Pharmacogenetics: a drug for each person

Sometimes, some people say that the medications prescribed by doctors are not good. Can this be true? Not all drugs work for the same population. Keep reading and discover the secrets of pharmacogenetics.

INTRODUCTION

The same that happens with nutrients, happens with drugs. Another objective of personalized medicine is to make us see that not all medicines are for everyone. However, it does not come again because around 1900, the Canadian physician William Osler recognized that there was an intrinsic and specific variability of everyone, so that each one reacts differently to a drug. This is how, years later, we would define pharmacogenetics.

It is important to point out that it is not the same as pharmacogenomics, which studies the molecular and genetic bases of diseases to develop new treatment routes.

First, we need to start at the beginning: what is a drug? Well, a drug is any physicochemical substance that interacts with the body and modifies it, to try to cure, prevent or diagnose a disease. It is important to know that drugs regulate functions that our cells do, but they are not capable of creating new functions.

Apart from knowing if a drug is good or not for a person, you also have to take into account the amount that should be administered. And we still do not know the origin of all diseases, that is, we do not know most of the real molecular and genetic causes of diseases.

The classification of diseases is based mainly on symptoms and signs and not on molecular causes. Sometimes, the same group of pathologies is grouped, but among them there is a very different molecular basis. This means that the therapeutic efficacy is limited and low. Faced with drugs, we can manifest a response, a partial response, that produces no effect or that the effect is toxic (Figure 1).

Figure 1. Drug toxicity. Different colours show possible responses (green: drug not toxic and beneficial; blue: drug not toxic and not beneficial; red: drug toxic but not beneficial; yellow: drug toxic but beneficial) (Source: Mireia Ramos, All You Need is Biology)

DRUGS IN OUR BODY

Drugs usually make the same journey through our body. When we take a drug, usually through the digestive tract, it is absorbed by our body and goes to the bloodstream. The blood distributes it to the target tissues where it must take effect. In this case we talk about active drug (Figure 2). But this is not always the case, but sometimes it needs to be activated. That’s when we talk about a prodrug, which needs to stop in the liver before it reaches the bloodstream.

Most of the time, the drug we ingest is active and does not need to visit the liver.

Figure 2. Difference between prodrug and active drug (Source: Agent of Chemistry – Roger Tam)

Once the drug has already gone to the target tissue and has interacted with target cells, drug waste is produced. These wastes continue to circulate in the blood to the liver, which metabolizes them to be expelled through one of the two routes of expulsion: (i) bile and excretion together with the excrement or (ii) purification of the blood by the kidneys and the urine.

THE IMPORTANCE OF PHARMACOGENETICS

A clear example of how according to the polymorphisms of the population there will be different response variability we find in the transporter genes. P glycoprotein is a protein located in the cell membrane, which acts as a pump for the expulsion of xenobiotics to the outside of the cell, that is, all chemical compounds that are not part of the composition of living organisms.

Humans present a polymorphism that has been very studied. Depending on the polymorphism that everyone possesses, the transporter protein will have normal, intermediate or low activity.

In a normal situation, the transporter protein produces a high excretion of the drug. In this case, the person is a carrier of the CC allele (two cytokines). But if you only have one cytosine, combined with one thymine (both are pyrimidine bases), the expression of the gene is not as good, and the expulsion activity is lower, giving an intermediate situation. In contrast, if a person has two thymines (TT), the expression of the P glycoprotein in the cell membrane will be low. This will suppose a smaller activity of the responsible gene and, consequently, greater absorption in blood since the drug is not excreted. This polymorphism, the TT polymorphism, is dangerous for the patient, since it passes a lot of drug to the blood, being toxic for the patient. Therefore, if the patient is TT the dose will have to be lower.

This example shows us that knowing the genome of each individual and how their genetic code acts based on it, we can know if the administration of a drug to an individual will be appropriate or not. And based on this, we can prescribe another medication that is better suited to this person’s genetics.

 APPLICATIONS OF THE PHARMACOGENETICS

The applications of these disciplines of precision medicine are many. Among them are optimizing the dose, choosing the right drug, giving a prognosis of the patient, diagnosing them, applying gene therapy, monitoring the progress of a person, developing new drugs and predicting possible adverse responses.

The advances that have taken place in genomics, the design of drugs, therapies and diagnostics for different pathologies, have advanced markedly in recent years, and have given way to the birth of a medicine more adapted to the characteristics of each patient. We are, therefore, on the threshold of a new way of understanding diseases and medicine.

And this occurs at a time when you want to leave behind the world of patients who, in the face of illness or discomfort, are treated and diagnosed in the same way. By routine, they are prescribed the same medications and doses. For this reason, the need has arisen for a scientific alternative that, based on the genetic code, offers to treat the patient individually.

REFERENCES

• Goldstein, DB et al. (2003) Pharmacogenetics goes genomic. Nature Review Genetics 4:937-947
• Roden, DM et al. (2002) The genetic basis of variability in drug responses. Nature Reviews Drug Discovery 1:37-44
• Wang, L (2010) Pharmacogenomics: a system approach. Syst Biol Med 2:3-22
• Ramos, M. et al. (2017) El código genético, el secreto de la vida. RBA Libros
• Main picture: Duke Center for Applied Genomics & Precision Medicine

 

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