From traditional medicine to personalized medicine

From prehistory, where medicine started began with plants, minerals and parts of animals; until today, medicine has evolved very quickly. Much of the “fault” of his fact is due to genetics, which allows us to talk about personalized medicine. In the following article we discuss this.

THE EVOLUTION OF DISEASES

To talk about medicine, we have first to know diseases. We cannot think that all diseases are genetic, but there are diseases related to anatomical changes, fruit of our evolution.

Chimpanzees are the closest animal to us, humans, with which we share 99% of our genome. Despite this, humans have very particular phenotypic characteristics as the brain most develop, both in size and expansion of the cerebral cortex; hairless sweaty skin, bipedal posture and prolonged dependence on offspring, allowing the transmission of knowledge for longer; among other.

Possibly, the bipedal position was key to the early development of the divergence between the chimpanzee lineage and that of humans; and is also the reason for the appearance of some diseases related to anatomical factors. Among them are hernias, haemorrhoids, varices, disorders of the spine, such as herniated intervertebral discs; osteoarthritis in the knee joint, uterine prolapse and difficulties in childbirth.

The fact that the pelvis was remodelled (Figure 1) and narrower resulted in obstetric problems millions of years later, when the brain expanded. Consequently, the skull as well. The heads of the foetuses were longer and larger, making birth difficult. This explains why the deliveries of humans are longer and longer compared to those of chimpanzees and other animals.

Figure 1. Comparison between human pelvis and chimpanzee pelvis in bipedal position (Source: Libros maravillosos – La especie elegida (capítulo 5))

The evolution towards modern life has behaved many changes in every way. In comparison to our hunter-gatherer ancestors (Figure 2), our diet has changed a lot and has nothing to do with what other primates eat. For the latter, the fruit represents most of the intake, but for us it is red meat. In addition, we are the only animals that continue to feed us milk after the lactation period.

Figure 2. Picture of hunter-gatherer humans (Source: Río Verde en la historia

If we add to the sedentary lifestyle and the limited physical activity of modern humans, it can help explain the seriousness and frequency of some modern human diseases.

Lifestyle can also affect us. For example, myopia, which rate is higher in western individuals who read a lot or do activities of near vision, compared to individuals of Aboriginal’s towns.

Another clear example is the alteration in the female reproductive stage. Currently, women have children more and more later. This is also linked to a decrease in the duration of breastfeeding. These changes, which can be considered socially positive, have negative effects on the health of the reproductive organs. It has been shown that the combination of early menarche, limited or no breastfeeding and later menopause are the main risk factors for breast and ovarian cancer.

Humans increasingly live more years and we want the best quality of life. It is easy for more longevity to appear more diseases, by the deterioration of the organism and its cells.

THE EVOLUTION OF MEDICINE

The history of medicine is the history of the struggle of men against disease and since the beginning of this century, is also the history of human effort to maintain health.

We have acquired the scientific knowledge of medicine based on observation and experience, but it has not always been so. Our ancestors experienced sickness and the fear of death before a rational picture could be made of them, and the medicine of that time was immersed in a system of beliefs, myths and rites.

However, in the last years it has been born personalized genomics, which tells you your risk factors. This opens a door to personalized medicine, which adjusts treatments to patients depending on their genome (Figure 3). It uses information from a person’s genes and proteins to prevent, diagnose and treat a disease, all thanks to the sequencing of the human genome.

Figure 3. Personalized medicine that treats people individually, according to their genome (Source: Indiana Institute of Personalized Medicine)

Molecular methods that make precision medicine possible include tests of gene variation, proteins, and new treatments targeting molecular mechanisms. With the results of these tests and treatments can determine the state of the disease, predict the future state of the disease, the response to the drug and treatment or even the role of the food we eat at certain times, which results of great help to the doctors to individualize the treatment of each patient.

To do this, we have within our reach the nutrigenetics and the nutrigenomics, that like the pharmacogenetics and the pharmacogenomics, they help the advance of a medicine is more and more directed. Therefore, these disciplines are today one of the pillars of personalized medicine since it involves treating each patient individually and tailor-made.

The evolution towards precision medicine is personalized, preventive, predictive and participatory. There is increasing access to information and the patient is more proactive, getting ahead of problems, preventing them or being prepared to deal with them efficiently.

REFERENCES

• Varki, A. Nothing in medicine makes sense, except in the light of evolution. J Mol Med (2012) 90:481–494
• Nesse, R. and Williams, C. Evolution and the origins of disease. Sci Am. (1998) 279(5):86-93
• Mackenbach, J. The origins of human disease: a short story on “where diseases come from”. J Epidemiol Community Health. (2006) 60(1): 81–86
• Main picture: Todos Somos Uno

Sequencing the human genome

Genomics is a new science which has had a very important boom in recent years, thanks to advanced technologies of DNA sequencing, advances in bioinformatics and increasingly sophisticated techniques for analysing whole genomes. And I will discuss in this article about whole genomes and their sequencing, mentioning the Human Genome Project, which allowed the sequencing of the human genome.

WHY WE SEQUENCED?

Sequencing is the set of methods and biochemical techniques aimed at determining the order of nucleotides (A, T, C and G). Its objective is to get in order all nucleotides DNA of an organism.

The first organisms sequenced were two bacteria, Haemophilus influenzae and Mycoplasma genitalium in 1995. One year later, the genome of a fungus was sequenced (Saccharomyces cerevisiae).

From that moment comes the eukaryotic sequencing project: in 1998 Caenorhabditis elegans (nematode) was sequenced, in 2000 Drosophila melanogaster (fruit fly) and in 2001 the human genome.

But, why we sequenced? In the case of human genome, there is the need to know to help alleviate or prevent diseases.

Some of the organisms sequenced are model organisms, which have:

• Medical importance: there are pathogens and we know diseases that they can cause.
• Economic importance: organisms that humans eat, they can improve with the molecular techniques.
• Study of evolution: in 2007 more than 11 species of Drosophila were sequenced and it tried to understand the evolutionary relationship between their chromosomes. It has also been made in mammals (ENCORE Project).

WHAT WE UNDERSTAND FOR GENOME SEQUENCED?

The human genome has 46 chromosomes, it means 23 chromosome pairs (22 autosomal chromosome pairs and 1 sexual chromosome pair, XX or XY depending if it is female or male).

The size of the human genome sequenced is 32,000Mb, 23 chromosomes plus Y chromosome.

The human genome was obtained from the mixture of human genomes to obtain a representation of all humanity genome.

PARADOX THAT WE FIND IN GENOME

A paradox is a statement that, despite apparently sound reasoning from true premises, leads to a self-contradictory or a logically unacceptable conclusion. In genomes we find two clear paradoxes.

The first one refers to the C-value, which represents the amount of DNA in the genome. As would be expected, if the organism is larger and more complex, the size of its genome will be bigger. However this is not true because there is not this correlation. It is due because the genome not only contains coding genome and proteins, but also contains repetitive DNA. In addition, the most compacted genomes are found in organisms less complexes.

The second paradox refers to the G-value, which represents the number of genes. There is no correlation between the number of genes and its complexity. A clear example is that in human genome has around 20,000 genes and Arabidopsis thaliana (herbaceous plant) has 25,000 genes. The reason is found in the RNA world, which is more complex and it is related to gene regulation.

THE HUMAN GENOME PROJECT (HGP)

The human genome sequencing project has been the most important biomedical research project of the whole history. With a budget of 3 thousand millions of dollars and the participation of an International Public Consortium, which was formed by EEUU, UK, Japan, France, Germany, China and other countries. Its ultimate objective was achieving the complete sequence of the human genome.

It started in 1990, but things get complicated when, in 1999, appeared a private company, Celera Genomics, headed by the scientist Craig J. Venter, who launched the challenge of getting the human sequence in record time, before the expected by the Public Consortium.

At the end it was decided to leave in a draw. The Public Consortium accelerated the process and obtained the draft almost at the same time. On 26^th June 2000, in a ceremony at the White House with President Bill Clinton, the two leading representatives of the parties in competition, Craig Venter by Celera and the Public Consortium director, Francis Collins found. It announced the achievement of two drafts of the complete human genome sequence (Video 1). It was a historic moment, as the discovery of the double helix or the first time the man went to the Moon.

Video 1. Human Genome announcement at the White House (Source: YouTube)

The corresponding publications of both sequences did not appear until February 2001. The Public Consortium published its sequence in the journal Nature, while Celera did in Science (Figure 1). Three years later, in 2004, the Consortium published the final or complete version of the human genome.

Figure 1. Covers publications of the human genome sequence draft in Nature and Science magazines in February 2001 (Source: Bioinformática UAB)

PERSONAL GENOMES

The genome of the year 2001 is the reference genome. From here we have entered in the era of personal genomes, with names and surnames. Craig Venter was the first person who sequenced his genome, and the next one was James Watson, one of the discoverers of double helix.

It took 13 years to sequence the reference genome. It took less time to sequence Craig Venter’s genome and only few months for Watson’s genome.

CLINICAL APPLICATIONS OF SEQUENCING

Without going to sequence the entire genome they have been identified disease-causing genes. An exome is not the whole genome, but the part of the genome corresponding to exons.

An example is the case of Nicholas Volker (Figure 2), the first case of genomic medicine. This child had a severe and intractable inflammatory bowel disease of unknown cause. With exome sequencing was allowed to discover a mutation in the XIAP gene on chromosome X, replacing an amino acid functionally important for another. A bone marrow transplant saved the life of the patient.

Figure 2. Nicholas Volker with his book One in a Billion, which tells his story (Source: Rare & Undiagnosed Network)

REFERENCES

• L. Pray. Eukaryotic genome complexity. Nature Education 2008; 1(1):96
•  Brown. Genomes 3, 3rd edition (2007)
• Bioinformática UAB
• BT.com
• E. A. Worthey et al. Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genetics in Medicine 2011; 13, 255-262

• Main picture: Noticias InterBusca