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Mendel’s Beans, Ourselves, Medicine and the Genes!

I must have been in the fifth class of the elementary school, when for the first time I heard our teacher speaking about the interesting experiments and pursuits of Gregor Mendel in relation to the laws of heredity. I remember that I was extremely impressed by the fact that these studies have been done on the beanplants and their beans, and it was then that for the first time I came to realize that plants are also living organisms that are subject to the same laws with animals as regards the presence of their hereditary characteristics, as well as their transfer from one generation to the next!

I very well remember how deeply I was enraptured by this knowledge, that I immediately started with a great zeal to investigate the mysteries of heredity! Very soon I collected a few watermelon seeds, and with the use of a small penknife, with a very sharp blade, I scarified on their husk different geometric forms such as a triangle, a square, the letter “A” etc and I kept them with great care in a cardboard box until next summer when I planted them in our garden. You can imagine my impatience until the time when these plants would have presented their produce and the moment that I would open up the first water melon in which, according to my innocent imagination, I would have find the imprinted descendants of the seeds that have been marked with my penknife! Naturally, my disappointment was great when in the end I had ascertained that the seeds in these watermelons did NOT in anyway bear the marks with which their progenitors were marked!

Indeed todate we know that my intervention had the right target, that is the seed which obviously contained the elements that ought to undergo the specific alteration. But I shoot wide of the mark as regards the magnitude of the tool I had used for that intervention, as well as the size of the target! But this I realised very much later.

As a matter of fact, the years went by and at last we nicely arrive at April 23rd of 1953, when we were surprised by the publication of the sensational article in “Nature” by Crick and Watson, about the possible chemical structure of the material of which our chromosomes are made and in which our genes (i.e our genome) abide. In this way, the morphology of the DNA molecule (Deoxy-Ribonucleic Acid) has been, in broad lines, discovered and described!

Since then and onward, and especially after 1962, when these two protagonists received the Nobel prize in Physiology and Medicine for their work on this subject, there followed an avalanche of announcements of research results which were made in Scientific Laboratories all over the world. All these announcements were related to the study of this giant molecule which it was already certain that it constitutes an unbelievable detailed program as regards the structure, the development and function of every cell in the body, as well as of the whole living organism

Since then, and up to the present time, this molecule has been studied as no other molecule, and proved to constitute the whole coded detailed diagram, a kind of functional program for all the cells and subcellular elements, complexes, organelles, etc., the tissues and the different organs of the body, which refers not only to their morphology and structure, but also to their evolution in time! Into the structure of this molecule, which is contained in the nucleus of all the cells of the body, and reproduced, with the astonishing rate of eight million copies per second, the whole design and program of evolution of the mystery of life is contained!

But what is the structure of DNA?

• It is a molecule made up in the form of two long chains, each consisting of alternately positioned molecules of ribose and phosphoric acid residues.

• These two chains are twisted between themselves forming a double helix.

• The two chains are connected between themselves at each link by a bridge consisting of nitrogen containing bases of purine and pyrimidine, connected with each other.

* The sequence of these bridges between the two chains can yield a great number of combinations, by which a large number of informative elements can be coded, and in this way the structure of at least 100.000 different peptides and proteins found in the body is determined.

• The size, and consequently the complexity of DNA is something that surpasses the imagination:

(a) First, the size: the bases of purine and pyrimidine contained in a single molecule of DNA are around six billion. Each one of these bases is connected to a ribose molecule and a phosphoric acid residue, that is, we have a sum of eighteen billion of nitrogenous bases, ribose and phosphoric acid residues. If we represent each of these elements with only one letter of the alphabet and print on paper this sequence of only one molecule of DNA, the result will be as follows: 6.000 letters per a bicolumnar page on A4 paper, we get 3.000.000 pages. These pages, printed on both sides of A4 size paper, piled up one upon the other, could make up a pile of 120 meters high, i.e. the height of a of 35 storey building!

(b) The complexity of this molecule is astonishing. In there, in a coded form, there are the forms of all the structural elements for all the cells of the body, on a moleculer level, in every detail, with a parallel codification of the evolution of every cell during the whole life of the individual. Moreover, most probably in there may be stored, in a coded but non functional form, the coresponding elements of all organisms which preceeded man, from the simple pro-virus up to the present time. Moreover, there are the signals for the commencement and termination of the synthesis of all the hundreds of thousands of peptides and proteins which can be synthesized by the cells, as well as the signals of covering and uncovering of large segments of DNA, such as to inhibit or restart their function, etc.

Theoretically, from the DNA which can be found in a single cell of the body, under appropriate or suitable circumstances, we could create an
embryo which can evolve into an organism idendical with that from which the original DNA was derived. To date this procedure is called cloning, and in practice has already resulted in admirable and many promising wonderful achievements.

Lately, different methods of recombination of the DNA have been developed, where, by transfer of selected segments of DNA into lower animals, for example into Escherichia coli and other microbes, these organisms are forced to synthesize various peptides and proteins that are used as pharmaceutical substances in medical practice. For example, using such biotechnology, since 1981, all insulin needed, on a universal scale, is produced, idendical to the insulin synthesized by the β-cells of the human pancreas and therefore, with its use we don’t see anymore of the immunonoligal problems we had with the use of insulins extracted from pancreases of cows and pigs. Using similar biotechnology today we produce growth hormone, which is idendical with the hormone secreted by the anterior lobe of the pituitary gland of man, as well as various other peptides which are used as pharmaceutical substances.

Moreover, since the description of the structure DNA, and up to no more than four years ago, there has been an unprecedented race between some Scientific Laboratories for the exact decoding of the sequences of the nitrogenous bases in this giant molecule., i.e the human genome. Evidently this will constitute the cornerstone for their useful use in the future. I am referring to The Human Genome Project (publications in Nature Journal) and to the Celera Genomics Inc (publications in Science Journal).

The inherited material. The material that is responsible for the formation of the mbryo of the human being are the parts of DNA that are contained in that specific spermatozoon and in that specific ovum that are fused together during the fertilisation process. This molecule of DNA, which is formed by this fusion, constitutes the genome of the new organism. This same genome is going to be tranferred (one half of it), by a spermatozoon or an ovum (according to the gender of this new organism) to the descendants of this individual, etc.

Positive Natural Selection. On the DNA contained in the earlier stages of the sperm, as well as in the spermatozoa themselves, and in the earlier stages of the ova as well as in the ripe ova themselves, different agents are acting as radiation, chemicals and others, which very probably bring about small as well as greater changes of the sequences of certain bases (transmutations). The final result is that these genes that have suffered this particular change loose the ability to code in the proper way for the sythesis of the peptide or the protein they are supposed to carry out.

The number of these changes is enormous, and their effect in nearly all cases as regards the function of the effected gene is negative. But as their distribution involves a colossal number of cells, the possibility that one or several of these changes would involve the specific sperm (or the specific ovum) that will be used to produce the new organism is indeed infinitely small.

On the other hand, it is a fact that a great number of these changes involving the molecule of DNA are automatically repaired in situ by mechanisms which are not yet clearly understood. In spite of this, it seems that this automatic repairing process is not 100% effective. Consequently, some sperms, as well as some ova, may contain DNA with some kind of deviation from normal.

Here we can note that the number of sperms that are produced in man during his whole life run into many trillions! Eventually, from this huge number of sperms no one is used (!), or one, two or three and in some cases may be four or slightly more sperms are used to fertilize a proportional number of ova for the genesis of human beings! On the other hand in woman, during her whole fertile period of her life no more than 300 to 400 ova mature. Of these no one, or one, two, three, and sometimes maybe slightly more are eventually fertilized and proceed to develop into human beings!

If one or more changes of the DNA molecule in a sperm has an adverse influence on its motility, then this sperm will rather not have the chance to fertilise an ovum! This fact let us say that it constitutes the first stage of The Positive Natural Selection which is realised before fertilization of the ovum and the formulation of the embryo. But, even after the formulation of the embryo in the uterus, there follows a rather rigorous period of Positive Natural Selection. Actually, the intrauterus life of the embryo constitutes a kind of life in the jungle! – which constitutes the most proper period for the action of The Positive Natural Selection process, because during this period, the presence of any anomaly of the DNA of the embryo which is incompatible with life entails the death of the embryo and the induction of automatic abortion. In this way the continuation of the life of only those embryos that are
viable is achieved, that is, here we witness the action of Positive Natural Selection on the criterion of the viability of the embryo, which naturally constitutes the prerequisite for the viability of the individual who derives from this particular embryo, but without ensuring it!

Our Immune system. The DNA of the genes contained in our germ cells (sperms and ova) constitutes the substratum on which eventually the effects of these chance actions are imprinted for the formation of our genes (our genome), which are inherited to the next generation.

According to the data contained in all these genes the new organism that is going to develop into a human being is configurated definitively in every detail. Important elements of this genome are related to the configuration and programming of the extremely complicated body functions that are performed for the effective confrontation, chiefly of infectious factors (pathologic viruses and microbes, etc) and even pathologic body cells, for the accomplishment of the survival of the individual, ie they are involved in the structure and function of our immune system.

Because of this function, our immune system holds a very special and extremely specific and foundamental position as regards the realization of natural selection in this particular individual. So, since the immune system of the individual is adequate, this ensures the survival of the individual, and the inheritance of this system to the next generation. In a contrary situation (i.e. in the case of inefficiency of the immune system), this person succumbs under the influence of pathogenic factors and in this way its genome with this inadequate system can not be inheritated to the next generation. This fact constitutes a process of Positive Natural Selection by which the conservation of the effectiveness of the immune system in the individuals of the next generation is assured to function on as high and most effective funtional level as possible.

Iatrogenic Negative Natural Selection. The development of Medicine, especially during the second half of the 20th century was spectacular, beyond any expectation and foresight, resulting in the amplification of the effectiveness of Medicine as regards the confrontation of disease, the relief from pain and the offering and ensuring maximun duration of life, to a constantly growing number of people, under unbelievably improved conditions, in comparison to the past.

Moreover, this development has consolidated and soundly founded, as never before, at least among the greatest part of the scientific community, the rationalistic view of the physical world, the phenomenon of life and of man, and has downgraded, dissolved and squandered the naive fantasies, the morbid superstitions and the capricious, erratic, paranoid philosophical orientations that in the past have been dominant in this field. We have the feeling that, at last, we are standing on “terra firma,” where everything is governed by logic and realism.

However, in spite of all these facts, in this area there abide other elements of supreme importance, which are pregnant with unbelievably unfavourable and extremely disastrous situations. And I proceed to explain: Indeed, medicine to day is ofering to the individual extremely valuable services as regards the confrontation of disease and the securement of health and longevity in a degree never achieved in the past. Moreover, it seems that in the future these services will be more numerous as well as more effective. But what is the situation as regards the quality and the effectiveness of our immune system, as well as of other elements of our genome, that is inherited to each future generation?

Here facts are extremely disappointing, and indeed pregnant with nightmarish situations for mankind on this planet! The outlook is that, in the event that the right measures are not taken properly in time, the situation could be evolving into a non reversible degradation and disorganization of our immune system. This is so because, with the intervention of medical care, individuals with an immune system that alone would be inadequate to ensure their survival, manage to survive, and bequeath their downgraded, and partly ineffective immune system to the next generation.

Indeed, such a situation began making its appearance and consolidating itself, for a substantial part of the human population, already by the beginning of the 19th century, and suddenly growing into gigantic proportions and peaking during the second half of the 20th century. In simple words: during the centuries preceeding the 19th century, epidemics such as small-pox, followed each other and swept over Europe every 22 to 25 years, that is every time the proportion of young people, not immunized by the previous epidemic, slightly exceeded the threshold needed for its propagation into the population. In this way, about one third of the people contracting the disease died, and so their downgraded genome, in terms of effectiveness of the immune system, could not be trasmitted to the next generation. Consequently, the final result was that the parts of the genome that code for the elements and mechanisms that comprise the immune system were kept in a high and most effective state of readiness and effectiveness.

However, this mechanism of positive natural selection gradually ceased to function, first with the initiation of vaccination against small-pox (after the first experiments of Jenner, 1796-1798), and afterwards with the use of still many other vaccines against numerous other infectious diseases. Apart from this, by the middle of the decade of 1940, still another important factor was added, namely the extensive use of the antimicrobial drugs (and chiefly of antibiotics), with the consequence of further alleviation of the immune system from the successful confrontation of the infectious diseases. Naturally, this results in the survival of a great number of people in whom the immune system could not, by itself cope successfully with disease, and consequently their downgraded genome is transmitted to the next generation.

In addition, a significant number of autoimmune diseases, such as diabetes mellitus type I, as well as many other diseases, which basically consist of disfunctions of hormonal factors and/or metabolic pathways, as well as many psychiatric illnesses are currently treated successfully and the patients survive up to maturity. These individuals are therefore capable of transferring their downgraded genes, which are responsible for the appearance of these morbit situations, to their off-spring. We presently know that there are over 500 inherited diseases, that are caused by disfunction of one or more genes (Mono- and polygenic diseases). In this way, these genes, will in time be dispersed and spread from one generation to the next, into larger groups of the population, resulting in downgrading of the common pool of the genome of man in terms of the efficacy of the immune system. By the same process we have an amplification and transfer of many other genes, each one of which is responsible for the appearance of one or more structural, as well as functional abnormalities.

Moreover, important consequences in the same direction of this Iatrogenic Negative Natural Selection we already observe in the results of the surgical reconstructions of different inherited anomalies, in which the patients indeed acquire the ability to survive, but at the same time they facilitate and ensure the transfer to their descendants of the defective genes that are responsible for their inherited anomaly.

With this process, genomic elements that have been formed and improved by the processes of natural selection over many million years, can be weakened, downgraded and in the end wiped out within time frames of a relatively small number of generations.

But this negative procedure does not only involve the biological hypostasis of mankind but it also entails the disorganization of its social and economic life. This happens because, with the progressive extension of this Iatrogenic Negative Natural Selection, the number of people that will be in urgent need for prompt, continuous and imperative iatropharmaceutical care will continuously swell up, and I am afraid that in the end, the expense for this kind of medical care will approximate the confines of the national revenue!

This state of consolidation of the process of Iatrogenic Negative Natural Selection, in populations that have the privilage of being served by medicine, and particularly when this medical care is of a high level of effectiveness will have, in the near future, to be confronted in a really drastic way. And this way, I can not see that it can be other than the enrichment of the common pool of the human genome with the proper elements through the creation of genetically modified individuals using genetic engineering. In other words, it must be made clear that the process of the positive natural selection, at least as regards our immune system, from now onwards can not yield positive results, there can be no future in it. On the contrary, natural selection alone, as it is realised within populations who are effectively served by modern medicine, can only result in producing a downgraded genome and this is why its replacement, by the use of genetic engineering is absolutely necessary, despite of all other consequenses it might imply.

The original Greek version of this text has been given as a lecture in the series of Professors’ Emeritus Lectures, on 7th June 04, in the Senate Hall, Athens’ University, Greece.

John Hadjiminas, MD, PhD. Professor Emeritus, (Physiology) Athens’ University Medical School.

 

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