Perspectives - Vol. 1, No. 2 - Towards An Epigenetic Biology And MedicineRichard C. Strohman, Professor Emeritus, Molecular and Cell Biology, University of California, Berkeley Updated: May 1st 1996 Modern biomedical science has replaced the concept of "organism"
with the that of a survival machine in which life is reduced to the
mechanistic workings of an evolved collection of genes. Our research
establishment is mistakenly dedicated to recreating genomes to reflect
a continuously degraded world. But genomes are actually adaptive and
conserved entities and are highly interactive internally and with the
world. They are difficult to change and their complexity does not
permit linear genetic prediction of health. or diagnosis of disease.
The logic of health and disease resides not in genes alone, but in
holistic, epigenetic regulatory networks in cells and in all organisms
- networks that are coextensive with the external world and which
require for a manifestation of wellness the presence of environments
reflective of our inherited and conserved genetic and epigenetic
capacities. Developments in the life sciences make it clear
that the current genetic paradigm is too limited by mechanistic and
deterministic models to accommodate new perceptions of the organism!
Despite the successes of the currently accepted genetic paradigm in
biomedical science, and the continuing pursuit of applied research
using its models, basic research has revealed conflicts and
inadequacies inherent in the assumptions supporting the paradigm [1].
What emerges from these challenges to concepts of genetic causality is
the beginning of a new biological paradigm, an epigenetic view that
embraces creative characteristics, fusion of genetic with environmental
signals [2] and other aspects beyond currently accepted biomedical
theory. Epigenetic Biology Defined The term
epigenetic has been used in the past to describe organismal development
as a nonlinear, complex process Usually it was used to distinguish
developmental complexity from the theory of 'preformation' which
claimed that the becoming of complex organisms was simply a matter of
growth of tiny preformed bodies In modern form preformation is
recreated in terms of DNA and genetic programs within which
developmental instructions reside. Of course, this version of
preformation based on DNA as the transcendent aspect of information is
also wrong. The new biological paradigm has an epigenetic basis.
Characterized by enormous complexity and by phenotypic (behavior)
possibility of great variability, biological systems actually occupy
many fewer phenotypic states than are possible. Choice is then a
scientific rather than a metaphysical concept observable at all levels
of biological organization [3]. Because functional states evolved by
biological entities (cells, organisms) are adaptive, creative choice
also comes into a scientific focus. 'Choice' is no longer an
anthropomorphic artifact, but an observable phenomenon. Organisms
display enormous fidelity in their developmental and growth patterns.
Memory, therefore, is an important characteristic of living things.
Biological memory, however, differs from memory in physical systems
(computers, other machines) because it does not reside in fixed
predictable locations. Instead, it is distributed throughout dynamical
system which themselves show enormous informational redundancy.
Holistic memory must, therefore, be a primary characteristic of living
systems. Four major features of living systems, down to the
cellular level, are a. creative choice, b. dynamical information
storage or holist) memory, c. non-linear or determinative chaos, and d.
informational redundancy. These features are not currently addressed by
the prevailing biomedical paradigm and consequent!, offer an
opportunity to develop a new paradigm. The epigenetic features
of life described here were formulated by the physicist, Walter
Elsasser [3]. These features do not presently move beyond axioms or
simple observables present in all life forms. They do not represent
mechanisms but rather new starting points for thinking about relations
between form and function. Since these features are not approached by
the present governing paradigm of biology, they also provide a new
opportunity at the level of biological epistemology and make insistent
the need for biological theory that goes beyond reductionism.
What is helpful in developing new approaches to biological systems is
to make clear where our present thinking is, or might be inadequate;
this analysis follows below. Points of Departure between Biomedical Reductionism and Emerging Epigenetic Biology
Currently, biomedical sciences focus on what is predicted to be useful.
Much work is in concert with ongoing basic research into fundamental
aspects of cellular and molecular biology. For example, analysis of
simple diseases with single gene causality is expected to produce new
drugs based on molecular biology of cellular structures, receptors, and
other molecules that mediate cellular function. However, this research
bound by the reductionist model will not address the major human
diseases. Because of the enormous complexity found in the simplest
biological system and the inability of reductionism in general and
determinism in particular to lead to new insights into these complex
systems, the current paradigm fails in the areas shown in Table 1.
These areas are discussed in the following paragraphs. | Table 1. Areas confounding genetic determinism in biomedicine. | | AREA | CONFOUNDING ELEMENTS | | Population Biology | Complex traits not accessible to linear genetic analysis. | | Disease Natural History | Most common diseases are not genetic. | | Evolutionary Biology | No relationship between genetic and morphological complexity. | | Developmental Biology | There are no genetic programs. | | Molecular and Cell Biology | Informational redundancy confounds linear genetics. | Population biology conflicts with genetic determinism
Genetic determinism in current biomedical technology is based on the
general equation of uniqueness between genes and phenotype: Unique
Genes --Unique Effects (unique phenotypes). Under this equation we may assemble the major assumptions of biomedicine as follows: - Genes determine diseases.
- Genes determine aging.
- Genetic analysis provides diagnosis and therapy for disease and aging.
These assumptions underlie the human genome project, the multi-billion
dollar national project to sequence, clone, and map the 100,000 genes
in the 23 pairs of human chromosomes. But fundamental rules
governing population genetics stand in at least partial opposition to
the uniqueness equation and to the assumptions. Essentially, the unique
relationship between genes and phenotypes is flawed because most
complex phenotypes (including diseases) have a unique genetic basis.
Rather the relationship between genome and phenome is characterized by
great complexity involving interaction between many genes, gene
products and environmental signaling. This interaction may involve 10,
100, 1,000 or more genes for any common disease like cancer or the
heart diseases [4] In addition, the interaction will be function of
personal natural history and present environmental setting, so that
even in simplified cases, where genetic connections may be traced, the
genes will have different effects in different environments. Population
genetics shows that a precipitating environment is required to produce
disease manifestation across the entire range of genetic variation
[4,5]. For cardiovascular disease, most cancers, non-insulin-dependent
diabetes, and most mental diseases, there is no evidence for
single-gene causality -- and certainly none that would support the
uniqueness equation. Disease natural history conflicts with
genetic determinism. Diseases determined at fertilization, as Thomas
McKeown [5] has made clear, are based in genetic abnormalities of one
kind or another. Examples are sickle cell anemia, cystic fibrosis, and
Duchenne muscular dystrophy. There are literally thousands of these
diseases, but they occur within the human population at extremely low
frequency and account for less than 2 per cent of our total disease
load. So, only 2 per cent of the time does the 'bad gene causes
disease' mechanism operate, while 98 per cent of the time humans are
born with genetic constitutions capable of supporting a life span of
over 100 years, an average life expectancy of about 85 years, and an
old age relatively free of morbidity [5] The human genome needs to find
itself in an environment for which it has adequate representation -
proper nutrition, housing, and sanitation, to name the obvious
requirements - but the deterministic/mechanistic model of sabotage from
within is not adequate to explain most human diseases. Evolutionary Biology Conflicts with Genetic Determinism
Most people, scientists included, are not aware of problems within
evolutionary biology having to do with genetic mechanisms. These
problems do not provide any weakening of the foundations supporting
evolution; they do provide concern that we may have oversimplified the
idea that evolution is to be explained by genetic mechanisms alone.
Again, this is a complex area but we can state the following. In the
area of evolution, genetic change is seen as one end point of
evolution, and change in genes (mutations) is seen as one element
providing a basis for phenotypic variance that may be acted upon by
natural selection. But gene changes alone will not and cannot explain
evolution. The mechanistic genetic model does not explain how
individual organisms generate their phenotypes in the presence (or
absence) of gene changes in a variety of environmental settings [6].
Individual development is one missing link in our current theory of
evolution, a link that is recognized, and one that the biological
community is now struggling to mend and incorporate into a more
complete picture of natural selection. As an illustration, there is the
absence of relationship between genetic and morphological complexity of
species. Some closely related species cannot be seen by expert
examination to be different (have different morphology), yet they show
great variation in complexity at both genetic and protein sequence
levels. Somehow organisms are able to take vastly different genomes and
construct nearly identical phenomes. This cannot be explained by a
simple linear genetic paradigm. Equally puzzling, humans and chimps
have a very different morphology, yet humans do not differ genetically
from chimps by more than one to two per cent Somehow we are able to
construct very different organisms from very similar genomes; this IS
currently not explained by genetic theory. Developmental Cell and Molecular Biology Conflict with Genetic Determinism
First, genetic determinism for complex traits has assumed the notion of
'gene programs' to help explain the causal linkage between genes and
phenotype. But this assumption has been found to be without
experimental verification. There are no genetic programs [7]. There are
only genes that encode for proteins. Some of these genes, and their
protein products, are extremely important. When they are mutated or
missing, the effects on a complex trait are profound. We have assumed
that these genes control this or that trait, but now we see that these
genes only supply an important protein used by the cell or organism in
constructing a complex trait. Genes, for example, do not control
developmental traits; they only contain information necessary for the
synthesis of proteins used in development -- in the assembly of the
organism. The control for this assembly is not found in the DNA; it is
elsewhere within the cell and it depends on a vast array of information
coming from many sectors of the organism. This control corresponds to
epigenetic regulation. Far from being controlled by simple, linear
genetic causality, development is seen to rely on a complex, non-linear
determinism closer perhaps to chaos theory than it is to genetic
theory. It is, of course, an amalgam of both. Creativity is evident, a
creativity at the cellular level that uses genetic and other
information to construct the organism. This creativity is hidden in the
epigenetic regulatory processes of living cells; a creativity that may
be illuminated by a new biological paradigm capable of going beyond and
encompassing the genetic paradigm. Second, informational
redundancy in organisms, and especially within cells, confounds the
uniqueness equation because more than one gene can bring about the
same. The uniqueness equation completely fails, as there is
informational redundancy not only at the gene level, but at the
epigenetic level as well. There are many examples in the current
literature of experimental biology testifying to the ability of the
organism to get along without what were thought to be crucial genes
[1]. The organism, when a gene is missing, finds other genes or finds
new ways (epigenetic controls) to use vast numbers of remaining genes
to produce the same or highly similar phenotypes [1]. Conclusion
The new biology is discovering important areas of conflict with the
prevailing paradigm of genetic determinism. These discoveries lead us
into new realms of complexity, and we see that obvious characteristics
of life such as purpose, and creative (as distinct from vital) forces
need to be accommodated. An epigenetic paradigm holds possibilities for
recapturing these characteristics within a scientific framework.
Through epigenetic controls or vast networks of genes, gene products,
and environmental signals found in living cells there is an opportunity
for a new understanding. This understanding may augment the idea of
body wisdom. Rather than the need to orient ourselves to a technology
devoted to engineering genes so we can fit imperfectly into a
persistently degraded world, we may come to understand how to
re-engineer the world to reflect the ancient and highly adapted genome
that we humans bring with us as our evolved informational capacity The
genome is well, changes only slowly and with difficulty; the
environment is not well and can be changed to reflect human needs
inseparable from the diverse needs of the planet itself. An epigenetic
paradigm, then, is a goal worthy of our highest priority and one toward
which we have taken the first steps. References
1. STROHMAN, R.C. Ancient Genes, Wise Bodies, Unhealthy People: Limits
of Genetic Thinking in Biology and Medicine'. (1993). Perspectives in
Biology and Medicine, 37 (I), pp.112-144. 2. WOLF, S. & BRUHN, J. G. (1992) The Power of Clan. New Jersey: Transactional Publishers. 3. ELSASSER, W. (1987) Reflections on the Theory of Organisms. Quebec: Orbis Publishing.
4. Wahlsten, D. (1990) 'Insensitivity of the analysis of variance to
heredity-environment interaction'. Behav. and Brain Sci.13 109-161. 5. McKEOWN, I. (1988). The Origins of Human Disease. New York: Basil Blackwell, Inc. 6. Gottlieb, G. (1992). Individual Development and Evolution: The Genesis of Novel Behaviour. Oxford: Oxford University Press. 7. NIJHOUT H. F (1990) 'Metaphors and the Role of Genes in Development'. BioEssays 12 441 446. 8. NEEL, J.V. (1961) a Geneticist looks at Modern Medicine. Harvey Lecture Series. pp. 127-150. New York: Academic Press. This article originally appeared in Network and is republished here with permission. Reference
Strohman, Richard C. (1996). Toward an epigenetic biology & medicine. [Online]. Network. [1996, May 15]. | 
