In recent years, genetics has become a cutting-edge science, not only in the professional field of biology, but also because of the enormous social reach of its discoveries and approaches. Not in vain, practically every day the press offers us the discovery of a new gene, a new hereditary determinant directly involved in the manifestation of diseases or physical characteristics.
Cancer and Parkinson's, height and obesity, longevity, etc. All this has a strong genetic base that is reduced to one or a few genes. But, in addition to physical characteristics, a large number of genes have also been described that entail an innate predisposition to develop behaviors as complex as alcoholism, sexual preferences, aggression, religious feeling and even driving skills. The reach of genes does not seem to have a limit, and although the social and natural environment is recognized as an important trigger, it is genetics that ultimately establishes the limits of what we are and what we can be. The concept of gene, therefore, seems that not only has a scientific importance, but has permeated in popular culture to become a topic of relevance and interest.
By Daniel Heredia Doval
Originally published in:
Naturist Medicine, ISSN 1576-3080, Vol. 6, No. 1, 2012, 42-49
But, what exactly is a gene?
Genes, in short, are considered as the minimum units and the final depositaries of biological information that, mediating with the deviations of the physical and social environment, determine the identity of each organism. Like any unit of scientific character, the gene must be able to be described in a clear, unequivocal and universal way. In this sense, a gene can be recognized as a nucleotide sequence, a small fraction of the DNA that comprises the entire genome, capable of expressing itself functionally through a linear and causal chain that ends with the production of a protein (or sometimes of some types of RNA) that acts directly in the development of a certain biological character. On these bases, a series of genetic postulates are erected, which I have summarized in the following points: 1) DNA constitutes the ultimate material basis of all biological information; 2) genes are defined and discrete units of genetic information; 3) genetics underlies all aspects of organic form and function; 4) genetic information is expressed linearly through the Central Dogma of Molecular Biology; 5) changes in genes (mutations) occur randomly and individually; 6) mutations and natural selection are the engines of evolution; 7) only characters with a genetic basis are certainly hereditary, while 8) characteristics acquired during the life of the organism in response to the environment do not persist beyond the stimulus and consequently are not inheritable. This conception of genes as discrete packages of linear and deterministic information is what prevails in the media and in society. But it is also the one that still guides a good part of the scientific and teaching community. However, this vision, anchored in the origins of the genetics of the early twentieth century, which established a linear chain between gene, protein and character, is not universally accepted. On the contrary, some of the latest advances in genetics lead us to a totally different path, a reality that is emerging within some areas of biology and that challenges the logic admitted until now.
Genetic information and the nature of the gene
One of the great revolutions of modern science has been to discover the enormous complexity that compromises genetic information. Once the challenge of sequencing the human genome was overcome, our complete inability to interpret the instructions contained in our DNA became clear. Today, thanks to the effort made over the last decade, it seems impossible to maintain much of the assumptions of classical genetics, which were practically indisputable only ten years ago. Classical genetics has been literally demolished, and the concept of gene has become so labile, so changeable and flexible, that it can hardly be recognized as a unit of scientific character. First, the number of "genes" contained in the genomes constitutes a minority fraction of the total DNA (about 2% in humans), and the number of them does not seem to have a direct correlation with the final complexity of the organisms. In fact, while humans have about 25,000 of these sequences capable of coding proteins, other animals such as anemones have 18,000 and some plants like rice more than 37,000. Hardly a unit of information can not be directly involved in complexity. These asymmetries are due in part to the different degrees of regulation and alternative expression that the coding sequences of each organism have. Far from the linear and causal chain that the dogma of molecular biology describes, the same coding DNA sequence (a "gene") can give rise to different end products. By using different mechanisms (such as splicing and alternative adenylation, editing, or the use of different promoters), the same "gene" can lead to a large number of alternative proteins (up to 38,000 in the extravagant case of the gene "Dscam" of the fruit fly), that are produced in response to the cellular requirements imposed by the environment and the life cycle of the organism. This phenomenon, which seems to be ubiquitous in animals and plants, affects practically all of the human "genes". Consequently, the same sequence can be read differently depending on the cellular and environmental context, and allows a different expression depending on the tissue and the moment of development. The linear and causal relationship between gene and protein is not sustainable any longer. On the other hand, the physical identity of genes does not have defined limits or a concrete structure either. A single physical fragment of DNA (a locus) can harbor several overlapping sequences, either in the same sense of reading or in opposite directions, while two or more fragments of the "gene" can be located at distant points on the chromosome, requiring of a trans-splacing process for its functional expression. But perhaps the most surprising thing about the vagueness of the concept of gene as a unit of genetic information is that it only includes a small portion of all DNA with expression. In fact, according to the preliminary report of the ENCODE Project, whose objective is to analyze at maximum resolution the expression of the information contained in the genome, practically all of the analyzed human DNA is transcribed to some type of RNA, the majority with function to be determined. In recent years, the idea that RNA (a molecule complementary to DNA that is synthesized to develop the functions conserved in the first one) has become the centerpiece of genetic information. It is well known that RNA serves as an intermediary in the production of proteins, participating both as a transcription of the messages that encode genetic information and in the manufacture of proteins within the translation machinery. What is really new is that, in addition to developing these fundamental tasks, non-coding RNAs (that is, their final function is not the production of proteins) participate massively in the regulation of genetic information through mechanisms such as RNA interference. (RNAi). Most sequences that produce some type of RNA (such as miRNA, siRNA, piRNA, and a long etc.) but do not code for proteins, are not considered as genes. This situation is a real blow to the generalized definition of the gene as a delimited unit of information, and has even led some scientists to ask a question that is as provocative as it is fundamental at this point. What is a gene? Is it something, after all? In view of the above, what we can ensure is that there is a complex genetic information contained in our genomes, as well as that this is not of a linear and standardized nature. And if this is so, the gene is a historical and methodological artifact, and the constructions erected around it are little more than a myth.
To make matters more complicated, the regulation and expression of genetic information is not left alone in the step that goes from the DNA sequence to the product that it encodes. Above, there is a level of epigenetic information that, especially by means of chemical marks on the chromosomes, is able to stabilize the genetic expression in a semi-autonomous manner depending on the environment. These epigenetic marks can completely alter the expression of genetic information and give a different result to that predicted by conventional genetics. We will come back to this subject later. In addition, at a cellular level, there is a truss of interaction networks between proteins, RNA, DNA and other biomolecules that participate as an integrated whole and in coherence with the environment, which ultimately manifest themselves in the production of a character. These networks exhibit non-linear behaviors, such as modularity and robustness, which condition a functional hierarchy within it. Consequently, variations within one of the components of the network (as a result, for example, of a mutation) can have different effects depending on the global context. And on the other hand, the same sequence can participate alternatively in several cellular networks. In summary, there are no simple rules that describe the effects of genetic variations regardless of the circumstances, but rather that each sequence of information has an effect that is conditioned both by the global genetic context and by the circumstances of the environment. Thus, it is difficult to establish a causality as direct as that presented by the news about genetics, as well as by some studies and lines of research.
The information loop between organism and environment
As revealing as the emptiness of linear and deterministic genetics, is the emerging notion of the capital importance of the environment in the construction and inheritance of organisms, including human beings. The environment, from a biological point of view, is made up of all those elements, whether they are living (other organisms) or inert (relief, climatology, temperature, pressure, etc.), with which an individual interacts. From the traditional point of view, the environment diffuses to a certain extent the information contained in DNA and has direct effects on the construction of organisms. However, the relationship between genetic information and information contained in the medium has been considered unidirectional since the rise of genetics in the mid-twentieth century. The inheritance of characters acquired during the life of organisms, in response to environmental conditions, has been dismissed for more than half a century by biology. However, this idea (commonly associated with the first theory of evolution, proposed by Lamarck) is reborn with strength within some specialties of the group of biologists. The epigenetic inheritance, the horizontal transfer and the integration of DNA fragments from other organisms, the acquisition of symbionts, and the recognition of mechanisms of genetic change in response to the altered conditions of the environment recover a leading role for the environment and generate a double-direction arrow between genetic information and signals from the environment. In this sense, the current rise of epigenetics has much to say. Epigenetics emerges as a level of interaction between the information of the genome and that of the external environment, as an interface of molecular mechanisms sensitive to the environment that can interact with DNA in a relatively autonomous way. Specifically, chemical labels (methyl, ethyl groups, etc.) that are selectively added to DNA and histones are one of the most relevant epigenetic mechanisms at present. These marks are capable of regulating the expression of genetic sequences, activating or deactivating them without modifying their content. This epigenetic regulation intervenes to a large extent in the development and differentiation of cell types. It should be remembered that while all cells in the body contain the same genetic information (except for notable exceptions), the shape and function of a retinal cell is very different from the kidney cell. Epigenetic marks stabilize patterns of expression depending on the context of embryonic development. But these chemical labels are also modified depending on environmental conditions, especially through nutrition and stress, altering cellular networks and stabilizing complex characters during the lives of individuals. But most interesting of all is that at least part of the new brands, established during life in response to the environment, are heritable and manifest in the offspring for several generations. In this way, the conditions of life and the history of individuals come to have a hereditary relevance. Our habits and circumstances condition the future life of our descendants. In fact, conditions such as extreme malnutrition, exposure to drugs, plastics and toxic substances, habits such as smoking, as well as the consumption of certain foods seem to be able to modify the epigenome (the set of epigenetic marks superimposed on the genome) and establish new regulatory states that are transmitted to offspring and that could be behind some diseases such as obesity or cancer. Even psychological stress seems to have behavioral consequences that can be transmitted to offspring through epigenetic marks. In addition to this epigenetics of chemical brands, there are other mechanisms that allow the inheritance of acquired characters without a strictly genetic basis.
Direct interaction with the environment can establish the parameters in which embryonic development occurs. During pregnancy in mammals, mothers can influence through the diet and their hormones through the placenta in the formation of their offspring. These maternal effects occur throughout the animal and plant kingdom, either during the formation of gametes or embryos. In fact, the environment is a fundamental part during the development of all organisms, establishing the physical-chemical and biological parameters necessary for this process. Changes in temperature, pH, pressure or in severity have an impact on developing individuals. In many cases, the physical information of the environment is necessary for the establishment of sex and other discrete characteristics. But the environment is also biological. It is increasingly evident that a fundamental part of the information necessary for the construction of organisms is not codified within them, but is provided by symbiotic microorganisms. Bacteria, fungi and viruses, inherited or acquired at an early age, participate in the formation of tissues and organs, in metabolism and even influence brain behavior and biochemistry. Finally, the environment can also directly affect the composition of genomes and the functions of genetic information. First, by acquiring DNA from other organisms. This is possible through the phenomenon of horizontal transfer, a phenomenon that seems to have had a major importance in evolution, by which DNA fragments of an organism (including viruses) can be transferred integral into the genome of other individuals of the same or different species through specialized mechanisms and viral infections. Secondly, by means of the implementation of mechanisms of evolutionary potentiation (such as transposition of mobile elements and endogenous viruses, release of silenced mutations, hypermutation processes, etc.) by which generalized or specific genetic changes are produced as a consequence of a strong stimulation of the environment. The environment is therefore a fundamental component in the regulation, expression and evolution of biological information.
Theoretical and practical implications
Under this scenario, the myth of the gene vanishes. It makes no sense to talk about specific genes of a character, nor about the inheritance and deterministic expression of genetic information. There is no cause-effect linearity, and speaking of a "genetic predisposition" is only possible if the variability of the global, internal and external context, where the genetic information is expressed, is ignored. Something that, on the other hand, happens constantly. On the contrary, what we find is a loop of information between the organism and the environment, a series of complex interactions between the genome, the epigenome and the environment that flow in a constant manner and in a bidirectional sense. And this change of perspective has severe repercussions on theoretical biology, but also on the ethics and practice of applied research. Basic sciences such as evolutionary biology, which acts as scaffolding for the rest of the disciplines, are deeply anchored in the classical genetics of discrete and deterministic inheritance. The modern or neo-Darwinian synthesis is based on the spontaneous, random and independent appearance of genetic mutations in the environment, which introduce a variability within the populations that is sifted by natural selection. However, the revalidation of the inheritance of acquired characters (via epigenetic and maternal effects) and the phenomena of evolutionary potentiation (via induced mutagenesis and transposition, etc.) add a neo-Lamarckist tinge to evolution, hardly compatible with neo-Darwinism. Neither does the evidence of a major relevance of environmental information in the construction of organisms help maintain a good degree of genetic determinism, which is necessary for natural selection to have some long-term effect. Finally, the strong evidence in favor of horizontal transfer, hybridization, and the integration of viruses and bacteria have perhaps been the most fundamental phenomena in organic evolution, makes it necessary to replace the classical silhouette from the tree of Darwinian life through a web where vertical and horizontal inheritance are elegantly intermingled. At this point, it seems necessary to rethink the basis of biology and direct the view towards alternative approaches such as those proposed by Máximo Sandín.
The theoretical approaches have applied consequences, and the implementation of the principles of an inadequate or erroneous theory can have catastrophic effects. This is true for all sciences, but the case of genetics carries certain added health and social dangers. Such is the case of some of the most ambitious research lines within biology, whose ultimate goal is to alter and control the genetics of organisms at will (through genetic engineering) for their use and consumption in humans. Such is the case of the production of transgenic foods and the new biotechnological eugenics.
Intimately related to the neo-Darwinian approaches are the eugenics programs developed over the past century and whose influence seems to be present in a more subtle, renewed way. Eugenics proposes that it is possible to direct the evolution of the human species through demographic control policies that would supplant the action of natural selection, now diluted by the social behaviors of our species. Eugenics believes that it is possible to eliminate the unwanted traits of humanity (including diseases and antisocial behavior) through the reproductive impediment of individuals with these characteristics and the promotion of arranged marriages. The key idea is to eliminate the genes responsible for these characters, the ultimate root of the problem, of human populations. To this end, policies of isolation, castration, sterilization and extermination over subjectively selected individuals and social groups were applied throughout the last century, a heartbreaking testimony to the violation of the most basic human rights under the protection of neo-Darwinism and population genetics. At least in regard to the Western world, this type of eugenic practices were falling from grace since the end of the Second World War, but new lines of research have taken up the final goal of eugenics (a genetic reconduction of our species), in a way that is frankly more subtle, although no less questionable in its ethics and foundations. The mere fact of trying to establish a strong genetic basis for complex characters and behaviors can lend a hand towards social discrimination, racism and xenophobia, as well as establishing the bases for questionable businesses based on personalized genetics (both at the biosanitary level and at the legislative). But even more worrisome are the hopes placed on genetic counseling (which would allow reproductive decisions to be made before and after conception based on a genetic profile of the future parents and / or the fetus), and even more in cutting-edge technologies such as gene therapy under the auspices of the latter, human genomes can be altered in a near future to replace "defective genes" and introduce "new genes" with a specific goal, such as enhancing longevity, intelligence and productivity. Once again we are faced with a debate on the ethics and subjectivity of eugenics. But even more disturbing is the realization of how these approaches dangerously ignore the complexity inside and outside the genomes, the epigenetic patterns and the environment organ loop. In fact, all genetic engineering is based on a series of classical premises that are unsustainable today. The technology of recombinant DNA consists of isolating a "gene" with a known function in a species, and introducing it by means of vectors (usually biological) into a different one. In the process, supplementary DNA fragments (such as antibiotic resistance sequences) are introduced that have nothing to do with the function to be transferred. Regardless of the questionable innocuousness of the technological procedures to which organisms, vectors and genetic material are subjected, the fact is that the theoretical bases of genetic engineering tend to ignore completely the genomic, epigenetic and environmental context of the organisms with which it works. It is not surprising, therefore, the high number of failed experiments that occur during the creation of genetically modified lines. However, even in those individuals where the desired character seems to have been achieved, researchers can not know with certainty how the addition of new information may affect other genetic networks, and therefore, what side effects may have been suffered by this organism. And this is roughly the procedure that is expected to be tested and applied in humans in the near future. Neither in the case of genetically modified organisms (GMOs) for human consumption, the so-called transgenic foods, these considerations suppose a trivial question. There are many independent studies that have pointed out possible pathological side effects derived from the consumption of these foods, as well as the request of various scientific groups and citizens for an exhaustive control of these products whose production is increasing. In addition to the health risks, the use of genetic engineering ignores other possible harmful effects derived from the ignorance of the complexity of biological information and its evolutionary dynamics. There are proven ecological consequences in the production of transgenic crops. The artificially introduced sequences in the GMO pollute the natural varieties through sex and horizontal transfer, and in addition, these sequences persist throughout the trophic networks with the risk of being assimilated by other species under unknown consequences.
To conclude, I would like to highlight how the lack of consideration of the environment as an integral element of biological information remains a problem to be taken into account in other areas, and specifically in the biosanitary practice. The race for production and patenting within the pharmaceutical industry tends to ignore the long-term scope of new drugs, and in view of the inertia of epigenetic brands, it is necessary to take into account the susceptibility not only of the patient, but also of their direct descendants. This adds a whole new dimension to date not contemplated for both the medical and food industry. Given that some drugs, as well as plastics and other toxic substances, can have epigenetic consequences, the transgenerational effects of consumer products must be seriously reconsidered. In view of this change of focus, from the gene to the sensitive and reactive organism, it is necessary to reconsider the security of all these applied practices of great social repercussion.
Every society has its myths. Our modern society is no exception and perhaps one of the most widespread, accepted and assimilated scientific myths is the myth of the gene. The existence of information delimited in the form of discrete and independent microscopic packets, which is innate and inherited, which largely predetermines the destiny of each one of us and explains the roots of the general behaviors of humanity and individuals of each individual. This is the myth of the gene. A myth that, like everything else, completes the gaps of reality through cultural artifacts that satisfy a large part of society and, on occasion, favor some collectives that feed on this myth. And the emptiness of myth is now more evident than ever. Contrary to the claims of James Watson and many later geneticists, our destiny is not in our genes. Biological information is much more than genetic information, and of course, genetic information is much more than a long series of bounded units, of genes arranged continuously along chromosomes. Far from the Cartesian machines described by classical genetics, we are the result of a dialogue, a loop, an elegant dance between the information we inherit from our parents and the information we incorporate from the environment, the complex interaction between molecules and signals physical, of the particular and general circumstances of our immediate environment, of the relationship with the infinity of microorganisms that live inside and outside of us forming a good part of our identity, of the web of interactions that we establish with our peers, of our acts and decisions, those that define us as subjects more than any gene there have been or will be.
The author is DANIEL HEREDIA DOVAL
The choice of the city of Helsinki is not incidental as the capital of Finland had hosted US-Soviet negotiations on the limitation of nuclear stockpiles in 1969