Libmonster ID: BY-1560
Author(s) of the publication: Pyotr CHUMAKOV

by Pyotr CHUMAKOV, Dr. Sc. (Biol.), laboratory head, Cell Proliferation Laboratory, Engelgardt Institute of Molecular Biology (RAS), Russia; laboratory head, Lerner Research Institute Laboratory, USA

Humankind in changing fast, changing before our very eyes. Where is this going to end? Will the frenzied pace of biotechnologies change the biological nature of Man, the Homo sapiens? These are no idle questions, though not quite so obvious a couple of decades ago as Acad. Ivan Frolov posed the problem of comprehensive multidisciplinary studies of Man. His ideas are as topical as ever today.

Logo of the international Human Genome Project.

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Human civilization is in for a qualitative leap in the technological sphere. And not only there for that matter. There is yet another revolution in the offing, one related to the biological nature of man, his inherited do's and dont's encoded in our genome. It is quite symbolic that at the very close of the past 20th century the hereditary information of our genome was decoded in full. This information codes for all characters and biological processes of the human organism. In keeping with the international Human Genome Project it has become possible to determine the sequence of the 3 bln DNA base pairs within 23 chromosomal pairs, which means we have full information on the potential structure of each of the 23,000 genes making up our genome. Proceeding from this information we can visualize the structure of proteins encoded in the genome. Biologists now hold a most detailed "roadmap" that will speed up genetic research tenfold and hundredfold.

In this country work on the Human Genome Project is closely associated with Acad. Ivan Frolov. Our biology was in a sorry plight because of the officially sponsored crackdown instigated by Acad. Trofim Lysenko in the late 1940s and early 1950s. Soviet genetics, once forward, was in fact routed by Lysenko and his henchmen. Its lag was truly great. Frolov certainly had a part to play in the recovery of molecular biology in the 1970s. A new generation of geneticists entered the stage, myself among them. We joined international programs of research into molecular basics of life, and that a decade after the breakthrough event of the 20th century, the discovery of the DNA double helix explaining empirical laws of classical genetics at the molecular level. Next came the structure and functions of individual genes. At first these studies were carried out on models of primitive living organisms, the viruses, and as of the early 1980s it became possible, what with the improved DNA manipulation methods, to get down to the gene structure and expression in man and animals.

Yet another decade had to go by when progress of scientific technologies enabled us to pry into the structure of the human genome. This became possible thanks to a solid technological base to ensure molecular-biological studies on a scale much superior to those conducted with the aid of medicaments. Specialized

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automatic devices were developed, and methods of analysis upgraded, for instance, in DNA sequencing. The scope of the task of determining the genome structure was truly fantastic: more than three billion genomic "letters" had to be read. Suppose you want to record the genomic alphabet. You have books, each with as many as 1,000 pages, each page having room enough for 1,000 letters. Well, you will need more than 300 volumes to do the job. It was obvious to us that years of international cooperative effort were necessary for that.

In the mid-1980s several US national laboratories supported by the Energy Department were involved in large-scale research in a high-precision mapping of individual genes in human chromosomes. Accordingly, in 1987 American biologists formulated the strategic objective for sequencing the three billion base pairs of human DNA. James Watson, who pioneered in the discovery of the DNA structure, was playing an active part in these plans. He became the first director of the human genome studies center at the US National Health Institute.

In our country Acad. Alexander Baev stressed the need of Soviet participation in world genomic studies. He won support from Ivan Frolov, who convinced Mikhail Gorbachev, the national leader, that such participation was necessary. The matter came up at a meeting of the Politburo, the Communist Party's presiding body, that gave the green light to the idea. This is how the Soviet human genome program was born. At that time HUGO, he Human Genome Organization, was set up. It distributed among HUGO member states particular chromosomes for DNA sequencing. Our country got three chromosomes (3, 7 and 19), very important for medicine as containing genes subject to lesions in some malignancies. The Soviet program was off to a good start thanks to financial support, and it yielded quite worthy results soon. But this financial backing was cut short with the breakup of the Soviet Union, and the Russian program faded away.

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As the only superpower, the United States took charge of genomic studies. In 1990 the US government allocated 3 bln dollars for a national project of its own for a period of 15 years when the human genome structure had to be determined. Although in the early 1990s two projects, the American and the international, were on, the Americans financed national programs of states affiliated with the international program. Most of the work was done at the National Institute of the Human Genome whose strategy was to sequence the genome "gene by gene". To do that one had to have an exact prior knowledge on the position of genes in chromosomes. First large genomic fragments containing proteins composed of several genes were to be obtained. Such blocks were then split into smaller chunks for reading at high-performance sequencers.

Craig Venter, one of the architects of the US national project, made a count and found that this approach was not justified strategically as being all too laborious and slow. He put forward an alternative strategy; sequence the genome by the "crusher" principle, that is by determining the sequences of random short DNA fragments, and then joining all these bits and pieces into a continuous structure through a computer program. Since his superiors were thumbs down, Craig Venter decided to strike out for himself. He founded Celera Genomics, a private company, and canvassed around 300 mln dollars in private donations, or a tenth of the national project bill. His work was making good headway-so fast that it jogged the government program toward improved technologies and speedier pace.

The competition of two programs became truly dramatic in 2000, just a few days before the official announcement on the termination of the two projects. Celera Genomics had a supercomputer capable of collecting solitary chunks into one continuous sequence. Its project was just in at the finish when the government-sponsored program scored a breakthrough on the final stretch by hooking fifty personal computers and lunging forward-so it came five days ahead of the commercial project. Thus, by the summer of 2000 the human genome project was completed five years ahead of schedule. The genome structure data were published in outline in the hope that the blank spots did not carry any significant structure-related information and were made up of insignificant repeats. These gaps were filled in later, in 2003, after the official termination of the project.

The genomes of other organisms-mice, rats, horses, monkeys, yeast, Drosophila flies and nematodes-were likewise deciphered. The data thus obtained made it possible to trace the evolutions of genomes at different stages. The higher sensitivity of sequencing methods allows to get down to genomes of extinct animals, such as the mammoth or Neanderthal man. In this case DNA is taken from remains found in permafrost or from bones. Determining the DNA structure of fossil organisms is but the first stage in the long and laborious search of reconstructing the long dead species. The strategy of this search has already been mapped out.

The decoding of the genome structure has led to many sensational discoveries. Whereas before we were in the know only about the structure of individual genes, today we are able to visualize the overall organization of genes, their mutual disposition as well the alignment of intergene sites. Only 1 to 1.5 percent of the genome was found to be implicated in protein coding, with the remaining part of DNA containing information on gene regulation, and being composed of silent, insignificant genes.

Our genome comprises only 21 to 24 thousand genes, or much fewer than predicted before. It is surprising indeed that the genome of the microscopic nematode C. elegans comprises only half as many genes as the human genome. Consequently, evolutionary differences among organisms are largely due to gene expression parameters and minor variations in the gene structure. The appearance of vertebrates called for an additional 7 percent of genes only. This finding underscores the significance of information obtained on simple biological models, for the basic cell functioning mechanisms are quite close even in organisms standing far apart on the evolutionary ladder.

Still, the genomes of evolutionally related organisms may differ greatly in size because of the different number of noncoding sites, all kinds of repeats, leftover viral DNAs and mobile genetic elements... Some of these initially silent sites could take on new functions by getting involved in the regulation of individual genes or else by coding for a new protein, that is, giving birth to a new protein.

Collating different genomes, we might as well guess that apart from the slow, sluggish evolution characterized by accumulation and fixation of mutations (that is replacement of certain links in the DNA chain), there could also be dramatic, explosive changes when

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a consideral number of mobile genetic elements were getting in. By violating and changing the functions of many genes simultaneously, such insertions were disastrous. True, the greater portion of organisms, if conceived during a catastrophe like that, were not born at all. And yet some negligible part of mutated organisms could survive, be born in twins, and proliferate as sibling species.

Knowing the structure of all genes, we can compare different genes for relatedness, combine them into groups, and predict the potential functions of hitherto obscure genes. Now we are able to follow the birth of new genes in the process of evolution as the new pairs of genes formed through duplication start diverging more and more, and acquire additional characteristic functions. Upgraded computer programs enable us to take our bearings in enormous genomic data arrays. Now we can assemble coding gene sites from disjointed pieces, and find every kind of regulatory and signal sequences. We can also isolate, in pure form, heretofore unknown genes, test their functional characteristics via experimental insertions into cells. Another potent tool of research consists in the specific exclusion of certain particular genes in cell culture and on an integral model organism (Drosophila flies, mice, and so forth).

All these good things concern scientists by and large, for they have gained a bounty of information to go on with their research. But what about the common run of men? What will they gain? They shall see the benefits very soon. The genome of a standard human being gives but a schematic, thumbnail picture carrying no data on the individual characteristics of the genome of one particular person. Meanwhile genetic information on one particular human individual, his or her look, likes and dislikes as well as predisposition to diseases is recorded in the genome. So, science is facing two strategic objectives: first, make it possible for the common run to determine the structure of one's individual genome and second, pick out from this data array information on one's individual characters.

Individual differences among people depend on the polymorphism, or multiplicity of forms, of individual genes. Each character is encoded by a pair of genes at least, since every gene in the genome is represented by two copies inherited from both parents. Genes contain variations or, in the specialist lingo, they are polymorphic; so, a combination of two different copies of one particular gene begets a particular character. At present an active search is on for a correlation of certain particular characters with the individual gene structure. Studying large groups of people united by the common structure of this or that gene, we get to know how this structure is related to a character and its manifestation. Proceeding from the structural gene-related specifics of a human individual, we can predict a character.

Finding correlations between the gene structure and phenotype (a manifest character) is the hardest part of the search. It is much easier with the DNA sequencing technology being upgraded and getting down in cost all along. The decoding of the first genome took more than ten years and cost around 3 bln US dollars. The situation is quite different today: the sequencing technology takes just two weeks, and the bill is 10,000 USD. In 5 to 10 years the cost is to be brought down to 100 US dollars, and the analysis, to a couple of hours. This means that each and everyone will be able to learn the structure of his or her DNA. Such assays would be made in maternity homes, too.

Yet even at this stage we are able to learn a good deal about the individual specifics of our DNA through an alternative and simple technology. Scientists know quite well what sites of genes are prone to display differences. The genome contains several million polymorphic sites like that. Saliva is taken as stock material from which DNA is isolated. By incubating DNA with a microchip that contains about a million individual variable DNA segments it is possible to pinpoint individual distinctions. There are several companies in the world to do the job at quite affordable prices. Digging into Internet, one will get complete information on individual distinctions and access resources making it possible to prognosticate predispositions to particular diseases and learn more about individual abilities, food preferences and even temperament. Although research into the correlation between genetic polymorphism and related characters began not so long ago, many useful prognoses can be made through genotypical analysis to help one assess more soberly his or her aptitudes, likes and dislikes and, if need be, change life habits so as to avoid disease. Such information will be useful for prevention and early detection of probable diseases. We know that about 26 percent people fall in for Type II diabetes. The probability of the incidence may be either 54 percent or 17 percent. Accordingly, individuals particularly predisposed to diabetes would be able to take prophylactic measures and opt for health diets.

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Sequenced DNA is helpful in predicting a higher probability of malignancies-in this case regular medical checkups are desirable. Now, smokers argue that one can keep smoking for life, live to be a hundred years old, and get no lung cancer. Yet lung cancer is probable even after five years of this addiction, and there are numerous cases to prove that. Statistical data show that smoking is the main cause of lung cancer. Genotyping data allow a prognosis about the probability of a malignancy in a concrete individual. If so, this will be a strong imperative for a smoker to kick the habit.

Data on the genetic status of a particular individual are of great importance to a medical doctor for choosing an adequate treatment strategy. One and the same drug may produce different effects. Take, for instance, caffeine: in some people just one cup of tea or coffee will provoke tachycardia (an abnormally fast heartbeat) and insomnia, while other people will exhibit no symptoms like that. Hence the new discipline, pharmacogenetics-the art of choosing medication optimal for a concrete individual.

The medicine of the future is visualized as personoriented. The genetic status of a patient will come first, and it will dictate an appropriate treatment strategy. This is especially true of carcinomas since each tumor is unique. In the process of their growth tumors trigger a consecutive accumulation of genetic lesions in many genes, likewise unique in different malignancies. Spotting a set of such lesions is possible by DNA analysis. Already in the near future a tumor DNA analysis will become routine along with the conventional microscopic analysis of biopsy material. A computer program will tell the doctor what cellular processes are out of joint and what preparations will serve best for the treatment of this particular tumor with regard to the patient's individual genetic status.

A knowledge of the genetic structure makes it possible to detect hereditary defects at the root of many grave diseases. Hereditary diseases usually manifest themselves when one inherits just one defective gene copy from both parents. It has been found for many hereditary diseases in what gene in particular a mutation occurs, with diagnostic tests elaborated for detection of lesions there. But how to free one from the fatum of hereditary predisposition and prevent the incidence of cancer? The medicine of today cannot eliminate the cause of this disease, the hereditary

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mutations. Treatment procedures are confined to removing the consequences and symptoms. Meanwhile research laboratories are working full tilt to evolve strategies for making good hereditary genetic defects and combat the primary cause.

In a more radical procedure, it would be best to prevent the transmission of a defective character by succession. Formerly one suggested all kinds of dubious manipulations like sterilization of hereditary disease carriers. Such steps were rejected for ethical, moral reasons. Today owing to the great strides of genetics it does not appear so fantastic to replace a lesioned DNA site right in the spermatozoon or in the egg cell. Such technologies are already in the making.

Our hopes are not at all groundless: relying on our knowledge of the genomic structure and knowing the site of a gene lesion (in a gene responsible for a particular disease), we shall be able to apply new treatment procedures within the next thirty years with the aid of targeted genetic recombinations. Furthermore, it will become possible to expand a set of characters to be modified. Used on a mass scale, such technologies will phase down the incidence of grave diseases like cancer, atherosclerosis, infarction, insult, diabetes, and so on and so forth. Humankind will get healthier, for its gene pool will be ameliorated. Such kind of eugenics*, as we take it, will answer the ethics of our time and will be accepted by society without objections.

However noble the aims of the proposed technologies and their universal benefits might be, they would pose new challenges. To what extent could interference in our genetics be considered acceptable? What if we try to insert some new gene into our genome so as to expand our individual abilities?

Unlike repairing lesions in the available genes, new gene insertions may entail unpredictable conse-

* The science that deals with improving the human race by controlling heredity, as by a careful selection of parents.-Ed.

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quences. We still know but little about the complexity of a living cell, let alone a living organism. Each segment of our DNA has a definite place within the cell nucleus. Many, if not all, messenger RNAs are preprogrammed for leaving the cell nucleus in definite, fixed pathways. Thereupon they are transferred to preassigned sites of the cytoplasm where they orchestrate protein synthesis. This space organization is conducive to an optimal functioning of the cell. It took form in the course of long evolutionary selection ensuring a delicate balance of sophisticated interconnected regulatory processes. What is going to happen to a foreign DNA insert? The consequences of such insertion will depend on the site of a specific chromosome. We cannot tell what site of the cytoplasm will offer optimal conditions for a synthesis and functioning of the protein encoded by the new DNA site and how the presence of this protein will tell on the all-out chain of balanced interactions and processes within the cell.

The cell also has an internal immune system (with protein p53 as the central component) reacting to all possible nonstandard situations, lesions and hang-ups by a self-destruction of the cell. This system is designed to ensure the structural immutability of our DNA and the correlation of cell processes with programs recorded in our genome. Most likely, the introduction of new genetic information could activate the protein p53 system and make such transgenic organisms less viable. Therefore, as I see it, the present transgene plant and animal organisms pose no ecological hazard: getting out of laboratories, industrial enterprises and cultivated fields into wild nature, they come to be less adjusted to the ambient environment than are nonmodified organisms.

While gene-modified agricultural organisms now being created on a wide scale do not pose grave ethical and ecological problems, such technologies, if transplanted to Homo sapiens for eugenic purposes, are utterly unacceptable. Fortunately such methods are too far-fetched to enable any prognoses concerning their actual realization. Medicine ought to save people from disease, not to substitute God. Once we learn to repair defective genes on eliminate them from the gene pool, man will still remain an acme of perfection. The average life expectancy will then increase to 100-120 years, and perhaps even more. Diseases will go away, people of all ages will live in harmony and depart from this world painlessly and in serenity, as long-livers do.

Yet another spinoff from human genome sequencing, one that will unite the human race into one big family someday. Comparing DNA polymorphic sites in different people, we can bring out their family relatedness. Wide-scale genetic testing builds up massive databases storing information on the individual structure of genomes in thousands and in prospect, millions of people. Upgraded computer programs make it possible to identify human individuals of distant relationship, even those whose ancestors became related more than three hundred years ago. Since gene testing results are promulgated in Internet, potential relatives can find their kinsfolk and get in touch with them. Social networks are coming into being for newfound kindred men and women who thus are able to look back into their family roots-exchange information on their family backgrounds and genealogies. Remarkably, such searches reveal kinship among people living in different countries, people of different nationalities, even races. Such data debunk the preposterous ideas about national superiority-in fact, the human race makes up a continuous network with myriad interethnic ties.

Contemporary informational and biological technologies have broken into our life just within a decade or so, and they have come to stay to change the world we live in beyond return. People and nations are merging into one human race united by common information and by a common awareness of their mutual kinship, by a real prospect of getting rid of diseases.

Acad. Ivan Frolov left this world ten years ago, at the dawn of the new era. A man of keen foresight, he divined its outlines. But how many new horizons have opened up during this short time stretch! The ongoing informational and biological unification of humanity inspires an optimistic outlook. We can look ahead with great optimism since any wrong step of a particular individual is being under ever greater social control. A collective Homo sapiens is taking body and form; its wisdom will turn into a reliable barrier in the way of any attempts at tampering with our biological nature.


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