Understanding the rough draft of the human genome sequence took 13 years (1990-2003), efforts from many countries, and an investment of over 1 billion dollars in a study that was called the Human Genome Project. Today, a person’s genome can be sequenced in a few hours, for less than the cost of a new smartphone.
The technological revolution in the last few decades has been incredible and today there are many super powerful machines that allow us to sequence a person’s DNA in an amount of the time that would have been unimaginable in the 1990s. However, data interpretation is still a problem. We still don’t have software capable of analyzing our complex genome, where genes and truly interesting and functional areas within DNA are very difficult to find.
Finding a gene in our DNA is like finding a needle in a haystack as most human DNA comes from other organisms and has been acquired over the course of evolution. Human genes have been diluted in a sea of virus and other parasite sequences that have infected us, introduced their DNA into ours and multiplied thousands of times until they filled us with repeated sequences that, in most cases, allow us to create useful products for our cells.
Our DNA is not very efficient; we carry a 100 kg backpack, but only use about 1 or 2 kg. Evolution hasn’t taken an engineer’s approach, but rather one better described as improvisational. If there had been someone responsible for designing the human genome the result would have been very different from what we have in our cells today. But one thing is clear: it works for us. Most of us are healthy and our genes function perfectly.
The human genome is comprised of 23 pairs of chromosomes that contain 23,500 genes with information to produce proteins representing around 1% of our genome. There are many types of changes in our DNA that make each individual quite different from everyone else. That individual genetic variability in humans affects many different areas such as variability in response to pharmaceuticals.
It is quite common to hear conversations in which different people comment on which medicines work best for them to treat a simple headache and frequently what works best for one person doesn’t work for another. It is also common for a doctor to change a patient’s treatment when they are not showing signs of improvement or when they show signs of undesired side effects. An estimated 38% of patients teated with antidepressants and 75% of oncology patients undergoing chemotherapy do not benefit from their treatment. Why? Perhaps behind these ineffective treatments lie DNA mutations responsible for the pharmaceutical not being metabolized appropriately.
Different DNA mutations would explain why a medicine is hardly effective or, otherwise, generates an adverse reaction that leads to a serious problem. It is believed that there may be close to 1,000 genes involved in the action of a drug, considering all the processes involved at the cellular and physiological level; and the variability of many of these genes may be incredibly clinically advantageous.
Pharmacogenetics, the science that studies the effects of genetic variability on individual response to pharmaceuticals, arose from the interaction of genetics, biochemistry, and pharmacology. Pharmacogenetics dates back to 510 B.C., when Pythagoras stated consuming beans would cause a potentially fatal reaction that, nevertheless, would not affect all individuals. We now know that this reaction was the result of hemolytic anemia induced by a deficiency of the enzyme Glucose-6-phosphate dehydrogenase. In 1956, Friedrich Vogel coined the term pharmacogenetics as we know it today.
The main goal of pharmacogenetics is to predict the risk of toxicity and/or therapeutic failure (lack of effect) when administering a certain compound to an individual. Let’s consider that adverse reactions constitute 4-7% of hospital admissions, entailing a high mortality rate (the fourth leading cause in the US) and, moreover, a strong economic impact. Advancements in pharmacogenetics are allowing the probability of positive results to be improved while reducing the risk of adverse reactions. This would entail a reduction in the number of hospitalizations and deaths and therefore a reduction in medical care costs.
Doctors would be able to abandon the traditional trial and error method to select the most appropriate drug for each patient from the outset, and thereby begin to practice precision medicine, with the knowledge of different details about the patient (genetic constitution, diet, age, lifestyle, etc.).
Will there be a day when genetic analysis will predict the pharmaceutical and dose an individual should take to tackle a specific disease? This is the main objective, and much progress has been made on it. For some drugs, a genetic analysis is already indicated and recommended before its prescription, in the leaflet. In many other cases, we have a full research project under way with no conclusive results yet.
The research team at Universidad Europea (called Human Genetic Variability) has studied groups of patients with breast cancer being treated with the drug tamoxifen with the hypothesis that mutations in different genes related to its metabolism may influence its effectiveness. Genes that encode for cytochrome enzymes CYP2D6, sulphotransferase SULT1A2 and glucuronidases UGT1A4, UGT2B7, UGT2B15 and UGT2B17, have proved to be of great importance in the metabolism of this drug. The presence or absence of mutations in these genes has been associated with plasma drug concentrations that vary greatly from patient to patient. Results of this research have been published in journals with a high impact index such as PlosOne or The Pharmacogenomics Journal where the research team has proposed a combination of variants in these genes that would increase drug levels in the patient’s blood, with the consequent impact on its efficacy.
Knowing the patient’s genotype will be hugely important for selecting the most appropriate drug and selecting the optimal dose for each individual. This is especially important when considering the aging of the population, which is occurring especially in developed countries. Above 70-80 years old, diseases begin to accumulate and the leading health problems are dementia, hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, and oncological pathologies. If you consider that seniors take an average of 6-12 different drugs per day, with their resulting adverse effects and interactions, it would be incredibly helpful to find a personalized alternative that would allow doctors to choose the most effective drug and dose with the lowest risk of associated complications.
In order to be able to accelerate the arrival of precision medicine, it would be advantageous to educate doctors on the advantages of using genetic and genome testing, standardize genotyping procedures for the leading classes of drugs, make progress on the validation of genetic tests for the most common diseases, and regulate the ethical, social, and financial aspects associated with all of these matters. Increasing the number of teaching hours in the field of genetics compared to what is currently required for medical degrees and especially creating a medical Genetics specialization in the Resident Physician program would be incredibly helpful to achieving this. Although a high number of Spanish hospitals currently offer genetics services where thousands of people receive genetic diagnoses, Spain continues to be the only European Union country that does not have a medical specialization in Genetics.
The fact that a specialization, which is already being practiced in reality is not officially recognized as such is surprising, but the economic impact of implementing it was what stopped it from being approved in 2016. We hope that in the near future doctors will be able to specialize in planning, conducting, and interpreting genetic testing in the clinical environment, as this is something absolutely key to progressing in the implementation of precision medicine, as well as optimizing public healthcare resources.