THE CENTURY OF THE GENE. MOLECULAR BIOLOGY.

In the twentieth century, human society has built massive technological development. For much of the century the greatest technological contributions have come from the derivatives of the physical sciences: automobiles, telephones, airplanes, plastics, computers, etc. The introduction of these factors has changed society and human rather than political and social developments own behavior. However, during the second half of the twentieth century, and especially in the last two decades, have appeared a biological technologies have enormous medical and social potential. These new technologies, extraordinarily powerful, are those derived from the explosive progress of molecular biology in the second half of the twentieth century. Offer a new image of the evolution of life on the planet and are destined to revolutionize the structure of human society.

Perhaps the person who has most lucidly delved into these ideas has been Sydney Brenner, one of the most brilliant scientists of the twentieth century will go down in history of science for their enormous contributions to molecular biology, science instrumental in creating. Brenner says that the new biology brings us closer to an understanding of ourselves, the understanding of humans as organisms: "For the first time can raise the fundamental problem of man and begin to understand our evolution, our history, our culture and biology a whole “.

In this presentation I will discuss the history of scientific developments that have led to this situation and speculate briefly about the implications of these new discoveries in the future society, and even in our own understanding of human nature.

The milestones of biological knowledge

Throughout the history of biology have been three great revolutions, understanding the revolution concept as the introduction of a discovery that is important in itself and also leads to a radical change in approach which until then was given to discipline. It is not only the significance of the new information but also the effect it has on the general approach to discipline.

The first revolution occurred in 1860 with evolutionary theories of Darwin and Wallace, who defended the universality of the origin of living things. The second revolution was the discovery of the universality of the mechanism of biological information given by Watson and Crick in 1953. The third revolution was the discovery of the universality of animal design and basic regulatory processes of biological functions. This latest revolution has happened between the years 1985-2000 of the last century and, unlike the previous ones, is the result of contributions from a relatively large group of researchers. These three facts have led to a new understanding of the evolutionary phenomenon and the biology of humans.

The evolutionary fact

The idea that species change over time is very old and certainly before the Darwinian proposal. In the year 520 ANE, Anaximander of Miletus, in his treatise On Nature, introduced the idea of evolution and that life began in the oceans. John Ray in his book Historia Plantarum, published in 1686, cataloged 18,600 types of plants and proposed the first definition of species based on common descent. Darwin's own grandfather, Erasmus Darwin, explicitly proposed that animal species change over time.

What sets Darwin and Wallace from its predecessors is that proposed a plausible evolutionary mechanism based on the idea of natural selection. Darwin, in particular, proposed that the survival of particularly favored individuals was the force of natural selection as its increased survivability them also endowed with a greater capacity to transmit their characteristics to their offspring. Through this process the characteristics of the populations of individual species gradually modified through successive generations.

Darwin plus information provided that their predecessors did not know and it helped a lot in understanding the evolutionary phenomenon. For example, it was known that the age of the Earth was much older than previously assumed, which gave more time for gradual change advocated the theory of natural selection. Also there was a very elaborate and allowing fossil record check for a gradual change in many lines of animals and plants, which clearly supported Darwin's proposal. It was also known that artificial selection is capable of generating very profound morphological changes in a short time. This is evident, for example, with the large number of breeds of dogs world. All derive from the wolf, but through 5,000 or 10,000 years of evolution artificial, not natural, man has created a wide variety of breeds, indicating to what extent is versatile biological material when subjected to selection.

If we were to summarize the implications of evolutionary theory we could focus on three points: 1) All living things have a common origin, 2) there has been a gradual change over many millions of years has given rise to all biodiversity of the planet and, finally, 3) the human species is just one more of the hundreds of millions of species that exist or have existed. The Darwinian proposal reflected a Copernican shift in regard to the position of the human species as a biological entity; man ceased to be the center of creation to become just one more species of the millions of species created by evolution. Not surprisingly, occurred a great social reaction at the time. Even at the present time is not accepted by many members of society. According to the Gallup Institute in 2004 more than half of Americans believed that man was literally created as the Bible says about 10,000 years ago.

Genetics and evolution: operational definition of the gene

Darwin provided a descriptive plausible explanation, but no mechanistic biodiversity. The point is: if all living organisms have a common origin, what biological function is common to all, is transmitted from father to son and is modifiable to generate biodiversity? In his time, Darwin could not answer these questions.

It was precisely the approach to these issues which gave rise to genetics, the discipline that studies how it is transmitted and modifies the biological information. The first sign of the existence of heritable genetic information due to Gregor Mendel, an Augustinian monk who showed that the shape or color of peas is faithfully transmitted from one generation to another.

However, the progress of genetics in the twentieth century is due in large part to the fruit fly, Drosophila melanogaster, an organism that has become the object of classic study of genetic research, since it is easily bred in the laboratory, its life cycle is very short-which is very useful to study the inheritance of various characters from one generation to another and is totally harmless to humans. Studies in Drosophila -genes- possible to identify many specific heritable traits, showed that they are aligned and located in the nucleus of cells and organelles called chromosomes that each gene is located on a specific location of chromosome. They also showed that appear in nature -mutaciones- heritable variations of genes and these mutations are the source of biological variation necessary for the evolutionary process. These mutations can also be induced artificially through the use of radiation or chemicals. Overall, what genetics of Drosophila discovered is that the real motor of evolution are genes that constitute heritable genetic information and are modifiable.

After more than a century of research in this fly, knowledge of their genetic is the most complete of the Animal Kingdom and developed some concepts and technologies that enable experiments that can not be done in any other species.

Nature of genetic information

The problem then arose about in the forties of the last century, was to know the physical nature of the gene; what their chemical composition.

DNA

The solution to this problem led to what I call the second revolution in biology: the elucidation by Watson and Crick of the nature and structure of genetic information, DNA. The famous article published in Nature in 1953 was the beginning of a biological revolution destined to change the course of humanity itself. The DNA molecule is a double helix structure formed by two long chain molecules of a deoxy-ribose sugar linked by phosphate. Connecting both chains like rungs on a ladder, other molecules called nucleobases maintain the stability of the structure. As noted immediately Watson and Crick, the structure of the molecule explains the mechanism of replication leading to identical molecules and, therefore, ensuring the loyalty of biological information through generations.

In addition, the structure of DNA biological information indicating that lay in the sequence along the molecule called four bases thymine (T), guanine (G), adenine (A) and cytosine (C). What an organism inherits from its parents and that will condition their biological characteristics is simply a written language four-letter sequence.

The discovery of the structure and function of DNA modified experimental biology approach: all organisms are coded in a language of four letters, A, T, C and G. Thereafter biology focused on the study of DNA their properties and structure. The first complete DNA sequence was obtained from an organism, bacteriophage ØX174, contains 5,000 bases--called letters. By comparing the DNA sequence of a nematode worm consists of 90 million base pairs; the sequence of the fruit fly Drosophila has 120 million base pairs and the human being consists of 3,300 million base pairs. Each of these sequences represents a kind of formula to determine the species in question.

A universal genetic code

The problem is that the vital processes are not catalyzed by DNA but by proteins; DNA is simply a recipe that must be translated in all variety of proteins, some 3,000 basic, which are responsible for vital functions, including replication and expression of the DNA itself.

Proteins are made ​​up of combinations of 20 amino acids, so that each protein is different from the others because it is formed by a specific amino acid sequence. So, you have to translate the sequence of four bases inherited parental sequences of 20 amino acids to produce proteins that are the backbone of biological functions. Deciphering the code translation, the genetic code, was one of the great early successes of molecular biology. Ochoa Laboratories, Nirenberg and Brenner were instrumental in deciphering the mechanism of translation. These investigators showed that each amino acid is encoded by a specific sequence of three -triplete- bases, thereby ensuring that each gene, which is a particular sequence of total DNA, resulting in a specific protein. The AAG triplet coding for the amino acid lysine, while GCA AGA encoding alanine and arginine. Thus AAGGCAAGA DNA sequence would result in the sequence arginine-alanine-lysine amino acids.

The interesting thing is that the genetic code is universal for all organisms. The universality of the code is in itself a proof of evolution. All organisms have the same genetic code simply because we all have inherited from an ancient ancestor.

Gene in this context is simply a particular DNA sequence codes for a specific protein responsible for a specific function, such as hemoglobin necessary for respiration or muscle myosin.

Development of molecular biology

The discovery that DNA is the instructions to make a living and the deciphering of the basic mechanisms of gene function, genetic code and protein manufacturing, mark the beginning of molecular biology. The study of DNA, its structure and properties became the main focus of this discipline from the seventies of the last century. This concentration of effort has led to concepts and extremely powerful techniques for manipulating the DNA with great efficiency. These techniques are those that allow the cloning of genes, the generation of transgenic animals and plants, the possibility of gene therapy and Genome Projects. The generation of transgenic organisms, ie, bodies to which they have been introduced genes from another species, is derived from the fact that all the DNA of any origin, and are chemically identical to a gene is simply a DNA fragment. This mixes by chemical methods -genes- DNA fragments of heterologous origin. Once you have developed methods to introduce these fragments in the host organism, it now has a gene from different sources. A clear example is, for example, yeast strains which are inserted the gene encoding human insulin. By this method the transgenic yeast manufacture human insulin.

The great development of these procedures in recent years has generated plants-wheat, soybeans, rice, etc., that are already on the market, and transgenic animals of many species, rats, mice, pigs, flies, etc. Importantly, the methods used for various animal species are very similar and are the basis for applications for therapeutic use in humans, to cure genetic diseases by gene therapy. In 2000 the first gene therapy trial through which it was possible to cure a severe immunodeficiency several children was published in the journal Science. Unfortunately, these trials had to be discontinued due to adverse effects of the procedure; three children cured cancer subsequently developed. This example illustrates the same time, the potential of these new methods and that are still in a very early stage of development. Given the speed with which progress is being made ​​is expected to be available in the not too distant future.

The genetic design of animal body

One aspect that molecular biology has progressed significantly and considerable applications in regard to human biology is in the area of genetic engineering body of animals.

Initially, used in molecular biology experiments cell organisms, bacteria or viruses for the study of the properties and function of DNA. These studies yielded significant results, as described above, but by its very nature does not allow conclusions about what the genetic control of development of complex organisms, like a fly or a mouse, associations formed by cells that have grouped correctly in a three-dimensional structure.

Consider a butterfly ; each individual cell has to perform the primary biological function, protein synthesis, DNA replication, etc., but also has to be arranged, grouped with other and differentiate to specific organs, eyes, wings, legs etc., which are to assembled with the other organs so that each appears in the right place. In the design of an animal must have the various parts of the body in the three dimensions of space; the antero-posterior, dorsal-ventral and proximal-distal axis. This issue of body design has been one of the great challenges of the genetics of higher organisms: how genes specify the positional information of the various body cells so that they will do eye know that they shall be provided in the front of the body and that will form the legs must be on the ventral side. In other words, what is the genetic description of a three-dimensional body? In an insect like a butterfly we distinguish morphologically cephalic hand, thoracic and abdominal part, but there is no guarantee that this description corresponds to the true genetic description of the organism. It is in this issue of genetic description of the animals that have progressed significantly in the last thirty years.

The keys to the genetic design of animal body are called homeobox genes, now called Hox. These form a genetic machinery that has been studied in great detail in the fruit fly Drosophila. The characteristic of these genes is that a transform its mutations in other parts of the body (Figure 3). A mutation as Antennapedia (Antp) transforms such leg antenna, or a mutation as Ultrabithorax (Ubx) transforms the appendix dumbbell wing, resulting in a four wings fly. The interesting of these transformations is that, even though the general construction of the body is in error, the morphology of the parts is normal: the leg shown in Antp antenna is normal, which is abnormal is the site appears. Similarly, the transformed wings that appear on the Fly Ubx have normal morphology and size of wings. The only abnormal is the site where they appear. The implication of these phenotypes is that Hox genes that control is not the morphology of the structures but the overall body design, positional information to which I referred to earlier, which makes each organ appears in the appropriate place.

The homeotic genes are regulatory genes as senior determining the type of development of the various body parts of Drosophila. A very important question asked in the eighties of the last century there were many homeotic genes. Identifying all expected to allow elucidate the genetic logic underlying the design of the body. Studies in the United States and Spain showed that, surprisingly, the number of Hox genes is small. In Drosophila there are only nine Hox genes that establish the spatial coordinates in the anteroposterior axis, recognize the positional values ​​on this axis and determining the acquisition of suitable development program for generating the corresponding body part. These results were certainly interesting but concerned the fruit fly; in principle not suspected that they might have a general value to explain the body design of other animals, including humans.

However, progress in molecular biology in the seventies and eighties of last century allowed the -clonaje- molecular isolation and sequencing of the Drosophila Hox genes. At the end of 1985 all these genes had been cloned and sequenced. An extraordinarily important discovery was made ​​when their sequences were compared is that all these genes contain a common sequence that was called homeobox. The implications of the discovery of the homeobox were important: 1) This sequence encodes a DNA binding motif, which indicates homeotic proteins function as transcription factors and regulate the activity of other subsidiary, 2) the presence genes thereof sequence in all Hox genes indicates that these genes have a common origin and 3) the homeobox sequence is a molecular marker of Hox genes that allowed identification in agencies-human species, for example where it is impossible to detect by genetic methods conventional. As we will see the latter proved to be of great importance.

A universal genetic design

The fact that the homeobox is a molecular marker of Hox genes identified the Hox complex in many groups of the animal kingdom, and made ​​of these genes the fundamental object of study of developmental biology during the eighties and into the early nineties. The overall result is that the Hox complex found in all animal groups that have been searched. It is therefore a universal feature of the genome of all animals, including humans. Humans have a complex Hox much like Drosophila, only instead of having one copy per genome have four.

Drosophila studies had previously established that the function of these genes was to determine the development of the various parts of the body, but there was no evidence on which function performed in other organisms. The difficulty in studying this aspect is that the genetic analysis in Drosophila is not possible in many vertebrates and totally impossible in humans therefore had to resort to other methods.

The molecular technologies developed in the eighties and nineties can generate individuals, Drosophila flies in this case, which can introduce them to a gene from another species and study in this heterologous system function. Experiments of this type have concluded that humans and other vertebrate Hox genes function similarly or equal to their counterparts in Drosophila. Functional preservation goes so far as to human or mouse genes are able to replace their counterparts in Drosophila, this is the case of the mouse gene Hoxd13 if it is introduced into the fly is able to program development back Drosophila as the fly gene itself. Other striking examples are, for example, genes of Drosophila eyeless apterous and having known human counterparts. Apterous need to make wings; mutations in this gene produce wingless individuals. Eyeless need to schedule eye development; mutants in this gene have no eyes.

Drosophila melanogaster

When a fly apterous is introduced mutant human gene is capable of forming fly wings. Although humans do not have wings to fly, have a gene capable of replacing Drosophila training program wings fly thanks to a mechanism of functional conservation.

Similarly, the mouse homologue gene eyeless, called small eye, is capable of inducing fly eyes (Figure 4). Similar experiments with genes from other organisms have led to the conclusion that the genetic design of the eyes of all animals, flies, octopi, humans, is the same. The evolutionary invention of a light receiving element connected to the brain occurred 540 million years ago and has been inherited by all multicellular organisms. These experiments illustrate a general principle of evolutionary phenomenon: when a mechanism operates properly, the genetic programming of this mechanism is fixed in the genome and, from there, not modified or changed very little appears.

The general conclusion from all this is that the general mechanism of genetic engineering of animals, based on Hox genes and derivatives, it is common for all the Animal Kingdom. Surely the Cambrian explosion, that is, the sudden appearance of Bilateralia with organs arranged along the three axes, is the result of the appearance in the Lower Cambrian of Hox complex and its derivatives. Sequence similarity in the complex indicates the genes derived from an ancestral gene that underwent several tandem duplications, thereby giving rise to the set of linked genes that form the set.

Therefore, we can say that all living things share the same basic biological functions. In all these studies has emerged a unifying vision of biological processes based, ultimately, in the evolutionary process. Organisms have a common origin, as proposed by Darwin and Wallace, share the storage and release mechanism of genetic information based on the universality of the function of DNA, RNA and mechanism of genetic code. Finally, all components of the Animal Kingdom share the same genetic process of body design.

An important implication derived from these observations is that many aspects of the development of the human body can be studied in model, flies, worms, mice, on the understanding that genetic / molecular basis of these processes is common to all organisms species and, therefore, many of the processes involved will be also. A typical example of this approach are the regeneration studies being carried out in chickens and amphibians. Is an old observation that amphibians and reptiles are able to regenerate limbs while birds or mammals do not. Ongoing studies are allowing identify related, several of which regenerative process genes are also present in species that do not regenerate. It seems that the ability to regenerate an organ or not to depend not so much on the presence or absence of one or more genes and the mechanism of regulation of common genes. Regenerating species are able to activate these genes after physical trauma while not regenerate are not. A well-founded speculation is that, when well knows the process of regulation of these genes could be involved in controlling its function in order to artificially induce regenerative process in the human species, which naturally would not.

The genome projects

The above discussion is itself a vindication of the entire evolutionary phenomenon, clearly state the functional universality of biological phenomena. But also new molecular technologies have provided a more direct demonstration of this universality. In recent years it has finished the complete sequencing of the genome projects-the DNA of many animal and plant species, which has led directly compare the degree of similarity or difference of biological information among different species.

In this context the nematode Caenorabditis elegans genomes, containing a DNA of 90 million base pairs, the Drosophila fly 120 million base pairs and the human genome with 3300 million base pairs are particularly relevant. DNA from five people-three women and two men -hispano four different ethnic, Asian, African American and caucasiano- groups used in the Human Genome (fig. 5) project. Interestingly, no significant differences were detected between them.

These projects have managed to identify all the genes in each species, determining its sequence and accumulate this information in databases, which together with the development of sophisticated and powerful computer software tools, has enabled significant comparing sequences. The comparison has produced many interesting results, but one particularly important (fig. 6) is the discovery that the human species shares about 50% of genes with Caenorabditis elegans nematode and 60% with Drosophila. This observation is a healthy reminder of our biological origins we share with other animals. Naturally, this is reflected in the DNA which is the common evolutionary line that unites us all.

Study humanaen disease model organisms

The high degree of genetic similarity in those species and, indeed, throughout the animal kingdom not only validates the evolutionary phenomenon, but also has powerful implications in the study of human biology and pathology. By having so many genes in common with organisms such as Drosophila there are many aspects of biology and human disease that can be studied in flies without experimental and ethical constraints of human material. The philosophy is that a lot of progress in the knowledge that get in Drosophila apply to ourselves. As we saw earlier, the study of Hox genes is throwing flies very important for the function of these same genes in our own species information.

With regard to pathological processes, latest estimates indicate that 74% of human disease-related genes are present in Drosophila. It is therefore a source of information of great importance to the basic knowledge of human disease. Currently, many laboratories around the world are using Drosophila as a body to study diseases such as cancer, Alzheimer's disease, ataxias, etc. An example of this approach are experiments to induce molecular syndrome Alzheimer's disease in Drosophila. Amyloid deposition (Aß) protein in neurons is a feature of the disease. Pathological form containing 42 amino acids instead of 40 and form aggregates called amyloid plaques. The technology allows induce Drosophila eye disease or brain of the fly and study the evolution of the disease. Can produce hundreds of individuals and many prove possible remedies or compounds that interfere with the development of the disease. These experiments have identified a drug-Congo Red- which greatly mitigates the effect of the disease in flies. But unfortunately this drug is toxic to humans and no use for the treatment of disease, clearly indicates the potential of this technology. Experiments of this type have already identified several drugs designed to treat cancer and other degenerative processes.

Can you alter the length of human life?

The high degree of conservation throughout the animal kingdom of fundamental biological phenomena can speculate on the possibilities of manipulating processes considered up, inaccessible to human intervention bit ago. One of the fundamental paradigms of society and human culture is the idea that aging and death are inevitable biological processes. It is assumed that there is an internal programming that establishes, within a relatively narrow range, the maximum life span of individuals of each species.

During the twentieth century the average length of life has increased significantly, mainly due to the improvement in living standards, hygiene conditions and progress in medicine, but it is estimated that the maximum duration is around 120-125 years. Could exceed this limit? This is a topic that has attracted much attention in international scientific journals (see Nature 458, 1065-1071, 2008), mainly because recently there have been discoveries that deal directly with the genetic programming of the lifespan .

The fundamental fact is that we have identified in the nematode worm Caenorhabditis elegans and Drosophila several genes whose function is directly related to aging program for these species. Given the ease of genetic manipulation in these organisms, has gotten substantially prolong life in individuals of these species. In the case of nematode worms have been achieved arriving to live between six and seven times more than normal. Extrapolating to the human species, the average life of the population would be about 350 years and would outweigh the 500 individuals.

An important aspect of these findings is that aging genes identified in Drosophila and nematode worm are also present in humans. The best studied of these genes, called DAF-16 in worms and FOXO in Drosophila and humans, is related to the insulin pathway and have been detected variant forms of FOXO appear to be particularly common in people over a hundred years. Mutations in the human species that affect the activity of the insulin pathway have also been detected in centenarian.

DAF-16 / FOXO has been cloned and constructed genetically modified worms, which have altered functional levels of this gene and which result in changes that come to double the life span of the worms. Manipulating the fact that a single gene is achieved this result illustrates the potential of these techniques.

As mentioned above, this gene is present in our own species, which opens the possibility of manipulation could be used to alter the length of life of human beings.

The future evolution of the human species: technological man

In closing, I would like to briefly reflect on the evolution of life on the planet and the human species. Life on the planet began 2,000-3,000 million years ago. Animals Bilateralia -the existing today-animal groups, appeared 540 million years ago. About 100,000-200,000 years ago Darwinian selection gave rise to the human species, as has produced many million more species, living or extinct. However, the intellectual / technological development of our species has made essentially immune to the process of natural selection, therefore normal evolutionary rules affect us little or nothing today.

Human culture began about 10,000 years ago and technological development two hundred years ago, while DNA technology began twenty ago. The progress of this technology has been very fast and has resulted in very powerful methods of manipulation. That is, the vehicle evolution, DNA, is being modified directly by human intervention. These methodologies, still very raw, are being used in experimental animals, flies, mice, worms, etc., but given the great genetic similarity is not far off that can be applied to the human species. The potential of these methods is huge, especially if one considers that began twenty-five years. It is impossible to imagine what it will be able to perform in fifty years, not to mention 500 or 5,000. The human species will be able to genetically modify itself a controlled manner. This perspective has enormous potential to determine their own biological future, their own evolution. DNA technology provides a new social paradigm; You can completely change the very essence of being human.

Ginés Morata for: EL PAÏS