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Mr. Chairman, Ladies and Gentleman,
it is a great honour to be talking to you today on behalf of Italian Universities as a
delegate of the President of the Conference of Rectors, Prof. Luciano Modica.
I am aware that the Italian participation to the Genome projects has, for internal reasons,
not been up to its potential level as measured by the extended know-how in the field
existing in our Country. We are however well prepared both in terms of knowledge and
of the necessary equipment for what has been called the “Post genomic era”, made
possible by the deciphering of the human genome and many others both eukaryotic and
prokaryotic.
As I am personally directly involved in the specific area of research I will avoid entering
into a detailed description of ongoing research in our Country which would have
anyway to be too extended to be given here, and will rather try to offer some items of
discussion into the future of this area of interest.
I will start with a few epistemological thoughts which have however in my opinion a
high relevance not only for the future of research itself but also for the outcomes of its
applications to biotechnology and medicine.
I think that the post genomic era is not only characterized by a switch from research
centered on sequencing to a new avenue of “annotation” aimed at the understanding of
the biological meaning of sequences in terms of the proteins coded for and at
distinguishing at the same time between coding and non coding DNA.
The time has come, in my opinion, for another parallel and complementary switch from
a “mechanistic era” to a new one concerning the functional dynamics of gene networks
and thereby of protein and metabolic networks.
This implies, at the epistemological level, a deep change in the very conception of life,
consistent with the extraordinary amount of data on its molecular basis collected but not
yet connected into a new unitary view. It should be noted that up to now the scientific
scene has been dominated by the search of the “qualify” of heritable information carried
through generations by DNA. By quality we simply mean the nature and functions of
proteins coded and the identification of genes involved in the control of specific
characters. From this point of view the rationale used has been the same which brought
Mendel to the discovery of the first “laws” of Genetics, a discipline born on the same
grounds. It may be remembered that the “mendelians”, winners of a harsh fight with the
followers of Galton, had precise and firm ideas about the structure and functions of the
heritable material the principles of which may be summarized as follows :
1) Genes and alleles are discrete elements, randomly and independently distributed
through generations.
2) The phenotype is univocally determined by the genes.
3) A genome is simply the sum of the genes and therefore the phenotype results from
the sum of genetic inputs.
This kind of view has been beautifully commented and supported by E. Schrödinger in
the early forties and has been the basis of the modern version of mendelian thoughts, the
“Central dogma of molecular genetics” proposed by F. Crick in the late fifties.
According to this dogma the information is colinearly transferred from DNA to proteins
which, in turn, will determine the phenotype univocally and in an additive manner.
Following this idea, genome sequencing at its early stages was thought to be a selfsufficient key for the achievement of Schrödinger’s dream, the “total prediction of the
hen’s phenotype through the reading of the genetic information of the egg”.
In later years and particularly after the mid-seventies this conception, although
remaining basically true, has been shown not to be sufficient for the global
interpretation and prediction of life’s dynamical processes, from individual life cycles to
evolution. This has been proven to be particularly true in the case of multicellular
eukaryotes to which we, the humans, belong. The reasons for this conceptual change are
many. First of all genes have been shown to be “ambiguous” in many ways in the sense
that a single sequence may be coding for more than one polypeptide chain because of
alternative transcription initiation, termination.
DNA “plasticity” is also fully supported by the finding that DNA conformation, far from
being only in the standard Watson-Crick model may fall into different minima in a
specific conformational landscape depending from the sequence , DNA interactions with
proteins and the global physico-chemical context.
All these data point out to a structural and regulatory role of the once called “junk
DNA” of increasing relevance along the evolutionary tree.
Regulation of gene action is then of a higher complexty in eukaryotes and seems to be
mainly determined by the complementary “matching” of DNA and proteins
conformational landscapes leading to complexes globally endowed with a higher
information content than DNA itself. Interaction rules of this complexes are being
described and simulated but require for their interpretation non linear equations systems
and sophisticated simulation tools developed by theoretical physicists and by
mathematicians specialised in this area.
Obviously, however, the passage from DNA structure to function is only one of the
steps mediating the transfer of information from sequence to phenotype the remaining
part being based on the dynamic rules of metabolic networks in their hierarchical and
highly connected structure.
The genetic and the metabolic network are strictly connected by a series of signals
coming from metabolism which induce, inhibit or modulate gene expression according
to the homeorrhetic (Waddington) rules of the networks themselves. The final step, from
metabolism to phenotypes is, in turn, strongly affected by exterior signals transferred to
genes through the cytoplasm, activating, inhibiting and modulating response-buffering
batteries of genes specific to different micro and macroenvironmental changes. These
are the reasons why only a small part of the entire genome is acting in each cells (around
7% of the total) and expression quantitative and qualitative patterns also change in
different times in response to the variations of the extracellular environment involving
also intercellular interactions.
All this conceptual framework strongly suggests that on the basis of the data obtained
from genome sequencing, if in the following steps of what is called postgenomics,
interpretation and prediction capacities are to be really improved , research must be
based on the knowledge of the dynamics of qualitative but also quantitative regulation
of life at all levels of the hierarchy of biological organisation. Paradoxically, our
prediction capacity will improve only if we abandon our earlier wholly deterministic
hypothesis for a new one aiming at the better possible level of control of the lack of
prediction known to be typical of biological systems.
In fact wholly predictable living beings would not be able to respond to the
unpredictable nature of context variation both at the extramolecular (particularly in the
case of the DNA-RNA- proteins machinery) and extraindividual levels.
In my opinion such a new vision leads to the need of a really interdisciplinary approach
unifying competences both theoretical and experimental, in mathematics, physics,
chemistry, biology, molecular genetics. Such a network of competences dedicated to the
solution of specific post-genomic problems are to be constructed starting from the
formation and education in contemporary knowledge of the languages of the different
areas and disciplines. A new generation of genome students has to be formed with the
expertise needed for the study of all the steps leading from sequence to phenotype
starting from the modelling and experimental study of specific DNA sequence
conformations, their interactions with proteins, proteins conformations, metabolic
network dynamics, developmental dynamics etc. This can be efficiently carried out only
if we accept the concept of intrinsic unavoidable levels of unpredictability of life history
and from there we start looking at the ways to limit it or to increase it with the aim of
improving plasticity of response. Such a realistic and synthetic view of life should also
open the way to a contemporary look at the effects of human intervention on humans in
biological, bioethical, socioeconomic terms.
I personally think that this way of thinking is fully consistent with European cultural
traditions where the “two cultures” have often been interacting in a positive, synthetic
attitude not afraid but interested in observing and interpreting the “multiversity” of life.
This should give Europe an advantage both in terms of comprehension of the dynamic
nature of heritable information structure, transmission, translation, and of the invention
of new molecular and biotechnological tools and products for human health and quality
of life improvement. The european heritage rich of science and humanistic studies
would then help in reestablishing a dialogue between supporters and opponents of the
new methods and products. Such a dialogue would be based on the conscience of
biological inborn plasticity and unpredictability, the consequent bioethical and
socioeconomic considerations, a new class of not dangerous, environment friendly
products, minds open to constructive criticism. This approach can lead Europe to an
increased competitiveness deriving from contemporary innovative science and
technology and common cultural traditions and restore the self-consciousness of
researchers and their acceptance by the public heavily challenged by the self defensive,
acritical attitude of many scientists and the sometimes irrational, dogmatic behaviour of
the opponents.
Prof. Marcello Buiatti