"Russian Trail" in the Discovery of DNA Structure

Ab initio...

Respectable inhabitants of Bruenn and the scholarly monastic community of the ancient St. Thomas Monastery of the Augustinian Order must have been intrigued by weird exercises of Brother Gregor. An average man can understand why people plant flowers, ingraft pears, raise pineapples, and study pests. The monastery garden and greenhouse provided excellent opportunities for these exercises. But one could hardly understand sweating over the beds of common garden pea on a garden-plot of two and a half hundred square meters! Why did Brother Gregor sort the pods and count up the peas before they went to the monastery kitchen?

How did the inquisitive peasant’s son Gregor Johann Mendel, who desired to become a priest, dare to apply algebra to checking ‘the harmony of nature’? We don’t know if he was inspired by the studies of mathematics and physics at the Vienna University, Blaise Pascal’s theory of probability, or long-term teaching of physics and natural history at the Bruenn school. We know only that he was the first to apply the methods of strict mathematical analysis to the results of his perfectly arranged experiments, and thus some of his colleague scientists ironically named him ‘botanical mathematician’.

Having studied the transfer of hereditary traits in ten thousand (!) pea plants, Abbot Mendel in the late 19th century concluded that there was quite a ‘material’ basis (later called gene) behind each trait of an organism. He formulated basic statements of the theory of heredity. The diligent ‘naturalist’ could not imagine that several kilos of pea seeds would contribute to a new science, eventually forming the foundations of modern biology.

Further development of genetics (from Latin geneo) — this name the new discipline got in 1906 — consisted, by and large, in checking the applicability of Mendelian laws to various kinds of organisms. Studying exceptions to the rules led to a wider understanding of heredity.

Alas, the ancestor of genetics was not crowned with laurels in his lifetime. His contemporaries recalled Gregor Johann Mendel as an outstanding citizen, esteemed abbot, and respected teacher who had an ordinary ‘botanical’ hobby. In 1900, 16 years after his death, Mendel’s laws were rediscovered independently by Carl Correns, Hugo de Vries, and Rich von Tschermak.

Before Dolly

During the first two decades since the moment of its second birth genetics tried to find a place in an organism where existing but abstract ‘incorporeal’ genes belonged. Chromosomes were suggested as gene ‘holders’ - by that time these intracellular structures were rather well studied but their purpose was not clear. Their involvement in the formation of sexual cells and fertilization clarified Mendel’s splitting of traits in the progeny. The concept of a chromosome as a sequence of gene-beads explained the coupling of attributes transmitted to descendants.

Thus, by the early 1920s the chromosomal theory of heredity was shaped and genes were given their permanent address in cells. Then a new question about chemical nature and structure of chromosomes appeared. An answer to this question was found only more than 30 years later.

First, it was believed that chromosomes were composed of protein molecules, but this was not confirmed. However, the concept that chromosomes were huge molecules encoding the basic principles of the entire organism was indeed prophetic. Then nucleic acids were considered because the functional niche of the high-molecular compounds composed of phosphoric acid, pentose sugars, and heterocyclic amine bases was not determined then. Bull’s eye!

From W. Bateson Science in Russia
W. Bateson is an outstanding English geneticist. This was Bateson who, in 1906, gave the name ‘genetics’ to the science of heredity and variability. In 1925, shortly before he died, Bateson visited the Soviet Union to take part in the celebration of the 200th anniversary of the Academy of Sciences, and gave a vivid description of his impressions on science in Soviet Russia.
<…> Wherever we went, we had the experience — to scientific persons novel and rather disconcerting — of finding ourselves conspicuously well dressed. It was indeed a little embarrassing to meet men of refinement and learning whose trousers were eked out with large and unrelated fragments.
One conclusion very plainly emerged, that the revolutionary government is perfectly sincere in its determination to promote and foster science on a very large scale. Signs were not wanting that science, especially perhaps in its applications, is regarded by the present governors of Russia as the best of all propaganda. It was interesting to hear the faith that the advancement of science is a first duty of the state proclaimed by professional politicians.
We saw many new institutions <…> Palaces and great houses from which the owners have been dispossessed have been hastily adapted for the purposes of science. <…> We saw laboratory benches improvised among the remains of Empire furniture and statuary, and under Boucher ceilings representing nymphs sporting with amorini.
Doubts might be entertained as to whether the best atmosphere for research has been created in the institutions, but no praise is too high for the zeal and vigor with which work is being conducted in the new circumstances. As typical of them may be mentioned the Institute of Zoological and Botanical Research under Prof. Philiptschenko and Prof. Dogiel, which has been set up in the house and parks of the [dukes] Leuchtenberg family at Peterhof. Besides the permanent staff, many hundreds of students are there accommodated in the summer months <…>. The whole gave the impression of a very active and well-organized school, which has already done excellent work both in fundamental and applied biology.
A very large house in Moscow has been assigned to Prof. Kol’tsov as an Institute of Experimental Biology. This includes numerous departments, especially a genetical station under Prof. Serebrovsky, work in experimental morphology, hydrobiology, etc.
Among the new organizations of a biological character, the most extensive is the Institute of Applied Botany and Plant Breeding. The immediate object is to provide breeds of cereals and other agricultural plants for the various parts of Russia. The work is in the hands of Prof. Vavilov, who has already built up a great establishment for this purpose, employing 350 people, of whom some 200 are trained workers.
We left with no clear conception of the principles or practice of communism <…>
We here are accustomed to think of science and learning as flourishing best in quiet places, where they may come to slow perfection, under systems providing a reasonable measure of personal independence and security.
Present conditions in Russia have brought about the very contrary, and among the grave indications of disharmony, which every visitor observes, the want of freedom is by far the most serious.
(published in: Genetics. 1999. V. 35. No.10. P. 1322–1325)

From the letters of N. I. Vavilov to G. Meller
7 March 1938
<…> I and my colleagues from the Institute of Genetics and Plant Breeding are deeply touched by the message about my election as a Chairman of the 7th International Congress of Genetics. I have already written to Prof. Crew, but I would also ask you to convey my gratitude to him for the great honor done to me and my modest work, the honor which I accept as recognition of achievements of Russian biology.
<…> The Institute of Genetics requires much effort from me. Construction of the building of the Institute is going well. I hope the greenhouses will be finished in May but official opening will not be possible before late fall. Bricklayer’s scaffold has already been removed.
<…> I am glad to tell you that considerable harmony has been achieved among the Moscow geneticists over the last months. Koltsov and his team, as well as Serebrovsky and selectionists – all of them now consider the Institute of Genetics as a real scientific research center in genetics.
22 May 1938
<…> The discussion is still ongoing. The main point, as I see it, is now whether the disintegration of hybrids is obligatory or optional and whether the ratio in individual families is 3:1 or not. Dr. Lysenko supposes that this law can be statistically correct for a great number of crossings, but not for individual classes. Thus the question about the fundamentals of Mendel’s laws arises. Therefore your book, as well as Morgan’s book, is very helpful. By now all classical literature has been translated into the Russian language.
18 December 1938
<…> Right now we are desperately fighting for mendelizm and ‘morganizm’ (which means ‘chromosomal theory’). There is rather fast evolution. The discussions that we started in 1936 are now more severe. The actors of this drama are almost the same. Now all doubts are focused on the validity of the 3:1 ratio. Recently there was a discussion about teaching of genetics and plant selection at universities and other higher schools. Some extremists from Odessa believe that mendelizm and chromosomal theory do not exist in reality and have to be replaced by darwinizm and the Michurin-Lysenko evolution theory. Today I have wrote an article for mass media in response to this criticism.
<…> Koltsov’s Institute now forms a part of the Academy of Sciences as a separate institute. Gershenson has recently defended a doctoral thesis without great success.
<…> New building of the Institute of Genetics has been almost completed from the outside. Both from the outside and inside it will be nice and next spring or summer it will be ready for staff accommodation. <…> Our experiments are successfully developing at all departments of the Institute of Genetics and of the Institute of Plant Breeding.
12 June 1938
<…> The discussion between geneticists and agrobiologists goes on. As I wrote before, it is about accepting Mendel’s laws and the chromosomal theory. Our opponents are neo-Lamarckists practically. They emphasize vegetative hybridization though they have no experimental data for it and other related issues. This is basically a matter of faith. <…> The only way out for us is to increase the determination in demonstrating the significance of modern genetics for selection.

From the letter of G. Meller to N.I. Vavilov
8 December 1938
<…> The Union of Soviet Socialist Republics, of course, can demonstrate very important results on gene research and mutation theory, as well as for other genetic problems, and it would be desirable if Soviet participants of the Congress could present several papers<…>

From the letters of N.I. Vavilov to G. Meller
26 July 1939
It is with deep regret that I have to inform you that none of us will come to Edinburgh.
26 August 1939
<…> In my opinion, genetics enters the period of even higher activity. You know that we all are internationalists and in our work we do not separate ourselves from the world science. I would be very interested to know your opinion about the Congress, about all the new achievements reported there. <…> I am very sorry about all the troubles we gave to you and Prof. Crew, but sometimes circumstances get in the way of even the best intentions.
Reproduced from Nikolay Ivanovich Vavilov and the Pages from the History of Soviet Genetics, compiled by I. Zakharov.

In the mid-20th century the spatial structure of DNA, the basic carrier of hereditary information, was deciphered. This success initiated a series of discoveries and generated new scientific disciplines. Molecular biology and genetic engineering were born.

Mendel’s laws were formulated almost 140 years ago, coinciding in 1865 with the birth of Shigechiyo Izumi, the longest-lived man in the world. The same year Mendel first made public his conclusions about heredity. Izumi died in 1986 - just one year after the method of polymerase chain reaction was designed for multiplying tiny quantities of DNA for biochemical analysis, which nowadays is widely used in medicine, ethnic studies, and criminalistics. Eleven years later Dolly the sheep was cloned and 17 years later human genome was decoded!

Thus, over the time commeasurable with a human life, though one of the longest, genetics has moved from abstract concepts of ‘germ-plasma’ to almost divine ability to create and transform living organisms. Two years ago the people of Brno (Czech Republic, former Bruenn) decided to immortalize Mendel’s spirit by creating a memorial complex in the abbey where Mendel had spent most of his life.

Blue blood

Last year the world widely celebrated the 50th anniversary of the discovery of the double helix structure of DNA molecules. The importance of this discovery can hardly be overestimated. Every student knows the names of James Watson and Francis Crick as well as Gregor Mendel. Less known are Maurice Wilkins and Rosalind Franklin who also contributed to the discovery. In 1962, Watson, Crick, and Wilkins were awarded the Nobel Prize in medicine. If Rosalind Franklin had not died four years before, there would have been four recipients.

No honorary titles and scientific awards can compete with the Nobel Prize, which is considered as recognition of outstanding achievements, as a kind of universal equivalent awarded for scientific merits to the best representatives of the intellectual elite. The triumphal march of genetics towards the discovery of carriers of heredity is marked by many Nobel prizes. Unfortunately there are no names of Russian scientists in the list of Nobel Prize winners in this field. We know that science has no frontiers and scientific discoveries have no citizenship, but still... Let us recall those who would deserve the Prize.

Erroneous Reasoning…

It is noteworthy that the idea of material carriers of heredity appeared almost simultaneously with the discovery of nucleic acids. At the end of the 1860s the nuclein, almost pure extract of cellular nucleus, was first obtained from human white blood cells. Unusual properties of the substance were studied by German biochemist Albrecht Kossel, who separated the first nitrogen-containing bases from nuclein. These studies were continued by Kossel’s disciple, American biochemist Feodor Aronovich Levin born in St. Petersburg.

It was Levin who revealed the nature of the carbohydrate components, which are included in nucleic acids (it took twenty years to separate deoxyribose!) and determined the structure of the molecules of nucleic acids. Levin devoted 40 years of his life to these studies but, unlike Kossel, did not win the Nobel Prize. Both scientists believed that monomers in the nucleic acid molecules repeat monotonely, which suggested that nucleic acids could not carry genetic information. Thus, Levin had no chance to be nominated for the Prize. The scientist died in 1940, 10 years before the moment of glory of nucleic acids.

Incidentally, Kossel, who separated, besides nuclein, histone proteins from chromosomes, pointed to a wide variety of polypeptides and in 1912 assumed that protein structure could be a chemical basis of heredity. For long these ideas braked the development of molecular concepts of genes.

Nevertheless, based on these erroneous assumptions, another outstanding Russian biologist Nikolay Konstantinovich Koltsov, the founder of the Moscow Institute of Experimental Biology, formulated a truly phophetical hypothesis about self-reproducing hereditary molecules. In 1927, he introduced the concept of chromosomes, huge macromolecules on which genetic information is inscribed by linear alternation of different monomers. Koltsov suggested that the molecules had a two-chain structure: in duplication the chains diverge, get into daughter cells, and then a mirror copy is synthesized at each chain. He erroneously thought that proteins were carriers of heredity, but his idea about matrix synthesis was included in the double spiral model by Watson and Crick 25 years later! It is noteworthy that 35 years later Watson admitted that he had never heard of Koltsov’s idea...

Nobel Quality

Further search for carriers of heredity were run in two directions: accumulation of proofs of the major role of nucleic acids in the transfer of hereditary information and deciphering of the stereostructure of hereditary molecules providing their self-reproduction.

Russian scientists made their contribution to these studies. The beginning of the last century is justly called the ‘Golden Age’ of Russian biology. At that time advanced genetics schools – Vavilov’s and Koltsov’s - were formed in Moscow and Petersburg. In the 1920s-1930s Russian genetics prospered. No one expected that soon it could be declared ‘pseudo science’ and geneticists would be claimed as ‘public enemies’ in the Soviet Union.

In the late 1930s, Koltsov’s disciple Sergey Mikhailovich Gershenson obtained mutations in the fruit-fly drosophila under the effect of alien DNA. But he had no time to examine the possible genetic role of DNA – the war against Nazi Germany began. The studies were resumed only in the late 1940s - just before another ‘witch hunt’ against geneticists. The consequences are anybody’s guess. At that time (1952) Alfred Day Hershey together with Martha Chase experimentally proved that DNA was the genetic material, for this discovery he was later awarded the Nobel Prize.

In the 1960s, Gershenson once again ‘missed’ his chance to be honored by the Nobel Prize for the discovery of the RNA to DNA reverse transcription. The Nobel winner Howard Martin Temin, who rediscovered this phenomenon and as a result of ten-year efforts separated the enzyme of reverse transcriptase, also knew nothing about the works of his predecessor, though Gershenson was declared the ‘Nobel class scientist’ by ‘Nature’.

X-ray methods have become one of the major tools in researches of molecular structure of a gene. One can state unequivocally that Russians were the first to discover the phenomena of radiative mutagenesis and artificial mutagenesis on the whole. If scientific research was to be compared with sport, one would say that the competition was held exclusively within the ‘Russian combined team’.

Whose guilt is it anyway?

In 1916, knowing nothing about the nature of genes, Koltsov assumed that stick-lip hereditary changes (mutations) could occur under the impact of environmental factors, for example, under the effect of radiation and active chemical substances. However, the idea could not be investigated immediately as the Russian revolutions burst out, which then turned into the civil war...

The hypothesis was examined many years later. In 1932—1938 Vladimir Vladimirovich Sakharov (Moscow) and Mikhail Efimovich Lobashev (Leningrad) established mutagen action of chemical substances (iodine and ammonia) on drosophila. A breakthrough in this field was made by Kozlov’s disciple Joseph Abramovich Rapoport, together with Charlotte Auerbach he was nominated for the Nobel Prize for the discovery of chemical mutagenesis. But the motherland decided that Rapoport, who was excluded from the Communist Party, did not merit the honor, thus he did not get the prize, which followed the logic of those times. Charlotte Auerbach did not receive the prize either, though she had nothing to do with the Soviet ideology.

Leningrad geneticists successfully ‘competed’ with their Moscow colleagues. In 1928, Maxim Nikolaevich Mejsel, graduate of Leningrad Medical Higher School, found the first evidence of chemical mutagenesis of yeast under the effect of chloroform. His teacher, microbiologist George Adamovich Nadson together with young Grigoriy Semenovich Filippov was the pioneer of radiative mutagenesis. In 1925, they obtained steady mutant races of mycelial fungi under the effect of ionizing radiation.

But since the concept of ‘genetics of microorganisms’ was nonexistent then, the Nobel Prize for radiation-induced mutagenesis (1946) went to Hermann Muller. It was Muller who during the visit to Koltsov’s Institute in 1922 made a present to the Institute, a complete collection of mutant drosophila races. He discovered the phenomenon of radiative mutagenesis using the classical genetic object — drosophila — in 1927, two years later than his Russian colleagues. It is noteworthy that since 1928 X-rays have been successfully applied in the USSR to increase the efficiency of agricultural selection.

The regularities of occurrence of radiation-induced mutations were studied by another Koltsov’s disciple, Nikolay Vladimirovich Timofeeff-Resovsky. In the mid-1920s, he worked for the Department of Genetics of the Berlin Institute of Brain Studies.

It’s a small World

Timofeeff-Ressovsky was the link that connected Koltsov’s ideas about the structure of a gene with the well-known spiral model of DNA through times and continents. Developing the concepts of the physical and chemical nature of chromosomes on the basis of the research results on radiative mutagenesis, Timofeeff-Ressovsky together with Max Delbrueck (1969 Nobel Prize) and Karl Zimmer confirmed the assumption about monomolecular structure of chromosomes and calculated the approximate size of a gene. Under the influence of the model the world famous physicist and theoritician Erwin Schroedinger, one of the founders of quantum mechanics, developed the quantum model of a gene-molecule in terms of physics and stated a consecutive series of physical phenomena that could underlie genetic mechanisms in his book ‘What Is Life?’.

The influence of Schroedinger’s ideas on the further development of molecular biology can hardly be overestimated. ‘What Is Life?’ was the reference book of Crick and Watson, the latter was an intern in the team of the former theoretical physicist Delbrueck who, after the joint work with Timofeeff-Ressovsky, completely devoted himself to molecular genetics. Watson, the world famous scientist and Nobel Prize winner, called himself a ‘scientific grandson’ of Timofeeff-Ressovsky. The circle has closed.

Thus, it is not a surprise that in the 1950s the expert of Russian genetics Timofeeff-Ressovsky was nominated for the Nobel Prize for his studies in gene structure. Small wonder that, as Rapoport, he never got the prize.

Plaything of destiny

Our brief historical sketch would be incomplete if we were to omit the major discovery that closed the search for the secret of heredity – deciphering the gene code.

The problem was stated by Schroedinger, and the key to its decision was also provided by physicist and theoretician George Antonovich Gamov, who at the age of 28 was elected the Corresponding Member of the USSR Academy of Sciences and one year later (in 1933) left the country. In the 1950s, Gamov became interested in molecular biology and proposed the model of genetic code using a pack of playing cards, whose colors correspond to the nitrogenous bases - purines and pyrimidines. He stated that coding groups can be only triplet, and 64 combinations obtained by alternation of four various nucleotides by three were quite sufficient for coding of 20 amino acids. Gamov also defined other properties of the genetic code — redundancy and degeneracy — which were later confirmed. However, the prize in this genetic ‘poker’ was won by experimenters Marshall W. Nirenberg, H. Gobind Korana and Robert W. Holley, not by Gamov.

We shall not conclude by blaming destiny, although there are no Russian scientists among those who were awarded Nobel Prizes for their advances in studying the secrets of carriers of heredity. There is so much controversion - merits and concatenations of circumstances - about the Nobel Prize. Even Mendel, who tried to get the official teacher’s certificate and failed biology exams twice, could miss it. The lack of Nobel Prizes does not disprove the unbiased fact that Russian scientists contributed in many respects to the progress and evolution of this great idea... Thus far there is no universal equivalent to life, passion, and talent!

The Editorial Staff thanks the Corresponding Members of RAS I. A. Zakharov and I. F. Zhimulev for their assistance in preparation of the article