The Importance Of Pharmacogenomics
Pharmacogenomics is the study of genes and their effects on medicine. When you are getting a suit tailored, the tailor takes your measurements so the suit that they tailor can genuinely be a perfect fit. That’s what pharmacogenomics does for medicine. And all this takes is one test normally done by blood or saliva.
Prescription medicines are such a big part of our medical system yet a lack of personalization leaves 2 million patients developing serious side effects and over 100, 000 dead. This is only in America. The lack of personalization isn't only a problem in pharmaceuticals it can occur in more serious treatments and procedures. Because mainstream medicine is so “mainstream” doctors don't give a second thought to a patient's true needs.
Pharmacogenomics makes sure that doctors have the chance to personalize their patient's treatments. With pharmacogenomics when prescribing antibiotics to a patient they won't prescribe the dosage just based on their weight. They'll include things like how fast the patient can metabolize medicines, or how resistant their genes are to treatments.
To explain simply, imagine if every day everyone wore the same sized clothes. No matter if you were 3ft or 7ft, 80 pounds or 300 pounds. That would be bizarre right? Yes, that would be considered crazy because these people are so different. Well so are all of our genes yet were still being given the same prescriptions.
With pharmacogenomics, doctors can finally understand your genes and personalize your medicine to your genes and how your body works, not just your weight and your symptoms.
Pharmacogenomics encompasses two main factors. First is pharmacokinetics, pharmacokinetics studies the absorption, distribution, metabolism, and excretion of the drug. While the second, pharmacodynamics studies the effects of drugs and the mechanism of their actions.
To put it simply, pharmacokinetics studies how a drug moves and distributes throughout the body. This process starts by entering the body and then to the bloodstream (Absorption), then it needs to reach the target site (Distribution). The drug then needs to be processed and broken down(Metabolism), and finally how it leaves the body(Excursion).
Pharmacodynamics is the more complicated factor of Pharmacogenetics. Because of the fact that it studies every detail of how the drug affects the patient body, and how well it works. This includes the receptor binding process and post-receptor effects, the molecular effects, the physiologic effects, the biochemical effects, and more.
To learn more about the basics of pharmacogenomics and what it is, read this article of mine:
https://medium.com/studentsxstudents/the-key-to-tailored-medical-treatments-4b551d233e77
A big problem we face with pharmacogenomics is that people don't understand the effect that implementing pharmacogenomics into our healthcare world can have. Or better yet, how important it is. So to understand the importance of pharmacogenetics I have created small samples of DNA that would be found in specific proteins. With these, I understand and explain their meaning and how pharmacogenetics will take these genes and curate an accurate prescription.
But before we look at those, we’re gonna understand how proteins are made in our body, and how to read their DNA/mRNA
How your body makes proteins:
Pharmacogenomics is the study of genes, genes are segments of DNA. This DNA determines the proteins you have in your cells. And the proteins you have in your cells determine the actions/functions of your cells, cells make up your body and have an effect on the medicine you take.
The process by which your body makes proteins is quite complicated. In order to make proteins DNA, mRNA, and tRNA all work together.
DNA is made up of nucleotides(A, G, C, and T are the DNA’s nucleotides). Think of DNA as the original “code” or “coding” of a protein. DNA is found in the nucleus, and inside a nuclease, there are chromosomes where long strands of DNA are found. (a small amount of DNA can be found in the mitochondria).
Once protein synthesis begins (the making of proteins). A gene gets activated (genes are a section of DNA). Once this section of DNA is activated the DNA starts to open up or “unzip”. (When the DNA strand is open people often refer to the nucleotides as free bases)
Then the RNA polymer attaches to the open DNA, this enzyme moves along the DNA. As it moves along the DNA a strand of messenger RNA(mRNA) is made. The role of mRNA is to pair with DNA so it can transport protein information.
Once the mRNA strand is made it leaves the nucleus and travels to the cytoplasm. In the cytoplasm, the ribosome translates the mRNA’s code so it can produce amino acid chains.
In the ribosome is tRNA, which links the mRNA to the amino so the amino acid chain can be produced. The chain of amino acids then becomes a protein
Now that you’ve understood the process of how proteins are made whats DNA? How do they encode amino acids? How does mRNA pair with DNA? What amino acids are proteins made of?
To start off we're gonna use the following sample to reference:
The underlined part is the original DNA, and the bolded/highlighted part is what the mRNA match would look like.
Let’s start with the DNA (the underlined part). As you see there are A, C, G, and T. These are the nucleotides, nucleotides are the chemical basis of DNA, adenine (A), guanine (G), cytosine(C), and thymine (T). Now for the mRNA (the highlighted part). The mRNA is made to pair with the DNA so guanine(G) and cytosine(C) pair. While thymine and adenine pair together, except for the fact that in mRNA instead of thymine there is uracil(U).
Reading:
The next step is understanding what all these nucleotides aka “letters” mean.
The first step to this is to break the nucleotides into codons. Codons are every three nucleotides. In the sample above you can already see the space between every 3 nucleotides. The important thing to know is that each codon encodes for an amino acid.
So for example let’s look at the first 3 “letters” in the sample I gave you earlier. The first 3 letters in the DNA are T, A, and C. The mRNA matches would be A, U, and C. Instead of writing T in mRNA you write U for uracil.
And now that we know that, we need to learn how to understand these codons. First things first, when determining the amino acids you only look at the mRNA. Because the mRNA is what goes through the ribosome the DNA is what provides the information for the mRNA to pair with and take through the ribosome.
When reading the codons you're gonna be referencing this sheet:
For example, say a codon is CAG. First, you look at the first circle for the C. Once you find the first C you look to the outer ring to get A then once you find the A you find the G. When your path reaches the last letter you get narrowed down to one amino acid, in this case, its gln(Glutamine).
The arrows or squares indicated the start or stop of a protein chain.
There is a multitude of amino acids each codon can encode here are all of them:
- Phe/Phenylaline — Involved in the production of neurotransmitters, norepinephrine, and dopamine, melanin.
- Leu/Leucine — Protein synthesis. Aids muscles and regulates several processes such as protein synthesis, regeneration and metabolism. It’s essential for growth in children. High levels can lower blood sugar.
- Ser/Serine — Plays a role in protein synthesis and intercellular metabolism. Serine is needed for the production of tryptophan(makes steroids) High levels of Serine indicate glucogenic compensation and catabolism.
- Tyr/Tyrosine — Tyrosine is made from Phe. Similar to Phe it's essential for the production of brain chemicals
- Met/Methionine- Methionine is the first/start amino acid of every protein. Essential to the creation of proteins.
- Lys/Lysine — Lysine is a building block for making proteins and helps make collagen
- Gly/Glycine- Glycine contributes to cellular growth and health
- Glu/Glutamic-Glutamic is the most abundant excitatory neurotransmitter in the vertebrae’s nervous system. It's used in almost all proteins.
- Arg/Arginine-Arginine plays a role in physiologic effects. It helps the body build proteins.
- His/Histidine- Histidine is essential for tissue growth and repair. Precursor for several hormones and helps protect nerve cells
- Thr/Threonine- Threonine is used in the biosynthesis of proteins
- Pro/Proline — Proline is a building block of proteins, helps metabolism and neutrinos, aids in the healing of wounds
- Asn/Asparagine- Asparagine plays an important role in the biosynthesis of glycoproteins and other proteins
- Cys/Cysteine — Cysteine is a building block of proteins and is used throughout the body
- Trp/Tryptophan-Tryptophan is needed for normal growth in infants and for the production and maintenance of the body’s proteins, muscles, enzymes, neurotransmitters
- Asp/Aspartate — Aparate is used in the biosynthesis of proteins
- Ala/Alanine — Alanine is s used to make proteins. Is a source of energy in muscles and the nervous system. Strengthen the imine system and helps blood sugar.
- Val/Valine — Valine is used in the biosynthesis of proteins
- Ile/Isoleucine — Isoleucine helps how hemoglobin is made. Contributes to the pigment in red blood cells. Controls blood sugar and raises energy levels
- Gln/Glutamine — Glutamine is a building block of proteins and a critical part of the immune system
So after each codon is read and you’ve identified what amino acids there are, the protein is then created. Your intercellular proteins help transport the drug, break down the drug, and more. It plays a great role in the effects of medicines and treatments. So to understand the importance of what pharmacogenomics does, I’ve written the following DNA and mRNA samples. Looking at them, I analyze them and explain what’s in them and the role the proteins play. And most importantly understand the effects they have on medicine and why this information would be important for doctors to know.
Observe:
To better understand the importance of pharmacogenomics, I’ve chosen certain intercellular proteins that have an effect on the medicine you take.
The ABCA3 protein falls under the ABC transporter category. And is a member of the superfamily of ATP-binding cassette transporters:
Amino Acids Found In This Sample of mRNA:
- Gly/Glycine- Glycine contributes to cellular growth and health
- Lys/Lysine — Lysine is a building block for making proteins and helps make collagen
- Pro/Proline — Proline is a building block of proteins, helps metabolism and neutrinos, aids in the healing of wounds
- Asp/Aspartate — Aparate is used in the biosynthesis of proteins
It is given that the genes or strands of DNA that encode proteins are much longer than this. So consider it as a sample size, to understand what specific protein this could be for you only look at the mRNA because that’s what the ribosome reads. The underlined part is only the DNA. From this sample, you can see different colours these colours are the different amino acids.
This protein (ABCA3) the gene for it is found in chromosome 16. Each cell has 23 chromosomes and chromosome likely contains 800 to 900 genes that provide instructions for making proteins.
Now that you know all this, why is it important that pharmacogenomics studies these genes, or any genes for that reason?
As I said the ABCA3 protein causes great multidrug resistance. An example of this is chemotherapy. In cancer tumours, this protein is found and has been seen to make the treatment process longer. In one study the median expression of the ABCA3 was three times higher in patients who had failed to achieve remission.
This proves the power of how resistant the ABCA3 protein is. In fact, ABCA3 is the most likely transporter to cause drug resistance. This protein is only one of the examples of why doctors need to use pharmacogenomics. If someone's DNA looks similar to the ones I’ve written above they would recognize the ABCA3 protein and adapt the treatment plan or prescription accordingly. But without pharmacogenomics, they wouldn't be able to adapt the medicine, and if a problem is detected they won't know the real reason behind it.
But what does this mean, let's say someone comes in with a cold, and gets prescribed cold medicine. Now the dosage of this cold medicine would be given based on a patient's age and weight. The problem is that the doctor hasn’t understood the patient's genes and how much medicine their body actually needs. More specifically, they don't know how much of the drug will actually fight the cold. Because of the fact that they haven't studied the patient's genes, it's possible that the patient could have high levels of ABCA3 which would require higher dosages.
A patient who has high ABCA3 will demonstrate higher drug resistance. This means that lower amounts of medicine can enter the circulatory system. The liver will metabolize drugs differently, and when done lower amounts of the medicine will reach the target site. Once it reaches the target site the transporter and bonding process will also be affected.
Another reason why pharmacogenomics testing is important is that it can lead to early discovery.
Although the point of pharmacogenomics is to personalize and improve medical treatments or prescriptions. It can also save lives through testing. For example in this case it's been found that patients with very low amounts of ABCA3 are at risk for lung cancer. So while a gene test is done even if it won't change a prescription amount it could lead to early detection of things like cancer.
Although ABCA3 is one of the proteins that have displayed high amounts of multidrug resistance there are other proteins that make your body more resistant to drugs as well.
The ABCC10 Protein is part of the MRP subfamily:
The amino acids you can see in the mRNA here are:
- Gly/Glycine- Glycine contributes to cellular growth and health
- Glu/Glutamic-Glutamic is the most abundant excitatory neurotransmitter in the vertebrae’s nervous system. It's used in almost all proteins.
- Leu/Leucine — Protein synthesis. Aids muscles, and regulates several processes such as protein synthesis, regeneration and metabolism. It’s essential for growth in children. High levels can lower blood sugar.
- Asn/Asparagine- Asparagine plays an important role in the biosynthesis of glycoproteins and other proteins
- Gln/Glutamine — Glutamine is a building block of proteins and a critical part of the immune system
- Trp/Tryptophan-Tryptophan is needed for normal growth in infants and for the production and maintenance of the body’s proteins, muscles, enzymes, neurotransmitters
- Pro/Proline — Proline is a building block of proteins, helps metabolism and neutrinos, aids in the healing of wounds
- Lys/Lysine — Lysine is a building block for making proteins and helps make collagen
These amino acids are commonly found in the ABCC10 protein.
The ABCC10 protein also displays multidrug resistance. This protein transports various molecules across extra and intercellular membranes. This group is capable of conferring resistance to a variety of anticancer and antivirus drugs, including taxanes and nucleoside analogs.
The DNA and mRNA above are only a sample of what the protein's instructions would look like. But if a patient's genes had overexpression of ABCC10 it would be important for doctors to know this.
Often when patients have a high resistance to drugs, doctors don't know why or whether the drug is working or not. In this case, say the patient has an overexpression of ABCC10 and the medicine is taking longer to work or she just needs more medicine. The doctor can just easily assume that the medicine isn’t working at all. This is just an example of why pharmacogenomics would be useful in this case, here’s another multidrug-resistant protein.
The ABCB1 Protein belongs to a group of genes called the ATP-binding cassette family:
If you look at the mRNA part the main amino acids found are:
- Phe/Phenylaline — Involved in the production of neurotransmitters, norepinephrine, and dopamine, melanin.
- Leu/Leucine — Protein synthesis. Aids muscles regulate several processes such as protein synthesis, regeneration and metabolism. It’s essential for growth in children. High levels can lower blood sugar.
- Ser/Serine — Plays a role in protein synthesis and intercellular metabolism. Serine is needed for the production of tryptophan(makes steroid) High levels of Serine indicate glucogenic compensation and catabolism.
- Ala/Alanine — Alanine is s used to make proteins. Is a source of energy in muscles and the nervous system. Strengthen the imine system and helps blood sugar.
- Glu/Glutamic-Glutamic is the most abundant excitatory neurotransmitter in the vertebrae’s nervous system. It’s used in almost all proteins.
- Ile/Isoleucine — Isoleucine helps how hemoglob is made. Contributes to the pigment in red blood cells. Controls blood sugar and raises energy levels
- Trp/Tryptophan-Tryptophan is needed for normal growth in infants and for the production and maintenance of the body’s proteins, muscles, enzymes, neurotransmitters
- Gln/Glutamine — Glutamine is a building block of proteins and a critical part of the immune system
These amino acids are commonly found in the ABCB1 protein. ABCB1 is known for its involvement in multidrug resistance of tumour cells preventing the intracellular accumulation of cytotoxic drugs.
An example of a situation this protein can have an effect on is nerve pain. Let's say a patient comes in with nerve pain, and a doctor prescribed them nortriptyline. Basing the dosage on the pain, weight and age. But what if the patient had high levels of ABCB1? This protein would potentially pump the drug back into the lumen, decreasing the drug's absorption. ABCB1 would also decrease bioavailability, which is how much of the drug would end up reaching the target site.
As you see all three proteins displayed above play a role in drug resistance. And they also prove the importance of pharmacogenomics. By looking at the DNA/mRNA examples that I've written, and after we've understood the potential effects they can have on patients. You can see how easy it is for a patient's body to be more resistant to drugs because of a few simple proteins. And the important part is that doctors can't uncover these genes/proteins without pharmacogenomics.
The CYP3A4 Protein is a member of the cytochrome P450 superfamily:
The amino acids found here are:
- Phe/Phenylaline — Involved in the production of neurotransmitters, norepinephrine, and dopamine, melanin.
- Ser/Serine — Plays a role in protein synthesis and intercellular metabolism. Serine is needed for the production of tryptophan(makes steroid) High levels of Serine indicate glucogenic compensation and catabolism.
- Ile/Isoleucine — Isoleucine helps how hemoglobin is made. Contributes to the pigment in red blood cells. Controls blood sugar and raises energy levels.
- Thr/Threonine- Threonine is used in the biosynthesis of proteins.
- Arg/Arginine-Arginine plays a role in physiologic effects. It helps the body build proteins.
- Asp/Aspartate — Aparate is used in the biosynthesis of proteins.
- His/Histidine- Histidine is essential for tissue growth and repair. Precursor for several hormones and helps protect nerve cells.
- Tyr/Tyrosine — Tyrosine is made from Phe. Similar to Phe it’s essential for the production of brain chemicals.
These amino acids are commonly found in the CYP3A4 protein. The CYP3A4 is responsible for the metabolism of more than 50 percent of medicines. The liver and small intestine have the highest CYP2A4 activity, the liver is where the majority of drugs are metabolized. High or low levels of CYP3A4 are important, it's important for doctors to know at what rate a patient can metabolize drugs. Meaning they should always be aware of the CYP2A4 levels.
After looking at proteins and samples of the DNA/mRNA sequencing, you can see how genes and proteins have an effect on medicine. So, even though pharmacogenomics can make a huge impact on the medical world, why aren't we using it?
There's one problem and it comes down to ethics. On May 21st, 2008, the GINA law was passed. GINA is the Genetic Information Nondiscrimination Act and was passed by congressmen to protect Americans from genetic discrimination. This focuses on preventing genetic discrimination between patients and doctors. It states that it is illegal to require genetic testing for patients. This prohibits insurance companies from using genetic information to adjust premiums, deny coverage or impose restrictions that relate to preexisting conditions. This law and its purpose are why certain experts are raising ethical questions about pharmacogenomics.
But let's not forget the many benefits of pharmacogenomics:
1. Increased Effectiveness: By taking into account a patient’s unique genetic makeup, doctors can more accurately target the root cause of a disease or condition. This can lead to more effective treatment and, ultimately, better health outcomes.
2. Fewer Side Effects: Personalized medicine can also help to minimize the risk of side effects from treatment. By targeting the root cause of a disease, personalized medicine can reduce the need for potentially harmful medications or treatments.
3. Improved Quality of Life: Personalized medicine can also improve a patient’s quality of life. By providing more effective and safer treatment, personalized medicine can help patients live longer, healthier, and happier lives.
4. Reduced Costs: In the long run, by allowing doctors to target treatments specifically to each individual patient’s needs, patients’ treatments will be more successful. This means that patients are less likely to experience side effects from treatments, and they won’t require multiple treatments/follow-up treatments.
Now, it's not like pharmacogenomics is some new discovery, there are many people who are constantly using and making new developments in pharmacogenetics. Now, these people understand how important pharmacogenomics is and its potential.
Many companies, both large and small, are working on developing pharmacogenomics-based solutions and applications. Some companies are using pharmacogenomics for more personalized at-home medicine:
- NalaGenetics is making pharmacogenomics simpler and more convenient. This startup offers personalized health and prescription solutions. Through at-home testing kits and solutions, they've found a way to make pharmacogenomics assessable to any patient. Their at-home testing kit gives you a personalized report and counselling from your phone in 5 easy steps. This gives you information on multiple prescriptions or conditions and gets rid of painful and frustrating side effects along with ineffective medicine. Their testing kits include “R Ready” and “R React.” “R Ready,” is a genetic panel that analyzes multiple genes to provide recommendations for pain management, cardiovascular treatments, psychiatry care and many other medications. “R React” is more specific and provides specialized pharmacogenetic tests for a certain drug class.
- Phenomics Health products predict and measure medications. Their platform leverages machine learning and bioinformatics to improve precision in treatments. An example of one of their products is PrecisView. PrecisView quantitates medications to enable dose optimization of therapy related to depression, anxiety, and chronic pain.
- Fagron Genomics is an in vitro medical device manufacturer specializing in the development and servicing of medical genetic algorithms. This startup makes at-home products to personalize your health care. An example of one of their products is the TeloTest. Their TeloTest provides the most appropriate formula recommendation to delay the effect of aging.
Ultimately, the purpose of pharmacogenomics is to better improve the world of medicine, and I hope this article helped you better understand what and why it studies your genes, proteins, and DNA.
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