FAS Memorial Minute for A.M. Pappenheimer, Jr.

A.M. Pappenheimer, Jr., known to his colleagues as "Pap", died

suddenly on March

21, 1995, in the 87th year of his life; his death ended a long academic

career that began and

ended at Harvard. Most of Pap's research was centered on the biology and

chemistry of the

bacterial disease, diphtheria. The discoveries he and his students made in

studying diphtheria

were seminal in understanding the mechanisms by which bacteria cause disease.

Pap was brought up in an academic environment in which science and

the arts,

especially music, were part of family life. His father, Harvard Class of

1899, was Professor

of Pathology at Columbia University and one of the leading experimental

pathologists of his

day. The excitement of his research permeated family life and had a

profound influence on

his children, all three of whom became professors at Harvard.

Pap entered the college in 1925, and he was one of the first students

in Biochemical

Sciences when this field of concentration was established in 1926. His

tutorial readings

included the now classical papers by Avery and Heidelberger on the chemical

structure of

polysaccharide antigens, and that was the beginning of Pap's lifelong

interest in

immunochemistry. Aware of the growing importance of chemistry for

biological research,

he sought the advice of J.B. Conant, who was then professor of organic

chemistry; Conant

accepted him as a graduate student, and Pap obtained a Ph.D. in organic

chemistry in 1932

with a thesis on the chemistry of heme-containing molecules, such as

hemoglobin.

Postdoctoral studies in bacteriology at Harvard Medical School,

followed by two

years as a National Research Council Fellow with Sir Henry Dale in London

led to his

interest in diphtheria toxin. In 1935 he obtained a position with the

Massachusetts Antitoxin

Laboratory, and it was there that he made his first major discoveryþa

discovery that could

only have come from curiosity, chance and a prepared mind. He noted that

diphtheria bacilli

grown on media in flasks made of soft glass produced more toxin than those

grown in Pyrex

glass. He traced this seemingly trivial observation to minute amounts of

iron leached out of

the soft glass, yielding concentrations in the medium just sufficient to

provide optimal

bacterial growth and toxin production. With this information he was able

to adjust the

concentration of iron in synthetic media so that gram amounts of almost

pure toxin could be

obtained for quantitative immunochemical studies of the antigen-antibody

reaction. For this

work he received the Eli Lilly Award in 1947.

In 1941 Pap was recruited by Colin MacLeod to join the Bacteriology

department of

the New York University Medical School. He spent almost two decades there,

probing

fundamental aspects of antigen-antibody reactions and the mechanism of delayed

hypersensitivity. Under the leadership of Pap and Colin MacLeod, the

department attracted

many brilliant students who later went on to become professors at

universities around the

country. In the words of Lewis Thomas... "Pap and Colin MacLeod were a

sort of twin

force and it was a marvelous experience to watch them influencing each

other and setting the

tone, making the air right for all their colleagues... (but)... I knew,

long before it happened,

that New York University was going to lose Pap sooner or later and would

lose him to

Harvard."

In 1958 Pap did return to Harvard, as Professor of Biology and Head

Tutor of the

Biochemical Sciences program. Before he left New York it was discovered in

his lab that

diphtheria toxin inhibits protein synthesis in cultured human cells. This

provided the basis

for his research at Harvard, which was to reveal over the next decade how

diphtheria toxin

acts at a biochemical level. The toxin proved to be an extraordinary

enzyme, consisting of

two parts: one part attaches to the surface of the target cells while the

second penetrates into

the cell and enzymatically inactivates a component of the protein

synthesis machinery. For

this work, he (together with his former student, John Collier) later

received the Paul Ehrlich

Award. The enzymatic mechanism (ADP-ribosylation) used by diphtheria toxin

to inactivate

its intracellular target molecule was later found to be common to many

bacterial toxins,

including those involved in such apparently unrelated diseases as cholera

and whooping

cough. The information revealed about diphtheria toxin also suggested that

this or other

toxins might be modified to target their lethal actions to unwanted cells,

such as cancer cells.

One such targeted toxin developed by Jack Murphy, another of Pap's

students, is currently

being evaluated in clinical trials for use against certain lymphomas.

Diphtheria itself is no

longer a prevalent disease in most parts of the world, but Pap's work on

diphtheria toxin

paved the way for understanding the mechanism of action of many toxins and

holds the

potential for therapeutic interventions based on molecular structure.

Pap's contributions to Harvard went far beyond his own research and

his formal

teaching responsibilities. He enjoyed being with undergraduates and shared

with them his

enthusiasm for music, literature, and sports, as well as science. It was

not surprising that he

was chosen to be Master of Dunster House, a position that he enjoyed

immensely for nine

years, even though it included dealing with the turbulent events that

occurred during the

Vietnam War. His integrity, common sense and insistence that the

atmosphere of Dunster

House remain conducive to academic pursuits despite political and moral

turmoil, earned him

the respect and admiration of students. Pap was an excellent musician,

proficient on both the

clarinet and the viola. Under his influence Dunster House became a center for

undergraduates interested in playing chamber music; the Sunday afternoon

Brandenburg

parties he started became a proud tradition of the House. He became

President of the Pierian

Sodality, the board that sponsors and oversees the Harvard-Radcliffe

Orchestra. He was an

avid sculler, rowing 2-4 miles every day before breakfast until he was in

his late seventies.

Pap enjoyed a lifetime attachment to France; it has been said that

his passion for the

French language and culture was only exceeded by that for Harvard (and

perhaps that for

diphtheria). He was first exposed at grammar-school age during a

sabbatical year of his

father at the Pasteur Institute, and in 1951 he returned to the Pasteur

with his wife (Pauline

Forbes Pappenheimer) and their three children to spend his sabbatical in

Jacques Monodþs

laboratory. Monod, Andr‚ Lwoff and others at the Pasteur became close

friends and often

visited Pap on their junkets to the United States. Papþs fluency in French

was always a

source of great pride.

After his formal retirement in 1979 Pap initially became a guest in

Fred Ausubel's

laboratory, and after Professor Ausubel left the Biological Laboratories,

Woody Hastings

invited Pap to join his group. Pap actively collaborated on the research

in his host

laboratories, while at the same time continuing his writing and editorial

work on bacterial

toxins and immunochemistry. He interacted with the students in these

laboratories as he had

with his own, reviewing results, challenging assumptions, and generally

serving as an

intellectual sounding board. He came to the lab almost every day during

term, through to

the day of his death. The summer months were spent at his beloved country

house in

Scotland, Connecticut, and at the summer home of his wife's family on

Naushon Island,

where students and colleagues were frequently invited.

Pap's scientific contributions will endure on their own merits. The

legacy he left to

his students and colleagues is the combination of Excellence, Veritas and

Grace for which

Harvard stands.

Respectfully submitted,

Harold Amos

Lawrence Bogorad

J. Woodland Hastings

John R. Murphy

John R. Pappenheimer

R. John Collier, Chairman