lJ

Fritz Lipmann:
CHRISTIAN

TKIUUT

in memoriam

DE DUVE

The Rockefeller University, New York, New York 10021,

Molecular Pathology, Brussels, Belgium

OF US ARE BRICKLAYERS. We are happy

to add a
stone to the edifice of science and we consider
ourselves
fortunate
to contribute
a cornerstone,
or the base of a
column,
or the keystone
of an arch. A rare few have the
vision of an architect.
They somehow
see the whole
building
long before
it is completed.
Fritz Lipmann
was such a visionary.
Another
was Albert Claude,
his
almost exact contemporary,
who died 3 years ago.
Like many biochemists
of his generation,
Lipmann
came to science by way of medicine.
He was born in
Konigsberg,
the capital of East Prussia,
at the turn of
the last century.
The son of a successful
lawyer, he grew
up in a happy and cultured
family environment.
His
admiration
for an uncle,
a very lovable
man and a
well-liked
pediatrician:2
led him to choose medicine
as
a career.
His studies,
performed
partly in Konigsberg
and partly in Munich
and Berlin, were interrupted
by
a 1-year spell in the army medical
service.
He saw the
end of World War I on the French
front and was later
a witness
to the murderous
influenza
epidemic
that
devastated
Europe
after the war. In spite of these grim
experiences,
he thoroughly
enjoyed his studies and his
early
clinical
activities.
As he was to write 50 years
later: The biological
education
to which the observant
student is exposed in medicine
is a superior
preparation
for any career.3 But when the time came to take up the
practice
of medicine,
he became uneasy, troubled,
as he
said, by the prospect
of charging
people money for trying to make them healthy.2 He drifted
to pathology;
then, having enough
of cadavers,
he enrolled
in a biochemistry
course given by Peter Rona, a former associate of Leonor
Michaelis.
This course and a small piece
of research
in the then-fashionable
area of colloid
chemistry,
followed by a short stay in the pharmacology
laboratory
of Laqueur,
in Amsterdam,
sealed his fate.
He was going to become
a biochemist.
Conscious
that the little chemistry
he had been
taught
during
his medical
studies
provided
an insufficient
basis for a career
in biochemistry,
he went
back to school and Spent 3 additional
years learning
chemistry
while staying with his family in Konigsberg.
In 1927, at the age of 28, he finally felt ready, eager to
do real biochemistry.3
Looking for a suitable laboratory,
he chose that of Otto Meyerhof
at the Kaiser-Wilhelm
Institutes
in Berlin-Dahlem,
then the best center
in
Germany
for the kind of biologically
oriented
bio-

and

USA,

International

Institute of Cellular and

MOST

chemistry

he wanted

to engage

in.

He

applied

Meyerhof
and was accepted
an indication,
no doubt,
that his qualities
were already
apparent
at that time.
-

0892-6638/87/0001-0003/$01

.25. FASEB

to

Fritz

Lipmann,

1899-1986.

Photograph

by John

Fritz Lipmann
stayed only 3 years
first in Berlin and later in Heidelberg.

Brook.

with Meyerhof,
His work, which

dealt largely
with the inhibition
of glycolysis
by
fluoride, was good enough for a Ph.D. degree, but
hardly earth-shattering.
Yet those 3 years played a key
role in his personal
development
and may well have
shaped
the whole of his scientific
output.
As he mentions in his autobiography,
In the Freudian
sense all
that I did later was subconsciously
mapped
out there;
it started
to mature
between
1930 and 1940 and was
more elaborately
realized
from then on.3 He does not
elaborate,
but we can try to guess.

First, he met many of the great biochemists

of that
time, the first pioneers of cell metabolism:
Meyerhof
himself, Warburg,
Neuberg, Embden, and some of the

This

talk was delivered

at a memorial

concert

held

at The

on December 12, 1986.

2See LIPMANN,
F. A long life in times of great upheaval. Annu.
Rev. Biochem. 53: 1-33; 1984.
3See LIPMANN,
F. Wanderings of a biochemist. New York: Wiley;
1971.
Rockefeller

University

gifted younger
scientists,
such as Hans Krebs and Hans
Gaifron,
who worked with them. He was particularly
influenced
by Karl Lohmann,
the discoverer
of ATP,
who taught
him the phosphate
ester chemistry
that he
was to use extensively
in later life.
A major preoccupation
in those days was mapping
the glycolytic
pathway.
But Meyerhofs
interest
in this
problem
was not just that of a chemist
who wants to
know how a reaction
takes place. As a biologist,
he also
wanted to know what for. His most important
contribution, that for which he shared the Nobel Prize in medicine with A. V. Hill in 1922, had concerned
the role of
glycolysis
in muscle.
Pursuing
earlier observations
by
Fletcher
and Hopkins,
he had demonstrated
that the
conversion
of glycogen
to lactic acid is the source of
energy
for muscle contraction
under anaerobic
conditions,
and established
the quantitative
relationship
between
lactic acid produced
and work performed.
Lipman
was actually
in Meyerhofs
laboratory
when
the devastating
news came from Copenhagen
that a
muscle poisoned
with monoiodoacetate
could continue
to contract
and perform
work for a while without
producing
any lactic acid. He was there when Einar
Lundsgaard,
who had made this discovery
and found
the phenomenon
to be correlated
with the hydrolysis
of
creatine
phosphate,
came to Heidelberg
in 1930 to
verify this correlation
quantitatively.
He was there also
when
Lohmann
discovered
that creatine
phosphate
provides
the muscle with energy
by way of ATE The
key concept
of phosphate-bond
energy
must
have
germinated
in his mind at that time. Then,
we may
speculate,
is when his luminously
perceptive
vision of
life started to take shape. No doubt he had the unique
kind of mind needed
to conceive
such a vision, but it
was in Meyerhofs
laboratory
that he found the right
climate
for the seed to be planted
and to develop.
Only 10 years later, having,
in the meantime,
studied
cell culture
with Albert Fischer in Berlin, isolated
serme phosphate
from phosphoproteins
in the laboratory
of Phoebus
Levene at the Rockefeller
Institute
for Medical Research
in New York, discovered
acetyl phosphate
as an intermediate
of pyruvate
oxidation
by bacteria
at
the Carlsberg
Institute
in Copenhagen,
and finally joined
Dean Burk in du Vigneauds
laboratory
at Cornell University Medical
School just before the outbreak
of World
War II, he wrote his celebrated
review Metabolic
generation and utilization
of phosphate
bond energy: published
in 1941 in volume
1 of Advances in enzymology.
This paper should be required
reading
for any student of biology.
It is a landmark.
I remember
the
impression
it made on me when I first read it. I was
familiar
with Meyerhofs
measurements
and had just
plodded
through
a painstakingly
detailed
review of the
energetics
of glycolysis
by Dorothy
Needham.
It contained
all the facts and it was about as exciting
as an
accountants
report.
Then
came Lipmanns
paper.
It
was a revelation
and everything
fell into place. The
notion of group potential,
the squiggle: the conversion
of electron-linked
to group-linked
energy, the key role
of group transfer
in biosynthesis.
It is all there, only to
be elaborated
on further in subsequent
reviews in 1946,
1948, 1960, and 1968.
4

From here on, the line of his research

is perfectly
straight.
He himself has referred
to it with characteristic modesty
as wandering,
following
ones instinct
without
knowing
exactly where it will lead?3 It could
strike the superficial
observer
that way, as it meanders
from
acetylation
to uncoupling
of oxidative
phosphorylation
and the action of thyroxin,
carbamyl
phosphate, the synthesis
of sulfate esters, poiypeptide
chain
elongation,
the formation
of bacterial
antibiotics,
tyrosine phosphorylation.
But it was no wandering.
Fritz
Lipmann
knew exactly where he was going. He knew
intuitively
what to look for because
he saw the broader
picture.
Occasionally
the results
did not come
out
exactly as he had anticipated.
He left adenylyl
acetate
for Paul Berg to discover,
the thioester
bond of acetylcoenzyme
A to Fitzi Lynen,
the prediction
of tRNA to
Francis Crick and its demonstration
to Mahlon
Hoagland and Paul Zamecnik
and to Bob Holley. He has bemoaned
this, exclaiming
how difficult
it is to see the
new because it is new and how badly one may be handicapped
by preconceived
notions,3
and again how a
pointer
in the right direction
may be neglected
if ones
mind is made up to look in a different
direction?3
In
fact, his mind was always in the right direction,
but he
sometimes
started
on a wrong
alternative
before discovering
his mistake
and switching
over to the correct
one.
His choices of topics, likewise, were never haphazard.
Ever curious
for new facts, he read voraciously
and
attended
lectures
with an eagerness
and enthusiasm
that remained
undiminished
almost up to his last day.
He would then take the facts home with him and mull
over them, trying to fit them within some sort of logical
framework
born from his deep insight. Finally, he would
come up with the decisive and original
approach
to the
problem
and go back to the lab. And so we have an uninterrupted
succession
of seminal
investigations,
each
addressing
a different
topic, each skimming
the cream
of the topic before moving
on elsewhere.
It all adds up
to an impressive
number
of original
discoveries.
More
important,
in my opinion,
is the view that has inspired
them, the first coherent
picture of how living machines
actually
operate.
I cannot
conclude
this brief survey
of Lipmanns
scientific
contributions
without
mentioning
another
founding
father
of modern
biochemistry,
Carl Con,
who was born three years before Lipmann
and died 2
years ago. The discovery
of glycogen phosphorolysis
by
Carl and Gerty Con in 1936 was a key step in the
development
of bioenergetics.
The
reversal
of this
reaction,
leading
in 1940 to the first in vitro synthesis
of a macromolecule
the so-called
blue glycogen remains
a landmark
in our understanding
of biosynthetic mechanisms,
even though it turned out to be biologically irrelevant.
It has inspired
the work of a whole
generation
of biochemists,
including
the discovery,
in
1948, by Arthur
Kornberg
of what was then known as
DPN pyrophosphorylase,
the paradigm
of all nucleotidyl
transferases,
including
DNA and RNA polymerases.

Fritz Lipmann
projected
a misleadingly
diffident
image to the world. I did not have: he confesses in his
autobiography,

and

still lack,

the

gift for making

an

DE DUVE

impression?3
Elsewhere,
however,
he tells us that he
unsuitably
presented
a certain
self-reliance
that often
impressed
others as arrogant?3
He was not a very good
lecturer,
even though his topics were always fascinating.
More often than not, he would look at his audience
with candid eyes, a gentle smile on his face, and slowly
his voice,
never very strong,
would
trail away into
inaudibility
while he pursued
some inner track of his
own. It would surge up again from time to time, but the
trend was not easy to follow without
access to the inner
dream.
Such traits do not go down very well with academic
circles and, despite
a rising scientific
reputation,
Lipmann had some trouble
finding a job after he decided
not to follow Dean Bunk to the National
Institutes
of
Health
in 1941. Eventually
he landed a position
in the
Department
of Surgery
at the Massachusetts
General
Hospital.
He spent 16 fruitful
years in this somewhat
unlikely
environment.
This is where, among others, he
discovered
coenzyme
A, for which he received the Nobel
Prize in medicine
in 1953, sharing
it with his old friend
of Berlin years, Hans Krebs.
In 1957, Det Bronk invited him to Rockefeller.
He accepted
with joy. He had
spent a year at Rockefeller
in 1931-1932
and, to him,
returning
to the Institute
25 years later was like coming
home. He loved our very special place with its tradition of excellence,
scholarship,
and freedom
a 20th
century
monastery:
as Bronk liked to put it. Fritz Lipmann remained
with us almost 30 years, during which
he continued
to work in the laboratory,
to inspire
others,
and to deliver
his unique
brand
of original
results,
up to the very end of his long and richly
productive
career.
Although
utterly
committed
to science,
Lipmann
had many other interests.
In his youth,
he had been
very close to his brother
Heinz,
his senior by 2 years,
and a very different
personality,
who wrote poems and
made a career
as a theatrical
producer.
Through
his
brother
he was introduced
to the world of performers
and of artists,
and shared
for a while their exciting
night life. He was a dashing
young man in those days,
we are told. His suit-he
had only one-was
always
very well cut, and he sported
Borsalino
hats, losing
them periodically
in the subway.
He loved life and
beauty
as he loved science,
and he derived
from his
work the authentic
joy of the artist, with no concern
for
either fame or money.
Love of beauty
created
a deep bond with his wife
Freda, an artist in her own right, whom he had met in
-

FRITZ

LIPMANN:

IN MEMORIAM

Berlin in 1929 and had missed greatly after Meyerhofs

laboratory
moved to Heidelberg.
It was to be near her,
much more than because
he wanted to learn tissue culture, that he left Meyerhof
for the laboratory
of Albert
Fischer
in Berlin. They were married
in 1931 and for
55 years were a devoted and endearing
couple, succeeding wonderfully
in combining
mutual
love with respect
of each others independence.
Gentle,
whimsical,
unpretentious,
and tolerant,
Lipmann could at times be impressively
firm and scathingly scornful,
when confronted
with moral shabbiness,
vanity, or duplicity.
Social injustice
and discrimination
made him very angry. He had a great affection for young
people
and is remembered
fondly
by all those who
worked
with him and now maintain
his tradition
all
over the world. He had a special regard for women
in
science
and felt strongly
that they should
be given
better opportunities.
I will always remember
my first meeting
with him.
It was in the beginning
of 1948, on my way back from
St. Louis where I had spent 6 exciting
months working
with Earl Sutherland
in Cons
laboratory.
I passed
through
Boston for the sole purpose
of paying a visit to
Lipmann,
as I did to Claude
in New York a couple of
days later. Their
work was quite unrelated
to what I
was doing at that time, but I just wanted to meet them.
They were my heroes. I am sure Lipmann
had no idea
who I was and no interest
in insulin
or glucagon,
my
obsessions
in those days. Yet he received
me with great
kindness
and even invited my wife and myself to dinner
afterwards,
in a Chinese
restaurant,
as I remember,
where we were joined by Freda Lipmann.
We spoke of
Berlin,
the Berlin of before the horror,
the Berlin of
Berthold
Brecht, of Kurt Weil, of Fritzs brother
Heinz,
and of their friend, the painter
Friedel Sebba - a Berlin
that I had not known, but of which I knew through
an
uncle who lived there and had shown me in 1939 how
the Nazis had butchered
the city. It was an unforgettable evening.
I never worked
with Fritz Lipmann
and I was not
even very close to him. I always stood a little in awe of
him, in spite of his great friendliness
and undisguised
friendship.
I was not his pupil, but I feel myself truly
his disciple.
I am deeply honored
and touched
to have
been given this opportunity
to pay homage
to this wonderful man and to express,
on behalf of all his friends
and admirers,
our deep sense of sorrow at his passing
and our feelings
of heartfelt
sympathy
to Freda
Lipmann,
their son Stephen,
and their family.