiments of  Avery and here's one of them.  He was actually a graduate  student here, Edward Tatum.  Where he studied with EB Fred,  the bacteriologist who  eventually became the president  of the university, and with WH  Peterson who was a biochemistry  prof the first half of the 20th  century.  After he left here, he started  his own laboratory, and he  worked on the question of what  makes a bacterium lose the  ability to grow with certain  foods.  He started out with bacteria  that were able to grow perfectly  well on a certain combination of  foods.  But when he radiated them so as  to break down the genetic  material, they lost that  ability.  And he studied that process very  carefully and slowly over the  years, came to the conclusion  that whatever genes were, each  gene encoded a protein, an  enzyme that was the functional  part of the cell.  So when you had a bunch of  genes, the way they work to make  a living cell was to make a  bunch of proteins. 

 And that's what did the work in  the cell.  So that was a backdrop to the  work that this guy did, Josh  Lederberg.  He had actually worked with  Tatum.  He was a graduate student with  him.  He worked in the building that's  just across the street here now.  The building that's in the  middle of this big construction  mess which most recently was the  journalism building, but which,  in those days, was the genetics  department.  He was a young, very bright guy  who had seen the papers about  the nature of DNA and wanted to  try to follow up the work that  he had done in Tatum's  laboratory by seeing if he could  find ways to actually map and  chart the DNA.  Here's a letter that he wrote to  Avery.  Again, I suppose you can't read  it but it says, "Since my  establishment here at  Wisconsin," this is January of  1948, "I've been occupying  myself with applying the genetic  techniques Tatum and I have  learned with E. coli  to the problems of gene  enzyme relationships."  So he was now looking in more  detail at how a gene was related  to an enzyme.  And in the course of doing that  work, he discovered that it was  possible to transfer genes from  one bacterium to the other in a  very systematic way. 

 And that certain genes always  transferred early in this  process and others always  transferred late as though they  lay along a long, thin linear  thing.  And the ones on this end got in  first, and the ones on this end  got in last, and by that means  one could actually map the genes  on the DNA.  And this was what Lederberg did.  He made a big beginning in this  direction and people picked it  up and went with it.  Lederberg was world-famous  quickly.  He won the Nobel Prize as a  quite young man.  He was quickly -- by a number of  other places, and at that time  Stanford Medical School had just  built a completely new medical  school from scratch and they  offered him a job.  The University of Wisconsin was  so troubled by his loss that  they went out and hired about 10  replacements for him.  There was a great jump in the  molecular biology on this campus  when Lederberg left because they  knew it was going to take more  than one person to replace him.  He went on to be world famous. 

 One of the few people that I've  known to be a true genius.  He, at Stanford, was the  chairman of genetics, but while  he was there he was already  thinking of the exploration of  Mars, he wasn't interested in  genetics anymore.  He eventually became the  president of the Rockefeller  University, and Josh died just,  I think, two or three years ago  having made a very big impact on  the world of science.  Another person that should come  into this story is Erwin  Schrodinger who was a physicist,  and he was one of those many  physicists who, as a result of  the bomb project during the war,  finished up the war years  feeling that he wanted to do  something useful rather than  being involved in anything so  destructive any longer.  And one of the things that he  did was to look at biology, he  was a physicist by training, he  looked at biology and asked,  could I bring my physics into  biology and solve some important  biological problem?  He tackled the toughest of all  problems.  He wrote a short book called  "What is Life?"  And he speculated from the point  of view of a physicist what it  would take to make life.  And in that book he speculated  about what a gene should be.  And this is before anybody had  any idea what genes were, this  was quite a while back.  The book was published in '45, I  guess.  He said it should be a crystal,  a very regular thing, but not  too regular because if it was  too regular it would be boring. 

 And it had to be something  regular, enough to be a  structure, but interesting  enough to have information in  it.  And that's a perfect description  of what turned out to be DNA.  So if you're a smart physicist,  you can be on money, and you can  encourage lots of other people  to come into the field.  And his books encouraged a  number of physicists to leave  physics, go into biology,  thinking they could clean up  this mess in a couple of years.  And some of them actually made  enormous contributions to  biology.  There was a period between 1950  and 1970 when half the Nobel  Prizes in biology medicine were  for physicists.  Chargaff was one of the people  who applied his chemistry to  DNA.  And discovered that the four  units of DNA were not always  present in the same amounts.  Two of them were always present  in one equal amount and the  other two in equal amounts, but  those four were not always the  same.  And his rules saying in this  group of four bases, there were  always equal numbers of As and  Cs, that's the name of the  bases, and equal numbers of,  sorry, As and Ts and Gs and Cs. 

 This was the so-called Chargaff  Rule which didn't help him to  figure out what the structure of  DNA was, but it turned out it  solved the structure of DNA for  somebody else.  And that somebody else was the  group in Cambridge at the  Medical Research Laboratory in  Cambridge, England, who were at  that time using a new technique  called x-ray crystallography, a  technique that was capable of  looking at things so small that  you couldn't see them in the  microscope and you couldn't see  them in the electron microscope,  you had to have tremendous  magnification, and x-ray  crystallography provided that  process, that magnification.  You took some object, shown here  in pink, passed a beam of x-rays  through it, the x-rays were  scattered by the material that  was in this object, and if you  put a piece of film back here,  the x-rays hit that film to give  a picture that looked something  like this.  So it's like a chest x-ray  except this is an x-ray of a  piece of DNA.  And by examining the position of  these spots and the darkness of  them, it's possible, in  principle, to figure out what  the structure was that you  passed the x-rays through.  So in 1950 in the MRC Laboratory  in Cambridge and in the King's  College Laboratory in London,  two groups were both trying hard  to figure out what the structure  of DNA was.  And one of them was a group that  you've probably heard of, the  Watson and Crick group in  Cambridge.  The other was these two, Maurice  Wilkins and Rosa Franklin, who  were working at King's College.  And they had actually obtained  this picture from a DNA.  But they couldn't interpret it. 

 They were trying hard to figure  out what this meant, but  mathematically it was a complex  problem and they couldn't solve  it.  But one day Watson and Crick  visited this laboratory, and  while they were there Wilkins  showed them this picture.  The picture was actually taken  by Rosa Franklin.  And she's not the one that  showed them this, and this was  bad scientific etiquette.  But in any case, the minute  Crick saw this picture he said  the structure has to be a double  helix, it has to be a helix.  And they ran back to their  laboratory, and the next few  days, Watson who was a young  American scientist and Crick who  was a brilliantly trained  physicist and a British citizen,  came up with this model.  This model shows two strands of  DNA twisted about each other in  which the As and the Ts and the  Gs and the Cs match up and meet  each other.  Here they are when they were  young kids.  Here they are 50 years later.  It's sad to see that time takes  its toll on people. 

 So they had Rosa Franklin's  information.  They solved the structure.  They published this  extraordinarily significant  paper in 1953.  It's two pages long.  It's probably the most read  paper of the 20th century in  biology.  And it put them and DNA on the  map forever.  The structure of the molecule is  such that it immediately tells  you how a cell can duplicate its  DNA to give two daughters  exactly the same DNA.  And it eventually told us how  the DNA sequence spelled out the  structure of the proteins that  would do the work of the cell.  This period is described in a  couple of interesting books that  are good reads and also are not  technically difficult at all.  One is the book that Watson  himself wrote at the time or  shortly after that, called  "The Double Helix."  It was a young man's sort of  over-ambitious look at the way  science was done. 

 People were put off by it  substantially.  Then years later, Francis Crick,  an older and wiser Francis  Crick, wrote a book called  "What Mad Pursuit," which is a  wonderful book written by  a really brilliant scientist.  And then Rosa Franklin who had  dropped out of the scene because  she died of cancer young.  She died before, for example,  she had a chance to win the  Nobel Prize, to share this with  those who did win it.    But two books came out to try to  show her role.  One of them was written by  Brenda Maddox who is a scientist  and an historian of science and  it's called  "The Dark Lady of DNA."  And this one on the bottom, I  guess it doesn't show, but the  author of this book is the  sister of the novelist Dorothy  Sayre.  Anne Sayre is her name and she  was a close friend of Rosalind  Franklin and wrote from the  point of view from someone who  knew her personally and not just  scientifically.  Some of you know a university in  Illinois has recently changed  its name to become the  Rosalind Franklin University  Medical School.  And I think that her  rehabilitation is about 40  years overdue, but I'm glad to  see that it's happening.  Now in just the few minutes that  I have left, I'm going to tell  you a little bit about how we've  come to be able to cut and paste  and alter and move DNA around to  do all the of things that people  now do routinely. 

 Here's Arthur Kornberg, who won  the Nobel Prize in 1959 for his  early studies that showed how  DNA copies itself.  And it turns out that it's a  very simple process.  You have these two strands that  are wound about each other.  They come apart and one strand  becomes a template for a second  strand that's laid down next to  it.  The other strand is a template  for one that's laid down next to  it.  The principle of templating is    that As always come next to Ts  and Gs always come next to Cs.  So it's easy to get the sequence  right.  And so one DNA becomes two and  two become four, and the exact  sequences of these DNAs are  passed on to daughter cells.  Van Potter was a scientist here  on campus in the Department of  Oncology.  He, as far as I'm concerned,  deserved richly his reputation  as a scientist, but he probably  was equally important as a  humanitarian. 

 Some of you may know his from  that point of view.  Van studied, among other things,  the way that animal cells,  Kornberg worked with bacteria  cells studying DNA synthesis,  Van Potter worked with animal  cells and showed how we,  animals, make DNA.    He also recruited to here a  young Indian scientist whom I'll  show you in just a moment.  And to my mind, even more  importantly, 20 or 30 years  before anybody else had talked  about the issue of bioethics,  Van Potter wrote a book called  "Bioethics."  He had already seen enough into  the future to realize that we  were wasting our environment at  a rate that we couldn't sustain.  And he wrote a marvelous book  about it.  It's still completely up-to-date  35 years later, and I recommend  it strongly.  It's just called "Bioethics."  Here's the young man he hired.  He turned out to be a brilliant  scientist.  A scientist who was primarily a  chemist but was interested in  the DNA and especially the role  of DNA as genes.  And when he came here, he began  to work with several other  scientists on this campus who  were also interested in DNA as  genes. 

 And -- developed techniques so  he could go into the laboratory  and chemically synthesize, first  small pieces, and then larger  and larger pieces of a gene and,  finally, the whole gene.  In chemistry, the way you prove  understand the structure is you  first figure out what the  structure is, and then you go  into the laboratory and you show  that you can synthesize that  structure from scratch, and you  get something that has the same  properties as the real structure  and then you know you got the  structure right.  That's what -- did.  He actually synthesized a gene  from scratch in his laboratory  with the help of about 20  postdocs in 20 years.  And was awarded with the Nobel  Prize for that work.  Here's another interesting  story, Kary Mullis is the one on  the left who won the Nobel Prize  in 1993 and then disappeared  completely from science.  He's a guy who had an  interesting idea one afternoon  while he was surfing at the  beach, he was a surfer.  And the idea turned out to be a  really good idea.  It was a way that one could go  into the laboratory, take a tiny  bit of DNA, way too small to  even see, and amplify it, make  many, many copies that were  identical to the starting  material.  And when you had done that,  you'd have enough DNA so that  you could get your hands on it,  and you could look at it in  terms of what the sequence of  bases was and so on. 

 When CSI people take a little  crime scene DNA, that's what  they do.  They use this technique, which  is called the PCR technique, to  amplify it, and then they have  the tools to look at it at that  larger level.  Here's another interesting  story.  It involves Frederick Sanger.  Sanger was a British scientist  who, in the 1950s, won the Nobel  Prize for his discovering ways  to determine the sequence of the  individual building blocks in a  protein.  It was a tremendously difficult  problem.  And probably substantially more  difficult in determining the  sequence in DNA.  But in any case he solved that  problem in the 1950s.  Won the Nobel Prize.  He actually determined the exact  structure of insulin, and that  was the first time we had such a  structure to look at. 

 But then when the issue of DNA  sequencing came up, he got back  into the game, having won the  Nobel Prize for his sequencing  of proteins, developed a method  for sequencing DNA and won the  Nobel Prize again.  One of very few people who's  done this sort of thing.  Now a graduate student can go  into a laboratory, take the DNA  from a whole organism, a  bacterium or an animal, and in a  very few hours prepare the DNA  in such of a way that you can  determine the sequence of the  whole animal's DNA.  It's an absolutely astounding  change.  Anybody who predicted this 10  years ago would have been  laughed out of the place.  But now we routinely do this.  The techniques for looking at  DNA are so powerful that we talk  now quite reasonably about the  future when you might go to a  doctor and get your DNA examined  to see if you're one of those  people who metabolizes drugs  this way or that way.  Or are susceptible to this  disease or that.  And this is a dream that in 1990  would have been a complete pipe  dream.  So it shows that when the  techniques are there, the  biology happens fast and it  certainly did. 

 Here's a person from Madison  that you should probably be  familiar with for several  reasons.  He's an interesting guy for  several reasons.  Fred Blattner began here I think  about the same time I did 40  years ago.  And he had the dream of carrying  on from what Lederberg started  in this department, namely  understanding the structure of  genes.  And Fred chose as his target the  bacterium, the very  commonly-studied bacterium  E. coli which has a single  chromosome with millions of  these bases in a row.  And Fred began to develop the  techniques that Sanger had  introduced to use in E.  coli, and little by little he  and his colleagues worked out  the whole sequence  of E. coli.  Again, an achievement which in  1980 would have been considered  absolutely out of the picture,  out of the realm of possibility.  But in 2000 we saw this, the  human genome, the first draft of  the human genome had been  determined.  And now we had available the  whole library of information  about how a human is developed  from a single cell, a sperm and  an egg. 

 Some of you may have known Bob  Bach, who was the dean of the  graduate school.  He was also a member of the  Biochemistry Department, and  Bach was a physicist who studied  the structure of biological  molecules, one of which was this  little thing here that turned  out to be a central piece in the  synthesis of proteins, and its  structure helped us to  understand that process by which  DNA was translated into  proteins.  Here's another of the colleagues  here.  -- was a physicist.  He used this technique called  crystallography to look at these  molecules.  That's the same molecule on the  last slide.  And -- actually sort of wrote  the ground rules for how  molecules like DNA can fold in  three dimensional space, what  you can expect from them.  He died in the tsunami of 2004.  He was in Sri Lanka, he was  unlucky enough to be there when  that terrible tsunami came and  his family was killed.  So we have now an amazing  collection of facts. 

 The library that shows the whole  human genome.  And we have, in addition, the  libraries of hundreds of other  organisms that we can compare  with the humans.  And we're beginning to be able  to use a computer to analyze all  this enormous amount of  information to ask very  interesting questions about how  we came to be, how we differ,  what things matter,  medically speaking.  Tom Link is sitting here and  Tom and I a year or so ago gave  a talk about the development  that his father made here.  He was KP Link, discovered the  value of warfarin for treating  heart patients.  But those of you who take  warfarin may know that it's very  hard to pick the right dose of  warfarin because some people  break that drug down like crazy  and other people don't.  And so depending on which kind  you are, you need a lot of it or  a little, and the doctor can't  look at you and know.  But now the gene that's  responsible for this break down  of the drug is known, and I'll  bet that some of us will  eventually walk into a doctor's  office and be tested for that  gene before the prescription of  that medicine is made.  It's a personalized kind of  medicine that's only possible  when you have detailed  information about the genetic  makeup of the individuals that  you're treating.  Well, this little girl is my way  of saying to you that I think  there's still a long ways to go. 

 We're almost always wrong when  we predict that something won't  happen.  And the people who predict crazy  things that probably will are  almost always right.  And it's because kids don't  worry about what isn't possible,  they just go out and do it.  Thank you for your attention,  and if you have questions, I'd  be delighted to answer them.  (applause)