fia

Re-dictation of the talk that Dr. Joshua Lederberg gave at Caspary Auditorium, the
Avery/McCarty celebration, February 3, 1994, taken from JL notes.

Once again, I’m the baby on this panel.

On February 1, 1944 I was a hospital corpsman at the USNaval Hospital St Albans -- in
the far eastern reaches of Queens -- my main job was diagnosing blood smears for malaria,
differentiating Plasmodium vivax and P. falciparum. Most of the Marine 3rd Division,
returning from Guadalcanal was passing through our hospital, and many of them had malaria.
I was not yet decked in the midshipman’s uniform (that you saw) which I was to acquire that
fall, when I entered Columbia medical school. I don’t have any good photographs of myself
as a gob; but the marine corporals and sergeants never let me forget that I was a lowly
apprentice seaman.

I had not quite reached my 19th birthday. As soon as I reached 18, I had enrolled in the
Navy and had qualified for the Navy V-12 medical officer training program. So I was
“working my way through college" with alternate spells of active duty and completing my
premedical course work at Columbia College.

Although I was off campus in February, I had already heard about the work at the
Rockefeller Institute from a herald who frequently made the trip across town to Morningside
Heights. This was Alfred Mirsky, who was collaborating with Arthur Pollister in
cytochemical studies of chromatin; and it was a topic of lively discussion throughout 1944.
Harriett Taylor, a graduate student who was completing her dissertation on the genetics of
budding in yeast, had a particular interest and in fact was negotiating to be a postdoctoral
fellow in Avery’s laboratory the following year.

As an undergraduate, I was spending most of my time in Francis Ryan’s laboratory,
learning how to do biochemical genetics with Neurospora. I continued to do this after I
began my medical studies in October: in fact shared an apartment with Kimball Atwood --
who died just recently -- near Morningside Heights to be close to the lab, which I valued far
more than my classroom studies.

I did not actually read the article , Avery, MacLeod and McCarty 1944, SLIDE, SLIDE,
until January 20th: Harriett Taylor lent me her copy, as the journal was not readily available
on the Morningside Heights campus. And here is my immediate reaction:

SLIDE

But what to make of this? I was less preoccupied with the chemical identity of the
Transforming Principle (TP) than with its biological meaning. The chemistry would, I was
sure, be resolved by a clearly defined path of analytical testing. In retrospect, it is hard to
recall how vague were our concepts of bacterial cells and bacterial genetics at the time. C.N.
Hinshelwood, a world famous physical chemist and President of the Royal Society of London,
would write a book replete with mathematical proofs that denied that bacteria could have
genes at all. There were many other competing hypotheses as I would later enumerate in a
review in 1956. SLIDE.
The simplest answer to these dilemmas of interpretation, I felt, would be to transform
Neurospora” in the same paradigm as the pneumococcal studies. I did not for a moment
dream of repeating the work reported from the Rockefeller Institute on the pneumococcal
system itself. This just seemed too hard, too dangerous and too difficult to get routinely
replicable results. So I spent the spring of 1944 trying to transform Neurospora. With
Francis Ryan’s very thoughtful encouragement and oversight, I prepared a number of very
crude extracts of Neurospora and found that one could indeed find what apparent transformed
clones, i.e., from leucine less to leucine independent by selection in minimal medium. But
unfortunately this occurred with equal facility whether the extract was added or not. They
were indeed spontaneous reversions. It is hard to believe that this was the first report of
reverse mutation in microorganisms. So that was just not going to work. (Parenthetically, it
would be about 35 years before anyone else learned all the tricks needed to transform
Neurospora with DNA). I concluded that we should turn the problem on its head and instead
look for a system of genetic crossing in bacteria, hitherto unknown, to provide a robust,
theoretical framework for the transformation studies. The experimental design was one that
would become quite routine in future years, SLIDE, SLIDE and amazingly enough it worked
and rather promptly!

The future would bring me the chance to meet Mac McCarty; for Norton Zinder to be the
first graduate student in my lab at the University of Wisconsin, and many other good things,
for which I do owe Mac a great debt. We have much to celebrate.