The Discovery of Niacin at UW-Madison | Wisconsin Public Television

The Discovery of Niacin at UW-Madison

The Discovery of Niacin at UW-Madison

Record date: Jul 12, 2017

Dave Nelson, Professor Emeritus in the Department of Biochemistry at UW-Madison, discusses the identification of a new vitamin found in fresh meat and yeast by Conrad Arnold Elvehjem at UW-Madison in 1937. Elvehjem’s experiments proved that nicotinic acid, also known as niacin or vitamin B3, was a cure for pellagra.

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Episode Transcript

- Welcome, everyone, to Wednesday Nite @ the Lab.

My name is Tom Zinnen.

I work here at the UW-Madison

Biotechnology Center.

I also work for UW Extension

Cooperative Extension, and on

behalf of those folks and

our other co-organizers,

the Wisconsin Public Television,

Wisconsin Alumni Association,

and the UW-Madison

Science Alliance,

thanks again for coming to Wednesday Nite @ the Lab.

We do this every Wednesday

night, 50 times a year.

Tonight it's my pleasure to

introduce to you Dave Nelson.

He's Professor Emeritus

of biochemistry.

He's also the founder of the

Wisconsin Science Museum.

He's here on both

of those roles.

Tonight he gets to talk to us

about one of the great

accomplishments out

of our university.

This year is the centennial of

several things at UW-Madison.

It's the 100th anniversary of

playing football in the new

Camp Randall Stadium,

it's the centennial of

Wisconsin Public Radio,

but it's the centennial

of the discovery of the

B vitamin family.

And we get to hear part

of that story tonight.

Dave will be talking with

us about Conrad Elvehjem,

who grew up in McFarland,

not too far from here.

As I like to say, McFarland is

right next to McNearland.

[laughter]

And that's

why I have this job.

[laughter]

Dave was born in

Fairmont, Minnesota.

That's where he went

to high school.

Then he went to Stanford,

undergrad.

No, for his PhD, excuse me.

Went to St. Olaf's

for undergrad.

Went to Stanford for his PhD,

then he postdocked at Harvard,

and then he came here in 1971.

Nobody has given more

 Wednesday Nite @ the Lab

talks than Dave,

and nobody has given better

Wednesday Nite @ the Lab

talks than Dave.

This is going to be a great

story of the discovery of niacin

here on the UW-Madison campus.

Please join me in welcoming

Dave Nelson back to

Wednesday Nite @ the Lab.

[applause]

>> Thank you very much.

Thanks, Tom,

and thanks to all of you

for coming out on a hot night.

During the period between

about 1885 and 1940,

there was a worldwide revolution in the life sciences.

And it actually began here.

Some of you have heard, those of

you who come to this session

regularly, about the role of

Wisconsin in the discovery of

the vitamin process for

making active vitamin D.

And you probably have heard

about the importance

of Wisconsin's participants

in the development

of the drug warfarin, KP Link.

But there's a less widely sung

and no less important discovery,

and I want to talk to

you about that tonight.

I'm going to take you through

about nine steps, and it may

look as if it's a crooked line,

but we'll get there.

I want to show you how, first of

all, in Madison, the discovery

was made that there are factors

required in the diet that are

not among the things that people

used to expect to be complete.

That is, there are factors

that are not carbohydrates,

fats, or proteins.

We, of course, know

now they are vitamins.

But I have textbook of nutrition

in my office from 1907 in which

vitamins don't even enter

into the table of contents.

Not in the index.

So this is a relatively new

development I want to talk about

how that began here.

The revolution that I'm talking

about was a sort of paradigm

shift, which is always

interesting to watch in science.

In this case, the shift was from

the way people thought about

the nutrition of farm animals

before, let's see, 1890,

and the way they think about it

now or have since about 1940.

That insight came in part by the

separation of foodstuffs

into two different categories.

Those that were essential to

growth and soluble in water

and those that were essential to

growth and were soluble in fat.

They became known as fat soluble

A, and A became actually,

with investigation,

a fraction that

contained vitamins

A, E, D, and K.

And there was water soluble B,

which, upon a long

investigation, turned out

to be several vitamins,

B1, B2, B3, B6, B12, and so on.

There was, with the discovery

of these accessories factors

in the diet, a world race.

I mean, every lab in the world,

it seemed, was trying to

figure out what their

essential cofactor was.

And I'll tell you just a little

bit about what went on

around the world, but

I want to focus here

on what went on in Madison,

of course.

This whole story comes, finally,

to the medical cure for a very

serious disease which was rather

common in the American south

in the period between about

1900 and 1920: Pellagra.

I'll tell you more about that

later, but it was the cure for

Pellagra that was sought and

found here in the shape

of a compound, a simple, cheap

compound called niacin

or vitamin B3, which

was discovered here

by the group headed by Elvehjem.

The other developments that help

us understand more fundamentally

what the vitamins do took place

in laboratories all over the

world, and we came to realize

that the reason that we need

vitamins is that they perform an

essential service in the

breakdown of our fuels from

which we derive energy.

And I'll show you a

little bit of that later.

If there is time, we'll talk

very briefly about the discovery

of the importance of iodine for

goiter also took place here.

So this is about 1910.

The dairy barn was over

here where it still is.

It was, in 1910, kind of green,

believe it or not.

And it was in this barn that the

first experiments that started

this revolution took place.

They were directed by and

thought through and brained by

Stephen Moulton Babcock, who was

one of the first members of the

faculty in the College of

Agriculture and Life Sciences.

And that experiment that he

planned and carried out with the

help of three others was called

the single-grain experiment in

which the objective was to test

the hypothesis that all you

needed to do to make a farm

animal healthy was to give that

animal carbohydrates, fats, and

proteins and enough calories.

That was the party line.

That was actually in a

textbook of nutrition,

published by the dean

of the college here.

But Stephen Moulton Babcock

doubted that on the basis of

reports from farmers all over

the world who had found that

not all feeds were equally good.

So Babcock planned an experiment

to test that hypothesis.

And the idea here was that you

want to ask if simply providing

enough protein, carbohydrates,

and fat is sufficient.

So he planned an experiment

in which he got four groups

of cows, young heifers,

and they were put into

separate categories,

one of which was fed all corn. All corn.

Another all wheat,

another all oats,

and a fourth one a third

of each of these things.

And in order to get the same

number of calories and the same

amount of protein and

carbohydrates from these various

grains, they had to use

different parts of the plant.

So the leaves, the stem,

the grain and so on.

But they matched things so that

the cows are all getting exactly

the same amount of what

was thought to be the

important stuff for nutrition.

And then they followed those

cows over a period of two years.

They watched their weight gain,

they watched their milk

production, they looked at the

health of the calves that they

produced, and it turned out

that the result contradicted

the standard party line

in a very striking way.

This is the single-

great experiment.

It was published in 1911.

It was done a couple

years before that.

These are the three people

who worked with Babcock,

who was, by the way, a fairly old man or middle-aged old man

when this was all done.

EB Hart was a younger man

who was sort of the brains

behind this effort.

Elmer McCollum, who was a young

man who I think we would call

an instructor now

in biochemistry,

and Harry Steenbock was

a graduate student.

These names all went on to fame.

But it was the three of these

with Babcock's advice who did

the experiment over a period of

two years, and they found a very

clear result: that the cows fed

on corn alone were healthy

and their calves were healthy

and they gave more milk,

better milk, than those

fed on wheat or on oats.

In fact, the wheat- and oats-fed

cows in their second calving

gave birth to cows

that were born dead.

So it was very clear that

these three sources of food

were not identical.

Something was in corn which

was not in the other two,

and it was unaccounted

for in textbooks.

So, what do you do?

Well, what these three did was

to take this not good diet,

let's say the oats diet, and

asked if there was anything they

could add back to it that

would make it a good diet.

So, for example, they took

the regular oats diet

and added butter, or in

another case added milk.

And it turned out that

in both of those cases,

the diet which was not good, became good.

So there's something in milk

and there's something in butter

that actually are essential

to growth and important.

And, of course, now

the question is,

what is it in butter or milk?

And at the time this question

was being asked, that was not an

easy one to answer because the

equipment, the resources that

they had to analyze molecules in

the food were simply not up to

the task, especially since, as

we'll see eventually, vitamins,

unlike a lot of other things in

cells, are present in very low

concentrations, and that means

that detecting them requires

sensitive instrumentation which

simply didn't exist in 1900.

So these three made that

discovery and published it

in 1911.

And it made the chemical analysis paradigm

no longer tenable,

and instead we needed

to ask with biological assays,

what is this cow missing?

And the only way to do that is

to use essentially a bioassay.

You have an animal who is not

well-fed, and you figure out

what to do to make

the feed good.

A new paradigm and this paradigm

was recognized immediately,

not simply here,

but all over the world.

And as soon as it became clear

that this was a way of looking

for new kinds of compounds,

new kinds of dietary factors,

everybody in the nutrition

world, all over the world,

began trying to identify what these factors might be.

Their approach was almost always

the same: feed a diet that was

not quite adequate and ask what

they can supplement it with that

made it good and then look

what's in that supplement

to figure out why it's good.

McCollum introduced

another important change.

The experimental cows

were very expensive.

Cows take a lot of space.

They take a lot of food,

they take a lot of tending.

They have a slow turn-around

for calves.

And so, in general, they were

important domestically

and the ag school was happy to

support them, but, in fact,

the experiments were too tedious

if you used cows, and McCollum,

therefore, went to the dean and

asked for a few dollars to buy

a couple of cages so

that they could use rats

in the basement of biochemistry.

The dean apparently threw him

out of the office and told him

that if the farmers of the state

ever figured out that the dean

was spending their taxes to

learn how to nourish rats,

there'd be trouble.

[laughter]

So he used his own money,

or maybe Babcock's money.

He bought a couple of cages,

went to Chicago and bought

a couple of albino

rat mating pairs.

This is apparently after

having unsuccessfully tried

to grab a rat in the barn. [laughter]

They're not the same

as albino rats.

So he bought these mating pairs,

brought them back here, and they

became the progenitors of

all of the white rats used

in research all over the world

for many years.

Madison actually had the two

largest rat farms in the world

for many years.

Rats are cheap to feed,

don't take much space,

have progeny very fast,

and because you can have lots

of them in an experiment,

you get data that are

statistically more meaningful.

And so it was an important

change in the protocol

for studying nutrition.

Using this idea of supplementing

minimal medium, McCollum and a

woman, Marguerite Davis, who was

his assistant, and I think an

unpaid, volunteer assistant,

which probably was the way a lot

of women were involved in

science then, there's a bad, bad

history there, the two of them

did experiments in which they

took the butter or the milk,

fractionated it in the ways that

were available in 1911, and

found that some parts of the

milk were of no use at all;

they could throw those away.

But one part that was clearly

important was something that

was soluble in lipids, it was a

minor fraction so you could

purify it and purify it away

from other stuff

until you had very little

but it was very potent in

remedying the bad diet.

And they published this

landmark paper in 1913.

The title doesn't sound very

exciting, but it really was a

major bombshell because it was

the first evidence that there

was a real compound that

was essential to the life

and they we didn't know

about before that.

McCollum actually had two

assistants, both of whom were

terrific and both of

whom had careers

even after he, McCollum,

left Wisconsin.

He was here from 1907 to 1917.

Then he went to Johns Hopkins.

Part of the reason for his

departure was the town

wasn't big enough for Steenbock

and McCollum both,

and one of them had to go.

It was he.

But he did take the precaution

of turning loose all of his

competitors' rats

before he left.

[laughter]

That's apparently

a true story.

Anyway, the two women were

Marguerite Davis

and Cornelia Kennedy.

Both of them published with him,

so they were acknowledged

as being important

contributors here.

And although the history is

a little fuzzy about this,

one or the other of them,

or maybe both of them,

actually were the ones that contributed the nomenclature

fat soluble A, water soluble B.

So, the race began, people

began to use this bioassay

to look for compounds

of interest.

And right away the compound that

Davis and McCollum had first

discovered was further

purified to become vitamin A.

And McCollum spent a good

share of the rest of his days

in science looking at vitamin A

and related compounds.

Also in the fat-soluble fraction

was the precursor to vitamin D,

and that was taken over by

Steenbock who had, of course,

been part of this one

great experiment too.

And Steenbock made the very

important discovery that the

stuff was turned into an

active vitamin and hormone

when the stuff, not the animal, but the stuff,

was irradiated with

ultraviolet light.

This was something

that was patented here,

that gave rise to

the Wisconsin Alumni Research

Foundation, an organization

that has a bank book with two

billion dollars in it now,

that's billion with a B,

and has made a huge

impact on this campus

where they invest all

of the money they make.

Elvehjem and Strong, Strong was

still here when I came in 1971,

took the water-soluble stuff,

and they purified from it the

vitamin I want to tell

you most about today:

vitamin B3 or niacin.

This was many years after

the original discovery

that there was something there.

Going from something to

an identified compound

took nearly 20 years.

Esmond Snell, who was a

member of the faculty here,

took vitamin B6.

Henry Lardy, a member of the

faculty here, took vitamin B7.

And eventually almost all of

the vitamins and minerals

were touched by somebody

on the campus here.

The vitamin C, K, and E were

looked at by Link, who was a

carbohydrate chemist and had

extensive notes about vitamin C

that led us about the fact that

it cured scurvy, vitamin C.

But he didn't get there first,

and so those notes

remain in his notebook.

Phillips studied vitamin E.

Baumann studied several of

these things including K.

So there was actually a large

community here in the College of

Agriculture in the departments

of biochemistry and the new

Department of Nutritional

Sciences that developed from it.

And if you look now on a box of

vitamins and look at all the

things listed on the back of it,

almost every single thing on

that long list of 20 or so items

has been the object of study

here sometime, and many of them

are still the objects of study.

For example, when Steenbock,

who studied vitamin D, he was

dealing something that had a

profound effect on animals,

but there was absolutely not the

slightest understanding of how

that effect was manifest,

how it worked.

And now we have a molecular

description of what vitamin D

does at the essentially

atomic level.

And so is that true for some of

these other vitamins as well.

50 years of work

has led to that.

We were not the only

school in the world

who's interested in this,

of course.

There was a hot competition

between Osborne and

Mendel at Yale.

And the group here in the early

parts of the 1915-1920 period.

In fact, there is a set of

letters that were exchanged

between the chairman in the Yale

department and the UW department

that were close to pugnacious.

They were trying to be nice

between fairly hardened letters.

Great entertainment.

There is a, there was and is

still a privately funded,

very well-funded laboratory

Rothamsted in the UK.

There was a group who began in

India and probably came as close

as anybody to beating the

group here to the punch that,

after making the original

discovery in India,

went back and worked

in Utrecht, Holland.

There was a group in Cambridge.

Hopkins was the head

of that group,

and he became famous for

his work on vitamins.

And there were others.

So we didn't have the

field to ourselves,

and during that period, I would say between 1911 and maybe 1920,

there was just tremendous excitement in the field.

The papers poured out.

Every journal you opened

from that period

has another interesting observation by somebody.

Very exciting time.

Here, the excitement

led eventually

not only to an understanding

of the nature of the compounds

but of their role

in curing disease.

And if you walk around campus,

I'm sure you have walked around

and seen these brass plaques.

Here are six of them,

which I suppose you may

not be able to read.

[laughter]

But they are here to

tell us that,

one, Wisconsin led in the discovery of this paradigm,

two, that discovery led

to cures for rickets,

pellagra, anemia, iron deficiency anemia and goiter.

And if we had time, we could

talk about all of them,

but I'm going to tell you

mainly about pellagra.

There was, coming from various

places, information that helped

one to plan an experiment

in those days.

There had been for a hundred

years the observation in the

literature that the disease, the

very serious, lethal disease

scurvy could be completely cured

by fresh fruits and especially

by fruit juices from things

like lemons and oranges.

That was in the literature

but there was no explanation

for how it did this.

There was no effort to

characterize the stuff

that was in the fresh fruits.

As I said, Osborne and Mendel

at Yale had used the same basic

approach that was used here.

Used an incomplete diet.

See what you need to add back

to it to make it better.

Eijkman and Grijns were

in India where they were,

they discovered by accident

that the disease beriberi,

a very serious

nutritional disease,

was essentially

caused by people

eating most of their

food as polished rice.

Rice with the brown

hull still removed.

And it turned out that

the reason for this,

the beriberi curer was the

stuff in the rice husk.

And, again, they didn't pursue

the stuff chemically.

They just said there

is something there,

so there's a

nutritional disease.

Both of these were said.

Casimir Funk, a Pole,

also read the literature,

did some experiments

that led him to think

that there were

accessory factors.

And he in fact got so far as to

guess that they were amines

and he therefore

named them vitamines.

That's where the

name came from.

The E eventually was dropped.

Hopkins, in Britain, wrote a

great book that summarized

the work that went back to

Aristotle, practically,

about all kinds of things

that affected the health

that came from the diet.

And Hopkins was a major

contributor in the whole period

from 1920 to 1940.

Goldberger, whom we'll turn now,

was not a scientist

in the usual sense.

That is, he didn't work

in the laboratory.

He was a public health physician

at the Public Health Service,

the US Public Health Service.

And he got into this story when,

in about 1905, there was a

terrible epidemic of pellagra

in the south of the US.

From a period of 1905 to 1910

it was extremely serious,

and it lasted until 1920 or so.

So the Public Health Service

put one of their best men,

Goldberger, on this

problem and asked him

to see if he could resolve

the cause of pellagra.

And the two causes that he

examined of course were either

it's an infectious disease and

you solve that by not infecting

each other and staying out of

each other's way, or it's a

nutritional deficiency in which

case you modify the diet.

On the bottom list here is

another person who figured

prominently into the

understanding of how vitamins

worked but who was not any

part of the evolution

that I'm talking about today.

Warburg was a German chemist.

He was the biochemist's

biochemist.

Won the Nobel Prize for his work

early in his life, spent a

lifetime of remarkable

contribution, and Warburg,

in the course of studying the

enzymes that carried out

the breakdown of sugars

from which we get energy,

discovered that there was a soluble factor, he called it,

that had to be added to one of the enzymes to make it work.

And the soluble factor,

it turned out, was made from

niacin, the vitamin that

Elvehjem discovered here.

So we finally, with his work,

had an explanation of the effect

all the way down to

the molecular level.

Pellagra is a tough disease,

and in some places led to a high

proportion of a population being

sick and many of them dying.

The four Ds, diarrhea,

dermatitis, dementia, death,

usually developed in that order.

So the first thing you see,

physically, is dermatitis,

and it eventually looks as

bad as what you see here.

In fact, pellagra is from

Italian pelle-agra, raw skin.

So this disease was occurring at

high frequency in certain places

in the south, and those places

were orphanages, prisons, towns,

cotton mill towns, for example,

where everybody was poor

or nobody could

afford beefsteak.

And so those places, those foci

of pellagra, became the target

for the investigations by both

the group that was interested in

checking for infection,

infectivity, and the group

looking for nutritional

explanations.

Here's Joseph Goldberger.

There are several really

good books about his life,

and they would justify a novel

along the lines of "Arrowsmith,"

I think, now.

He made remarkable improvements

in the techniques for

epidemiology, set the pattern

for this for many years,

and he sacrificed

himself in a way

that I'll tell you

about in just a minute.

But what he did, basically, was

to convince the public health

service and the states of

Mississippi and Alabama to go

along with him as he tested the

hypothesis that giving these

patients a good diet

would cure their pellagra.

And they, on a small scale,

supported this.

So he had two orphanages and

two prisons that he went in to.

It was very common at that time

for half the people in a

prison to have pellagra.

And it was very common for a

quarter of them to die from it.

So this is no joke.

It was a serious business.

He didn't have an institutional

committee to satisfy,

and he therefore did experiments

of the sort you couldn't do now.

But he got the results that made

the whole thing seem now,

in retrospect, to have

been worthwhile.

He went to these prisons, first

of all, took careful notes about

what the people there were being

fed, and it was soon apparent

that the prisons and orphanages

in the south at this time had a

diet that was very rich

in corn and very poor

in protein-rich things,

like beans, peas, meat,

liver and so on.

That was the sort of universal

finding in all these places.

He also found that the staff,

in these orphanages and prisons, never got sick.

And, of course,

it's because

they ate their lunch

someplace else.

They weren't being fed corn

every day, every hour.

So, he did the

logical experiment.

I think there were something

like a hundred children

in each of two orphanages.

He provided them with

really good meals.

That is breakfast with eggs and

milk, meat for several of the

meals in the week, and very

quickly found that the kids that

were sick immediately responded.

The rash that's so

characteristic disappeared.

If those people had reached

the stage of a dementia,

even the dementia

was reversible.

So this is really a

pretty dramatic result.

At the time, there

was a powerful lobby

that wanted the other answer.

It wanted to believe that this

was an infectious disease.

And as far as I can figure from

reading the history of this

period and the stuff

about Goldberger,

the problem was that

the wealthy people

in the south, Mississippi

and Alabama particularly,

valued their reputation for

being visitor heavens.

And they didn't want the word to

get out that poverty was causing

illness in their population.

So they actually grubstaked

another committee to go out and

investigate the same question,

and that committee came to the

other answer, namely that this

was an infectious disease,

which forced Goldberger

to try even harder.

And he eventually got the

governor of Mississippi to let

him work with 11 prisoners in a

long-term prison setting with

the deal being if they would eat

everything that Goldberger gave

them for a year, they'd go free.

A nice trade-off.

And they all managed to do it.

Although, when I read the

composition of the diet,

I don't know how they did it.

But in any case, the diet had

things that were good for them.

He had another group to

whom were not showing signs

of pellagra, and he fed

them an inadequate diet

and they developed

signs of pellagra.

So it certainly looks as though

he's the one who's got the data.

But to be on the safe side

and to show how seriously he

believed his own results,

he held what the television

calls the filth party.

And this involved a small group

of people, his coworkers in the

Public Health Service, his wife,

himself, ingesting in various

ways, swallowing or being

injected with, the scabs from

pellagrans, the blood from

pellagrans, the feces.

And I don't know how they got

around the problem of blood

types, but they actually

injected five mills

of blood from somebody with

pellagra into themselves,

including Goldberger

and his wife.

That's serious support

at home, I'd say.

[laughter]

And none of them,

none of them developed pellagra.

The other committee that I was

talking about, by the way,

is the McFadden-Thompson

Committee, and they eventually

faded after he came through

with the hard data.

Now, at Madison there was a

group of four who took up the

problem of the water soluble

vitamins that had been

discovered in the early 1900s.

And these two led the group

that discovered niacin,

the vitamin that cures pellagra.

Conrad Elvehjem

eventually became chairman

of the department,

dean of the graduate school,

president of the university,

and died young.

Actually, he died

literally in office.

Frank Strong was a younger man

who was with Conrad Elvehjem

in these studies.

Elvehjem was a nutritionist,

Strong was an organic chemist,

and the two of them got

together to do what they could

to purify the

anti-pellagra factor.

They published this discovery in

1937, and I have actually got on

the screen here

the entire paper.

The one-page paper that put this

bombshell on the world lines.

There are two things

in it that I think are

really very striking.

A single dose of 30 milligrams

of nicotinic acid,

that's niacin, gave a

phenomenal response

in a dog suffering

from black tongue.

These dogs were on the point

of death and they immediately

started to be better and

came back completely.

30 milligrams, if you have a

piece of, if you have an

aspirin tablet in your hand,

that's 350 milligrams.

Imagine cutting it into 10

pieces, taking one of those

little pieces and

giving it to a dog

and seeing a dramatic change.

These things are potent,

and I'll come back to the

explanation for why

they are so potent.

The other thing that's

interesting here is their

statement: "The observation that

a deficiency of this material

"may be the cause

of black tongue."

I'm sorry I didn't, I left

something out here.

A veterinarian who treated lots

of dogs had discovered years

before this that there

was a disease in dogs

that mimicked pellagra in

humans called black tongue.

It affected all the things

that are affected in humans.

The mouth, of the dog

particularly, developed sores.

And it turned out that a dog

with black tongue was the

experimental animal that

Strong and Elvehjem used.

They had the dogs in the

attic of the building

right across the street.

They gave them a diet

that was inadequate.

The dogs developed this disease,

and then they added niacin back

and cured it just like that.

So, the observation that a

deficiency of this material

may be the cause of black

tongue is most interesting.

There's only one other paper

that I know of that has this

kind of low-key announcement,

and that's the paper

by Watson and Crick that

announced the structure of DNA.

They said in their

one-page paper,

"It has not escaped

our attention..."

[laughter]

And the same thing here.

I guess maybe it's a Midwestern

tendency not to blow their horn.

But they didn't have to.

The word was out.

They immediately corresponded

with six different physicians

around the country, all of whom

expressed interest in treating

their own patients with stuff.

And Tom Spiece is the one whose

publication came out first.

He managed to cure

human pellagrans

with very lose doses of niacin.

By low dose I mean

milligram quantities.

And the story was

pretty well complete.

The people involved in

this were appreciated,

not just here,

but in the world.

The Nobel Prize nominations

have always been secret,

but the Nobel people

have just, in the last year,

allowed you to see

everything that took place

before 50 years from now,

50 years back.

And this period, of course,

is now open in their archives.

So Elvehjem was nominated nine

times for the Nobel Prize,

twice in one year.

Strong, the organic chemist who

really determined the structure

of niacin, was nominated twice.

Madden and Wolley, who were the

graduate students involved in

this discovery, were themselves

actually nominated.

And I think in the case of

Wolley, the nomination came as

much for the work he did after

Wisconsin as before, but,

in any case, they were

widely, highly regarded.

McCollum was nominated

six times or seven times.

Steenbock twice.

And Karl Paul Link, who

actually had had a role in the

determination of the structure

of niacin, when they got the

purified stuff that Frank Strong

as a chemist had developed,

they needed to do an analysis

of the carbon/hydrogen/nitrogen content,

and KP Link's

lab did that.

Link later made other important

discoveries that led to his

nomination for the

prize five times.

So it's a really

remarkable group of people.

None of them won the Noble

Prize, and part of the reason is

that the other groups,

that were studying nutrition,

trying to run

down these factors,

were no slouches either.

So, Eijkman, whom I said

had figured out a way

to study the vitamin

thiamine, won the prize.

Hopkins from the UK.

Henrik Dam determined the structure of vitamin K.

Each of these people made an

important contribution either

in the discovery of the vitamin

itself or in its isolation or in

its actual chemical structure,

synthesis or structure.

And you can see that during that

period of about 19, what is it,

1929, I guess, until about 1940,

there was a lot of hot action

in the field of vitamin

chemistry and biology.

So, to recap what I've said, the

discovery of essential factors

really was something that

took place in Madison.

That's in red.

The paradigm shift that led

people to approach nutrition

from a different angle,

that was from here.

It quickly was adopted

elsewhere and used.

The separation of vitamins,

quote, into fat soluble A and

water soluble B surely was a

Wisconsin development, and it

was the very beginning of a long

series of chemical studies.

There was the international

effort to identify factors.

Pellagra was defined, finally,

after Goldberger's work

as a nutritional deficiency,

and then the structure of niacin

itself was discovered here.

The effectiveness of niacin

in curing black tongue

and pellagra was initiated here.

And the work on this vitamin

fell together with and took

place almost at the same time,

1935 about, when the biochemists

in Europe, especially Warburg,

Otto Warburg, were figuring out

that the cofactor that there

were enzymes needed to break

down food was made of the same

stuff that was curing pellagra.

And it became clear,

there were two things

that came out of this

that made sense.

One is that chemists and

biologists had missed

the presence of vitamins

earlier because nobody had

instrumentation sensitive

enough to detect

such small quantities

of these things.

And the reason that they were

present in such small

quantities, these cofactors, is

that, like enzymes themselves,

they didn't get used up.

If you have a hundred grams of

sugar in your hand and ask your

body to digest it, it'll do it

all right and pretty fast.

So a large quantity of stuff is

used, but to do that, enzymes

that are present in such small

quantities by comparison,

you can't see them do it.

And the reason is that the

enzyme keeps cycling.

It does it, does it again,

does it again, does it again.

And the cofactors for the

enzymes, similarly, recycle.

So you don't need very much.

Some of the cofactors, some of

the vitamins are needed in the

range of micrograms.

You can't see a microgram

in the palm of your hand.

So they're extraordinarily

potent, but that means they're

present in living cells at low

levels and that's what it made

it so tough to discover them.

Okay, so there is, let's see,

there is time.

So let me just tell you a little

bit more about a couple of

things here that figured into

this story that I've told you.

One was the discovery by Buchner

in the turn of the 20th century

that yeast not only could make

alcohol from sugar but broken

down yeast, yeast completely

destroyed so their guts are

spilled out, their guts

convert glucose into wine.

And this cell-free fermentation

allowed the biochemists to go

in there and start picking and

choosing things and putting

together the sequence in which

the sugar was broken down

in what turned out to be

10 steps into its product.

So Buchner actually, who won the

Noble Prize for this discovery,

opened up the whole of biology

to biochemical approaches.

And now the biochemists could

go in and define pathways.

Otto Warburg I've said was one

of the people who did that.

He showed that there were 10

steps that all of us, ants,

elephants, people, alligators,

we all do it the same way,

and for each of those 10

steps there's an enzyme.

For one of those 10 enzymes

there is a cofactor,

which Warburg discovered as

something that was water soluble

and had to be added back

to make the fermentation

go in the test tube.

So, he was zeroing in

on this as a chemist,

and everything fell together.

When they looked at niacin, they

looked at the stuff he purified,

and it was the same stuff.

Suddenly it was clear why these

vitamins were so essential.

And that's true not

just for niacin,

all of the vitamins

do the same thing.

They all function catalytically.

They all are essential

to normal metabolism.

And their lack in the

diet is seriously felt.

In the years since Warburg

started this work,

scientists have discovered that

there are more than 400 enzymes

that all use niacin

as a cofactor.

And so it's no wonder

that if you don't have

niacin, you're hurting.

Here's a picture for those of

you who like to see the

structures, but, basically,

here's niacin over here,

and if you just look at this

hexagon with the nitrogen.

You see the same

thing right there.

That's the business end of the

cofactor, which is called NADH,

and the name of this compound

comes from the structure of

nicotine, which is otherwise in

no way related to this story.

Nicotine happens to be something

that you can use

to prepare niacin.

You break this bond

and now you have

that same hexagon with nitrogen.

But, except for that

structural resemblance,

nicotine has nothing

to do with niacin.

Just a couple of slides about

one more serious disease

that was cured by research

that took place here

in that same period

that we're talking about.

Goiter is something

common in, it was common

in the Midwest and

the Pacific Northwest.

It resulted in the swelling of

the thyroid gland, which is

right here, and the swelling

could be quite extreme,

as it is in the case of the

man that I'm showing you here.

The problem with goiter is that

the thyroid gland, which is

supposed to make a hormone

called thyroxine, can't.

And because it can't, it grows

hoping if I can get bigger,

I can do it.

And eventually you have

this enormous thyroid,

but it still isn't working.

And so the patient still is ill

from the lack of the product

of this gland, the normal

product thyroxine.

Don't worry about the structure

here, but I want simply to show

you that thyroxine has

four iodine atoms in it.

One there, one there,

one there, one there.

This is very unusual in biology.

I can't think of

any other compound

that's just so full of iodine.

If you take a swig of iodine,

it'll just go straight

to your thyroid gland.

If you've ever had therapy

when they're trying

to work on your thyroid, they'd

use spoonfuls of iodine.

So thyroid hormone contains

iodine, and the people who get

goiters get them because their

diet doesn't include iodine.

The ones in the Midwest

weren't getting any seafood.

And the seafood, because the

ocean is full of iodine,

seafood provides iodine.

So, there was sort of

a plague of goiter.

And Hart and Steenbock, Hart,

the professor, Steenbock,

the student, discovered

that the problem

was simply a lack of iodine.

And something like two billion

people still live without

iodine, lived in parts of the

world where there is no sea

water available and no iodine

in the Earth to speak of.

I was surprised but I

actually confirmed this.

This is, the lack of iodine is

the leading preventative

cause of intellectual and

developmental disabilities

in the world.

A very common, very

serious problem.

And, shockingly, it could be

cured by this kind of thing.

150 micrograms, which I've said

is barely visible in the palm of

your hand, daily, costs a nickel

a year to solve this problem.

And the fact, that the

world still has people

suffering from goiter,

is criminal.

Hart not only discovered this

role for iodine but figured out

a way to solve this very easily,

and that is if you simply

supplement some food that

everybody eats with iodine,

that should solve the problem.

It turns out that everybody eats

sodium chloride, table salt,

that he figured out a way to get

iodine into the table salt

in such a way that

it would stay stable,

which wasn't trivial to do.

And now when you buy salt,

it always says,

as this one does here,

iodized salt.

So you see very, very

infrequently goiters.

Okay, then let me just close

by telling a little bit

of what happened to Elvehjem

after this initial important

scientific phase of his life.

Elvehjem must have been an

amazing organizer because he was

able to be the chairman of the

Department of Biochemistry

during this incredible active

period of the 1920s and 1930s

and to be the graduate dean

and then eventually to be

the president of the university.

And he kept the

research group going.

He was responsible for a lot of

really important

changes around here.

For example, it was his

work that resulted in the

establishment of the

Enzyme Institute,

a unique organization

which for many years

distinguished the

University of Wisconsin.

He trained 88 doctoral students,

which is just inconceivable.

And he died at the age of 62.

He very likely would

have won the Nobel Prize

if he hadn't died early.

This is a portrait of

him by Aaron Bohrod,

who was the university's

artist in residence.

This rosemaling is no doubt

his Norwegian background.

This is the, the winged victory

of Samothrace,

is the statue on top of the Lasker Award, which he won.

The Lasker Award is

usually the last thing

that happens before you

get the Nobel Prize.

I might say that KP Link,

whose son, Tom, is right here,

won two Lasker Awards.

Here we have somebody who

clearly has pellagra.

Okay, thank you very much, and

I'll be glad to take questions

if you have them.

[applause]

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