Pharmacogenomics: A study of personalized drug therapy

With the increasing advancement of technology and research progress, modern medicine has found cure for several diseases which were considered to be incurable few decades ago e.g. cardiovascular diseases, various cancers, tuberculosis, malaria and infectious diseases. However, till date no single drug is shown to be 100% efficacious for treating a certain diseased condition without exhibiting adverse drug effects. It is now a well recognized fact that each patient respond differently to a given drug treatment for a similar disease. With a particular drug, desirable therapeutic effects could be obtained in few patients where as others may have modest or no therapeutic response. Besides, many patients might experience an adverse effect that also varies from mild to severe and life-threatening. Studies have shown that with a similar dose, plasma concentration of a certain drug might vary up to a difference of 600 fold among two individuals of same weight. Such inter-individual variations occurring in response to a drug might be a consequence of complex interaction between various genetic and environmental factors. Genetic factors are known to account for approximately 15-30% inter-individual variability in drug disposition and response, but for certain drugs it could also account for 95% variations. For the majority of the drugs, these differences are largely ascribed to the polymorphic genes encoding drug metabolizing enzymes, receptors or transporters. These polymorphic genes mainly influence important pharmacokinetic characteristics of the drug metabolism e.g. drug absorption, distribution, metabolism and elimination.

Origin of pharmacogenomics:

The first report of an inherited difference in response to a foreign chemical or xenobiotic was inability to taste phenylthiocarbamide. Another example which showed that drug response is determined by genetic factors which can alter the pharmacokinetics and pharmacodynamics of medications, evolved in late 1950s, when an inherited deficiency of glucose-6-phosphate dehydrogenase was shown to cause severe hemolysis in some patients when exposed to the antimalarial drug primaquine. This discovery elucidated why hemolysis was reported mainly in African-Americans, where this deficiency is common, and rarely observed in Caucasians. Other established evidences of inter-individual variations observed in response to suxamethonium (succinylcholine), isoniazid, and debrisoquine were also linked with a genetic connection. The discovery that prolonged paralysis following the administration of succinylcholine was the result of a variant of the butyryl-cholinesterase enzyme, and peripheral neuropathy occurring in a large number of patients treated with antituberculosis drug isoniazid was an outcome of genetic diversity in the enzyme N-acetyltransferase 2 (NAT2) are excellent examples of “classical” pharmacogenetic traits altering amino acid sequence.

These observations of highly variable drug response, which began in the early 1950s, led to beginning of a new scientific discipline known as pharmacogenetics. Vogel in 1959 was the first to use the term pharmacogenetics but it was not until 1962, when in a booy by Kalow, pharmacogenetics was defined as the study of heredity and the response to drugs.

Pharmacogenomics in new era:

The term pharmacogenomics was later introduced to reflect the recent transition from genetics to genomics and the use of genome-wide approaches to identify the genes that contribute to a specific disease or a drug response. The term pharmacogenomics and pharmacogenetics are many times used interchangeably. Pharmacogenomics is an emerging discipline that aimed at studying genetic differences in drug disposition or drug targets to drug response. With the availability of more sophisticated molecular tools for detection of genetic polymorphisms, advances in bioinformatics and functional genomics, pharmacogenomic based studies are generating data which is used in identifying the genes responsible for a specific disease or the drug response. There is emerging data from various human genome projects on drug metabolizing genes that is rapidly elucidated and translated into more rational drug therapy towards a personalized medicine approach. Many physicians are now reconsidering whether “One Drug for All” approach is ideal while prescribing medicines to treat a certain condition in different individuals. Various studies have now reported genotype- phenotype association studies with reference to many diseases where respective drug metabolizing genes and receptors are highly polymorphic. In the last decade, FDA has increasingly acknowledged the importance of biomarkers and formulated new recommendations on pharmacogenomic diagnostic tests and data submission.

Applications and challenges of Pharmacogenomics:

Personalized medicine is at times deemed to be a future phenomenon; however it is already making a marked difference on patient treatments especially in various cancers. Molecular or genetic testing is now available for colon, multiple myeloma, leukemia, prostrate and breast cancer patients, hepatitits C and cardiovascular diseases where one can identify their genetic profile and based on that it can be predicted whether patients are likely to benefit from new drug treatments simultaneously minimizing adverse drug reactions. Recently, at MD Anderson Cancer Center, “Institute for Personalized Therpay” was created particularly to implement personalized cancer therapy for improving patient outcomes and reducing treatment costs.

Personalized medicine might guarantee many medical innovations but its implementation is associated with several challenges regarding public policy, social and ethical issues. Individual may not opt or participate in the genetic research as they feel it might breach their right for privacy and confidentiality. To tackle these challenges, “2008 Genetic Information Nondiscrimination Act” was designed to shield individuals from genetic discrimination. Apart from this, other existing concerns are: ownership of genetic materials, medical record privacy, clinical trial ethics, and patient’s knowledge on the consequences of storing genetic materials and phenotypic data. These concerns must be addressed for the satisfaction of all the stakeholders, especially the patients on reaching a common consensus as how to manage pharmacogenomics applications into clinical practices.

Interdisciplinary research – Nobel Prize for Chemistry was awarded to two Biologists

Modern scientific research does not confine itself to any restricted boundary.  Nowadays, it is all about interdisciplinary research. In 2012, Nobel Prize for Chemistry (http://www.nobelprize.org/nobel_prizes/chemistry/)was awarded to two eminent biologists, Prof. Robert J Lefkowitz and Prof. Brian Kobika, for their crucial contribution in unveiling the signalling mechanism of G protein-coupled receptors (GPCRs). It’s a lifetime work of both the scientists. Dr. Lefkowitz, an investigator at Howard Hughes Medical Institute (HHMI) at Duke University, is also James B Duke Professor of Medicine and of Biochemistry at Duke University Medical Center, Durham, NC, USA. Dr. Kobika, earlier a postdoctoral fellow in Dr. Lefkowitz’s laboratory, is currently Professor of Molecular and Cellular Physiology at Stanford University, School of Medicine, Stanford, CA, USA.

Transmembrane signalling of one GPCR “caught in action” by X-ray crystallography

GTP (guanosine triphosphate) binding proteins (G-protein) act as molecular switches in transmitting signals from different stimuli outside the cell to inside the cell. However, for doing this G-protein needs to be activated, and that is where GPCRs play the most important role. They sit in the cell membranes throughout the body. GPCRs, also known as seven transmembrane (pass through the cell membrane seven times) domain proteins, detect the external signals like odor, light, flavor as well as the signals within the body such as hormones, neurotransmitter.1 Once the GPCRs detect a signal, the signal is transduced in certain pathway and finally activate the G-protein. In response, the activated G-protein triggers different cellular processes. Binding of a signalling molecule or ligand to the GPCR causes conformational changes in the GPCR structure. As a result of extensive research of 20 long years, Dr. Lefkowitz and Dr. Kobika not only identified 800 members of GPCRs family in human but also caught in action how these receptor proteins actually carry out the signal transduction with the help of high resolution X-ray crystallography. The crystal structure of ß2-adrenergic receptor (ß2AR), a member of the human GPCRs family was reported by Dr. Kobika and his colleagues in 2007.2 The hormones adrenaline and noradrenaline are known to activate ß2AR, and the activated ß2AR triggers different biochemical processes which help in speeding up the heart and opening airways as body’s fight response. The ß2AR is a key ingredient in anti-asthma drugs. One of the major breakthroughs came in 2011 when Dr. Kobika and his co-workers unveiled for the first time the exact moment of the transmembrane signalling by a GPCR. They reported the crystal structure of “the active state ternary complex composed of agonist-occupied monomeric ß2AR and nucleotide-free Gs heterotrimer”.3 A major conformational change in ß2AR during signal transduction was discovered.

Now what is so special about GPCRs? Well, these proteins belong to one of the largest families of  all human proteins. GPCRs are involved in most of the physiological activities, and hence are  the targets of a number of drugs. Determination of the molecular structures of this class of receptors not only helps the researchers to understand the actual mechanism of different cellular processes but also help them to design life saving and more effective drugs. So, in a nut shell, this scientific breakthrough was possible due to the involvement of experts of different areas of science such as, chemistry, biochemistry, molecular and cellular biology, structural biology, cardiology, crystallography.

 

References

 

  1. Lefkowitz, R. J. Seven transmembrane receptors: something old, something new. Acta Physiol. (Oxf.) 190, 9–19 (2007).
  2. Rasmussen, S. G. et al. Crystal structure of the human b2 adrenergic G-protein coupled receptor. Nature 450, 383–387 (2007).
  3. Rasmussen, S. G. et al.  Crystal structure of the b2 adrenergic receptor–Gs protein complex. Nature 477,  549-557 (2011)