L'enzyme allostérique est soumise à différents potentiels biochimiques. Ceci demeure vrai pour autant que l'on ne réalise pas l'omission de l'interupteur biologique; c'est-à-dire que l'on ne ramène pas à 0% concentration en effecteur l'un ou l'autre des effecteurs allostériques. Ce qui renverse le déterminisme de l'activité enzymatique. L'enzyme allostérique est un relais, qui conbine deux configurations possibles et ne les oppose pas simultanément. La transition allostérique est une illusion biochimique.
Lors de la réplication du HIV; le virus utilise l'inverse transcriptase pour réaliser un brin ADN complémentaire. Ceci va permettre au virus de s'intégrer au génome de la cellule. De là rien n'empèche que ce brin ADN soit lui-même transcrit avant son intégration à l'ADN génomique en réalisant ainsi une production artficielle d'ARN messagers par une polymérase I, qui suivrait l'inverse transcriptase. Ceci va nous permettre de freiner le virus à chaque cycle de sa réplication grâce à un microsystème inverse transcriptase-Polymérase I.
Omission or Invisibility
the Biological Switch
A Virus as a HIV Drug Therapy
10. 12. 2014
It is a great pleasure for me to to talk to you about what we can call the rescue replication of the HIV and the inertia station in Biochemistry. It is one of the greatest event since the discovery of the DNA by Watson and Crick.
It began in 1982 as Paul-Etienne Montandon had the amiability to give me one of the exemplars of his thesis called "Transcription of the Polyoma Virus". I was as a laboratory apprentice very honoured, but I really did not expected what I was ready to read. And the all delivered at the very last experiment on the thesis. This is what we can call scientific communication or collaboration.
But the scientific significance and impact of this thesis on the scientific discourse is difficult to establish; it is a small step for the man, a giant step for mankind.
It demands me 25 years to construct a model based on the results of this very important thesis. The model is now called the Stéphane André Schmutz's model of the Second Infection by HIV-1 and HIV-2 derived virus.
During the last two decades, the deep impact in science by the thesis of Montandon was similar to what happened in the decades after the discovery of the genetic code.
Before I talk on the main subject of this Nobel Lecture let me mention the events that conduct to the model.
The experiments of the Pensylvania University on the recombined virus called vrx496 were made during the construction of the model and the results of these experiments are sensational, this in spite of the fact that they are yet on security trial testing. I mention the pioneer work of Levine and others scientists. Now we have the real necessary tool, which will make us in the ability to do miracles. Let me also notice the excellent work of researchers like Barbara Maria Guarino and Joseph Lamarange.
Since decades we thought that fighting a virus necessarily implicate that we must keep it for replicating itself. I am on the opinion that this time is over and that we yet can admit that fighting a virus like HIV means that we can permit it to replicate itself. But this in a way that is autorised, this in a sense that is without danger for the human. This new way of replication of the virus is now called the rescue replication of the HIV.
The Montandon and Schmutz model is very clear on this procedure. We must induce the lytic pathway of the virus inside the lymphocyte. This with the help of a thread of CD4+ or CD8+ membrane receptors introduced into the cell through the new genetic therapy. The lytic pathway induced, we must reorganize the replication of the virus, which is now acting between the genomic DNA and this thread of membrane receptors.
I define this thread of membrane receptors as the inertial station in Biochemistry. It is a new area in Biochemistry. That inertial station is more than a thread of membrane receptors; it is a new science inside Virology. We could call it the science of the kinetic and lytic pathway inductance inside the lymphocyte or others cells.
These considerations are very importants because we will step by step be able to know how the virus can be forced to replicate in a loop of replication. And we will step by step be able to induce the lytic pathway. This loop of replication will be similar to a loop of an informatic program.
In order to understand such a new science and to discourse with accuracy upon it, what I will do now, we must understand clearly all the regulation systems. Because this inertial station in Biochemistry is of such importance, that we can also discourse rightly upon it inside the regulation systems.
So I will talk to you about the Monod's lactose operon. I think that, without a more appropiate understanding of the regulation, we can not be able of a more appropiate understanding of the subject of this Nobel lecture. Times have changed and we are not so far from finding a new way of replication for dangerous virus, which produce serious illnesses in the mankind.
I think that it is not wrong to consider that we have either a lysogenic or a lytic pathway, but I prefer to think that we have a lysogenic pathway and a lytic pathway; that means; they are conjugate and not mutually exclusive, as it was admitted in 1961 by Jacques Monod, André Lwoff and François Jacob.
But once again the model of the lactose operon is not wrong, but we can still ameliorate it nowadays. In order to do this, we must think now that the allosteric protein is a protein that conjugates two configuration forms and not mutual excludes them. The operon lactose of Monod is issued from a time in which everyone was thinking upon the revolution in the air, that was the computer revolution and everyone thought like a computer machine. That means either one or zero. Anastasoff was the hero of the century. who can pretend, that these people did things wrong. But the lactose operon is based on the mode of thinking, on the mode the people thought at the time.
If we consider the lactose operon of Monod, we do no have the impression of informatic like we know it today, the biological switch makes the operon lactose of Monod and others a heavy thing to deal with. "To switch on the genes, to switch off the genes; excuse me but the all think makes me think of an electric panel!
So we have on one side on of the most important discoveries in Biology, wich will affect all our understanding of Biochemistry and on the other side something very heavy to deal with, which seems more to function with electricity than electronic.
And the questions we are supposed to answer are not easy things, think of the PIP OFF system or others regulatory systems espacially in the case of HIV or others aspects in cancer questions.
We need to review all our regulation systems because of the biological switch and who said that we need absolutely a biological switch to understand our regulation systems.
We are not supposed to make such fondamental error. I said fondamental error because people are dying every day from HIV, from cancers and others very difficult to understand illnesses.
Once again at Monod's time, it was not wrong to say that genes could switch on and switch off, but nowadays it is purely scandalous.
So let me talk to you about this established inertial station in Biochemistry and I will suggest simply to omit the biological switch in the form that we know since decades. In my opinion the biological switch must be omitted or in a way reduced to invisibility, that in order to give more fluidity to our regulation systems and for a better understanding of all the regulation processes in Biochemistry. I think it is the real big step for the man and a giant step for mankind if we could manage without the biological switch, which in my sense seems nowadays inaccurate.
What is suggested in this Nobel lecture is that Monod and others did not do really the passage to the electronic thinking in Biology because at their time the computer machines were very heavy things to deal with and the necessity of a lot of electricity was evident.
So the operon lactose is impressed by the mode of thinking of the time and by the beginning of the computer revolution. The operon lactose can consequently have a very heavy biological switch.
I will try to remediate to these difficulties in proposing a fluidly way of notification of the regulation systems and to realise the needed passage to the electronic pathway in Biochemistry.
The new notification must be written as follows:
INVISIBILITY OF THE BIOLOGICAL SWITCH
OMISSION OF THE BIOLOGICAL SWITCH
In this notification we indicate that we omit the biological switch or reduce it to invisibility in the regulation systems. If there is any trouble with this notification and if we must absolutely show the biological switch, we can make a circle around the plus or the minus. So we indicate that we understand better the regulation systems with a biological switch.
SHOWING THE BIOLOGICAL SWITCH
(ONLY IF REQUIRED)
A: ON in the previous notification(notice that the circle around the minus is indicated just for the convenience of the picture.)
B: OFF in the previous notification (notice that the circle around the plus is indicated just for the convenience of the picture.
Let us imagine chess players who play a particular game, I would call it the game of the regulation systems. So in that particular game, the figures on the chessboard are several aspects of the regulation systems. The chess players play the game and the aim is to discover the mysteries of the regulation. The players begin the game and move the pieces on the chessboard. But instead of thinking of particular strategic plans, they think a lot around the plus and minus notification. And this is the mode of thinking that preludes and remplace the traditional way of playing chess.
They move their chess pieces into different combinations of the plus and minus and if they have samtime difficulties they make circles around pieces on the chessboard and so understand better the regulation game.
You know you can do a lot of things during a chess game, I know somone who asked me if I would not be disturbed if he did his English exercices during I was thinking upon a game move!
My best thanks go to James Watson, Henry Kissinger and Nelson Mandela for their support to this Nobel lecture.
We will make a pause, then I will read the poem the Tyger by William Blake. During the pause I will take a plane and...My heart will go on. Thank You for your attention.
I am born on the first July 1965 at the clinic of Monbriant in Lime of Bottoms in Switzerland. As a coincidence it was the year of the 1965 Nobel Prize of Jacques Monod on the regulation, but at the time I was not really preoccupied by the Nobel Prize. I did not imagine that I would do an important contribution in this field. My father was a Swiss technician and had a wealth in hauses and my mother was a French woman. He trys to awake my interest for Science and Technology. I was a normal student with a great devotion to Marilyn Monroe. I had a great picture of this star on the wall sideways of my bed. My interest for sciences was going stronger later by a beautiful Sciences teacher in the last class of Modern at the Collège des Forges in Lime of Bottoms. Then I decided me for an apprenticeship as a laboratory assistant at the university of Neuchâtel. I had the oppotunity to see the film Alien during a mealtime. It does a very hard impression on me. I do not know if it was simply the film or Sigourney Weaver but I decided to become a scientist. In fact I had always in mind and this since I was very young the inverse RNA interference but it takes me decades to enonce the precise concept. But Alien forced my interest for HIV. On the impulse of my mother I went to the Collège Saint-Charles of Porrentruy to pass a Literature maturity. At the time I interested me very for German language, Artistic Education and Philosophy. But more I read Monod in German language and Traité du Vivant of Jacques Ruffié. But what interested me the most was the double helix of James Watson. I read all about the discovery and the picture of Rosalind Franklin impressed me a lot. I began to image a text constructs on the form of a double helix with the codons introduced inside the text. But it takes me twenty years to publish what at the beginning was just an intuition. Then I came back to the university of Neuchâtel as a student in Biology. During my studies my interest for HIV and inverse RNA interference was going stronger. I learned also a lot upon Biochemistry, Photosynthese and Molecular Biology. I try sometimes to find me a beautiful student but this hopelessly. One of these students falls asleep during I was using all my charms. During my student time I thought much upon the possibility to inhibate the inverse transcriptase by an RNA antisens. And it becomes step by step clear to me that it would create a second chain reaction inside retroviruses. Imagine an RNA antisens that would be positioned on a gen of HIV and produces the inhibition of the enzyme and it would that way also produces a chain reaction that break down all the gens of HIV. I wrote the novels with a DNA structure with the intention to study the invisible DNA. But in this quest I stop at the molecule of ARN poly R(a). Imagine an RNA molecule with the structure in double helix. But in fact the bests are those who make visible this molecule.