Regulomics after Genomics: A Challenge for the 21st Century

By Emile Zuckerkandl
Institute of Molecular Medical Sciences
P.O. Box 20452, Stanford, California 94309, USA

Inroads into the field of regulomics are already being made in the name of genomics, proteomics, and functional genomics. Regulomics is constituted by the study of the totality of specific molecular interactions that determine gene expression in any given organism, and includes the topological (circuitry) characteristics of the interaction networks as well as the quantitative variations of their components. The field may indeed merit a name of its own, one that would help place upon it an emphasis commensurate with its central importance for biology and medicine. Vast as it is, and of momentous potential impact, the field cannot be properly developed unless public and private agencies allocate extraordinary means for that purpose. Serious consideration, in the author's opinion, should be given to initiating a Human Regulome Project.

Suggested research areas in regulomics were presented that may be of special promises Problems of basic research include the determination of brachiations in gene deployment programs of extreme and less extreme biological antiquity. This would entail a study of the shape, as a general profile as well as in detail, of the topological features of "fossilized," gene and protein interactions, observed during development and in the adult. Furthermore, an appropriate basis would be available through regulomics for making possible at last a resolution, long elusive, of the problem of homology, a resolution for which an improved theoretical foundation can now be offered. This second problem is not properly handled unless the treatment includes regulomics as a key component above and beyond the traditional comparative studies carried out at higher hierarchical levels of biological integration.

Among medical developments expected in the wake of a Human Regulome Project are the diagnosis and treatment of controller gene diseases (Zuckerkandl, l964). Whereas molecular diseases may be considered to be those that result from alterations in the structure of proteins, controller gene diseases express changes in quantity of proteins without changes in their structure. Regulome maps will be established for health and disease, namely, data bases for networks of regulatory gene and protein interactions, with quantitative features and alternative routes incorporated. Such maps will have many uses and will need to be extensive if scientists and physicians; are to be able to chose the best targets for an intervention. Regulatory therapies will be devised by reference to regulome maps, and pharmaceutical companies will be busy identifying molecules whose specific action will be limited to a particular regulatory target. Software-directed pleiotropy tests could in the future predict specific side effects that an intervention on any individual component of the regulatory system is likely to have.

Some late-onset degenerative diseases may represent controller gene diseases and be brought about by the progressive decrease over a lifetime in the activity of a regulatory factor that was initially present in borderline, but sufficient amounts. Regulomics and corresponding pharmacological endeavours would thus lead to therapies for factor deregulation, including deleterious increases in factor production (or in the Production of their active species). An extended form of this approach would include regulatory therapies for aging. These, unpromisingly, would probably entail multiple highly specific interventions in, various cell types. The molecular therapy of predisposition to disease will be another new medical discipline. One possible application might be a therapy neutralizing the predisposition to alcoholism. Predisposition to disease surely, often has a regulatory component. However, even structural defects in proteins, when they lead to only moderate functional impairments, could be compensated by increases in the expression of the damaged proteins -again a problem for regulomics and a target for regulatory therapies. There may also develop a field around regulatory optimisation treatments. Many individuals may suffer from regulatory indispositions rather than from outright controller gene diseases, and would lead happier lives if their condition could be diagnosed and treated thanks to regulomics and regulatory therapies.

Special attention was given to a particular aspect of regulomics, namely, increases in regulatory complexity that occurred as organisms or parts of organisms became more complex over evolutionary time. The main argument was developed in five stages:

1. A two-step mutational system of regulatory damage and restoration should be applicable to both temporal and spatial functional differentiation. An initial slightly deleterious mutation would spread by neutral drift. (There may be more than one such slightly deleterious mutation in a row.) Full regulatory adequacy would, subsequently, be restored by compensating mutation that, would again, be fixed by drift or, more often, by selection.
2. Such regulatory restoration will, rarely but significantly, be achieved by the addition of a further factor to a regulatory complex of factors and cofactors.
3. Because of the probable sharing of additional factor with factor systems that are in charge of the expression of other genes, the increase in factor complexity targeted to the gene under consideration represents an increase in gene interaction complexity.
4. As a result of increased gene interaction complexity, there is an expected increase in deleterious pleiotropy of mutations and an expected correlated decrease in the organism's adaptability.
5. This is an obstacle to further increases in complexity and, thus, to further evolution in the direction of higher organisms. The obstacle can be, and was, removed during evolution by the multiplication of cell types. These represent varied barriers to otherwise freely intercommunicating molecular signals and signal receptors. Such barriers ensure that complexity in organisms is compartmentalized, namely, that high degrees of complexity are contained, as it were, in complexity compartments. In such compartments, complexity in gene/protein and protein/protein interactions can increase relatively independently from the status of complexity in other parts of' the organism. Thus, the complexity in the functions and performances of organs and systems (such as the central nervous system) can continue to increase. When it becomes too high, the complexity compartment might bud off a further compartment in the guise of the development of a new cell type; for example, through the establishment of DNA sequences required for sectorial repression around a gene for a master transcriptional activator (master in the sense of commanding a subprogram of gene deployment).

It can be expected, that the processes sketched out will be testable and made more concrete by the study of gene and protein interactions subsumed under the term of regulomics, and that further investigations will reach into the evolutionary process of growth in gene interaction complexity, the silencing of regulatory genes during development, and the evolution of such developmental silencing.