{"id":37,"date":"2020-02-27T23:53:39","date_gmt":"2020-02-27T23:53:39","guid":{"rendered":"https:\/\/www.omnipgx.com\/blog\/?p=37"},"modified":"2020-03-05T22:05:33","modified_gmt":"2020-03-05T22:05:33","slug":"the-history-of-pharmacogenomics","status":"publish","type":"post","link":"https:\/\/www.omnipgx.com\/blog\/the-history-of-pharmacogenomics\/","title":{"rendered":"The History of Pharmacogenomics"},"content":{"rendered":"

We now know what pharmacogenomics is<\/strong><\/a> and why it’s so important<\/strong><\/a>, but where did it all start, and when? Who recognized the need for personalized medicine? And how did pharmacogenomics<\/a> become what it is today? In this article, we will explore the history of pharmacogenomics<\/a>.<\/p>\n\n\n\n

First, pharmacogenomics<\/a> is the study of how inheritable genetic differences can affect they way individuals react to certain medications. Everyone is different, and we metabolize, absorb, and respond to treatments in different ways. The goal of pharmacogenomics<\/a> is to figure out how a patient will respond to particular treatments. From there, doctors can reduce the prevailing trial and error method of drug therapy<\/strong> used in healthcare today.<\/p>\n\n\n\n

An Illuminating Discovery<\/h3>\n\n\n\n

The history of pharmacogenomics<\/a> starts all the way back in 510 B.C. with Pythagoras. You may remember him as the same man who discovered the Pythagorean Theorem<\/a><\/strong>. However, outside of mathematics, he was crucial to pharmacogenomics<\/a> as well. Pythagoras was the first to discover that the ingestion of fava beans causes a potentially fatal reaction. This fatal reaction involved hemolytic anemia<\/strong> <\/a>and oxidative stress<\/a>.<\/strong> <\/p>\n\n\n\n

After watching the phenomenon happen multiple times, Pythagoras realized that the reaction didn’t occur in everyone. It only affected certain individuals. This was the first glimmer of a pharmacogenomic discovery. In the 1950s, scientists eventually validated Pythagoras’ identification of the lethal reaction some people experience after eating fava beans. They attributed it to a deficiency of the gene<\/a> that codes for the protein<\/a> called G6PD<\/strong>. This deficiency was fittingly called favism<\/strong><\/a>. <\/p>\n\n\n\n

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Few people are aware that Pythagoras conceptualized gene<\/a> variants.<\/figcaption><\/figure>\n\n\n\n

The Formative Years<\/h3>\n\n\n\n

Fast forward a couple thousand years to the 1950s. Many people regard the 1950s as the unofficial start of pharmacogenomics<\/a>. However, several important scientific discoveries occurred before then. Without these discoveries, pharmacogenomics<\/a> probably would not be what it is today. For example, in 1866, Gregor Mendel established the rules of heredity<\/a><\/strong>. His contribution successfully laid down the groundwork for others to advance the field of genetics. Likewise, in 1906, Sir Archibald Edward Garrod published his book ‘Inborn Errors of Metabolism<\/a><\/em>’. <\/p>\n\n\n\n

Garrod was the first to propose that diseases were the result of missing or false steps in the body’s metabolic pathways. Also, he hypothesized that the atypical metabolism<\/a> of external substances, such as food or drugs, could cause abnormal reactions. <\/p>\n\n\n\n

Additionally, in 1932, geneticist Laurence Snyder discovered that some humans can taste the bitter compound phenylthiocarbamide (PTC)<\/strong><\/a>, while others cannot. He revealed that an autosomal recessive gene variant <\/a><\/strong>allows some people to taste it.<\/p>\n\n\n\n

Pharmacogenomics Started to Take Off in the 1950’s<\/h3>\n\n\n\n

In 1956, the scientific community finally accepted the influence of heredity on drug response. This occurred after doctors began reporting instances of their patients suffering prolonged paralysis or even death after they had been given anesthesia. Scientists linked these instances to genetic variants that caused certain proteins associated with metabolizing anesthesia to be missing. <\/p>\n\n\n\n

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A standard dose of anesthesia may cause some patients to respond negatively.<\/figcaption><\/figure>\n\n\n\n

Furthermore, during and after World War II, doctors reported the first cases of genetically determined adverse drug reactions (ADRs)<\/strong>. The ADRs in these reports referred to the development of hemolytic anemia in African-American soldiers after exposure to the antimalarial drug primaquine<\/strong><\/a>. Scientists found that all of the soldiers who experienced adverse reactions had a G6PD deficiency<\/strong>. Thus, soldiers who developed hemolytic anemia in response to primaquine did not have the protein<\/a> (G6PD), which properly metabolizes it. Coincidentally, G6PD deficiency is the same enzyme<\/a> deficiency that Pythagoras discovered in 510 B.C. <\/p>\n\n\n\n

A new advancement in pharmacogenomics<\/a> occurred two years after the discovery of the genetic predisposition for primaquine-induced toxicity. Arno Motulsky<\/strong><\/a>, a scientist at the University of Seattle in Washington proposed that the inheritance of genes causes the differences in drug response among individuals. <\/p>\n\n\n\n

Then, in 1959, Friedrich Vogel<\/strong><\/a> of Heidelberg, Germany coined the term ‘pharmacogenetic’, relating to how people respond differently to drugs based on their DNA.<\/p>\n\n\n\n

The History of Pharmacogenomics in the 60’s and 70’s<\/h3>\n\n\n\n

Research on pharmacogenomics<\/a> accelerated in the 1960s. Scientists around the world began conducting studies to uncover more connections between genes and drug response. For example, in the late 1960s, studies on twins supported the hypothesis that genetics influence drug metabolism<\/a>. Scientists deduced this from observing that identical twins share remarkable similarities in drug response. In comparison, fraternal twins<\/strong> generally do not<\/strong>. <\/p>\n\n\n\n

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These newborn identical twin boys are more likely to share similarities in drug response than two fraternal twins.<\/figcaption><\/figure>\n\n\n\n

Additionally, in the 1960s and 1970s, scientists began measuring the concentrations of drugs and their metabolizing enzymes in plasma. They were looking to define outlier patients<\/strong> who were negatively affected by those drugs. <\/p>\n\n\n\n

Scientists determined the outliers by singling out patients with unusually high or low plasma concentrations. Those abnormal concentrations were then associated with adverse drug reactions (ADRs). <\/p>\n\n\n\n

Piggybacking off those earlier studies, geneticists produced new studies that allowed researchers to define variants in key drug metabolizing genes. These variants serve as the basis for specific drug responses. <\/p>\n\n\n\n

One study, carried out by Mahgoub et al.<\/em> in 1979, led to the discovery of the variant in the debrisoquine hydroxylase sparteine oxidase<\/strong> gene<\/a>. This variant causes an adverse reaction in response to debrisoquine<\/strong>, a drug used to treat hypertension.<\/p>\n\n\n\n

Major Projects in the 80’s and 90’s<\/h3>\n\n\n\n

In 1988, the U.S. Congress commissioned the Department of Energy and the National Institutes of Health to plan and carry out the Human Genome Project<\/strong><\/a>. The goal was to sequence the entire human genome<\/a> by 2005, and mapping officially began in 1990. <\/p>\n\n\n\n

They finished the project two years ahead of schedule in April 2003. The final version of the Human Genome<\/a> Project contains 99% of the gene<\/a>-containing sequence, with 99.9% accuracy.<\/p>\n\n\n\n

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The Human Genome<\/a> Project had the goal of sequencing the entire human genome<\/a>.<\/figcaption><\/figure>\n\n\n\n

The Human Genome<\/a> Project created a resurgence of interest in drug response based on genetics. It also reignited the fervor to discover more about the association. Consequently, the term pharmacogenomics<\/a> first began to appear around the 1990s.<\/strong> The International Conference on Harmonisation defines it as “the study of variations of DNA and RNA characteristics as related to drug response.” Also, they defined pharmacogenetics as “the study of variations in DNA sequence as related to drug response.” Today, many scientists use pharmacogenomics<\/a> and pharmacogenetics interchangeably.<\/p>\n\n\n\n

While the completion of the Human Genome<\/a> Project was underway, between 1988 and 2000, scientists continued to identify certain polymorphisms, or variants, in many drug metabolizing enzymes and drug transporters in the body. <\/p>\n\n\n\n

These studies uncovered numerous ADRs. For example, one study found cases of malignant hyperthermia<\/a><\/strong> during anesthesia. A different study discovered prolonged paralysis in some patients following treatment with muscle relaxants. The paralysis in these patients was due to a pseudocholinesterase enzyme<\/a><\/strong> deficiency.<\/p>\n\n\n\n

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Patients who have a specific enzyme<\/a> deficiency could become paralyzed after being treated with succinylcholine.<\/figcaption><\/figure>\n\n\n\n

Pharmacogenomics in the 21st Century<\/h3>\n\n\n\n

In 2000, the International SNP Map Working Group <\/strong>completed the map of the human genome<\/a> sequence variation. Around the same time, The International HapMap Project<\/strong><\/a> pushed to create a public database of common gene<\/a> variants in the human genome<\/a>. <\/p>\n\n\n\n

The HapMap project allowed pharmacogenomic scientists to go beyond the scope of genes from specific candidate studies. This broadened the field of pharmacogenomics<\/a> itself. From there, multiple genome-wide association studies (GWAS)<\/strong><\/a> have led to numerous discoveries of genes that are linked to drug response. <\/p>\n\n\n\n

For example, in 2008, scientists created the 1,000 Genomes Project. Their goal was to create a comprehensive list of uncommon genetic variations using a DNA sequencing approach.<\/p>\n\n\n\n

Aside from the revolutionary strides being made on the scientific front, pharmacogenomics<\/a> hit mainstream recognition in the 2000s. In 2007, the U.S. Food and Drug Administration (FDA) updated the label on the common blood-thinning drug warfarin<\/strong> (also known as Coumadin) to include that a person’s DNA could influence their response to the drug. <\/p>\n\n\n\n

\"*Not<\/figure>\n\n\n\n

Also, the pharmacogenomics<\/a> definition became more specific to describe the idea that multiple variants across human genomes, which differ between populations, can have a significant effect on drug response.<\/p>\n\n\n\n

In the past decade, leaders of the National Institutes of Health (NIH) and the FDA have outlined the scientific and regulatory structure necessary to address the multiple challenges that bringing personalized medicine into the mainstream healthcare system would face. We<\/strong> explore these challenges in our Pharmacogenomics<\/a>: Barriers to Implementation article.<\/strong><\/p>\n\n\n\n

Looking ahead: The Future of Pharmacogenomics<\/h3>\n\n\n\n

In 2020, the field of pharmacogenomics<\/a> will only expand. Likewise, the extent to which we understand the variability in drug action will only increase within the coming years. <\/p>\n\n\n\n

Many believe that in the near future, pharmacogenomics<\/a> will allow the development of personalized drugs that treat a wide range of health problems such as asthma and cardiovascular disease. <\/p>\n\n\n\n

Pharmacogenomics<\/a> may also aid in quickly identifying the best drugs to treat certain mental health disorders. For example, many patients suffering from depression usually do not respond to the first drug they are given.<\/strong> If they do not respond, or respond poorly, their doctor needs to try a different drug. The amount of time it takes for each antidepressant to reach full effect is around a month, and the patient’s depression could worsen in the time it takes to find them an effective treatment. Therefore, identifying the right drug through pharmacogenomics<\/a> is crucial to improving the lives of many people.<\/strong><\/p>\n\n\n\n

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Pharmacogenomics<\/a> in the general healthcare system could change the way doctors prescribe treatment and medication.<\/figcaption><\/figure>\n\n\n\n

There are multiple ongoing trials that will further inform us about the field. In addition, there are large personalized medicine programs that are being organized around the globe. These programs could lead to future insights on subjects ranging from single disease whole genome<\/a> sequencing. The results of both would be given to health care providers and their patients. So far, there aren’t many companies that have taken steps to do this.<\/p>\n\n\n\n

CRI Genetics is one of the first companies forging a path towards bringing pharmacogenomics<\/a> into the general healthcare system. By developing a comprehensive product for both patients<\/a> and clinicians<\/a>, we are effectively eliminating the one-size-fits-all mindset in medicine and revolutionizing healthcare. <\/p>\n\n\n\n

To learn more about our exciting project go to omnipgx.com<\/a>.<\/p>\n\n\n\n

Resources:<\/h3>\n\n\n\n