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

 

The plants and the climate change

Since a few years ago, we have heard about the climate change. Nowadays, it is already evident and also a concern. This not only affects to us, the humans, but to all kind of life. It has been talked enough about the global warming, but perhaps, what happens to the vegetation has not been much diffused. There are many things affected by climate change and vegetation is also one of them. In addition, the changes in this also affect us. But, what are these changes? how can the vegetation regulate them? And how we can help to mitigate them through plants?

CHANGES ON PLANTS

Biomes distribution

In general, due to climate change, an increase of precipitations in some parts of the world are expected, while in others a decrease is awaited. A global temperature increment is also denoted. This leads to an alteration in the location of the biomes, large units of vegetation (e.g.: savannas, tropical forests, tundras, etc.).

Biome triangle classified by latitude, altitude and humidity (Author: Peter Halasaz).

On the other hand, there is an upward trend in the distribution of species in the high latitudes and a detriment in the lower latitudes. This has serious associated problems; the change in the species distribution affects their conservation and genetic diversity. Consequently, the marginal populations in lower latitudes, which have been considered very important for the long-term conservation of genetic diversity and due their evolutionary potential, are threatened by this diversity loss. And conversely, the populations in high latitudes would be affected by the arrival of other competing species that could displace those already present, being as invasive.

Species distribution

Within the scenario of climate change, species have some ability to adjust their distribution and to adapt to this.

But, what type of species may be responding more quickly to this change? It appears that those with a faster life cycle and a higher dispersion capacity will be showing more adaptability and a better response. This could lead to a loss of some plants with slower rates.

The Purple milk Thistle (Galactites tomentosa) is a plant with a fast life cycle and high distribution capacity  (Author: Ghislain118).

One factor that facilitates adjustment in the distribution is the presence of wildlife corridors: these are parts of the geographical area that enable connectivity and movement of species from one population to another. They are important because they prevent that some species can remain isolated and because they can also allow the movement to new regions.

Another factor is the altitudinal gradient, which provides shelter for many species, facilitates the presence of wildlife corridors and permits redistribution of species along altitude. Therefore, in those territories where there is greater altitudinal range, the conservation is favored.

In short, the ability of species to cope with climate change depends on the plant characteristics and the territory attributes. And, conversely, the species vulnerability to climate change occurs when the speed to displace their distribution or adapt their lives is less than the climate change velocity.

At internal level

Climate change also affects the plant as an organism, as it causes changes in their metabolism and phenology (periodic or seasonal rhythms of the plant).

One of the effects that pushes the climate change is the carbon dioxide (CO₂) concentration increase in the atmosphere. This could produce a fertilization phenomenon of vegetation. Due the CO₂ increase in the atmosphere it also increases the uptake by plants, thus increasing the photosynthesis and allowing greater assimilation. But, this is not all advantages, because for this an important water loss occurs due that the stomata (structures that allow gas exchange and transpiration) remain open long time to incorporate CO₂. So, there are opposing effects and fertilization will depend on the plant itself, but the local climate will also determine this process. Many studies have shown that various plants react differently to the CO₂ increase, since the compound affects various physiological processes and therefore there are not unique responses. Then, we find a factor that alters the plant metabolism and we cannot predict what will be the effects. Furthermore, this fertilizer effect is limited by the nutrients amount and without them production slows.

Photosynthesis process (Author: At09kg).

On the other hand, we must not forget that climate change also alters the weather and that this affects the vegetation growth and its phenology. This can have even an impact on a global scale; for example, could produce an imbalance in the production of cultivated plants for food.

PLANTS AS CLIMATE REGULATORS

Although one cannot speak of plants as regulators of global climate, it is clear that there is a relationship between climate and vegetation. However, this relationship is somewhat complicated because the vegetation has both effects of cooling and heating the weather.

The vegetation decreases the albedo; dark colours absorb more solar radiation and, in consequence, less sunlight is reflected outward. And besides, as the plants surface is usually rough, the absorption is increased. Consequently, if there is more vegetation, local temperature (transmitted heat) intensifies.

But, on the other hand, by increasing vegetation there is more evapotranspiration (set of water evaporation from a surface and transpiration through the plant). So, the heat is spent on passing the liquid water to gas, leading to a cooling effect. In addition, evapotranspiration also helps increase local rainfall.

Biophysical effects of different land uses and its consequences on the local climate. (From Jackson et al. 2008. Environmental Research Letters.3: article 0440066).

Therefore, it is an ambiguous process and in certain environments the cooling effect outweighs, while in others the heating effect has more relevance.

MITIGATION

Nowadays, there are several proposals to reduce climate change, but, in which way can the plants cooperate?

Plant communities can act as a sinks, carbon reservoirs, because through CO₂ assimilation, they help to offset carbon emissions. Proper management of agricultural and forest ecosystems can stimulate capture and storage of carbon. On the other hand, if deforestation were reduced and protection of natural habitats and forests increased, emissions would be diminished and this would stimulate the sink effect. Still, there is a risk that these carbon sinks may become emission sources; for example, due to fire.

Finally, we must introduce biofuels: these, unlike fossil fuels (e.g. petroleum), are renewable resources, since they are cultivated plants for use as fuels. Although they fail to remove CO₂ from the atmosphere or reduce carbon emissions, they get to avoid this increase in the atmosphere. For this reason, they may not become a strict mitigation measure, but they can keep neutral balance of uptake and release. The problem is that they can lead to side effects on social and environmental level, such as increased prices for other crops or stimulate deforestation to establish these biofuel crops, what should not happen.

Sugarcane crop (Saccharum officinarum) in Brazil to produce biofuel (Author: Mariordo).

REFERENCES

• Notes of Plant Physiology, Science of the Biosphere and Analysis of vegetation, Degree of Environmental Biology, UAB
• Hample & R. J. Petit. 2005. Conserving biodiversity under climate change: the rear edge matters. Ecology letters 8 (5): 461-467.
• Botanic Gardens Conservation International. 2015. How does climate change affect plants?. https://www.bgci.org/climate/climate_change_effects/
• Earth Observatory. 2015. How plants can change our climate. http://earthobservatory.nasa.gov/Features/LAI/LAI2.php