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MEMORANDUM = Research on Mental Retardation
Notes by Joshua Lederberg, Stanford University

1. Requirements for and limitations of basic research bearing on mental retardation -

It is difficult to see how we can make outstanding progress in mental
retardation and cerebral disfunction without some better understanding of the
mechanisms of normal cerebral function, particularly learning. After many
years the biology of intellect remains a deep mystery and there is no concensus
as to the soundest approach, although exciting results certainly continue to
appear from electrophysiological studies.

Under the pressure of urgent need for the solutions to human problems it
is easy to misconstruct the possibilities of basic research in supplying the
information needed for the solution of such problems and there is always an
understandable tendency to push research that seems to be most immediately
related to the critical disease situation. If carried too far, this may be
a misguided, even harmful bias. Many of the most outstanding advances in our
comprehension of the complex problems of mental retardation have come from
entirely unrelated fields. For example, the brilliant new insight that has
been achieved in the ideology of mongolism stems directly from the most genera!
investigations of the chromosome number in man which in turn has its bases in
the studies of chromosome variation in the formation of species amd varieties
in domestic plants. Our present techniques for the accurate diagnosis of
galactosemia depend on basic studies on the metabolism of sugars by yeast which
could not have been directly motivated by concern for mental retardation.

These examples could be multiplied many fold. Are we then helpless in attempting
to accelerate the development and application of basic research information
through the problems of mental retardation? A constructive answer is possible
and has two elements:

1. To provide continued encouragement for the opportunities for basic
research in a variety of Fields with special emphasis on the provision of
adequate facilities to insure the most efficient use of existing technical
manpower in the development of scientific information and

2. Disseminating information on and a more acute interest in the
more immediate problems of mental retardation among such scientists. If we
on the panel do our jobs well, it will be these scientists and not we who will
discover the salient opportunities.

It should be stressed that the resource of creative scientific talent
is not an unlimited one. Much still remains to be done in providing adequate
educational opportunities, especially at the earlier stages of academic training,
to insure the most effective development of career opportunities for creative
talents. At the present time the most effective scientific talent is spread
very thin and has many demands for the development of basic knowledge and for
the application of this to applied problems in many fields of human endeavor.
Probably the most effective course that can be adopted for the immediate future
is to provide adequate facilities so that this talent can have its most
efficient application to meet the social demands upon it. An indescriminate
distribution of research funds could have the opposite effect, of attracting
into new research areas an ever more marginal range of personnel with what

may be indifferent and even negative consequences for the total output of
creative scientific work. The same result is likely to be achieved if an
unbalanced program that does not give adequate attention to the free range of
research inquiry is overstressed.

2, Ina few cases we can hope to achieve some insight into ideology and nosology
of mental retardation without fully understanding the terminal mechanisms. For
example, the chromosome nondisjunction in mongolism; a homozygous recessive

gene in phenylketonuria or galactosemia. By differentiating specific diseases
within the complex of mental retardation we can at least focus on some more
specific problems and begin to ask pertinent questions.

In critical research then we should place strong emphasis on explicit
characterizations of the defects among different cases of mental retardation.
For example, some children may be worried to death of the word blind due to
central failures ~ in an ordinary educational regime they may be found to be
quake ''unteachable''. The further development of analytical techniques may
help to analyze other defect patterns in a more meaningful way so that we
have some starting point for research as well as diagnosis and therapy. Needless
to say, such studies have important implications for the differentiation of
pedagogical technique among normal as well as diseased children. We have to
educate ourselves and our audience to stop thinking of mental retardation
as a fundamentally unified disease, an approach which can only obscure the
analysis of the specific defects which operate in different examples of it.

The development of sophisticated analytical technique, behavioral,
neuralogical, biochemical, is also essential for the earlier diagnosis of
mental retardation. So little is known about the details of delivery and
immediate postnatal experience among normal children that it is difficult to
evaluate the role of marginal traumatic injury, cerebral ischemia, delayed
respiration and inoxia, virus infection, and so forth, ina large segment of diseases
attributable to perinatal accidents.

3, The bearing of research in a) molecular biology and biophysics, b) cell
biology, c) genetics.

a) The electrophysiology of the nervous system remains a highly
promising area of investigation, especially with the growing application of
computer methods to the analysis of output data. This field in relation to
the whole area of biomedical electronics and instrumentation needs more
financial support - it is inherently very costly and this has discouraged
many investigators from the ambitious planning needed for ihovations here.
The chemistry of the nervous system is in a discouragingly primitive
state. It is impossible to frame significant questions about deviations in
development when we cannot properly describe the variety of proteins and other
specific compounds in the intact adult normal brain. If we only had this
framework we could then begin to dig into the bases of cellular specificity,
metabolic interaction, developmental patterns and their variation with genetic
factors and environmental disease. At the present time it is as if we were
trying to cope with the anemias as a clinical problem while lacking any
knowledge of the chemistry and physiology of hemoglobin.

b) Morphological and functional investigations have talked a great
deal about the organization of the central nervous system, but we still have
only the most primitive understanding of the functional relationships of
different cell groups in the brain, and more particularly, the developmental
mechanisms by which these are brought into effective working relationship with
one another. Such studies of developmental neurology as are typified by
Sperry's work of some years ago should be expected to give us a tremendous
insight into the biology of neural patterning. Unfortunately, these studies
were stymied in midpath for lack of the chemical insight alluded to in the
previous section. More recently, related question of specific functional bio-
chemical relationships of cells have appeared, for example, in Morrell's
studies of functional changes induced by epileptiform discharge - once again,
these are blocked by the virtual nonexistence of a science of molecular biology
of the nervous system.

We are at a similar impasse in our attempts to understand the mechanism
of cellular intoxication in two diseases for which we have some biochemical
insight, galactosemia and phenylketonuria.

c) Genetics - Studies of human population genetics of a rather general
kind, especially the effects of consanguinity such as are going on in Hawaii,
Northern Italy, Japan, and elsewhere can be expected to throw tremendous light
on the role of genetic factors in mental retardation. From such a general
approach, we may hope to be able to analyze specific syndromes attributable to
particular genes having individualized by chemical effe cts.

Mongolism represents one of the most formidable problems in this area
and the recent discovery that this is based on chromosome nondisjunction and
the production of viable individuals carrying an extra chromosome has given us
a tremendous lead in this field. However, a great deal remains to be done
1) in the understanding of the cell biological mechanism of the chromosome
abarration - why it happens in the first place in the developing egg, and what
bearing maternal age has on the cytological process and 2) the identification
of other genetic factors located on this extra chromosome that may give a better
understanding of the way in which the development of the child is influenced
by it. It is quite likely that many other syndromes based on chromosome aberration
*

are now included in the waste basket of mental retardation of unknown #deology
and these should yietd to more extensive cytological investigation.
Additional Note -

As a laboratory scientist, | can point to some of the most urgent
difficulties that we face in endeavoring to expand our basic research programs
so that they can take proper account of the challenges posed by problems
such asmental retardation. Over the years, the National Institutes of Health
program of research grants and research training grants have developed
splendidly, and their present level and rate of growth promises very well for
the availability of essential resources in such research. However, for
reasons that are entirely inexplicable to me, the pattern of nongovernmental
support suffers from a serious distortion in the curious unwillingness of many
donors to furnish funds for the one aspect of research expansion that is most
difficult to develop from other sources: the physical facilities in which
people can work, BRICKS AND MORTAR. The availability of federal funds for
Operational costs of research programs in medical science and the constructive
evolution of the techniques for program review and evaluation within the NIH
can give us a splendid national program which hardly needs to be duplicated
by nongovernmental agencies. However, Congress has been reluctant to face the
urgent needs for more research facilities = the past and existing programs
under the health research facilities acts being grossly inadequate. This is
the area in which private donors should concentrate their activity in order

to make the most effective use of available funds, since these will be amplified

many times in the operating funds which effective research workers can obtain
for the manning of such facilities.
Memorandum to Dr. Davens

This note is outside the research question, but surely it must have
occurred to many people that we need more adequate provision for insurance
to mitigate the financial burdens of special care for such congenital diseases
as mongolism. The penalties to the family and siblings in incidents of this
kind are severe enough that we should have some better means than we now
do of preventing the impact of the additional, sometimes very serious, economic
burdens. [It seems questionable whether the Congress is yet ready to incorporate
such a program into the general social welfare system. But perhaps here, more
than in other areas of family security, a great deal could be done to start
with even by a strictly private voluntary insurance program. Apart from its
obvious social benefits, such aprogram could also generate a very useful
research tool by defining a well characterized and well examined population
in which the incidence of mental retardation and its variety was under the most
careful,> uniform study.

cc: Dr. Leonard Mayo
Mrs. R. Sargent Shriver, Jr.