Notes for Cartwright lecture at P&%S 10/18/61
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Sat Nov 14 17:40:43 EST 1981 puBcicAtaa

Wed Nov 18 07:52:15 EST i981
PL Ter [Cut ©

Patched:
Mon Dec 21 18:18:55 EST 1991

When I received this invitation, I leaped to reply, being entrained
by a profound sense of returning to my intellectual and personal roots.

But ph ek

What does one say at alma mater, amidst professional colleagues still
deeply immersed in own lab work, over 3 years after being seriously
involved in own expt.

So

please forgive a somewhat personal statement in lieu of the latest

intelligence from the lab. bench.

2 obsessional themes on my mind
1) goes back 35 years, yes when I was a second year medical student here

July 1945, and began thinking about genetics in bacteria,
largely in response to my instruction that bacteria were devoid
of genetics in my introductory bact. course.

{show notes page?

2) second more recent vintage, perhaps about 1970, began to wonder whether
the canonical model of medical science was correct. This model, as
expressed in NIH planning documents, is the pyramidding of practical
advance in orderly progression from the foundations of basic science.

The question was whether practical applications of biological science
e.g. of molecular biology, were perhaps unduly delayed a/c flaws
in this model, or of other structural features in the organization
of medical research. Issues of the intercommunication of more
basic disciplines with medical practice were at issue: and my
ruminations were perhaps connected with my growing frustration
about the development of medical genetics beyond the provision
of counselling for a few moderately rare syndromes.

Hasten: I do not voice these concerns except in the intimacy of a
closein family discourse like this, since they are subject to
gross and mischievous misinterpretation at a time that the
‘integrity of research efforts is threatened by budgetary and
political pressures of the most alarming kind.

Not my style to maximize dramatic effect in lectures, so let me telegraph
conclusions that there is some merit to each of these concerns: but
that in large measure they reflect cyclical patterns in research.in
a changing environment. My main conclusion is that we should be
preparing for revolutionary changes in human impact of medical science
at a time when many others have become fainthearted: and hope this
may be more credible as coming from more than an enthusiastic and
uncritical devotion to my own guild.
REMINESCENCES: .......

recollections of microbiology in 1945

Telationships of Morningside Hts., P&S campuses

origins of bacterial genetics and molecular biology
Impact of Avery 1944-45. H Taylor: steps of
Neuro Institute / H Waelsch lab

CConvergences of disciplines in own experience as medical
student still doing genetics research with Ryan at M.H. campus]
Diagram the strands.

Why wasn’t bacterial genetics discovered in 1905?

Blakeslee experience: no. yobs in 1902

Recall exponential growth of science: how few investigators were
actually there. (<< Rockefeller Institute]

SEMINAL PROBLEMS OF SCIENCE: analogs to icons of 19457
(bacteria asexual; gene sanctum sanctorum, and == protein)

Obvious, and unachievable challenge to identify contemporary
prospects. My reactions are surely idiosyncratic, probably
even cantankerous.

Cshould be abvious how my own style of research would be
influences by that experience. Look for large leaps!)

Instances where main streams of current research seem unlikely

to reach ultimate aims: happily science is more densely populated
and almost always there are mavericks that are welcome exceptions
to my chagrin. Will proyect review system -- that exacts approval
of the proposal itself, not just tolerance for diversity of
outlook an part of peers -~ allow venturesome initiatives.

What chance would my proposal in 1945 have had??

Scorn of so-called fishing expeditions illustrates this outlook.

something here on clinical research paradigms: life cycle of the
clinical investigator (the more successful; the less proportion
of investigative time on human subyectsi but need to remain in
contact with clinical problems. {implications for stand-alone
clinical research hospital like RU}...

Other difficulties include academic organizations wedded to existing
disciplines and turfs: general slowdown of new entry: obsession with
tenure, with peerhaps excessive pressure on visible accomplishment

in early years (esp. in clinically related disciplines): deflation

of Ph.D... and prolonged infantilism of student status in combined
multi-degree programs: Mexican jumping beans -~- Ph. D., postdoc,

tenure ladder in rapid succession, tafther than longterm commitment to
young investigator ’s own problemi
Impediments to real discourse in academic communities, besides
structural barriers, our styles of presentation that proclaim
what we know more than what we seek. {I try to set good example
in seminars by not fearing to display ignorance in asking ‘dumb’
questions. }

LINKAGES OF BASIC SCIENCE TO MEDICAL PROGRESS
Slide of Health and expenditure statistics.
(Should put research and care on same scale?

PATTERNS OF EMPIRICAL PROGRESS
actual role of basic science since 1950, exc. vaccines and (??}
almost irrelevant to NIH-supported research:
new wave today. Tagamet; Captopril
Medical Research training is clouded by rational reductionist
model, and an abandonment to industry of the” realities of new
pharmaceutical development. But with the burgeoning of more

rational opportunities inthe current tide of scientific advance, -

tha universities will play a larger role in pretical development
-~ and in turn face many new dilemmas of relationship to
profitable opportunity.

Evident problems of internal competition, freedom of
publication, freedom of judgment. Fortunately, DNA bubble
is largely a stockmarket phenomenon, and may be a passing
transient in the extreme form of these difficulties.

Future prospects: threshold of revolution, from concept to technology
DNA reductionism as analog to germ theory
COMPLEXITY of human organism/ reflected in genome.
SLIDE:: the reductionisit agenda.

Dilemmas of success looming: e.g. in aging of population.

ce ee EY ENE NE UN Ca SE HUN Ste NO

SOME MORE SPECIFIC EXAMPLES WHERE CANONS SHOULD BE QUESTIONED?
(If aven one of these stands up, worthwhile exercise):

{reconsider order of presentation}

Intelligence -- human {Need developmental plasticity)
Do we need a revolutionary successor to the prewired switchboard
model? Certainly abundant evidence for abundant cell migration,
replacement in vertebrate brain: deterministic networks in
simple invertebrates may be lacking in some elements of
complexity: however suitable they may be for primary device
analysis.

-~ machine (theory of highly parallel computation?
computer scientists locked into linear, von Neumann model.
Eobiology (origin of life)
We should acknowledge how unsatisfactory our current theories
are. But there remain unexplored experimental opportunities,
especially the more concerted search for missing links: e.g.
organisms much simpler than bacteria . requiring specialized
habitats.
Exobiology ("are we alone in universe")
exptl. harassment; skepticism of astrochemists
But odd, large molecules are being found in space!
Ontogeny
dogma of genetic uniformity of somatic cells. Overthrown with
theory of antibody formation. {Own experience, having mastered
problem of elective enzyme induction, misread the data on antibody
diversity -- or is that yet the final story?}

still many problems related to preexisting cytoarchitecture: will
there be self-assembly in face of CBloebel] zipcode sequences

model of phase variation in Salmonella. Exciting culmination, but
still not environmentally induced

Surprised more attention not given to grossly obvious histological
differentiation of nuclear and chromosomal structures -~ the bands
in polymorphs, the dimples in monocytes .... must be epiphenomena
of underlying chemical differentiation; and I will be rather
surprised if they are not associated with fairly specific segments
of DNA information and their current expression.

Aging ;
not yet a clearly consensual phenomenon, to use as a standard model
clearly differences between mouse and elephant:
which are diagnosable in isolated cells. and
to what extent do they reflect populational distribution among
samples. field needs a Delbruck/ his discipline on phage studies.
Cancer under enormous pressure: everything tried.

finally have some satisfaction in most fundamental approaches, namely
DNA differences amongst tumor cell lines ..... Too hot to comment
Heart Disease
Clumsy delays in exploitation of HDL/LDL polymorphism
Is exercise hest inducer we can find?
(12/81: norbutaline induces HDL '! -- see NEJM)

Moralistic lifestyle movement may be having effects comparable
to doctrinal pressures on treatment of venereal disease.

Psychosomatics
really not controversial (recall my lectures from Wolt??)
but methodology today still grossly deficient
~~ training of psychologists still grossly deficient: human biclogy
curriculum as intended experiment -~- yes pre-Meds, but education, law,
social sciences: psychology even more welcomed
Psychiatric disease
ONLY leads are a) psychotropic drugs
bigenetic influences in disease
Almost noone looking at polymorphism in drug metabolism, which would
reflect compounds of undoubted influence.
May need deeper grounding in DNA probes for polymorphisms linked to
psychiatric diseases susceptibility

Physiology, Anatomy ~~ orphaned founders.

who looks at nicotine addiction?

how exercise influences muscle hypertrophy

organ size regulation: problem I worked on as medical student
(liver regeneration after partial hepatectomy is till
unsolved. Paradigm: look for a regulating substance and
a receptor!!! has never failed when tried hard}
skin ~-e.g. corns.

nerve root distributions. Fluctuating back syndromes attributed
to hysteria: 3 rediscoveries of dural anastaomes between
Toots.

Some stupidities: too close demands for relevance, e.g. reyecting

birds for reproductive physiology

Public Health. Orphans: scientifically informed epidemiology
Tyranny of blind clinical trials (narrowness of hypoth.)
Parasitology
Happily are seeing rapid renascence of interest in problems like
malaria. tryps. and recruitment of young mol. biologists through
programs like the summer workshops at Woods Hole. :

Toxicology: may be most visible application of fundamental mol. biol
categorical need to develop predictive theory, not clinical trials,
to assess environmental hazards. Must be elevated from stepchild
of pharmacology to a central responsibility in health sciences,
against all obstacles of funding, political turmoil.....

Compararative toxicology must face up to growing public unrest
about ethics of animal rights (esp. in re higher primates!!>.
Quite apart from these issues, untold waste in routine testing
for regulatory purposes that adds nothing to our scientific
knowledge of biological mechanism.

Historically, toxic substances {metabolic inhibitors} had been
central to unravelling of metabolism ~- and colchicine / tubulin
neurotoxins/synaptic mechanisms more modern examples -- but displaced
by more sophisticated tools of microanalysis, tracer methodology,
genetic lesions for pathway analysis, and direct isolation of enzymes,
has left a generation only dimly aware of that history.

vacuum of policy analysis (Harvard/MIT main exception?)

METHOD OF SCIENCE
AGNOSTICISM s/ self-foolishness. Display ignorance.
Proyect (not peer) system problems
Dilemma of Big Science: equipment vs. ideas (Cunenviable)
ef Thackray. use quote

Philosophy of science -- descriptive, almost never captures conviction
of practitioners.
~- normative, since Leibniz’ dream, has never succeeded
in providing formal notation and logistical criticism.
(Smullyan?, Woodger)