STANFORD UNIVERSITY
MEDICAL CENTER
PALO ALTO, CALIFORNIA

DEPARTMENT OF GENETICS October 25, 1960 DAvenport 1-1200
School of Medicine Cables STANMED

JM Dr. Le L. Cavalli
Istituto de Geneticd
Via Sant 'Epifanio, 14
Pavia
Italia

Dear Luca:

There are so many details of things to talk about that | am not sure
we are going to get them all done, but | would rather not have them pile up
too far. | was happy to see Giovanni at Princeton and we did have a good
chance to talk over a great many issues. To answer one of your main questions,
we can certainly wait until February for you to come to a definite conclusion.
The first consideration is perhaps that you should be able to put your own mind
at ease and we can just hope that this will be forthcoming as soon as possible
for your sake as much as ours.

Through Giovanni and in your letter, you indicated a definite interest in
coming to Stanford at least for the spring quarter which begins about the first
of April. We will be very happy to have you here at that time, in particular
as this is when we will be giving the regular course to the medical students.
This is only one hour a week, on Saturday morning at 11 otlock, so it is really
not too strenuous a program. However, as probably the first and second year
class will be enrolled in it, it will be rather a Large group and it may be
profitable for at least part of the course to divide it into two sections and
this would be a logical point of division of labor between us.

Paradoxically enough, | may have to be away for one or two weeks in April
and quite possibly this will be in Milan. In that case, for that interval, you
would be very helpful indeed by taking over the two courses. 1! have no plans,
hopefully, other than this one of being away for any appreciable time during
the spring quarter. For the three months of April, May and June - but this is
subject to some official v@rification which | can hardly doubt - we can offer
you a stipend of 4,000. | trust you will have some other help in obtaining
your travel expenses. Likewise, | would still hope that | could do some
interest business with Giovanni and your associates in April and that this
could help subsidize the trip in which Esther could also take some part.

If you could manage to be here by the first of April, this would give us
several days for planning discussions before I had to go myself. 1 hope
Dr. Cavalli, cont. 2. October 25, 1960

that you can manage such a schedule. Please let me know whenever you can as
to your final plans on this so that we can make any necessary arrangements.
This time, | will try to see if we can manage to have a car leased on your
behalf rather than put you to all the trouble you went through. Also, please
let us know if Alba will be able to come with you, as we very much hope but
have to doubt as a practicality; we will also have to make a start again on
the simple visa arrangements. In this connection, | hope that you can have
some forethought by way of a tentative application, if this is possible,

if this would simplify your obtaining a regular visa later on should this be
indicated.

Giovanni has the Subtilis strain that you asked for - this is a histidine
tryptophan mutant. However, as | discussed with him, | am not sure this is the
most appropriate system jin which to look for a specific pattern of resistance to
related antibiotics, since you would probably be dealing with a polygenic system
| would think that you would have better hope of unraveling it with sexual
recombination analysis than with DNA transfer in which only one element at a
time could be transferred. In fact, it is not impossible that he would have
some luck in finding such specific phenotypes among the diverse recombinants
of crosses between highly selected resistant and sensitive strains. The types
you are looking for may, after all, be relatively poorly adapted combinations
of genes which could defeat your finding them by simple progressive selection.

You and Alba were very kind to be so thoughtful in sending the several
gifts through the mail and with Giovanni. Thank you so much for them. Giovanni
will have to tell you about the straw slippers.

As | should have mentioned in my last letter which crossed yours of the
tenth, Norman and | have listened carefully to your suggestions about the
consanguinity questionnaire and we are going ahead on a tentative basis. |
think we are in good agreement as to the desirability of what is to be done
and in general, how to go about it. At the very least, Norman has laid the
ground work for the accumulation of data during the next months or year or two
by his discussion at the meeting of the Academy of Pediatrics. 1 did have a
chance to talk about this with Jim Neel and he had another very useful suggestion,
namely that Newcombe's record linkage system might present another very useful
approach. I have written to Howard to ask whether he would be able to obtain
the necessary linkages from the accumulated cases of childhood deaths
attributable to drug reactions.

At the Macy Meeting in Princeton, as Giovanni will tell you, we discussed
not only chemical mutagenesis, for example, by caffein, but also a possible
chemical basis for chromosome nondisjunction. The only reasonable suggestion
how to verify a caffein effect in man was your own, namely, to classify the
grandparents with respect to their beverage habits and determine whether there
was a significant difference in the slope of sex ratio with respect to grand-
parental age. You certainly should get every encouragement for this type of
study. As to nondisjunction, in view of the obvious effect that compounds like
Colchicine would have, | am beginning to wonder whether there may not be a
Dr. Cavalli, cont. 3 October 25, 1960

chemically induced component in mongolism. This was the first thought to cross
my mind when | first heard of the trisomic story, but like most people, | did
not see how this could relate to the major fact of the dependence on maternal
age. However, | think it is at least intuitively obvious that the consumption
of drugs also has a strong age dependence. In fact, Luca, this is¥set of
Statistics that ought to be carefully collected and tabulated as a background
for all such discussions. | do not know which drugs one might point to but

at least such compounds as ethyl ether, chloral hydrate, and barbiturates are
already known to have spindle-inhibitory effects. Perhaps there are others
that are not so obvious. To test this proposition, one should have the
Statistics on different populations with different habits of drug consumption.
Perhaps you would already be able to quote me some data, for example, on rural
Italian populations, that would refute the proposition that say, one-half the
incidence of mongolism was induced by chemicals. Are there any hints at all
as to the etiology of mongolism from its geographic distribution? The age
effect may well have obscured this problem from several standpoints.

If indeed there are any significantly controllable populations which have
distinctive habits of drug consumption, they might be most valuable in several
similar connections. Do you think the Christian Scientists fall in this
category? If so, on the other hand, would it be possible to obtain reliable
diagnoses bearing on the distribution of causes of death?

In connection with the Kefauver investigations and some similar reactions
to the overeggressive distribution of drugs by some companies, there is going
to be more than a little political interest in drug-induced disease. While
some of the hysteria is exaggerated, there is no question that this is an
extremely important problem and we ought to be on the lookout for ways of
investigating it.

That's all for now. Our best to Alba and the ‘children.

Yours sincerely,

Joshua Lederberg
Professor of Genetics

JL/jh

P.S. 1 have in mind your request for Volume I1 of Supey's Geometry when it

is published. Also, | am enclosing two references to papers on the medical
use of computers by Ledley. I am also trying to find other sources for you.
By separate mail you should get a copy of a book called ''The National Purpose'!
that Alba should be very much interested in. Please let us know if there is
anything else along these lines that we could get for you. Has she had time
to look at Lear?

Ledley, Robert S., 1959. Digital electronic computers in biomedical
science. Science 130: 1225-1234,

Ledley, Robert S. and Lee B. Lusted, 1959. Reasoning foundations of
medical diagnosis. Science 1430: 9-19.