In the winter of 1869, a young Swiss physician named Johann Friedrich Miescher discovered and isolated a substance of the cell nucleus whose chemical composition was different from that of proteins and from that of any other compound known until then. This is how Ralf Dahm, from the Brain Research Centre of the University of Vienna, begins his 2008 article on the discovery of DNA - published in the journal Investigación y Ciencia (October 2008 issue, pp. 77-85).

Miescher wanted to practice medicine, following the steps of his father and of his maternal uncle, Wilhelm His. Both his father and his uncle were physicians and well respected professors at the University of Basel. However, young Miescher could not fulfill his desire because of a hearing impairment caused by a disease suffered during childhood. Despite this, his fondness for science led him to undertake scientific research. The guidance of his uncle, who thought that the unresolved questions of biology would be answered by chemistry, led Miescher to study biochemistry. He was taught biochemistry by Felix Hopee-Selyer, one of the pioneers of the recently appeared ‘physiological chemistry’.

Miescher, through uncomfortable, awkward and tedious methods, managed to discover a compound he called “nuclein”, a molecule which acts in a manner different from proteins and lipids. Furthermore, to his surprise, its elemental composition contains phosphor. This led him to conclude that he had discovered a new type of fundamental cell substance.

The century of research inaugurated by the works of Gregor Mendel (1865), who discovered that genetic traits are inherited following a specific set of laws, were followed by the work of Ernst Haeckel (1866) who stated that the cell nucleus contains the factors which transmit hereditary traits. Their work was further continued by Miescher who isolated DNA, and then by a number of discoveries which culminated into the works of Watson and Crick (1953). They proposed that the molecular structure of DNA has a double helix shape, whereas Rosalind Franklind and Maurice Wilkins used X-ray crystallography to demonstrate that DNA has a helicoidal structure which repeats itself regularly.

By the mid 1960s, the works of Niremberg, Matthaei, Ochoa and Khorana, among others, had resulted in the discovery of the genetic code, leading to the emergence of molecular genetics.

On the other hand, in the late 1960s Werner Arber discovered the phenomenon of restriction, and the enzymes which cause it. This, and the follow-up experimentation by Hamilton O. Smith in 1970, opened the gateway to genetic modification since they resulted in the description of a new type of enzyme which acts in a identifiably specific way, and is therefore capable of recognizing certain DNA sequences and of cutting certain spots in the DNA. Two years later, the experiment of Merz and Davis by adding an enzyme, DNA-ligase, to a mix of fragmented DNA in order to rebuild the phosphodiester bonds, set the bases to obtain recombinant DNA molecules. However, this technology required the introduction of recombinant DNA into living cells in order to express genetic information.

The advances towards obtaining genetically-modified organisms having possible commercial uses gave birth to modern, or biotechnology based on the use of molecular technologies. This put an end to the development process of the classical, or “old” biotechnology, based on the use of fermentation processes supported by the developments of chemical engineering or biochemistry.

The historical development of the concept of genes forming a structure, led from the very beginning to the concept of gene mapping. Gene mapping would identify the location and relations between genes, and would therefore pursue the sequencing of its chemical subunits. This research dynamic led in turn to the objective of the sequencing of the human genome, the so called ‘Holy Grail’ of biological research. The great advances in the sequencing of the human genome led to the development of ‘omics’ which have been reflected upon in our ‘Biotechnology in the mirror” section. This work has facilitated the evolution from a “reductionist view of biology” towards a biology searching for integration, i.e. systems biology, as well as the synthesis of life organization through synthetic biology.

This long and spectacular trajectory of the development of biology supported by DNA did not evolve at constant speed and acceleration. On the contrary, there was a long maturing process, but, once overcoming the initial period of lethargy, it entered a truly expansive phase which encompasses the second half of the past century; growing exponentially during the first decade of the present century.

In view of the present situation, it is an opportune time for reflection, and to this end I will review some articles published in several different media, paying special care to Investigación y Ciencia, the Spanish version of Scientific American, and even commenting on news appearing in general information press.

During the year 2010, Melinda Wenner Moyer, contributor to the journal Scientific American, dealt with the problem that the variation in the number of genes as the factor explaining gene-based complex diseases did not fit well in simple genetic models. Examples of this problem can be autism, schizophrenia or Crohn disease. The Spanish translation of the article appeared in the October 2010 issue of Investigación y Ciencia, (pp. 14-15).

This author acknowledges that, ten years after the public presentation of the first draft of the human genome, research of the relationship between genes and disease remains an unresolved issue. The research initially centered on the identification of unique changes in codifying AT and CG base pairs. However, as researchers advanced along these lines, they could find evidence that these changes, i.e. these mutations, are but a small part of the whole problem. The focus, then, has recently switched towards the variation in the number of copies, data which cannot modify the normal characteristics of the genome excepting through the lack or repetition of certain sequences.

This abnormal phenomenon was first discovered in 1936, when it was found that flies which inherited a duplicated gene had very small eyes. Two decades later a variation in the number of copies was identified as the cause of Down syndrome. Those affected by this syndrome have an additional copy of the chromosome 21. Sixty eight years after the discovery associated with the flies, came the publication of the first maps on Variation in Number of Copies (VNC) of the entire genome which served to illustrate that this phenomenon is quite common. This first VNCs represented an important leap forward.

Most of these are inherited by the human body, though the effects of these variations are still under research. This research associates VNCs to several complex diseases. Although complex diseases are not always linked to the same genes, the variation in the number of copies might help explain the genetic inheritance of them. According to the opinion of Steven McCarroll, an expert in genetics at the Massachussets Institute of Technology and co-author of some of the aforementioned works on complex diseases such as autism, schizophrenia and Crohn disease, the variation would modify the probabilities of suffering these diseases. Whether a person ends up contracting a given disease would then depend on additional factors, be they genetic or environmental.

The research group of the Toronto Children’s hospital headed by Stephen Scherer, working together with Matthew Hurles from the Wellcome Trust Sanger Institute (Cambridge, United Kingdom), is exploring new variants of smaller size, from 20,000 to only 500 pairs of bases. Their analysis suggests that every person contains around 1,000 copy variations. This represents at least one per cent of the genome.

This is a line of research which is expected to expand, by discovering increasingly small and more common VNC’s associated to diverse diseases.

The advances in genomics have led to a questioning of the traditional definition of the gene. In fact, it has been put forth that all of these wide ranging genomic studies demand a new approach for the molecular classification of life.

Michael Seringhaus and Mark Gerstein, genomics and bioinformatics researchers at Yale University, published an article in the March 2009 issue of Investigación y Ciencia (pp. 73-80) which discussed gene ontology on the basis on the wide scale genomic studies which are putting into question our standard definition of genes. Nowadays, state-of-the-art genomics provides us with thousands of gene products - opening our views to wider landscapes.

Genes are much more complex than previously imagined. We can no longer associate them to a DNA fragment which transcribes into a protein with an exact amino acid sequence and function. The research of the international ENCODE Project (Encyclopedia of DNA Elements) has revealed that non-genetic transcription is a very common process. However, we ignore what is the role of that non-genetic transcribed material. From a transcriptional point of view they look like dead genes which are revived, or that might even participate in other genes’ regulation.

The alternative phenomenon of cut and paste (“splicing”) deserves particular attention. Contrary to the common idea that the transcription and PODA of the introns (long, non-coding DNA regions) so that exons (short, coding regions of the DNA) can fabricate proteins, there have been found hints that, depending on the genetic locus, this cut and paste process is carried out in multiple ways. When this process happens outside of the limits of a gene sequence, the number of variants increases.

The idea that the coding portion of the gene and its regulatory sequences were necessarily close by have been revised in light of the data of higher organisms.

These regulatory and transcriptional specificities never, in the opinion of Seringhaus and Gerstein, fit within the traditional concepts; the scientific community comforting themselves believing that non-close regulatory sequences were exceptional cases. However, the results of ENCODE point out that the deviation of the traditional model might be the rule.

The definition of the genetic function has thus been subjected to an evolutionary process. Initially, the genetic function was defined from the phenotypic effects of the genes. But these effects do not explain the molecular function of genes. This is why researchers have tried to determine the importance of a given gene investigating the biochemistry of its products as well as the process or pathways that, in a given cell, follow the gene’s products.

All these approaches are based on a lineal, hierarchic classification scheme. The generalized sequencing of the genome, and the subsequent avalanche of data which followed, gave birth to a new system: Gene Ontology or GO. This system involves a Directed Acyclic Graphs structure or DAG. Both the hierarchic and the DAG system of classification are organized from general to specific; however, the DAG system is more flexible because in this system there can be multiple progenitors, unlike the single progenitor (functional classification) of the hierarchic system.

In order to reflect the molecular complexity of life, new research will be required in the following fields: definition, nomenclator and a classification system.

The aggressive publicity of genetic test companies has raised some questions and criticisms about the reliability of these tests. Some national general information media have reflected these doubts (See J. Prats, El País, Vida & Artes section, Saturday August 14, 2010, pp. 24-25).

The article, entitled “Demasiadas Dudas para un diagnóstico serio” (Too many doubts for a serious diagnosis) refers to the investigation, backed by the US Congress, of four of the main companies performing genetic tests: 23andMe, Pathway Genomics, DeCode Genetics and Navigenics. The conclusions of that study, which involved sending samples of the same people to the different companies, were astounding; the results of the same person varied highly; the same person had many different possibilities of suffering the same disease depending on the company consulted. There were collected examples of “false publicity”; but the fact which exceeded the patience of the US regulatory agency (the FDA, Food and Drug Administration) was the mixing of the data of 93 patients of the 23andMe company. This mistake was considered very grave by the FDA because of the measures which a wrong diagnosis might lead patients to take. This case led the FDA to ask for special permission to regulate these tests. Regarding the European Union, since 1998 there is a directive regulating this activity, although some countries are considering additional regulatory measures.

However, in spite of this uncertainty, these tests seem to continue attracting the business of “home Health care”. The article by Jaime Prats says that there are several companies in Spain (in Alicante and San Sebastián de los Reyes) which work, or plan to work, in this field.

The scientific community has reacted strongly to the problems deriving from this risky practice. There were articles published in Nature when this thorny issue burst in the US, and two leading experts in molecular genetics, Francis Collins and Craig Venter, have raised the alarm about the limited reliability of their results.

As the author of the El País article points out, there are determining factors stemming from the growing complexity of the genome: mutations, on one hand, and polymorphisms, on the other. To them we must also add the population variants as well as environmental conditions, and finally the ontology of genes issues that we have been previously discussing.

In regard to environmental conditions, I think it is appropriate to remember an interesting article by Dan Fagin that appeared in October 2008 at Investigación y Ciencia (pp. 12-19) which shows data on the effects of environmental pollution in the health and development of the child population of a Chinese city.

It seems evident that 150 years of scientific research of DNA biology have brought great advances in its knowledge, and in its practical uses to improve Health care. However, precisely because we now know more, we need to exert better prudence and control. The importance of regulatory science is growing, but its practice also requires in depth knowledge and prudence; wisdom, in sum.