Beyond one size fits all

Imagine a scene where you and your best best-friend both go down with a bad headache and you both take the popular over the counter painkiller. But here's the twist within 30 minutes your friend is back playing fifa, listening loud metal music in his headphone but you …you're still in the bed moaning and groaning from the pain wondering if you took a wrong medicine.

Why does this happen ? Why does a certain medication work for one and does not have an effect on another person or at times even harm the other person ?

For time immemorial, medical treatments have been working on a one size fits all model where the medication or dose which worked for the average population was prescribed to everyone as the first-line medication. Works for many but for a substantially large number of people- the journey ends up being a medical roulette filling it with agony, pain, frustration in the search of finding ‘The One’ medicine for them .

But this game of hide and seek is ending soon, the world of medicine is ushering in a new age powered by your DNA and your genes. Welcome to the world of personalized medicine fueled by the engine of Pharmacogenomics .

What is Personalized Medicine?

Personalized Medicine, also known as Precision Medicine, is an approach to healthcare that customizes disease prevention and treatment by considering individual variability in genes, environment, and lifestyle. [1]

The aim is to treat individual patients instead of treating the disease. Factors like age, diet and environment play a role but a major role in medicine is played by your genetic make up. This is where the fascinating field of Pharmacogenomics comes into play.

Medicine behind the scene:  common man’s guide to pharmacogenomics

The term might sound intimidating, but it's simple when you break it down:

-Pharmaco-: Relating to drugs 

-genomics: Relating to the study of genetics (your gene). 

So, Pharmacogenomics is the study of how your genes affect your body's response to drugs.

Let’s understand this concept by an analogy .Think about your DNA as a cookbook which contains all the recipes needed to build and run your body. Each individual recipe is a gene. These genes contain instructions for making proteins. Proteins are one of the most important molecules of your body. They act as messengers, build structures and, crucially for our topic, they act as enzymes that process or metabolize everything you consume, including medications. Even though we all have the same cook book there can be small variations (typing error or due to having different versions of the book) in our individual book (gene). These small differences are what make us unique. A single typo (variation) in a gene that codes for a drug-metabolizing enzyme can drastically change how that enzyme works.

This variations lead to different metabolic profiles of metabolizers like-

1.Poor Metabolizers : They have enzymes (recipe error) that makes the resulting enzyme slow or inactive. When they take a standard dose of a drug, their body breaks it down very slowly. The drug can build up to toxic levels, causing severe side effects. Imagine a sink with a clogged drain – the water (drug) level rises dangerously. 

2.Normal Metabolizers: This is the standard expected recipe the drug was designed for. The enzyme works at the normal speed, and the drug is effective and safe at a standard given dose.

3. Rapid Metabolizers : They have enzymes (recipe error ) that break down the drug extremely quickly. A standard dose is cleared from their system so fast that it never reaches a high enough concentration to have any therapeutic effect.

A simple DNA test can help to find out to which category the given patient belongs to.

                               Pharmacogenomics in real world 

The case of Blood thinners

Warfarin is a widely used anticoagulant (blood thinner) to prevent blood clots, strokes and heart attacks. But the problem with warfarin is to determine its accurate dose. If the dose is too much it may cause bleeding- which is life-threatening and if the dose is less it may lead to clotting . In 2007, the US FDA came up with a solution for this whose basis was pharmacogenomics . They updated the label for Warfarin to include information on how variations in two specific genes,CYP2C9 (which metabolizes the drug) and(VKORC1) (the protein the drug targets), can impact dosing. 

Clinical guidelines now recommend using this genetic information to predict a more accurate starting dose, dramatically reducing the risks of bleeding or clotting during the initial phase of treatment. [2]

Finding the Right Antidepressant

Often patients with depression have to go through a painful process of trial and error to find the right antidepressant for them . Many anti-depressant especially SSRI's, are metabolised by enzymes CYP2D6 and CYP2C19 enzymes. A patient who is a 'poor metabolizer' for CYP2D6 experiences great side effects when given a standard dose Clinical guidelines from CPIC provide dose recommendations for l antidepressants based on a patient's genetics  for these enzymes, helping doctors make more informed choices. [3]

Targeting Cancer at its Genetic Core

Chemotherapy which is currently predominantly used to treat cancer kills both cancerous and healthy cells, thus we see several side effects . Using pharmacogenomics we can test the cancer of patient and find out the specific genetic mutation that has caused the cancer and possibly treat it. Example: some of the cases of non-small cell lung cancers are caused due to mutation in the Epidermal Growth Factor Receptor (EGFR) gene. Patients with this mutation can be treated with drugs like gefitinib, which specifically targets the faulty EGFR protein. For such patients such targeted therapy is much more successful than non specific chemotherapy. [4]

 Genetics for lungs 

 Another example we can find is of the drug (Kalydeco) is used to treat cystic fibrosis, but only in patients who have a specific genetic mutation (G551D-CFTR mutation), for approximately 4-5% patients with this mutation drug corrects the defects leading to improvement in lung function  For anyone without that mutation, it is ineffective [5]

  FUTURE VISION  AND CHALLENGES 

While personalized medicine has immense potential,we are still in early stages of the field . There are numerous hurdles like cost, management of immense data and the need for continued education for clinicians. Though the ray of hope is the cost of sequencing a human genome, which has fallen at a rate far faster than Moore's Law, from billions of dollars during the Human Genome Project to under a thousand dollars today, making it more accessible than ever.

We can now imagine a future- perhaps in a decade or two from now, your check-up would include accessing your genetic profile . When you get sick, your doctor won't just ask about your symptoms; they will consult your genetic data. A new prescription would be cross-referred with your genome data for potential side effects . Genetic risks for conditions like heart disease or diabetes will be established beforehand and allow for truly preventative and personalized lifestyle.

We are moving away from the era of 'one-size-fits-all' medicine and into an era of unmatched precision. We are not just creating better drugs, but building a smarter, safer and more personal future for healthcare by using our DNA codes. Your DNA is now no longer a mystery for health but a solution to healthier life.

References :

[1]  .Sadee W, Wang D, Hartmann K, Toland AE. Pharmacogenomics: Driving Personalized Medicine. Pharmacol Rev. 2023 Jul;75(4):789-814. doi: 10.1124/pharmrev.122.000810. Epub 2023 Mar 16. PMID: 36927888; PMCID: PMC10289244.

[2] Božina N. The pharmacogenetics of warfarin in clinical practice. Biochem Med (Zagreb). 2010;20:33-44

[3]  Biernacka JM, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, Altman RB, Arolt V, Brockmöller J, Chen CH, Domschke K, Hall-Flavin DK, Hong CJ, Illi A, Ji Y, Kampman O, Kinoshita T, Leinonen E, Liou YJ, Mushiroda T, Nonen S, Skime MK, Wang L, Baune BT, Kato M, Liu YL, Praphanphoj V, Stingl JC, Tsai SJ, Kubo M, Klein TE, Weinshilboum R. The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response. Transl Psychiatry. 2015 Apr 21;5(4):e553. doi: 10.1038/tp.2015.47. Erratum in: Transl Psychiatry. 2016 Nov 1;6(11):e937. doi: 10.1038/tp.2016.187. PMID: 25897834; PMCID: PMC4462610.

[4] Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., Louis, D. N., Christiani, D. C., Settleman, J., & Haber, D. A. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of Non–Small-Cell lung cancer to gefitinib. New England Journal of Medicine, 350(21), 2129–2139. 

[5] ght, C. E., Konstan, M. W., Moss, R., Ratjen, F., Sermet-Gaudelus, I., Rowe, S. M., Dong, Q., Rodriguez, S., Yen, K., Ordoñez, C., & Elborn, J. S. (2011). A CFTR Potentiator in Patients with Cystic Fibrosis and theG551DMutation. New England Journal of Medicine, 365(18), 1663–1672.