my name is William Diehl associate dean

and professor of medicine at the

University of Alabama School of Medicine

in Birmingham it is also a privilege to

serve as president of Alpha Omega Alpha

Honor Medical Society as president of

the Society I am pleased to introduce

this taped interview of a leader in

American medicine one of a series

entitled leaders in American medicine

this series is made possible by a

bequest of the late doctor's david and

beatrice siegel both were faculty

members of the Columbia University

College of Physicians and Surgeons they

were distinguished physicians in their

own right the purpose of these taped

interviews is to record for the benefit

of current and future generations the

character and spirit of some of the most

distinguished physicians and surgeons of

our time an interview format is used and

the interviewer is either a former

student or a colleague each of whom will

recognize leaders in their disciplines

therefore it is a great pleasure to

present a leader in American medicine

you entered medical school Arthur I know

with the intention of becoming a

practicing physician and yet you became

a biochemist a basic scientist how did

that actually occur well it's a long

story Bob try to make it brief I was an

eager student and when I left College in

1937 and the depths of the Great

Depression there were no jobs and even

if I want to go on in chemistry which

might have been my preference the surest

way to survive late in the 30s mister

keep going the method keep on going to

school which I enjoy doing and I was a

good nigger student and so I went to

medical school which ensured me four

more years of school but once I was

there I very much enjoyed the curriculum

the excitement of the curriculum and

intended to be a doctor and in fact it

was an intern in internal medicine from

1941 to 42 but in the during that year

Pearl Harbor came along and I had to

join military service and so I joined

the public health service and I was

assigned to the Navy and I was a ship's

doctor for an interval of time and then

as a result of some research I done in

medical school I gained the attention of

the director of the NIH then made a

place for me at the NIH and I was

assigned to do research I worked in rat

nutrition I fed rats and observed their

weights and how many he lived and died

on one or another nutritional deficiency

diet and discovered that I enjoyed it

unlike the rather haphazard nature of

clinical events and practice here I

could control the diets and the

experimental details and after about a

year I decided it was more interesting

work with rats and more fulfilling than

working with the assortment of problems

one has in the clinic and so I just

continued with that I made decision then

terribly overt but quite naturally

decided this was a good way of life how

long were you actually involved in your

nutrition research well I was at the NIH

from 42 to 45 roughly three years you

decided to go into nutrition research

developed a large rat colony developed a

important laboratory for the study of

rat nutrition would you cite one or more

important discoveries that came out of

this work that you carried out in rat

nutrition yes I had a rather large rat

colony but turned over every week to

some measure and explored a variety of

vitamin and mineral deficiencies and so

forth so it was a very flourishing

enterprise and producing lots of papers

- could you cite one or two would you

consider to be outstanding or unusual

discoveries that you made during that

time well one in particular was the

demonstration that folic acid is a

vitamin that's needed by mammals and

whereas it had been isolated or was in

the course of being isolated by two or

three groups in the pharmaceutical

industry as a bacterial nutrient it was

quite clear that it must have some

importance in animal nutrition I think I

was the first to show that a restricted

we call a purified diet fed to rats

resulted in a certain number of cases

and folic deficiency and it also showed

that celfon amines which were toxic

and cause nutritional deficiencies among

them was folic acid and vitamin K and

learned something about the importance

of microbial flora in furnishing

vitamins to mammals rats mice and humans

as well so of this early recognition of

the nature of folic acid and the need in

the diet of animals is novel and

gratifying

now I understand although I was not

active in those days that biochemistry

was to a large extent work in rat

nutrition in fact certainly in the

United States many of the perhaps most

of the laboratories biochemical

laboratories were engaged in research of

that kind is that correct well yes no I

came into nutrition in its Twilight and

already it was clear to me that the most

exciting and vigorous nutritional

research was being done with bacteria

people like Snell and Willi we're doing

exciting things that I couldn't possibly

do do it with that microbes that I

couldn't possibly do with animals let

alone humans to use a hunting metaphor

that I think I've only used perhaps in

this century as you know the microbe

hunter is who were in the Senden sea

during the early decades were then

succeeded by the vitamin hunters but

those were the decades of the 20s and

30s when the B vitamins and the fat

soluble vitamins were being discovered

when I came into it in the 40s they had

already been exhausted and now when

wanted to learn what the vitamins did in

metabolism and clearly want to do more

with microbial studies and when could

with rat studies you've had a very

successful laboratory studying rat

nutrition however you decide

to abandon that and begin a study of

enzymes enzymology why did you do that

looking back on it I guess it was

courageous but because it succeeded it

might have been called foolish and some

people thought to abandon a productive

area of research and start in something

to which I had which I had no training

whatever but I was excited by sporadic

reports and experiences in which people

were talking about enzymes and ATP and

even genes which I had never really

heard about or understood very little of

but these were the agents that clearly

determined how a cell and organism

operated these were the metabolic

machines in to which vitamins

contributed in some remote an undefined

way so there was a dynamism about

understanding how energy was obtained by

body and how the energy was transduced

into various functional forms and what

made a cell grow and where did folic

acid actually come into the picture and

we knew it had something to do with the

formation of blood cells I knew that

folic acid efficient rats couldn't make

red cells or granulocytes or other white

cells and perhaps most of all I sense

that this is where the excitement was

this was the frontier of biologic and

medical science and this is where great

discoveries could be made so you were a

public health service officer at the

time your commissions officer yes so how

did you actually how did you learn about

enzymology what did you do to educate

well know it there were papers there

wasn't much research going on during the

war but there were names like those of

Lippmann fritz Lippmann Hermann calc are

these sifted through I remember hearing

a lecture by ed Tatum talking about

the one gene one enzyme hypothesis that

he and beetle had elucidated from their

work on the rostra he's made a big

impression on me although not much I

might say on other people in the

nutrition section in which I was working

I to repeat I sensed that this is where

one could begin to understand some of

the most basic features of a living

system and I was also influenced by

Bernard Harker we were very close

friends really neighbors and Bernie had

been an entomologist before the war then

during the war he worked in the civil

service department and then got a job at

the NIH giving cockroaches DDT an

important industrial hazard and with the

conclusion of the war he was liberated

to return to his work on cytochromes and

cytochrome oxidase --is and I

assimilated some of the possibilities

and excitement of bioenergetics and they

did meet area metabolism from Bernie and

so I began working with him and isolated

sucks knocks today's inside of chrome C

and we had a new Beckman to use

spectrophotometer in which he took the

readings and I recorded the readings on

a pad of paper he didn't trust you to

use the instrument no I don't think so

although I did work with pig hearts and

bovine hearts to extract cytochrome C

and in sucks in oxidase and got my hands

wet but then I understand you decided to

actually go off on a sabbatical yes I

where seriously Mike and not do this

part-time looked into where enzymology

might be learned had the blessing

somewhat reluctant of Henry C brow who's

my chief and before this there had been

no sabbatical or training in of

that people could take at the with the

support and the expense of service and

the health as a Public Health Service

Officer I identified severo ochoa a

young Spaniard who is doing the kind of

enzymology that both Bernie Harker and I

thought was very exciting getting out

the enzymes of a Krebs cycle to try to

figure out how oxidative phosphorylation

took place how the energy of metabolism

could be funneled to make ATP this was

the Holy Grail as I saw it at the time

and the Cho was doing this as a guest

investigator at New York University

Medical School I met him very taken with

him as a personality his devotion to

science and he was agreeable enough to

take an utter novice like myself who

didn't know ATP from ADP or how to spell

enzyme to work in his lab and there I

moved in December of 1945 Arthur you've

been a very strong proponent of basic

research why why is that so yes i i've

been vocal about it i've written about

it and i believe deeply in it because it

is counterintuitive to people including

my fellow scientists that the solution

of an urgent practical problem can be

attained by working on something that

seems esoteric arcane and utterly

irrelevant and yet we have examples that

illustrate to us that most major

advances in medicine were made by people

pursuing some line of research whether

it be in physics chemistry or biology

that was awfully unrelated seemed

totally irrelevant to the practical end

to which it was

we applied and then Sheen quickly x-rays

a physicist curious about discharges in

the vacuum tube penicillin Ernst chain

curious about an enzyme which he thought

it was which lyse the walls of bacteria

turned out to be a small molecule and

chemotherapeutic lee obviously a great

milestone

how did culture cells in define media

culturing those kidney cells enable the

engineering of the polio vaccine by Salk

and Sabin and in our own work to which

you've contributed so much

finding the ligases the polymerase is

the nucleases this gave our colleagues

the chance to make recombinant DNA and

the genetic engineering revolution which

occupies medicine agriculture

not to mention Wall Street so these are

a few examples in which the pursuit of

curiosity about some aspect of chemistry

or biology or physics has led in some

serendipitous circuitous way to the

major advances in medicine I might add

that just one really derivative of what

you were saying earlier your curiosity

about how nucleotides are made and

metabolized has led to the discovery of

a normal of a number of compounds for

uracil for example and others which are

very important chemo therapeutic agents

in the treatment of cancer well you're

absolutely right Bob not only cancer but

the best drug for AIDS that's now

available drugs for herpes autoimmune

diseases transplant retention these are

all designed to interrupt the synthesis

of RNA or DNA and these drugs were

fashioned with the end in mind of

interrupting one or another of the

enzymes that we and our colleagues

defined

in the synthesis of the building blocks

in their assembly into DNA and RNA but

still we the latest oxymorons out of

washington our targeted basic research

or strategic basic research which

clearly indicate a ignorance or an

abandonment of these very basic historic

facts these very logical facts that we

can't create a crusade for cancer as

Nixon did in the early 70s when we don't

have the weapons we don't know the

blueprints and so we've not made it the

kind of progress in cancer the same is

true of AIDS Bill Paul at the NIH you

have directs research on AIDS made it's

very clear that one has to get to do a

lot of basic work in immunology and

virology to struggle and cope with this

very difficult important virus and the

disease of causes so to repeat basic

research is the lifeline of medicine in

fact an industry I've learned through

associations that necessity isn't the

mother of invention inventions become

necessities and some creative genius may

have made an airplane or discovered

xerography and then it took years maybe

decades to an interest commercial

companies to make it and supply it and

fax machines I discovered recently were

available 30 years ago but it took a

deteriorated postal service to make them

a necessity as we find them today so

creativity whether it's a medicine or an

industrial fear is what leads us to the

most important tools and means we have

to advance our health and our welfare

around this time I understand you

decided to leave the NIH

and take on the chairmanship of the

microbiology department at Washington

University in st. Louis

yes but what prompted that well I it was

a both push in the polls

I was rather unhappy with the

bureaucracy at the NIH I'd reached the

level of administrative authority which

was pretty much the limit that I wanted

to go and for the most part didn't

respect the administrative people who

were my managers and superiors secondly

there was the poll of very flattering

invitation to join a faculty that I

regarded as among the most distinguished

in science in medicine in this country

that was a washing University School of

Medicine with notables like Corey and

Erlanger and of the Nobel laureates all

of a Lowry and some others I could

mention and I thought being in their

distinguished company is a member of an

executive committee of chairmen of the

Medical School faculty would be another

kind of social and communal experience

as it turned out I might add as an aside

I was disappointed because at in those

meetings of the executive committee of

medical school of people discussed their

salaries and other bureaucratic problems

and rarely touched on issues of science

and education and also of the facilities

were have a primitive at Washington or

City as you may recall when you got

there 1955 I got there 53 compared to

rather elegant laboratories the NIH and

to this very day I wonder whether it was

wise to have

moved from the NIH to wash University at

that time so let's continue then with

you the sort of trail of research you

you had focused then you had taken a

diversion through phospholipid into

phospholipid biosynthesis decided that

that was not really gonna tell you how

the phosphodiester bond in nucleic acids

is made and then you went after a

nucleotide biosynthesis well because as

you point out Bob one didn't know what

the building blocks were and I thought

that if one could figure out how a cell

assembled of purine or pyrimidine with

the sugar and the phosphate but that

would then give us a clue as to what the

true intermediate was in the pathway to

assembling them into the polymers RNA

and DNA and Buchanan Greenberg Navas had

been working on purine nucleotide

biosynthesis and so I decided to work on

primitives which hadn't been done before

erotic acid certainly a primitive that

resembled uracil an epoxy group was very

likely intermediate on the pathway and

focused on that I learned how to use

enrichment cultures finding bacteria in

the soil that metabolized a compound and

at that time we believed that pathways

of utilization and biosynthesis were

reversible and anyway one could get

clues as to how something was made by

the enzymes that were found that

degraded it so we worked on enzymes that

used from organisms that used erotic

acid as a source of carbon and nitrogen

and energy and did get clues as to how

erotic acid was made of lieberman who

was a postdoc with me at first and then

an instructor Wash University whom you

recall very well join me in defining how

a primitive nucleotide is truly

assembled the course that we discovered

PRPP frost arrival pyrophosphate which

is the committed first step in purine

biosynthesis and also is the means by

which a perimeter is built up into a

nucleus I you I attended the the meeting

the Federation meetings at which the

structure and role of prpp in nucleotide

biosynthesis was revealed you never told

me that oh and it was tremendously

exciting the room was packed and it it

came like a bombshell here was the long

sought for in immediate in the synthesis

of purine and pyrimidine nucleotides in

Weld intermediate well it eluded so many

people for so long and when can look

back and reflect on all the things one

did that kept it elusive and then the

lucky things one did that brought it to

light but you know Bob one looks ahead

rather than back and so those are almost

bygone days but once we had the

nucleotides and when knew there were

nucleoside five-prime phosphates then

there was the urge to label them and

look for some extract some juice of some

cell whether it be bone marrow or

bacteria whatnot that would then put

them into a chain which would then be

large enough to be insoluble in acid

compared to the solubility of these

presumed building blocks so tell us how

that how this line of research went

because that occupied you now was really

the beginning of work that occupied you

for 3035 years yes it was I won't go

into all the details but one fine day

given a c14 thymidine by Morrie Friedkin

he'd synthesized it from thymine and

deoxyribose phosphate I found that that

could be incorporated into something

acid insoluble by an extract from

Escherichia coli this is a common gut

bacterium yes what's more these few

counts just a few cows about background

could then be rendered acid soluble

broken down by DNA's

and I recall looking at that counter and

seeing those counts relatively few to be

sure but clearly an indication that

thiamine II was entering something that

had the properties of DNA and that it

was a substrate for DNA's they're

walking down the hall and stopping in

your lab now you were a postdoc at the

time you've been there just a few months

to three months and you're already well

started in identifying how this unique

nucleotide in phages t even

bacteriophages was being put together

this was the hydroxymethyl cytosine that

is the hallmark of the teaming phages

and how does the virus make such a

unique compound and you already had

extracts but we're doing just that and

I've always been impressed that I showed

you these crude data and you said it

once I would like to work on that

subject which was remarkably courageous

and within a few days you've moved your

lab into my lab which was a little

larger and started working on the

activity responsible for converting

thymidine into a component of DNA I'd

like to say at this juncture Bob if I

may he it erupted that the work you did

thereafter which led to the purification

and naming of DNA polymerase identifying

that one needed for components

discovering the four deoxynucleotide

triphosphates going on the show that

unlike any other enzyme reaction known

until then was template directed you did

those things and I'm forever grateful

well well no I was your student and it

was a group of us and maybe I can

elaborate on this even though I'm the

interlocutor there were a group of us

yourself Sylvie her late wife Marie

specimen

Ernie Simms your research assistant

myself in this small room working 18 to

20 hours a day on what was what the most

exciting problem that any of us had ever

been involved with probably the most

exciting problem in biology then in

existence and it was a an exhilarating

time for all of us where discoveries

were being made daily we all shared in

the tremendous excitement and joy of

these discoveries and it was in all

together a remarkable experience for all

of us I in my own experience unmatched

by any other in science

well Bob as I mentioned just a month ago

on the occasion of that wonderful 70th

birthday anniversary that was given for

you and attended by hundreds of your

students and colleagues and friends that

in those early days nineteen the early

months of 1956 and thereafter as well I

had a family of three young boys and

went home in the evening and the only

news that I anticipated it was not from

the radio or TV but a call from you to

tell me what the results were and that

late afternoon experiment I join you and

feeling that those were among the most

exciting day

I can in my experience well so let's go

on then so this research evolved DNA was

being made the question was the major

problem was what was the mechanism how

was how indeed was Howard indeed were

chains of DNA being assembled by this

this marvelous enzyme that was being

extracted from Ecole I did this common

gut bacterium

well it's disappointing to my family and

lay friends to tell them that having

outlined this problem which in essence

seems simple that we're still working on

it thirty years later and really you

don't understand it adequately in terms

of the three dimensions of the enzyme

and how it does this remarkable template

directed synthesis of these genetically

defined chains but along the way I would

recall that some dozen years after we

discovered DNA polymerase people still

ask me at the end of a seminar in which

we describe details of the enzymes

action whether we could make a gene with

this enzyme whether we could make a

length of DNA that had biologic activity

and that had eluded us and then in 1967

you discovered ligase an enzyme that

links chains together and we used a

substrate a template a small virus of

bacterial virus that was circular but

now we were able to copy it with our DNA

polymerase complete the circle with the

ligase isolate the product and show that

we had made infectious DNA and that

created quite a stir it was called

creation of life in the test tube and in

1967 when Friday in December the media

all assembled here at Stanford and there

was a great deal of perhaps excessive

exaggerated excitement

about our capacity to make a DNA chain

with synthetic nucleotides and then pure

we thought of pure enzyme and evoke the

curiosity of people whether one could

create life as it was called in the test

tube that was a milestone looking back

on it it had some very notable features

because we realized at once that once

since we could put a chain together we

could insert analogs or non uncommon

nucleotides and so we could make

mutations in a synthetic DNA and later

on actually shown source of Nobel Prize

for Mike Smith that he could use this

very kind of enzymatic synthesis to make

point mutants along a DNA chain another

milestone was the discovery of how DNA

chains are initiated

even though DNA polymerase is a

marvelous enzyme and can do a lot of

things it is incapable of initiating the

synthesis of a new chain however you

were able to discover how DNA chains

were synthesized we didn't know how to

start a DNA chain we knew that the DNA

polymerase we had couldn't and we knew

enough about the progress of a

replication fork to realize that first

because DNA chains have opposite

polarity they point up and down and DNA

polymerase that one in others that we

were finding copied a template in only

one direction so it wasn't clear how it

was clear how one of the chains of the

parental DNA can be copied but the other

presumably would need starts and there

was no enzyme available and no DNA

polymerase available that could start a

chain

it was at that point that there was a

cartoon by somebody whose name I've

probably purposely forgotten picturing

our knowledge of the replicating fork as

discreetly covered with a fig leaf and

the fig leaf was there to indicate that

we didn't know the working parts of the

replicating machinery for reasons I

won't go into we did eventually discover

that that those starts were made with

RNA unlike DNA which is indelible in

cells RNA turns over and so RNA was laid

down as a very little bit of primer

which was then extended by DNA

polymerase and later that RNA was

removed and so yes we had not solved but

certainly made a lot of progress on how

chains are elongated and now we had a

clear insight into how chains are

started and generally not universally

chains are started with a small RNA

primer and that occupied us for some

time and in the course of that we also

learned that there were other let's say

more important flim races in the cell

that we've been called to and three

actually discovered by my son Tom and

then studies of how bacterial viruses

phage fyce 174 is replicated in e.coli

stumbled upon an array of enzymes

including these priming enzymes and a

very complex form of a polymerase called

DNA polymerase 3 at many different

subunits and while I was frustrating

that it got so complicated the good news

was that we were actually looking at the

replicating machinery of the cell itself

how it made its own chromosome so again

is it fair to say I think it is fair to

say that by the me

ATS you had been able to reconstruct

with purified enzymes purified cofactors

purified substrate the complete

replication of a chromosome the

bacterial ecoli chromosome well we've

skipped something Bob we given a

replicating fork given a started fork we

could more or less define the elongation

process and the initiation process but

we didn't know how chromosome was

started in the first place at the origin

of replication replication and again an

episode among the few that one has in a

scientific lifetime June Day 1981 after

what I calculated was 10 man years of

futile effort we found an enzyme system

that would start at the very origin of

the e coli chromosome and that opened up

a whole vast array of opportunities to

understand how a chromosome was started

and so by the mid 80s as you've said we

began to understand that system as well

but so by the mid 80s you had in fact

defined the component that were required

given a chromosome to initiate at a

specific site the origin of replication

and complete the semiconservative

replication that chromosome be more

precise Bob for you know this very well

but for others the chromosome we were

using as our substrate was a mini

chromosome we had in a plasmid a

thousandth the size of the e coli

chromosome incorporated this origin of

replication and so but it behaved

genetically physiologically in the cell

this plasmid in as a mini chromosome and

yes in the test tube we could take this

mini chromosome and

replicated in a fraction of a minute and

get a valid copy of it and I think it's

fair to say this work is not going on in

isolation people in other laboratories

we're trying to understand how human

chromosomes are replicated again using

model systems much like your own the

sv40 tumor virus being one example and

the what's come out of those studies

correct me if I'm wrong is that the way

in which these model human chromosomes

are replicated are not different in any

significant way from the way in which

the E coli chromosome is replicated well

I think you're right and let me reflect

on that for a moment Bob because I have

followed a certain Dogma in my research

and it's clear from the things we've

discussed already that I believe in

enzymes the in fact the book that I have

written as a scientific autobiography is

for the love of enzymes not a pitch for

sales but so yes I love enzymes

passionately but logically the dogma is

that enzymes are essential for every

important event in a Cell there may be

exceptions but they're rare secondly

that if one takes the enzymes apart as

we've been discussing and then has the

opportunity to put them together you can

elucidate a major biological whether

it's photosynthesis or oxidative

phosphorylation more or less may not be

perfect example replication and then to

reflect on the comment you made is a

third element a third article of faith

in this dogma

that's in the universality of

biochemistry it was found at the turn of

the century by the early biochemists

that the juice of a yeast cell can

convert sucrose from a grape to the

effervescent miraculous alcohol by a

succession of a dozen discrete reactions

which then were found to be virtually

identical to the reactions that a muscle

cell carries out when it converts sugar

to lactic acid to furnish energy for its

contraction and since that time whenever

we look at a pathway whether it's in the

synthesis of an amino acid or a

nucleotide or some other fundamental

reaction the same thing is true nature

having learned a certain lesson whether

it's in a microbe a fungus a plant or an

animal has conserved that pathway almost

intact throughout a billion or more

years of evolution now as you know

better than I very exciting things have

been done in your lab and other labs

with regard to the mechanisms of

eukaryotic replication imagine cells

Drosophila animal viruses but as you've

said the basic themes are the same the

polymerase is the ligases the binding

proteins pretty much the same the

variations of fascinating and they're

terribly important for further

understanding of how these systems work

in the particular place where we find

them so to continue then this was a

tremendous achievement without dwelling

on it never though it represented the

first instance in which a chromosome

could be replicated from purified

enzymes substrates and cofactors this

was a tremendous achievement but as you

say there was

a tremendous amount of work that needed

to be done about the mechanism clearly

you had defined you and her students had

to find all the components that were

required you would certainly ordered the

process the sequence of reactions but as

you yourself have pointed out very

little is known about the

three-dimensional components of the

system it's incredibly complex a lot of

work remain to be done nevertheless you

decided to stop working on DNA

replication

at a fairly late stage in your career

and took on another problem Oh Bob if I

may add to what you've said the ultimate

understanding comes from having the

three-dimensional structure of the

enzyme this marvelous little machine and

knowing how it works and that brings us

into various structural chemical

techniques and approaches that are

really beyond me there's another aspect

in figuring out how this works in a cell

we know how to works in the test tube

again a vast array of physiologic and

genetic approaches that again I don't

feel as if I can master quickly and

easily so here I was in some central

area of defining a pathway defining

reactions in a gross way and so many of

my students and colleagues were doing

that terribly well and I felt a

hankering to do something different I

wanted to start an area of investigation

that had some novelty that was not going

to duplicate or compete with what others

were doing and so I became infatuated

with another molecule much much less

sexy and DNA polyphosphate inorganic

polyphosphate it's inorganic which

immediately makes it uninteresting and

it's a monotonous chain of phosphates it

has the virtue when you look at it of

having bonds and hydride bonds much like

you find the ATP so we call them quote

high energy and so for the last three or

four years pretty much switched in fact

in the last two years completely

switched and DNA has not worked on

inorganic polyphosphate was probably

present on earth long before organic

molecules it's simply a condensation at

high temperature of phosphate which is

found in rocks the question immediately

arises what's it doing water it's

functions and this is a challenge we

want to find the uses to which this

forgotten polymer is put in the variety

of circumstances in which one finds it

in the living world may I add one thing

with regard to our approach to this most

people I would say at least nine out of

ten of our colleagues and students would

approach this genetically they look for

mutants that either failed to make

polyphosphate and a given organism or

make much more of it and fail to utilize

it some would take a physiologic

approach and find conditions nutrients

and whatnot that favor its accumulation

or its disposition my approach is you

would gasp but few of us well others my

two is to find the enzymes that make it

and use it and nowadays there's so much

reason to do that first it's easy much

easier to isolate enzymes

and when you have a pure enzyme as you

know Bob you immediately have an insight

into the mechanism of reaction a clue to

the pathway but nowadays you have the

pathway of reverse genetics you know a

polypeptide sequence you infer the

nucleotide sequence you fish out the

gene get the gene knock it out over

express it immediately you see the

consequence of the under or over

functioning of the enzyme in question

but what attracted me immediately as an

approach to this problem and getting a

pure enzyme that makes polyphosphate and

uses it is that a pure enzyme gives you

a reagent and in this case the methods

for analyzing polyphosphate were both

cumbersome and in exact and not

definitive and so we've isolated four or

five enzymes now that are specific for

polyphosphate and they've given us

precious reagents for the rapid

sensitive definitive determination of

polyphosphate even when its present in

minut amounts as it is in many animal

cells so we're excited about it let me

turn away now or from this sort of

description of your research activities

and Arthur you've been a extraordinarily

successful scientist your Nobel laureate

you founded a very distinguished

department of biochemistry here at

Stanford you have been very successful

as an author you have published a

definitive treatise on DNA replication

you've published a widely read

autobiography of your life as a

scientist and you've been a very

influential and important teacher would

you reflect on these aspects of your

career and when I reflect on them I have

enjoyed them all

as an administrator since you allude to

the biochemistry department yes I

organized the department serves as

chairman for 10 first 10 years and have

been active in its growth and vitality

since then but I've never wanted to go

beyond that level of administration I

never felt comfortable in the politics

of larger organizations whether it be

institutional national or international

this level of administrative

responsibility and activity has been

just right for me and as you know we've

had a small department a biochemistry

department had eight nine people in it

much of its life and nevertheless had a

very good place and the estimation of

our colleagues around the world I felt

that the success of our department which

you know in Italy and you served as

chairman for at least one term more has

been in the wisdom of its people that

altruism is in their self-interest

so our colleagues have been very

generous they respect what their

colleagues do and we've engaged in

something that possibly illegal we've

shared our grants now in the letter of

the law we may have violated some Clause

or something else but by sharing our

space our reagents our equipment we have

made very prudent use of them they've

not been duplicated at the same time

it's brought us

physically together so that it's one of

the hallmarks of our department that

there is no territorial integrity each

of the working labs has people in it

from at least two or three groups the

students and postdocs who leave here as

you know find that one of the most

exciting elements of their experience

and by virtue of sharing space and

equipment and reagents we also share

ideas and the success of the department

rested on the fact that we focused in

one area as well we focused on nucleic

acids and their interactions we were not

a broad-based Department criticized for

it but ultimately we could make a

contribution that was unique so this is

the home where recombinant DNA was

discovered and where some of the most

fundamental aspects of nucleic acids and

proteins and their interactions were

found that's given me a great deal of

pleasure but Bob in the order in which I

rank these various activities I would

say that with all that I've said I would

give that a lesser ranking than I would

the science which has really been the

essence of my being and which I feel is

the fiber that unites all the other

activities whether it's writing teaching

or administration

I should add as far as teaching is

concerned teaching not in a sense not

only in the sense of appearing before a

classroom and and and and lecturing but

teaching if your students at the

pre-doctoral and postdoctoral fellows

your students have are spread throughout

the world many very very distinguished

scientists including a Nobel laureate

Paul Berg

members a very distinguished scientific

organizations chairman of departments

and Institute's and very very active

scientists so you created a school of

scientists and that I would think would

be a very source of tremendous pride to

you well I am uneasy about that

there are no controls if you do an

experiment that no one's done before and

it reveals something discreet and useful

that can be built upon that belongs to

you even though it's built upon other

people's ideas and reagents and so forth

but you come along as a postdoc you've

had a good experience your scientific

works been outstanding

renowned you've been a great teacher

I've enjoyed our friendship enormous Lee

but have I been your teacher there's no

control you might have done better under

some other circumstance so whether it's

an elector or in the one-to-one

experience one has with graduate

students and postdocs I try to convey

the spirit I have about science my

curiosity and enthusiasm for data its

assembly that is properly written and

displayed and presented but to what

extent I have taught someone or perhaps

even misled someone hard to tell having

said that I have enjoyed the maturity

and the achievements of over a hundred

people to whom I owe a great deal

because it's their effort and their

responses that have made this worthwhile

life