cc >> Welcome to Wednesday Nite
at the Lab. We do this every Wednesday
night, 50 times a year, here at the University
of Wisconsin-Madison. Tonight, it's a great pleasure
to have two presenters who will help share the story of the
75th Anniversary of the saga of the discovery of Warfarin.
Our two speakers tonight are: Tom Link, who is the son
of Karl Paul Link; and Dave Nelson.
You may notice that Dave is particularly relieved tonight
because just yesterday the 5th Edition of his Biochemistry
textbook came off the press. So if you think having a baby
takes a lot... ( laughter and applause )
He's a much relieved person. So it's my pleasure to be able
to introduce to you both Dave Nelson,
Professor of Biochemistry and Chronicler of the
Department of Biochemistry, and Tom Link,
son of Karl Paul Link for the "75th Anniversary
of the saga of Warfarin." Thank you.
( applause ) >> Out on a cold night
like this. My connection
with Karl Paul Link, and my connection with Tom
goes back a long time. We've been working on tonight's
presentation for about 30 years. ( light laughter )
Tom and I went to graduate school together.
And I first met his dad, Karl Paul Link,
when he used to come out and visit Tom at Stanford.
He would always come with an armload of PNAS Journals
to bring Tom. And I can remember seeing him
come down the hall, barely able to keep from tipping over
from all the journals. So, when Tom and I discovered
that we were going to be in the same town here some years ago,
we started plotting to get at some of the wonderful materials
about Karl Paul Link that still exist on the campus--
some instruments that I had saved and that Tom had saved,
a lot of the papers that Karl Paul Link had saved
himself, some of the books that he had, because we
really felt that this is a life that is worth talking about.
And tonight happens to be a wonderful occasion to do that.
It's the anniversary of the discovery of Warfarin.
I actually went back and tried to kind figure out exactly what
day the anniversary fell on. And this is one of those things
that doesn't nicely fit. It's not like a birth date.
But I looked enough to find out that tomorrow is your dad's
birthday, so we could celebrate that if we wanted to, too.
Okay, so I'm going to talk about sort of the professional
side of K.P. Link, and about the science that he did,
and primarily about the science that had to do
with blood clotting, because that's what probably made him
most famous. Tom will tell you more about
K.P. Link's personal life, which of course,
he knows pretty well. And we will begin by just
reminding you that the time that Link came here,
in the early part of the 1900s, was a time when the place
had a collection of heroes that read like this.
The first member of the Department of Agricultural
Chemistry, housed in this old building called Agricultural
Chemistry, which is of course still across the street where
it has been for all these years. There was Babcock,
Hart, McCollum, Tottingham, who was Link's teacher.
Peterson, Steenbock, Link himself,
Elvehjem, Phillips-- The list, of course, goes on
of heroes. But I tried to use those
that bracketed Link's own time of arrival here to give you
an idea of what he walked into when he came.
The place was famous by that time for the studies
of vitamins here, which had been done by Babcock and carried out
by Hart, McCollum, Steenbock, Elvehjem, and others.
And in fact, those of you who are familiar with the building
across the street know that there is in it a mural
that depicts the social benefits of Biochemical research,
which was painted during WWII by John Steuart Curry.
I guess that's probably not very easy for you to see here,
but the mural actually depicts, on the left, children
and animals that have suffered the problems of bad nourishment.
Here is a boy over here with the bowed legs of rickets.
On the right, are people and animals who are healthy.
And across the back here are the people, the scientists,
who have done the work. This I think probably is
Stephen Moulton Babcock for example.
So there were these traditions already of people who were doing
work with a clear advantage, a clear social value
to their public. And that was the notion
of a land grant university then. If you walk around the campus,
since about five years ago, you see these brass plaques
scattered around that announce, or remind us, of what went on
during that period. Here is one that talks about
the general idea of the Scientific Approach
to Agriculture, which began early on here under
the deanship of Harry Russell. And as you walk around,
you'll see a plaque here for Elmer McCollum,
the discoverer of Vitamin A. For the process developed
by Harry Steenbock for producing Vitamin D
that would cure rickets. For the Process developed
by Hart, Elvehjem and Steenbock for treating
Iron Deficiency Anemia. The process for curing,
the means of curing the very serious disease Pellagra,
endemic in prisons and orphanages
during this period of history, by simply feeding the Vitamin
Niacin that was discovered here. Here is the work of E.B. Hart
and Harry Steenbock in preventing goiter
by iodizing salt. Here is what we're here
to talk about tonight. This is the plaque
that commemorates the work that Karl Paul Link did
with his laboratory group on the control of blood clotting.
And it is there that I want to begin with you
to talk about his work. Here he is.
This picture, and many of the other pictures that Tom
and I will show you tonight were recovered, either from
personal photo manuals that Tom has
or from the university archives. They actually have quite a lot
of stuff, 30 boxes full of Link's professional things,
including a lot of photographs that we've scanned.
Anybody who's interest in those should talk to us.
We're glad to share them. This picture, I take it
probably is Link, either as an undergraduate or certainly as
a very young graduate student. Here is his career, and one
of the people that influenced his career the most.
Link got his degree here at Wisconsin in Chemistry in 1922.
He stayed on for a Master's and got his PhD in 1925.
That work was done with Tottingham, who was then
a professor in Biochemistry. He was a carbohydrate chemist.
And so Link became a carbohydrate chemist.
After finishing his work here, he went to Europe
and wandered a little bit. But one of the most important
things that he did there was to work in the laboratory
of Fritz Pregl in Graz. Pregl, at that time,
was in the process of winning the Nobel Prize for his
development of techniques for microanalysis.
Techniques that allowed one to look at very small quantities
of a chemical compound and to determine its structure
and therefore its identity. And while he was in
Fritz Pregl's lab, Link learned these techniques.
And he brought back with him one of the first of
the microanalytical apparatuses that ever came back
to this side of the ocean. It's an apparate that
I'd give anything to find now. I don't know whether it still
exists someplace in Madison. If anybody has any clues,
I'd love to hear about them. But it's dropped out of sight.
The other part of that apparatus, however,
is this microanalytical balance, that Tom brought in
that he has at home now, which came from the Link laboratory.
And the combination of these things allowed a scientist
in those days to isolate a compound from nature,
to determine its structure, and in some cases then,
to improve on its structure by chemical synthesis,
to make another compound that might have the same
or a stronger effect. And that's where Link began.
He started his career looking at onions,
found a compound in onions that protected them
from fungal infections, identified it chemically
and was well on his way towards being a world class
carbohydrate chemist when something happened
that really changed his life, which is that he became involved
in the study of blood clotting. And before I talk about how
he became involved personally, let me just say a few words
for those of you who are not up on the idea
of blood clotting, or that haven't thought about it much.
Is there a way to see that screen better
with less light on it now? ( inaudible )
Pardon? ( inaudible )
Yes, I think so too. Well, I'll go on, but if there
is a way, Tom, to dim the lights a bit, that might be good.
This is the picture taken from the inside of the blood vessel.
And here it is, that's the bore of the blood vessel.
Over here, is a tear in the blood vessel.
Something has happened to this individual to tear
the vessel, the blood has started to leak out of there.
And without such mechanism for repairing,
for clotting the blood this individual would have
continued to lose blood, and before long, would have
suffered the consequences. We have six quarts of blood,
and it carries our oxygen from the lungs to the tissues
and our waste products out, and our nutrients to the tissues.
And without that continual flow of blood to all the tissues,
heart and brain particularly, we're in deep trouble.
So anything that prevents blood from flowing, or allows it to
leak out of the system is bad. That's not as good
as it was before-- Okay, so what we have here
is a little picture of what I'm going to describe.
What happens at the site of a wound that closes it.
What happens is that proteins, that circulate all the time
in your blood, get the signal that there's trouble.
And they go to that place, and a series of events
transforms proteins that are normally soluble
into things that form long, thin fibers
and that close over that wound. They enclose blood cells,
red blood cells. And the result is the formation
of a thick, tough, fibrous mat that closes over the vessel
and prevents any further blood from going away.
Now, we live in a sense on a knife's edge
with blood clotting, because if your blood doesn't clot,
then any kind of a wound can be fatal.
You can bleed to death. If your blood clots
just a little too soon, or a little too much, that's bad
too, because a blood clot, no matter where it forms,
let's say in the leg, can pass through the circulatory system
and hit a critical place in the lungs, or the brain,
or the heart, and you have a heart attack or a stroke
and it's curtains. So, it's critically important
that the process of blood clotting
be perfectly well controlled. And when it is not,
there is medical trouble. Here is a picture, a close up
of a blood clot. And what I want you to see
is two things. These are the blood cells
that accumulate at the point of the clot.
And more importantly, the yellow fibers are fibrin,
which is the end product of the process of blood clotting,
the stuff that really closes the clot.
This slide is not intended to scare anybody, but it's just
a way to show you that the blood clotting process
is actually pretty complicated. Each of these squares represents
a separate protein that is circulating in your blood
all of the time. And those proteins are all
poised to clot, but they don't clot until a signal comes,
normally. When the signal comes, one of
them activates the next, which activates the next
which activates the next, the next, the next, the next,
the next, and a clot forms. Down here near the bottom is
a protein called Prothrombin, which has to be active
for a blood clot to form. So we're going to talk about
Prothrombin as the major thing here.
But I want you to also remember that in the blood there are
a number of other factors, proteins, all of which
have to function normally if the blood is to clot properly.
In 1943, the Nobel Prize was awarded to these two,
Henrik Dam, who was a dean and Edward Doisy,
who was at St. Louis University, who together, working separately
discovered the role of Vitamin K in blood clotting.
And Vitamin K, it turned out, is one of those Vitamins which
had originally been uncovered here on campus by McCollum
when he discovered that you can separate the classes of vitamins
into the fat soluble vitamins, which were A, D, E and K,
and the water soluble vitamins which were B1, B6, B12,
and so on. So this problem, this issue
of Vitamin K actually had an origin in Madison.
But the role of Vitamin K in blood clotting was worked
through by these two elsewhere. An idea of how critical
blood clotting is can be had by looking at what
happens in a family where blood clotting doesn't work right.
You all know the story of Queen Victoria
and the Romanov family. Queen Victoria up here was
a carrier for hemophilia. And that simply means that she
had a mutation that knocked out the function of one of those
many proteins I showed you on the last slide.
And her blood therefore didn't clot properly.
She had a genetic tendency not to clot.
She didn't actually show it, because she didn't have
the full gene dose. She passed it on to children,
her daughter. And her daughter passed it on
to another daughter. And eventually, I know it's hard
to see here, but one of these branches is the Romanovs,
the dynasty that ruled Russia up until 1917 or 1918.
One of those Romanovs, Alexi, the son of the Czar Nicolas
turned out to have full-blown hemophilia.
He was continually sick. Every time he bumped himself,
he bled and was in danger of losing his life.
This actually had an impact, not only on the family,
but on the country because it turned out that Alexi's mother,
Czarina Alexandria had as a consultant, Rasputin,
who was a disreputable, dirty, big, crude, but apparently
very powerful personality, who somehow got her ear.
He convinced her that he and only he could properly
deal with Alexi. And she therefore accepted
his advice, which she passed on to her husband the Czar,
and the result was not good for the Romanovs or the country.
So much for what can happen if your blood doesn't clot.
( laughter ) But back to the Link story
and back to Wisconsin. In the 1920s, farmers here,
especially in northern Wisconsin, dairy farmers fed
their cattle, very often, sweet clover which grows well
up there. It's a good food.
It grows well in poor soil so it's actually economical.
It can grow places where you might not otherwise
be able to grow feed. It has a sweet smell.
That sweet smell is attributable to a compound called coumarin,
which is fairly rich in this plant.
And cows like it. And they thrive on it,
and they flourish. Except that if this stuff
is stored improperly, it becomes infected with fungal
pathogens that degrade it in a way that converts this
nice harmless, nice smelling coumarin into something
that's very bad for them. And it is the acquired disease
called Hemorrhagic Sweet Clover Disease.
It was not new when Link came across it.
It had already been worked through fairly well, and
was understood in some detail. In the 1920s, it showed up
in the Dakotas and in Alberta. It arrived in Wisconsin
not long after. It came to be attributed to the
Hemorrhagic bleeding agent in improperly cured sweet clover.
And it affected, primarily, cattle, although sheep,
rabbits and other animals were susceptible as well.
The result was that over time, the cattle affected by this feed
lost their ability to clot their blood.
And they got to the point where if they cut themselves
on a piece of barbed wire, they could bleed to death.
A very serious disease. It occurred at a time
when farmers were going through the Depression.
They couldn't afford to lose their cattle.
It was therefore economically of tremendously great importance.
It was known then, too, that you could reverse this disease
in cattle by either of two things
if you did them fast enough. One is to switch them
to good feed. For a farmer in the Depression
who only had one kind of feed, this wasn't practical.
You couldn't just throw away your whole barn full
of sweet clover and start over again with somebody else's.
The other thing you could do was if you transfused your cattle
with blood from healthy cattle you could overcome this problem.
But neither of these things was really economically feasible
for farm people in the middle of the Depression
when nobody had any money. And so this was
a disastrous disease. Link became involved in this
one Saturday. He's told the story 1,000 times
in print and elsewhere, and I think the story probably grew
in drama with the re-telling. But the basic story seems to be
that one Saturday in the middle of the winter a farmer
from Deer Park, Wisconsin, drove from up there,
in a blizzard, down to Madison with a pick-up truck with a
heifer dead in the back and a bucket of blood
that wouldn't clot. He came, actually,
to the State Hygiene Lab, but they were locked on a Saturday.
He therefore sort of stumbled across the street
into Biochemistry and bumped into Link.
And said, you know, "You've got to help me.
My cattle are dying. Their blood won't clot."
And this appeal apparently grabbed Link's attention
to the point where he decided to change substantially the
direction of his own research and to take off
after this problem. It's very hard when you
look back at the way a scientific problem develops
to reconstitute how it really happened.
And very often, it's more subtle than what I just described in
this case, but it's pretty clear that this was a dramatic event
in Link's career. And it had the effect
of changing what he did. He quoted this guy,
and I'll let you read. And this quote has been
suspected of a little doctoring, but it covers the ground
pretty nicely. So, that was the motivation
to get involved in the study of the effect of spoiled
sweet clover on the health and disease of cattle.
Link developed, in his laboratory, a simple and
pretty good assay, or a way of measuring
whether a certain food or a solution derived from that food
contained the stuff that they called the Hemorrhagic Factor,
that whatever it was that caused animals to bleed.
He developed a way to do this. One of the things that
they found very early on, I think maybe it was known
before Link entered, is that somehow this disease
affected the animal's ability to make one of those proteins,
that I said had to be in the blood, and that was crucial
to the clotting process, prothrombin.
The same protein that the people who studied Vitamin K
said depended on Vitamin K. So he used a measure
of how fast the blood clotted. He used test animals,
exposed them to the food that was bad and then to extracts,
to more and more purified extracts of the food,
asking can we reach the point where we have in hand
the pure stuff that causes this problem.
And this was a formidable problem at the time, but he was
well-equipped to tackle it, because he had the training
of Pregl, he had the equipment that was built, rare equipment
that was available in only a few places,
to analyze chemical compounds just like this and to determine
their structure. And so he set to work on this
with a lab full of people. And they did, over time,
eventually purify completely the Hemorrhagic Factor
from the sweet clover. It must have been a major effort
because there is relatively small amount of this stuff,
and their techniques require that you have quite a large
amount of material to see it. Here is Link.
I don't know, I suppose, Tom, is he 40 years old here?
35 years old? So this is probably
fairly early in his career. This is Mark Stahlman.
This is the Link Laboratory. And it has all the earmarks
of a laboratory at that time. Every single thing
that everybody is doing in this picture is illegal now.
( laughter ) But as a result of this work,
they were able to finally purify the material.
Let's see, this paper is dated September of 1940.
It was actually submitted then, so it probably was published
in 1941. Here is the paper.
Here is the microscopic view of the purified crystals of
the compound, which was called bishydroxycoumarin
or dicumarol. That's the stuff, when given
to an animal that caused the animal to quit clotting.
The stuff took a little time. It's not like cyanide, where
you give it now and the animal is dead in two minutes.
It needed to be ingested over a period of time.
And it becomes clear why when you look at the details
of the mechanism. But what it was doing,
we know now, was preventing the animal from making prothrombin
properly, so that the animal didn't have enough prothrombin
in the blood at a steady state. And when the time came
for the blood to clot, there just wasn't enough to do it.
That's what caused it. Link recognized right away
that this compound or compounds like it, had the possible value
as rodenticides. They had used rats, among other
animals, as their test animals. They knew that the dicumarol
killed them, killed them pretty fast.
And he recognized-- But by this time, Steenbock
had already established the Wisconsin Alumni Research
Foundation, and had established the pattern of a UW Scientist
patenting a compound in the name of WARF.
So, when Link approached this problem, he knew already
what to do with it. He patented this with
his several co-workers. The proceeds, like the proceeds
from Vitamin D went to WARF. One of the reasons that WARF
now has a bank balance of a billion dollars is this.
So, he called the compound "Warfarin" for Wisconsin Alumni
Research Foundation and the last part of the name
of Coumarin. It became, quickly, the world's
number one rodenticide. And as far as I know,
today it still is. The world market is enormous
for this. And with the exception of
those places where rats have become Warfarin resistant,
it still is a huge public health aid because it kills rats
that are so devastating to public health.
I don't want to delve into the chemistry of this in any
kind of detail, but just for those of you who are curious,
let me show you a bit of what is going on here.
Here is the compound Warfarin. Here is a small part
of the protein prothrombin as it's being matured.
What happens is that a certain small part of that protein is
slightly changed from glutamate to gamma carboxyglutamate.
It doesn't matter what the names are.
And that small change converts inactive prothrombin
to active prothrombin. If that small change
can't take place, the blood will eventually not clot.
And that small change requires Vitamin K.
The Vitamin K gets converted into this and then recycled
back into that, and converted and recycled.
So you have to constantly be regenerating the Vitamin K
to make this process continue to go,
and Warfarin blocks this step. And without that step, you can't
regenerate the stuff you need to make prothrombin, and
the animal feels the effects. That's how Warfarin
kills animals. Simple.
Link promoted this Warfarin as a rodenticide
very actively himself. He didn't simply turn it over
to WARF, but he was out there pitching with the farmers
and the legislators, developing simple, cheap, effective methods
of exposing animals to the bait. And I think in this sense
he was a perfect example of a scientist who really took the
land grants charge seriously. He went out there and he did
what the state paid him to do. And he helped an awful lot
of farmers learn how to use this drug, this compound, and
saved a lot of crops this way. Here he is.
"Kill Rats!" he says. ( laughter )
So, he was famous by this time. He was bringing a lot of money
into the coffers of the UW, to WARF rather.
He was well known in the world. He had made a major contribution
to public health. And he actually won, I've
forgotten the year, the Lasker award, which is very often
the last thing you win before you get the Nobel Prize.
One of these is the Lasker Award he won for that important
improvement in public health. At the time that he was dealing
with this drug as a rodenticide, nobody thought very seriously
about using it in any other application, because it was
assumed something so poisonous for rats wouldn't be very good
for people. But it became widely used
for rats. And once, in 1951, a sailor
tried to kill himself with Warfarin.
He took a huge overdose of rat poison and he lived.
And people looked at this and said, hey wait a minute
here, this is interesting. The stuff kills rats
and it doesn't kill people. But it blocks blood clotting.
So, Link began to think immediately about the
possibility of using this in human medicine.
And over time in collaboration with clinicians in various
places including the people, I think, at Minneapolis
and at the Mayo Clinic. I'm not very familiar
with this part of the story. They brought the drug
into clinical use. It became widely known
that it was available and useful in this respect in 1955
when President Eisenhower, with a heart attack,
had a physician who actually asked for the drug from Link
and treated Eisenhower with it, successfully.
We just talked earlier, before the talk tonight about
a book that came to K.P. Link, and then to you, from
Paul W. White, the physician of Eisenhower, in the sense
thanking for the stuff. So, it became clear that there
was a second, very important use for this drug.
Warfarin came into use to treat patients who had
deep vein phlebitis, the kind of clotting that
happens in lower extremities. People who had any valve
problems with their hearts. People who had a cardiac
arrhythmias, and others who were at risk for clotting.
And it is still widely, very widely used.
I bet that there are at least five people, maybe 10 people
in this room who take the compound
or one of its derivatives. And I'm one.
( laughs ) So, here's Link
getting famous killing rats. Here's Link becoming famous
saving presidents. Here, he's standing next to
President Harry Truman. And if anybody in the room knows
who the other person here is, I'd like to know.
I've never been able to identify this character.
I've had some people guess, but I don't know who it is.
But in any case it shows you that the medical benefits
really rolls all the way up to the White House.
So these famous Warfarin recipients included the suicidal
sailor who got the stuff on the shelf in the first place,
President Eisenhower, and then we learned more recently
that maybe Joseph Stalin was a recipient of Warfarin, too.
Stalin died a kind of a mysterious death.
He had dinner with four of his henchman, Beria, Molotov,
Khrushchev-- I've forgotten the fourth--
Bulganin-- He got a stomach ache after
supper, excused himself, went to bed and sort of dropped
out of sight for two days. When somebody finally checked
on him he was on the floor, not looking good at all.
So, he had last had the meal with his friends
and competitors it turned out, one of them who was qualified
to kill people, Beria. And the suspicion is that Beria
actually gave Stalin Warfarin, that he bled to death.
He died of stomach hemorrhage. This suspicion was more or less
confirmed in the 1990s. Well, Khrushchev, actually, in
his book, "Khrushchev Speaks," already kind of hinted at this
in 1980. And in the early 1990s,
Molotov wrote his memoirs. And he said that Beria
had told him, "I did him in." So, it may well be
that Warfarin had an effect on Russian history again.
I can't push the button hard enough
to make it work here-- Link had a tendency
to antagonize the people around him.
He seemed to enjoy doing this, and that included his colleagues
in Biochemistry and administrators here.
In fact, anybody that he thought he could jerk his chain
a little bit on. He was in a wonderful position
to do this. He was bringing in money
hand over fist for the university.
They couldn't very well criticize him too seriously,
or certainly couldn't can him. And so he kind of had people
where he wanted them. This is a picture of him with
E.B. Fred on his right on our left, and
Conrad Elvehjem on the right. It's amusing to me
that he is smiling with them, because in his personal papers
his description of his interactions with them
is not written with a smile. He called Fred, "Old Smoothie,"
apparently feeling that he was a little too good at schmoozing.
And he had his problems with Elvehjem too,
as I understand it. ( inaudible )
Well, let's go back. I don't think so.
Anybody here who remembers Elvehjem well enough?
No, definitely not. Okay, so let me just close
a little bit of the scientific part of the picture by noting
that Link was widely recognized, not just here in the state
in the country, but in the world.
He was elected a member of the National Academy of Sciences
at a very young age. I think he was 45, or so,
and this is not common. He won the Kovalenko Medal of
the National Academy of Science, a very high honor in 1967.
These are several medals he won. As far as I know he's unique.
I don't believe I've ever heard of anybody winning
the Lasker Award twice. The first one was for
the public health benefits of Warfarin as a rodenticide.
The second was for the heart benefits of the human medicine.
He left behind a lot of very interesting problems
when he retired in 1970 or 1971, one of which was
the real target of Warfarin. And John Suttie, my colleague,
and his colleague who has just very recently retired after
a long career in Biochemistry, carried on the work of Link.
He wasn't Link's student, but he picked up the problem
and made major advances in trying to understand exactly
how Warfarin and Vitamin K worked on the enzymes
of blood clotting. So this is another of those
many cases where one can actually trace a problem
from a very practical issue of agriculture
or health, human health from the animal, to the organ,
to the tissue, to the cell, to the genes.
We now have people around the campus who are
working on the genes and trying to understand things
at the most fundamental level. There's hardly anybody on
campus that can't, in some way, be traced back to a precedent
that was more physiological, or more agricultural,
or more applied. Now before I quit, I want to
just go through a couple of things to illustrate
one more fact about Link that many of you know, and probably
came here to hear about. The fact that he was
something of a showman. And I said earlier that he
liked to yank people's chains, and he didn't let people
push him around. He was actually pretty
strong minded about a lot of things.
That brought him into conflict with the other strong minded
people around here. This is not
one of the examples. This is just an example
of how he was able to publicize his work in a way
that was good for everybody. That's something that
we scientists actually need to learn to do better.
We don't tell the public what we have to offer them.
And Link did that, that's for sure.
He also, however, got into trouble with his colleagues
every so often. I'm not going to talk about
any of these things I'll show you in any kind of detail,
but just read the headlines. Well, that's not much
of a headline! There was a celebrated
fist-fight over this. Link, all of his life,
called himself, "Ratter." He always was proud of the fact
that he was one of those people who did in a lot of rats,
and this made him a "ratter." This telegram is a small tip
of an iceberg that somebody could profitably investigate.
There was a longstanding disagreement between
Karl Paul Link and Mark Stahlman about who had really made
the major contributions to the work on Warfarin.
And this spilled over into the press when "Reader's Digest,"
for example had an article about this, and there was
an exchange of opinions between the author of the article
and Link, and others, about who should be cited.
I want to leave you with the idea that we're talking about
somebody here who was a tremendous scientist.
Nobody has any question about that.
He was one of the first people around here, maybe one of
the first people in the country to really get to straddle
the chasm between the university academic research,
and industrial or commercial applications of that research.
Not just on the farms, but I mean drugs and big money.
And now of course, we take this for granted.
Scientists as a rule, an awful lot of us become involved
in some way or the other with patenting things and money.
So we probably spend some of our time thinking about patents
and lawyers, when we should be thinking about science.
But he was one of the first who got into this situation.
And I think his life would be interesting to look at
from the point of view of its effect on his science.
I've always thought that there was a book for somebody here.
This is a fascinating personality to write about,
a colorful, fascinating, bright, introspective man
who left behind a lot of clues about himself.
He left behind many many pages in the Steenbock archives
of his longhand memoirs that he never got past the stage
of just notes. But it's a rich source
of information about him. So, with that I want
to make the conversion here, the change from my discussion
of his science to Tom's discussion
of his personal life. And perhaps of the way his
personal life interacted with and affected his science.
Now Tom, I have this picture, I have the thing of the car
and the corn, which I can either show now,
or if you want me to, I'll show it later.
Do it now, okay. Tom's going to tell you
about it. I think this was some kind of
a controversy with WARF. And just because of the way
we've got the computers rigged here, it will be easier
for me to show you something that he'll talk about later.
Tom found an old piece of 8mm film that showed Karl
Paul Link in a characteristic, "don't push me around"
state of mind. Here we go.
This is all staged, okay.
He's throwing corn at the Wisconsin Alumni Research
Foundation headquarters. The first man you saw was
Ed Ward Ross, who didn't want anything to do with it.
This is Ed Ralston. And these lanterns represent
the search for truth, I think. ( laughter )
Corn means many things. Perhaps here it has
something to do with money, but this is my speculation.
1964. ( laughter )
A patent log, is that what that says?
Joey-- An attorney, I think at WARF.
This is at home in his study.
( laughter )
( inaudible ) I wasn't around.
I don't know what was going on. Will the lights
go back up again? Will this go back on?
I don't know if that's good enough.
At any rate, it is with great honor and respect that I come
here to speak about my father, Karl Paul Link.
He married my mother, Elizabeth Feldman, and by 1930
they had three boys, Jon 1937, myself 1941,
and my brother Paul in 1953. We all, I suspect in emulation
of our father obtained PhDs. My brother Jon in physics,
myself in biochemistry, my brother Paul in geology.
And, yeah, put that slide up. Okay here we are in 1958.
I'm the one there. That's my brother Jon
and my little brother Paul, born in 1953.
And like I said, I think we all went into science
in emulation of my father. And he had a wonderfully warm,
compelling personality. And when we went out, I became
transformed from this shy, rather average child into
somebody who was all of a sudden very important.
I was his helper and it made me just feel wonderful.
Quite honestly, Karl had very little time for parenting.
He was preoccupied with his promoting Warfarin dicumarol.
And for his teaching, and also with his encounters
with university administrators. He'd be up early in the morning
rehearsing what he was going to say...
( laughter ) and whatever it was.
So, we boys, I don't know if we can get that sixth slide up.
We were basically helpers. And the number 6, yeah.
So here I am. Go back.
Here I am being directed how to rake leaves.
( laughter ) And of course he certainly
did teach us how to work and that was a great benefit.
Now if we go back in time here a little bit, actually
it was exactly 56 years ago, it was the coldest day
I have ever experienced. If you look in the paper
tonight, the record temperature in 1951 was -26 F.
And this was the day after, I assume.
We were out at a farm on Highway 14 near Cross Plains, with
the farmhouses on one side and the barn on the other side.
And he was doing experiments with Warfarin here.
And I'm the one in the back there, and the farmer
and the farmer's kids. Maybe there's a couple more
slides shown of that. And here he is
preparing the bait. I'm not sure if he was giving
them both solid Warfarin and a liquid,
but there's another slide. Here I am inspecting
the bait box. And the reason that
there are these photographs is that reporter John Newhouse
came along on the trip, because it was kind of a special
occasion, and as I said, I never remember ever being
so cold as that day. ( laughter )
Here is the farmer and with the pigs.
I think that must be a bait box up there on the wall
of the corn crib, so the rats could get directly,
didn't have to travel too far to get the bait.
And at any rate, we grew up on the west side
in a place called the Highlands. And we had a large lot there
and a garden. There was something about it.
My father needed help. And I had these friends,
my associates, we had a den, cub scout den, whatever.
And after the Cub Scout thing was over, there was work
to be done. And so, the boys would work
and they would be paid with a bottle of beer after the work.
And so the kids would flock to my house for the rewards
from this work. And you know, one can speculate
today what might happen to someone if he were to offer
13-year-old boys beer. But anyway,
it was a special time. Another thing I remember
about this period, I was probably 10 or 11.
We had these cages in the yard of 8 x 4 x 10 or 8 x 6 x 10
with wheels. There were all these chickens
in there, and he was feeding the chickens.
And it was my job to make sure that these chickens--
the cages were moved. Depending on how big
the chickens were, they would eat all the grass up
within a matter of a few hours when they got to be big.
Once the chickens were full grown, they were shipped
off. There was a slaughterhouse down
there on Pheasant Branch Road in Middleton.
And they were frozen, and we of course ate them.
Now what I didn't know was that he was trying to kill them
with Warfarin. ( laughter )
But he couldn't, because of, as you learned from Dr. Nelson,
because of the amount of Vitamin K they were eating,
you could give them any amount of Warfarin
and the effect of that was that it was counteracted
by the Vitamin K. So, the chickens did just fine.
We ate them and we did just fine.
( laughter ) There's one final story that
I'll tell you of this period. This was in Spring of 1957,
I'd come back-- It was a beautiful spring day.
I'd come back from track practice.
And I come into the house, and he comes and he offers me
a shot of Bourbon and he says "C'mon drink up!"
Joe McCarthy died. ( laughter )
Of course, the irony here is that Joe McCarthy
died of Cirrhosis of the liver, and I developed a taste
for bourbon. ( laughter )
And then a year later, '58, I was on a football team.
Pete Combs had already left, but we had a game
in Edgerton at night. Somehow, my mother convinced
my father to come to the game. And we won the game,
and everything. Then later that night he
developed wet pleurisy again. This would have been the third
time in his life that he had serious bouts with Tuberculosis.
So he spent the last year that I was at home
and in high school in the hospital, the sanitarium.
And so, his life was kind of punctuated.
There were three times when he had Tuberculosis.
In Europe, then in '45, and then again in 1958.
And when he was young, I guess he almost died
when he was two years old from pneumonia.
So at any rate, I will digress now a little bit
and talk about his family, because I think that
he was highly impacted by some of the events
surrounding his father and his father's death.
The family came over-- I don't know if you can
get over to that slide there. Yes, this is it.
The family came over from, the grandfather,
the one in the middle with the beard.
Yeah, the wife. How many pointers do I need?
This is the grandfather and the wife.
I suspect they came over from Europe in Germany in 1848.
Karl was born in 1863. And they said of the father,
the grandfather, this guy, George.
There are three George's, but this is George one.
This is George two. And this one here
is Karl's father. They said of George "one,"
he was one of the best known and most prominent members
of the Missouri Synod and held some of the highest
charges in the district. George Link, Karl's father,
was born in Lebanon, in Dodge County, Wisconsin,
in 1863. Concordia Academy
in St. Louis in 1876-1878. Concordia College
in Fort Wayne, 1879-1882. He studied Hebrew, German,
Greek, entered Concordia Seminary in St. Louis
and studied the theological and practical theology
and pertaining sciences: philosophy, logic, metaphysics.
In 1887, he married Frederica Moore and they
produced 11 children in 18 years.
Karl was number eight, born in 1901.
Now this Reverend Link, number "two," this one.
I don't know, maybe we have another slide.
He got a job then in LaPorte, Indiana
as the minister there. Now this is Karl's father.
This is George, Senior. And this is George Junior,
my father's older brother. In 13 years there
in LaPorte, Indiana, he baptized 767 people,
confirmed 638, married 237 couples,
buried 389 people and carried out 242,030
Holy Communions. If you do the numbers,
that's over eight per day. How he did this I don't know.
It seems physically impossible. ( laughter )
At any rate, beginning in 1899 he developed a throat condition,
which caused his congregation much uneasiness.
Worrying about his condition brought about
a serious nervous trouble. In fall of 1902, he gave up
the ministry in fear of losing his mind.
In 1904 he became elected the Clerk of the Circuit Court
as a republican, and he had a highly successful year there.
However, in 1910, he fell ill again,
survived six operations for colon cancer,
died at age 50 in 1913. And then there's this article.
Let's go on and see the article. There's the family,
the children. There's one more
of the good man dies, that one. This is interesting,
just because it kind of, it's certainly a historical way
of saying things here. This is one sentence
I'll read you. "A man among men, an ideal type
of citizenship. A man of integrity, honor,
and uprightouesness, George Link, pastor
of St. John's Lutheran Church and also two terms
Clerk of County Courts, passed away at 1:30am
this morning at his home after an illness of three years
during the greater share of which he suffered
untold agony and endured the most excruciating pain
with Christian fortitude and forbearance.
Conscious almost to the last, he's ready to go,
prepared to meet his maker and to begin that life
of eternal joy and happiness, which is promised to all those
who lived lives of righteousness."
Well, we don't really know what happened here.
The story was that he had some throat whatever.
But you know I think, basically there must have been some kind
of cognitive dissonance. And psychosomatic illnesses
were not defined in those days. And so we don't know.
And there's no indication that he broke in any way
during this, it would have been almost 13 years of suffering.
He always looks like this. He always has the same stern,
no smile. And so we don't know
what went wrong. One would think that with
all that suffering that he might have gathered some humanity,
some humility, something, but that didn't
seem to have happened. And they tell the story
that there was a member of the congregation
who sold life insurance. He went to George and begged him
"Please, just don't preach against life insurance,
and I'll give you this free $100,000 policy."
But of course, Reverend Link, being incorruptible
turned him down. And when he died in 1913,
he left seven minor children. He left a house, a piano
that his wife's parents had bought for him from Europe,
a number of good books and no money.
So I don't know if you can see a picture of the family.
If we go back. It's an interesting family.
That's it. So here we are.
This is probably a few years before he died in 1910.
Here is the father and the mother.
This is Karl. He had an older brother,
George Link, who got a PhD in Botany, had an illustrious
career at Chicago, translated Greek.
There was another brother, Theodore.
I'm sorry, that's not him. This is, at any rate
another brother. Perhaps this one was a judge
in LaPorte, Indiana. Alfred had quite a career there.
Another brother, Theodore, got a PhD in Geology.
And they tell the story of him. I don't know when it was,
in the '50s. They wanted him to go
to the Sahara Desert to see if there was some oil.
And he said, "I don't want to go there."
They said they'd give him, whatever it was, $50,000,
and he said okay. So, he goes to Paris,
looks at the samples and says "Yeah, there's oil there."
and he went back home. And there was oil
and he collected his $50,000. ( laughter )
So then there's this fellow who's also an oil geologist.
So of the ten of the six boys here, five of them
were highly successful. You wonder how this could be,
you know, basically growing up with nothing but hard work.
And you see kind of the generational divide here
that the women, the three older women
did not go to college, and basically stayed home and helped
take care of the family. At any rate, I think Karl
was profoundly affected by his father's illness and death.
He reports that he was in danger of flunking freshman English
when he came here in 1918. He reported his themes were
littered with misspelled words, broke all the rules of grammar
and were deemed "unfit to read."
In one entitled, "I Do Not Believe in God"
he was indescribably sad. "Three days before my father's
death..." I'm quoting.
"I cried so much that on the day of the funeral, no more tears
could be produced. My dear sister Agnes
was asked to get me. I refused.
She was crying. I couldn't.
And what did that sweet innocent girl tell me?
'You will go to hell if you don't cry and pray.'
I said, 'Go away, leave me alone.'
I had undergone a transformation.
I cannot remember anything from that day until nine months later
when I was confirmed on Palm Sunday."
So, then he went to high school in LaPorte, Indiana.
Here's a picture of the kids. I don't know which one he is,
probably this one. It's the C-Street Gang.
He grew up in LaPorte, Indiana. And that's just a curious
kind of a time photo there. What's the next one we've got?
Here is, he's the one in back, with his younger brother
and his sister, and another one there.
Here he is again. That's him there with--
I don't know if this is a sister.
And maybe that's the brother. So any rate, he went to
school in LaPorte, Indiana. And from his yearbook,
he did a number of things which were of interest.
He was the president of the Boy's Community Garden,
which raised crops valued at $700 under the call
"Food Will Win the War." Karl also was sent to Chicago
for a competitive exam on May 10, 1918, where he took
the exams in history and German. He also participated
in track, German/English club and basketball.
There's one more picture there that shows--
This was a play and he had the lead role.
I think this is him. It was a play called
"The Country Gentleman." And I think, you know, he had
a theatric bent early on. It's obviously a huge cast,
and he had the lead role. So then he came to Wisconsin
in 1918 and he wrote. He did a very unusual piece
called "The Dances for Seven Years."
And this, I'll just read you some of this, because
it gives you a flavor of the man that you wouldn't really get
anywhere else. "To those fortunate ones
born and raised in poverty whose early life and training
was inspired by them with the ideal of toil
and the search of truth. These dances of seven years
are dedicated." And he goes on here, and
I don't know how much of this I should read to you.
This is a fore note. "It is now some time ago
since the dances of seven years started upon the journey
into this book form. In the Autumn of 1918,
when I came under the influence of the shadows of this great
university, all the beauty of its one-time liberal
and constructive policy was crushed to the ground
by the mania of patriotism. The environment seemed cold
and cruel to me. I was, by nature, a youth
inclined towards the theoretic than to the active life.
Hence, I naturally turned away from the influences
of the cold environment, a lonesome,
individualistic life followed. In the struggle to acquire
the difficult art of knowledge, I found my greatest friend
in nature: the trees, the waves, the winds, the shadows,
the clouds, all seemed to touch me
with a kindly hand. Some the impressions received
in my contact with nature, and many of the numerous thoughts
that ran through my mind which I hold,
held communion with her, I reproduced here in the dances
in verse and in prose. In the dances, I originally only
thought to make I knew not what, to make something
I did not undertake hereby to please myself or anyone
with the finished book. I did it of mine own self
to gratify which the dances danced in the booklet form.
The joy and happiness seemed to lie in the making
rather than the finished book. I had no thought of a reviewer,
no thought of a reader. I just made it to make."
I don't know, I could go on, but we've got other things
to talk about. So, one of the things
that is perhaps most interesting about Karl is that he really
wanted to make a difference, and he wasn't willing
to limit that to science. He was willing to take
political stands. And over the years, he has been
criticized by some for that. And I'll say a
little bit about that. Robert Burris, who was a member
of the Biochemistry here, wrote a great autobiographical review
of Karl. In summary, Burris states
Link was a superb teacher, ran one of the best labs
in the department, trained many excellent students
and installed them with an honest concern for
the acquisition of valid data, and he and his co-workers
have had a global impact on medicine and rodent control.
Burris goes on to say, "People tend to play Karl up
as a great liberal and defender of unpopular causes.
In my opinion, Link did not really embrace, or actively
promote the radical causes, but he was happy to serve
as a frontman." I very strongly disagree
with this. I'll just read you one thing.
What else have we got there? Here, let's digress a bit here.
Here he is. He went to Europe, as Dave
mentioned, and here he is dressed as Uncle Sam.
This is in Edinburgh. This is some kind of a holiday,
and he's dressed here as you can see.
We've got another one here. Here he is, I think, after
he came back from Europe. He sported a beard.
His mother refused to kiss him, and so then of course
he entered the faculty. I don't know what else
we've got here. We'll show you some pictures.
Here he is in his canoe. Here he is with my mother,
transporting something, they probably went to visit
the family in LaPorte. Here they are posing.
I don't know if we've got one more there.
Here he is, yes. At any rate, let's go back
to the political bent here. He wrote this in 1946 while
he was interned in the hospital. "A Jeffersonian democrat
would not sign... If the government becomes too
offensive, he would not hesitate to take up arms against
to restore the original form or order."
He then, in those years, was active as a faculty advisor
for certain left winged groups. The one was John Cookes'
discussion club from '47-'50 and then another student
Communist Organization from 1950-'56.
He claimed he did this because no one else would do it.
And I suspect that's true. But to get back
to what Burris is saying. I remember both my parents
were profoundly distressed by the political drift
that occurred after WWII. The cold war was launched
and as we know as children the Korean War
and the Vietnam War have cost unfathomable human suffering
and resource depletion. My parents knew that these
imperialist ambitions were driven, as Eisenhower said, by
the military industrial complex. And over the 60 years
of this historical drift, you can see how
in the current situation, how the administration
has lied us into a war against Saddam Hussein.
Basically, in my opinion, to control Middle East Oil.
Now approaching 50% of the Iraqi population of 25 million
has been killed, forced into exile,
lives in extreme poverty or has been forced to move to
a different location to live. Now, is this
what you call democracy? At any rate to go back to Karl,
he believed very strongly that it was anybody's right
and everybody's right to speak their mind.
And he said to the Wisconsin High School graduation class
of 1955, "...to oppose any form of tyranny over the
mind of man." In 1956-'57, he joined
Linus Pauling and 9,000 other scientists
and signed a petition against asking the United Nations
to halt atmospheric testing as the beginning
of general disarmament. He also joined Pauling
in a suit against-- in the International Court
of Justice, seeking to enjoin the United States Government
and the Soviet Governments from further nuclear testing.
Karl was also involved in an effort to save Bascom Woods
that was destroyed to build the Social Sciences building.
In 1964, he was named chairman of the group "Scientists
for Johnson Humphrey," which included 75%
of the living Nobel Laureate's in science.
In May of 1965, he joined protests against HUAC.
And in '68 he gave $400 to the Regents as a trust fund
to defend students against legal problems resulting
from their Vietnam protests. In '69 he refused to be
photographed or carry an ID card that was required
of all UW Students and Staff. He wanted to know
what they were going to do with this information.
( laughter ) In 1973, in a rather candid
article in the "Daily Cardinal Summer Edition,"
he characterized Richard Nixon as "a vindictive son-of-a---,
a bas--- , a slippery eel..." ( laughter )
"To think this guy had the guts to run on law and order.
What a crook." ( laughter )
So, you know, I don't know if we got in the
light of the political tradition that my parents represented,
in '03 I hung this banner on an apartment building that
my brother and I own downtown. And within one day, the city
sent me a letter and said, you know, "Take it down.
It's a code violation." And I persisted for 56 days and
eventually removed the banner got a lawyer.
And a week later, the attack on Iraq began.
And if you don't mind, I'll quote myself.
( laughter ) And I said
to the "State Journal," "I have this image of
the demented cowboy from Texas who is unaware of the risk
he is taking. He is flaunting world opinion,
United Nations and the Rule of Law.
This is the ultimate arrogance of power.
I hope the horror of this unilateral invasion
will show us finally that war and violence
are no longer options." At any rate, my father
may have been photographed with a former president,
and he may have contributed $20 million,
or his products made of Warfarin would have gained
that much money for WARF, but he never got his picture
on the front page of "New York Times."
( laughter ) ( applause )
( inaudible ) >> I'd like to ask of Dave,
what was the impact of-- ( inaudible )
Did the Warfarin research here help manage that disease,
or were other ways to manage the cattle?
There was no way to manage the disease,
except change your feed. And that was not economically
possible in most cases. So what developed was
was a realization that if you fed them Vitamin K-rich food,
or injected Vitamin K, you could overcome this.
So it had a huge impact on agriculture.
( inaudible ) >> Well, at first he had
a heart event. Then he had
congestive heart failure. Then eventually,
he died of a stroke. I don't think he was taking
Warfarin at the time. ( laughter )
Other questions? If not, or you'd like to talk
to them afterwards, come on down.
Otherwise, thank you all very much for coming.
( applause )