(Les Di@logues Stratégiques® N°54 – 05/05)

In his latest book « Neither God nor gene. For a new heredity theory »(1), the biologist Jean-Jacques Kupiec popularised his research on embryogenesis (2) to the general public and the scientific community. Five years later, the researcher has refined his theory about « random selection » (or Darwinian theory) thanks to computer processing simulation. His work leads to an unexpected track: a new approach that helps understand cancer formation in a new way.

Véronique Anger : Could you explain in simple terms what embryogenesis is?
Jean-Jacques Kupiec : Among mammals, there exists a multiplication process which generates billions of cells from a germinal cell (the fertilized egg). Among this important population of cells, specializations are created: the cells that are all genetically identical do not all have the same functions. For example, a blood cell will not do the same thing as a cell in the nervous system, the skin or a muscle. We say that cells « do not express the same genes ». In other terms, over all the genes that all cells possess, only a small number of genes will be active in these cells. These genes will then make proteins that will enable cells to exercise their properties. For example, a blood cell will make a protein (globin) that is necessary for red corpuscles to carry oxygen. A cell from the nervous system will engender a protein (myelin) that is necessary to make nerve fibres.

VA : What difference has computer simulation made compared to standard experimental method?
JJK : The basis of the experimental method is to make experiments on real objects. Computer simulation is a form of experimentation of a new kind. It enables to virtually reproduce a natural process in order to study it. Thus, you can create virtual cells and make them behave according to certain laws: For example, in order to control or test hypothesis concerning « the random selection » model (Darwinian model of cellular differentiation). The environment is mastered and the parameters controlled. The purpose is to better figure out the rules that prevail in cells behaviour, especially concerning the different stages of embryogenesis, a process that leads to an adult organism, via a multitude of interactions between tissues. Computer programs (3) mime, create cells that behave according to the Darwinian laws of random selection. Thanks to these models, we have completed the creation of organized tissues.
We have also brought to the fore unexpected properties that are very important because they lead to a new vision of cancer. We have realized that cells stopped proliferating spontaneously whereas the program did not contain any instruction specifying that cells should stop multiplying. This observation is fundamental: it means that the system evolves spontaneously towards a stage of equilibrium and that it stops developing as soon as it reaches that stage. ( see the article signed with Bertrand Laforge, David Guez et Michael Martinez(4) « Modeling embryogenesis and cancer : an approach based on an equilibrium between the autostabilization of stochastic gene expression and the interdependence of cells for proliferation » in « Progress in Biophysics and Molecular Biology »).

VA : Does this new theory of embryonic development have effective consequences to understand a disease such as cancer? Can you tell us more about this?
JJK : Our vision is completely different from the classic vision of the control of cellular proliferation by the genetic program, according to which signals tell the cell « become a neuron » or « multiply » or « stop multiplying ». We have been searching those signals since the 1960’s. When the first cancer gene was isolated in 1976, we thought we had discovered the specific signal commanding the cell to stop growing or, on the opposite, to develop. Instead of that, we found phosphorylation enzymes that are the most common enzymes of the metabolism. Since then, we found many genes, but we have not succeeded in discovering their specificity as signal.
Our model does not require specific signals. The stage of equilibrium depends on the quantitative values of the parameters and not on qualitative signals dictating or commanding cells behaviour. Thanks to simulation, we have been able to demonstrate that if we modify one quantitative parameter (by modifying the properties of a protein for example) in order to slightly disrupt the equilibrium that was reached, we can observe the break out of tumours and cancers. (cf. figures in the article  » le darwinisme cellulaire: une nouvelle théorie de l’embryogenèse et du cancer « )
This model is not in contradiction with what we experimentally know. It is a new conception of the carcinogenesis phenomenon.

VA : In what way does your model keep away from determinist models?
JJK : The theories that have been put forward to explain embryogenesis have always been determinist ones, such as the recent theory of the genetic program. Cells receive orders via signals conveyed by proteins, molecules. In response to these signals, cells are constrained to fulfill a precise mission. To make it simple, we can say that when a cell receives the signal « become a blood cell », it becomes a blood cell; when it receives the signal « become a nerve cell », it becomes a neuron, and so on…
We consider that this signal is encoded in a gene. The development would thus be the result of the activation of regulation genes emitting signals. That is what we call the « genetic program ». It is a rigorously determinist phenomenon since the setting up of the program composed of signals encoded in genes would entirely command the destiny of the cells. In my opinion, this theory cannot function, and, nowadays, more and more arguments tend to prove it.
In 1981, I suggested a model reintroducing randomness in the functioning of cells. To simplify, rather than stating that cells receive signals commanding something in the gene expression (which makes a gene be active or not, produce a protein or not), I introduced some sort of « molecular lottery », linked to the fact that cells move according to Brownian randomness (5). I use the word randomness, but I should speak of stochastic mechanism (6). Here, « randomness » does not imply a lack of cause or non-reproducibility. I use it in the sense of statistical theory: a probability phenomenon, whose result you can statistically plan, thanks to the « law of large numbers ». By the interplay of randomness (that takes place at the genome level), some cells will start making proteins that are necessary to the making of blood cells, and others will make proteins that are necessary to the making of nerve cells (neurons). In this probability theory, cellular interactions (we say there is an interaction between cells when a signal passes on from one cell to the other) stabilize this lottery corresponding to the activation of genes once (thanks to the interplay of randomness) the right combination of cells necessary to create a functional person has been produced. So the regulation happens afterwards. In the « genetic program » theory, interactions between cells imply the changes of the cell state; in my model, cells randomly change state and cellular interactions stabilize afterwards what was randomly obtained. It is an entirely different logic.
Today, the stochastic gene expression is an unquestionable experimental fact. It has been the subject of many articles published in great journals such as « Nature ». However, the supporters of determinism qualify the role played by this stochastic phenomenon and consider it as a marginal background noise. The fact of introducing randomness in the functioning of genes breaks with traditional embryogenesis theories and genetic theory that are completely deterministic. Yet, it is obvious that a probability mechanism (which, by definition, generates adaptability, flexibility and diversity) is useful to a biological system. Why would these cells not use it.

VA : How did your colleagues react to the publication of your latest results? Has this new discovery convinced the more sceptical ones?
JJK : We were not expecting the results to be so spectacular and swift. Our researches were published on the 23rd of December on the website of the review « progress in Biophysics and Molecular Biology ». It is too soon to anticipate my colleagues’ reaction. I wish to be more specific about the fact that a model is a simplification of reality that enables to understand. We still need to adapt this logic to a concrete situation, which implies a collaboration with cancerologist-experimenters. I doubt this will happen soon but I think our experiment leads to new perspectives for research.

VA : As you mention it in an interview that you gave to the website « Vivant » with the physicist Bertrand Laforge from the LPNHE, your research is the result of an interdisciplinary work in biology and physics. You regret the lack of financial and institutional support granted to your researches. How do you explain this lack of interest for the crossing of researches?
JJK : I hope this option will be seriously taken into account. It was not the case in 1981 when I first made the hypothesis of the stochastic gene expression. Americans are currently publishing on the subject. It would be mind-blowing if those discoveries (initiated in France) came back to us from the USA with everyone being ecstatic. In the USA, interdisciplinary researches -that we call biology of systems- that combine computer simulation with experimentation are developing very quickly. We should not lag behind.

VA : What is the next step?
JJK : Many years ago, I suggested a model of stochastic gene expression . We are going to carry out a computer simulation by introducing a simulation program in the current model. We will have a cell in which a DNA will express itself in a stochastic way. It will be a two-level-model: a molecular level and a cellular one. Thus, we will be able to observe if what happens on the molecular level has any impact on the cellular level and vice versa.
We would also like to experimentally test the stochastic gene expression. For that purpose, we need financial support. If we want to remain competitive, we need more means: experimental research is far more expensive than theoretical one.

*Jean-Jacques Kupiec a biologist and a researcher (INSERM, Centre Cavaillès de l’Ecole Normale Supérieure Paris. France).

(1) « Ni dieu, ni gène. Pour une autre théorie de l’hérédité » (Editions du Seuil. 2000)
(2) Embryogenesis : formation and development of an animal or plant organism from the embryo stage to the birth. We define an embryo as the organism developing from the egg (resulting from the fertilization of the ovum by the spermatozoon) to the form capable of autonomous life. We call foetus the human embryo that is over 3 months old. Jean-Jacques Kupiec presented his research for the first time in 1981, within the context of a congress in France
(3) The programs are developed in langage C++, under Linux operating system
(4) Bertrand Laforge teaches at the university Pierre et Marie Curie (nuclear physics and high energies lab (LPNHE), CNRS/IN2P3, université Paris VI et VII). David Guez (nuclear physics and high energies lab, université Paris VI- Pierre et Marie Curie). Michael Martinez (nuclear physics and high energies lab, université Paris VI- Pierre et Marie Curie). For more info, see the press release INSERM/CNRS
(5) Randomness, or Brownian movement (stochastic movement): the phenomenon was observed in 1827 by the British botanist Robert Brown. In 1905, Einstein quantitatively explained the Brownian movement by applying the law of large numbers (if you repeat a certain amount of times one random experiment whose result is a numerical value, the average of the results thus obtained tends to get closer to the mathematical expectancy of the experiment). More info onhttp://ivan.boyer.free.fr/IE/TPE2004.htm and http://membres.lycos.fr/villemingerard/Probabil/GdNombre.htm
(6) Random : that can be studied with probabilities

We also recommand:
A recent interview with Jean-Jacques Kupiec, and the physicist Bertrand Laforge sur le site « Vivant, l’actualité des sciences et débats sur le vivant » :
Darwinisme cellulaire : une nouvelle théorie de l’embryogenèse et du cancer (février 05)
Roger Guillemin, la recherche sans confort (Le Monde édition abonnés du 05.05.05)
Recherche fondamentale : le gouvernement fait fausse route (signé Yves Coppens, Gérard Fussman, Axel Kahn, Jean-Claude Pecker, Gabriele Veneziano, Jean-Pierre Vernant, Hubert Reeves. Le Monde du 04.04.05)
L’Amérique se construit un quasi-monopole dans les biotechnologies (Le Monde édition abonnés du 22.04.05)
Le CNRS cherche, dans la douleur, à se réformer (Le Monde édition abonnés du 22.04.05)
BIOTECHNOLOGIE : Les entreprises européennes à la traîne (Courrier International du 24/06/05)
Les Américains garderont ils le leadership dans les nanotechnologies ? (Jean-Michel Billaut pour AgoraVox. 05/07/05)

To go further:

About the human genome: http://www.genoscope.cns.fr/externe/Francais/Questions/
« L’homme et les gènes » (Man and genes) – Cité des Sciences : http://www.cite-sciences.fr/francais/ala_cite/expo/tempo/defis/homgen/index.htm
Also : http://www.cite-sciences.fr/francais/ala_cite/expo/tempo/defis/encyclobio/index.htm
and « L’Université de tous les savoirs » : http://www.canal-u.education.fr andhttp://www.lacinquieme.fr/concepts/W00081/7/26386.cfm
The web site Futura Sciences