UNIVERSITY OF CALIFORNIA, BERKELEY 8

Keegy

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SANTA BARBARA * SANTA CRUZ

 

 

DIVISION OF MEDICAL PHYSICS : : BERKELEY, CALIFORNIA 94720
DONNER LABORATORY .

February 19, 1970

pola Pt.. 20

“Professor Albert Sabin ‘ .
President. of the Weizmann ,

Institute of Science
Rehovoth, Israel

 

Dear Albert,

I did not write you for such a long time since it has taken me several
weeks to run in my research project and the lecture courses, which I am giving
in Berkeley. Now that my lectures on membrane biophysics are.well under way,
I can sit quietly and write you in more detail a report on the activities and

the plans of my department for the near future. 1

 

Let me start with some biological aspects. 1: One of the major inter-

'. ests of molecular biologists is in the polymerization of amino acids and. -

nucleotides under prebiotic conditions. For many years my co-worker, Dr. Mela
Horowitz, and myself studied the poly-condensation of amino acid phosGanhydrides

in aqueous solution at pH 7 and at room temperature. We have developed synthe-,

 

. . ~ .
tic_methods for the preparation of the highly unstable anhydrides on amino
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acids with free orthophosphoric acid, as well as the anhydrides with the sub-

—

stituted phosphoric acids. All the anhydrides polymerize in aqueous solution
to give low polypeptides, up to hexa or hepta peptides. A few years ago we
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turned our attention to the adenylates of amino acid which are well-known

aa precursors of protein synthesis and which might be the initial step in.the

_prebiotic synthesis of proteins. Indeed as was shown by various authors, both

amino acids and ATP are formed spontaneously under primeval conditions so that
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[Ueaino acid adenylates could form readily under primeval conditions. All experi-

ments, however, on the polymerization of amino acid adenylates in a physiolo-

 

 

 

 

 

gical medium were disappointing. In a homogeneous medium we succeeded to get
only low peptides, since hydrolysis was the predominant reaction which competed
effectively with chain formation. About a year ago we started a new series of

experiments in which we added heterogeneous catalysts to the polymerization
\ . .
Professor Albert Sabin -o- February 19, 1970

mixture. After scanning a wide range of catalysts, including colloidal metals,

ion exchanges, and silicious earths,we found at long last the real stuff: in
Pe

 

, the presence of clays; and in particular montmorillonite, we got a rapid and

Istrong polymerization to chains of 25 to 40 amino acids with practically no;

 

hydrolysis. This was particularly gratifying since it provided experimental «+ .
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evidence for the correctness of the Biblical ‘statement that life started with:

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_o1syees At the present moment we know that alanine adenylate, proline adeny-

 

_late and dialanine adenylate give very similar results and extensive experiments
are now being carried out by Dr. Mela Horowitz and her co-worker, Dr. Berger,
on the effect of the nature of the montmorillonite particles, the temperature

land the ion strength. ‘There are a few interesting side lights to these experi-

{
‘ments. First, we found that the major fraction of the peptides coming off the.

 

clay particles still carry bound adenylic acid and presumably form short poly=
adenylic acids. (If the analysis will substantiate the fact that adenylic acid .
‘polymerizes too, then we will have in hand the clue not only to primeval poly-

! peptide synthesis but to a simultaneous formation of polynucleotides. This
will resolve the question "What prgcedes what - proteins the nucleic acids, or

visa versa?" for the answer would be that both form simultaneously. Secondly,

 

we found to our amazement that the distribution of the molecular weights of the
polypeptide chains is not Gaussian or Poissonian, as found in all regular . .

polymerizations, but has a spectral structure. The molecular weights segre-

 

gate around sharp peaks which may be the reason why proteins started off with
a relatively sharp molecular weight distribution. This finding is also of
special theoretical interest and seems to indicate that on the montmorillonite
surfaces we have simultaneous operation of polymerization and diffusion.
processes, which have recently been shown to create "dissipative structures."
I am now working on the theory in Berkeley, together with a young: doctorant,
Alan Perelson, and we hope that in a short while we shall be able to interpret
quantitatively the results of Mrs. Horowitz's experiments. The theory is
important not only for intellectual reasons but since it may provide us with
a plan for the preparation of higher polypeptides and indicate how to carry
out poly-condensation experiments which will lead to structures closer to those

of the proteins.

I reported on these results at two closed meetings. The first meeting.

 

was arranged by the Council of the European Molecular Biology Organization, of

 
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Professor Albert Sabin -3- , February 29, 1970 °

which I am a member, and was attended by Crick, Watson, Kendrew, Perutz and
Klugg. Their response to the lecture was very warm and Crick and Perutz told
me that this seems to be the first important break-throu ugh in’ molecular

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biology after the discovery of the double helical structure of DNA. The

 

‘second meeting was organized by the Neuro-Research Program at the American
Academy in Boston and was attended, among others, by Manfred Eigen, Melvin
Calvin, Jerry Edelman, and Frank Schmitt. The excited_as the EMBO

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group and Melvin Calvin, who has just published a book on chemical evolution,

 

 

 

 

told me that this ig_the step to which all the workers in the field were look-
Uy ing during the last twenty years. Indeed, Calvin and.Eigen want to organize a

_Special symposium on chemical evolution in_ which we-could discuss the conse~

es of our discovery.

. Encouraged by the support of eminent specialists, I feel that it would be

 

 

 

 

advisable to extend the group of Mela Horowitz and to add to the equirment

which, will facilitate her work and will allow us to proceed more quickly with
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those fundamental experiments which should be published as soon as possible.

 

2: My other field of interest here is the application of. non-equilibrium
thermodynamics to mechanochemical conversions. You might know that some ten
years ago Professor Ora Kedem and myself introduced the thermodynamics of

_—— ens

irreversible processes into, biophysics and by now it has become an integral

part of biophysical teaching and study throughout the world. Our primary inter-

 

est at that time was the thermodynamic description of membrane phenomena and

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we succeeded to establish the correct equations for both passive and active

 

 

 

trans port in cellular membranes and tissue covers. At about the same time, I

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developed with my co-worker, Oplatka, me chemical corvertors which trans-
» Fommed-davectly chemical ener into mechanical work. Although the models

worked out by us have no direct significance for the interpretation and the work
({ of the muscle or of cilia and flagella, the physical principles underlying the
i conversion are identical, so that mechanochemical studies have an important
4 bearing on the biophysical understanding of living motility. They are also of
technological interest, and I hope that by now you have seen the machine shown
at the Weizmann Institute exhibition of scientific innovations. Indeed, °

Professor M. Sussman of the Tufts University, who worked for some time in my
4 ‘ .
Professor Albert Sabin -4. _ February 19, 1970

laboratory and developed a different mechanical model which I published

together with him in Science, made quite a fuss about the invention and

 

Published it in most important American daily newspapers. But from a funda-
mental point of view, our theoretical analysis of mechanochemical conversions
was always based on reversible. equilibrium processes. It is evident, however,
that both in the muscle and in the technical models the conversion is irrever-
sible and should be treated by the thermodynamics of irreversible processes.

It appears, however, that the classical non-equilibrium thermodynamics, on :
which I have written a biophysical book, published by the Harvard University
Press, is not good enough for the study of mechanochemistry. It should be
extended in some new directions related to ‘the network and graph theory success-
fully developed by the electrical engineers and by the specialists on general
systems theory. I am now working with a young post-doc, Dr. George Oster, on

a new thermodynamics of flow processes which should be able to describe both
linear and non-linear processes in steady and non-steady states. Such a thermo-
dynamics should comprise biophysical phenomena as well as technical processes
and adequate for the description of organismic systems. During this month, we

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made considerable progress and indeed we started_a dy to'write a monographic
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article describing the new approach and its _ application to numerous systems.
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Among the applications the most important case is mechanochemical systems

 

 

which we feel could now be described in sufficient detail and full generality.

Since the theory imposes new experiments, it would be advisable to help also ,

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Dr. Oplatka in my department to strengthen his group by additional equipment
“and manpower. The international interest in mechanochemistry and the fact that
not only technical firms but also cell physiologists are recognizing mechano-
‘chemical processes as fundamental in cellular and membrane transport makes the

experimental and theoretical study of these phenomena of real significance.

3: _The last item of a biological nature is the study of membranes. The —

 

original intention of developing biological non-equilibrium thermodynamics by
Dr. Kedem and myself was the interpretation of membrane behavior. Professor
Kedem, together with Professor Vofsi, the leader of the Plastics Laboratory,
have developed rather successfully a series of membranes for desalination and
for the separation of various materials from industrial mixtures. Their

— a ;

——
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A .
Professor Albert Sabin -5- . February 19, 1970

achievements will be surely brought to your attention in the proposals of the
Plastics Laboratory. Here I would like to mention primarily the > biological
ZS pects. § and, in particular, the possibility of analyzing active transport and
“related t biophysical phenomena. — During the last years, we have published

several papers in this field, and my department has become a recognized center

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examen aca
are new-comers to the field, the experimental set-up is lagging behind the

for the study of biological membranes. Since from a certain point of view we

theoretical knowledge, and we are very eager to_supplement our equipment with

 

additional apparatus which will allow us to study some fundamental - membrane _
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aspects. JI would like to mention in particular two directions of research:
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the classical studies of membranes were devoted primarily to stationary state
flows. The results from stationary state measurements, however, provide only
limited information about the details of the transport of matter across mem-
branes. During the recent years, powerful relaxation methods were developed
for the study of chemical processes, in particular by Manfred Eigen and his
group, and I would like to introduce these methods for the investigation of
membrane behavior. I discussed the matter several times with Eigen and it is
his feeling that despite the fact that relaxation methods are rather expensive,
they are within the range of the Weizmann Institute. Another group of investi-
gations which I would like to introduce into my department ig-eonnected. with
the thermal behavior of membranes. A true thermodynamic analysis of biological
membranes requires some information on the dependence of the transport coeffi-
cients on temperatures and on the flow of matter under a temperature gradient.
Indeed, some work on these lines was initiated under my guidance in the Labora-—
tory for Marine Biology in Miami, Florida. Recently, however, an important
advancement was made by my friend, Professor Isador Edelman of: the Medical
School in San Francisco, which indicates that the active exchange of sodiun ~
potassium in mammalian tissue may be responsible for the temperature regula-
tion of homolothermic animals. This relation between membrane transport and

thermal homostasis of higher organisms makes the investigation on the tempera-

I feel that installing the suitable experimental facilities in my laboratory

 

 

 

ture dependence of biological membrane transport of particular interest, and }
°

Professor Albert Sabin -6= , February 19, 1970

I would like now to turn your attention to the non-biological aspects

 

 

a work going on in my department. For many years we have been involved

 

in the study of charged polymers -- the so-called polyelectrolytes. The
‘electro-chemistry of polyelectrolytes is of fundamental biophysical interest
Since the nucleic acids, polyuronic acids and some of the proteins are typical
polyelectrolytes, whose solution properties are determined by the strong .

electrostatic field surrounding the polymer molecules. My colleague,

Alexandrovich, who is working for several years on the statistical mechanics

of polymer solutions in general and polyelectrolytes in particular, obtained
rather interesting results by treating the effect of excluded volume on equili-
brium and transport properties of macromolecules. Among others, particularly
important is the evaluation of the viscosity of polyelectrolyte solutions,
which could not be explained adequately hitherto. Since his work is by and
large theoretical, no additional equipment is asked for at this instanee. Very
interesting research on polyelectrolyte solutions is carried out by my
colleague, Professor Eisenberg, of this department. Eisenberg has developed

a thermodynamic treatment for multicomponent mixtures which permits the
analysis of biological systems, which generally comprise three components:

a biopolymer, salt and water. In addition to his important theoretical contri- ©
butions, Eisenberg, who is primarily an experimentalist, carried out precise
and careful studies on the light scattering and centrifigation of polyelectro-

lyte and biopolymer solutions which are recognized internationally. For his

 

 

 

 

experimental work he needs rather sophisticated and precise apparatus on which °
“he will surely apply to you directly.
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ty ‘ . . . ay
%. last item to be discussed in this letter is the problem of polymer nO
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sics. As is the case in the historical development of other branches of
éhemistry, the research workers on polymer systems started with the study of
solutions. During the last few years, however, the interest in solid polymer
systems has grown appreciably. One has developed a larger number of experi-
mental methods which allow the interpretation of the crystalline structure of _
polymers and provide a fundamental basis for the interpretation of the physical
properties of plastics, fibers and rubbers. Indeed, polymer physics is today .

——— g
the basis of the modern developments in plastic industries leading to some of

 

the remarkable materials found on the world market... It is an old dream of

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Professor Albert Sabin -T- February 19, 1970

wsracli industry. to enter the field of plastics and synthetic fibers and.

_although some important beginnings were made in the production of certain.

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brends of nylon, Israel is lacking in the scientific foundations on which an

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advanced industry of this type could grow. In line with the ideas advanced by
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you at the meeting with the senior. staff of the Institute, we feel that a -
Section on polymer physics would be a logical development of the polymer depart-

. r eed
ment. We are fortunate that Professor Alex Silberberg, who is the acting head

 

 

 

‘of the department in my absence, is_a specialist in some aspects of polymer
physics. Professor Silberberg worked for many years on rheology of polymer

‘solutions and gels; he is one of the leading personalities in the International

 

Society for Biorheology. I was happy to discover that Professor Silberberg is_
. So
¥ ready to help in the establishment of a section for polymer physics, for which
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his competence in statistical mechanics and in the general mechanics of polymer
systems will be of great value. At the same time, Professor Vofsi is very
interested in promoting the development of polymer physics as a basis for. the
further development of his work .on the synthesis and application of new plastic
materials. A laboratory for polymer physics is a rather expensive enterprise I

Since it should be provided with X-ray equitment and a series of apparatus for

 

mechanical and electrical measurements. There is no need, however, to start at

once on a large scale, and we feel that a small group of, say, five workers
attached either to the Polymer Department or to the Plastics Laboratory could
be an adequate beginning. If you feel inclined to look into this proposal, I
am sure Professors Silberberg and Vofsi will be happy to meet with you and

discuss in some detail the project.

This is about all that I wanted to tell you in this instance. I hope I
didn't exhaust your patience in reading through this too-long letter. It is my
intention to be back home in several weeks' time so that we could continue our

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Aascussion in a friendly meeting.

 

With cordial regards and best wishes.

Yours,

Shave

AK/m1.q ,
Prof. A. Katzir-Katchalsky -