GENETICALLY TARGETED DRUG THERAPY: WHAT IS THE FUTURE - Essay Example

GENETICALLY TARGETED DRUG THERAPY: WHAT IS THE FUTURE Pharmacogenetics is the new line of research in pharmacy industry that is increasing our understanding of drug interactions. Polymorphism in the various genes leads to variation in the response of each individual to each drug. This is the prime area of research of pharmacogenetics. The aim is to understand the genetic causes of variation of drug metabolism and to design drug therapies that are able to treat diseases according to the variation in the bodies. GENETICALLY TARGETED DRUG THERAPY: WHAT IS THE FUTURE Drug therapy has long suffered from that particular population of patients who demonstrate adverse drug reactions in response to the pharmacological regime given to them. While the newer drugs are safer with a higher therapeutic index, the problem does not go away for the 6% of the Caucasian population that is not able to metabolize drugs properly. (Wolf and Smith, 1999, pp 366) Safer drug regimes do not necessarily obviate the possibility of adverse drug reactions or idiosyncrasies. Adverse drug reactions are seen to be a high occurrence with 20, 000 cases reported annually in the UK. The consequences can be fatal and therefore, it is important to carry out informed decision by considering each patient prior to medicating. Still even with the best decision making processes, there is no guarantee how effective a drug will be on a patient. In the US the adverse drug reactions are termed the fourth highest cause of death. (Wolf and Smith, 1999, pp 367) There are estimates that 1 in every 15 individuals hospitalized suffers from adverse drug reactions. Around 106, 000 individuals die annually and 2.2 million are injured each year due to adverse drug reactions. (Wolf et al, 2000, pp 987) The genetic variation and responses are a new line of investigation in this regard. However, the genetic difference in the response to various drugs is an element that came later into play. Before these, factors such as age, body size, diet, gastrointestinal absorption, compliance with therapy and the characteristics of the drug were considered for each individual. These are still one of the primary considerations for any physician prior to drug dosing. The genetic component came into being by studying patterns of drug behavior in different populations, especially syndromic patients and in those who suffered from cancer or metabolic diseases. The pharmcogenetic variation was a very important discovery in the case of oncology. (Brice and Sanderson, 2006, pp 109) The variable responses of the drugs and their toxic effects have been especially vexing for physicians for treating cancer patients, whose resistance to external insults is already reduced considerably. For every drug to be therapeutically effective, it must be present in the body in a particular concentration for a fixed amount of time, and then should be able to be metabolized or removed from the system before it accumulates within the body. The individual responsiveness of a drug in the body is not possible to carry out in each individual. However the advent of genetic analysis and therapies are making this a reality in the clinical practice. While still in the formative phases, the pharmacogenetics holds major potential in predicting adverse reaction cases, and the thereby preventing them. While therapeutic synchronicity and adversity among different drugs is well documented and reported, the genetic predisposition at the individual area was not documented as thoroughly. (Wolf and Smith, 1999, pp. 367) Now researchers understand the role of genetics in the predisposition and nature of the disease progress, and how it can be prevented or treated accordingly. Media is playing an important role in promoting the use of genetics and its role in treating disease, while these facts are true, the media often fails to highlight the complexity of the issue. Pharmacogenetics is not simple identification of genes and then creating medicines that treat them. It requires understanding the complex inter-regulation of the whole genome of a person, and how, change in one gene sequence can influence change in other gene expressions as well. Regardless of this, many people are now getting conscious about their will to have genetic testing regarding their various medical problems. (Emery and Hayflick, 2001, pp 1027) It is therefore, the future of medicine that the role of genetics will increase with time in our clinical practice. Drug therapies and genetic predictions can help us in tailoring drugs and treatments that can help us cure particular diseases, with limited failure rates or side effects. This however is just one side of the coin, for genetics is not as simple as locating one gene, fixing it, and curing the patient. (Zimmern, Emery and Richards, 2001, pp 1005) While understanding of the human genome system is a significant leap in the human health, it is still a first step towards realizing the full the potential of these genes and how they interact with each other to constitute an individual. Same applies to the various medical conditions, syndromes or various diseases that the person may possess, which are often caused by a myriad of genes and not one single entity alone. Added to these are the role of environmental factors that contribute to the predisposition and the progression of the disease. Ignoring the role of environmental factors in the etiology of the disease must not be ignored in the face of genetic information and development. (Zimmern, Emery and Richards, 2001, pp 1006) There are potentially two lines of research in the directions of pharmacogenetics. The first line of research is identification of specific genes and their products and their individual association with diseases. The second line of research is identification of genetic variations accounting for individual responses to drugs. (Wolf et al, 2000, pp 987) With the introduction of toxicogenomics, and the identification of genetic composition in the individual response to a drug, the future of pharmacology is bright. Now with the help of genomic technologies, it can be expected that safer drugs with better therapeutic profiles can be created, with minimum side effects. This can lead to a new classification system of drugs, based on the genetic and metabolic profiling. Genetic profiling can help deduce the safety profile of a drug even prior to test experiments, and thereby save time and resources. Current methods of assessing drug mechanisms are usually done so with the help of animal models. However, these are at best guess work, as they cannot predict the reactions in the humans due to species differences. Toxicogenomics can help addressing these problems with definitive results. The economic implications are a very large factor contributing to this field. This is because drug manufacturing and testing is a very expensive and time consuming procedure, which amounts to huge cost, with very little number of drugs screened clear for clinical use. (Boverhof and Zacharewski, 2006, pp 357) The economical implications are therefore another strong element that will come into play in pharmacogenetics. Still it is important to remember that toxicogenomics and pharmacogenetics are relatively new areas of research and require extensive investment and development of infrastructure for its development. This means that in order to harvest the full benefits of these fields, there is need to invest in such areas. The information received from these areas needs to be integrated in the various medical and pharmacological fields. (Boverhof and Zacharewski, 2006, pp 358) There will be need to develop and create new tools for interpretation of the data obtained. These should be able to interpret data of genomic, proteomic and metabolomic nature. These include the traditional methods such as pedigree analysis and positional cloning. These techniques identify the genetic regions of susceptibility within individuals, and then through progressively finer mapping procedures, locate the candidate genes. (Orphanides and Kimber, 2003, pp3) By utilizing this data, the disparities in the mechanism of action of various drugs can be reduced, leading to more accurate dosing regimes and safer drug profiles. The investment in this area however is high, and it is with reason that researchers are still questioning the effects and contributions of the fields for clinical medical practice. So far, the data on the effects of the drugs in clinical practice is limited. Clinicians ask for the costs of pharmacogenetics in routine clinical practice and its overall efficacy in improving patient outcomes and treatments. (Boverhof and Zacharewski, 2006, pp 360) Moreover, in simple terms, they ask whether it is worth the effort. A popular anticancer drug, the 6 mercaptopurine was among the first drugs that were evaluated for genetic variations and responses. Much information has been gained about the reason of variable responses in different patients. The metabolic activity of the drug is dependant upon the action of the gene Thiopourine S- Methyl Transferase or TPMT. TPMT activity has been found to be associated with other drugs as well such as azathioprine.(Davies, 2006, np) Studies have shown that one in 300 persons are likely to lack activity or TPMT, while 11% may have intermediate activity of the gene. This means that these persons will not be able to metabolize the drug and achieve therapeutic activity. Indeed in cases where the gene is non-functioning, instillation of these drugs can lead to toxicity reactions. The group at most risk is children with leukemia, who have none or limited TPMT activity which can lead to blood dyscrasias. By application of pharmacogenetics, the use of the drugs may not take place or may be dose adjusted according to the capability of the body. The concept of "personalized cancer therapy" is well influenced from this field, which works to identify and dose determine the drugs that will work for an individual cancer patient. (Davies, 2006, np) However these are still initial stages in the pharmacogentic therapies, and there is much that needs to be done in order to make it a definite clinical reality. GENETIC VARIATIONS IN DRUG REACTIONS AND POLYMORPHISM: Pharmacogenetics is actively working towards identifying the differences in various drug reactions due to genetic differences. This polymorphism of genes can result in a myriad of reactions, coupled with problems of correlated genetic interactions. The polymorphism of the various genes includes many areas of genetic responses which include coding of drug receptors and transporters, cell signaling pathways, drug metabolism and disposition. Polymorphism has been identified as feature of above 20 human drug metabolizing enzymes. These features are present in a wide variation between humans and include a component of ethnic variation. Two enzyme systems are well known and documented for their genetic variation. These are the cytochrome P450 and thiopurine methyltransferase. (Wolf et al, 2000, pp. 988) This variation in the human genome accounts for 0.1% of the three billion base pairs of the DNA. The genetic components are showing increasing presence in different conditions not thought so before, and presenting itself with varying severity. It is also showing high differences in the reactions to the various drugs and xenobiotics. These variations have been found to be caused by single nucleotide pleomorphism or SNPs. This SNP is found in every 1000-2000 base pair in average of which only 1% can present them in some form. (Orphanides and Kimber, 2003, pp 1) Cytochrome P450 is an enzyme system found in the liver and is responsible for the metabolism of a large variety of drugs. It is also an enzyme that has a wide variation in the degree of metabolism of drugs. The lack of active enzymes may be due to inactive genes, which in turn can cause defects in the metabolism of the different drugs. P450 has many actions on a drug, and these include conversion of an active form to an inactive form or vice versa. Any defect in the system can lead to failure of these processes, or failure to metabolize and thereby eliminate the drug from the body. This is especially in the case of the 6% of the Caucasian population that has inactive P 450 systems in their bodies. The variation in the metabolism of different drugs due to the activity of the P 450 system makes it difficult to predict the dose for every patient with certainty. (Wolf et al, 2000, pp. 988) It is now known that many genes of the total 63 cytochrome P450 genes are polymorphic in nature. The number of variations that it can lead to is many, and can affect the metabolism of many environmental, chemical and medicinal agents in the body. It is these variations that are termed as idiosyncrasies in medical drug administration, and which in many cases can lead to adverse reactions. One of the most common drugs that are affected through this enzyme system is warfarin. Warfarin can have a wide variety of effects with a single miscalculation about dose and its metabolism ratio. Similarly, decreased clearance of the drug can also cause severe medical problems. (Orphanides and Kimber, 2003, pp 3) Polymorphism can take place in proteins of both phase I and phase II metabolism. Phase 1 metabolic variations can lead to difficulty or variation in initial drug metabolism, while Phase II proteins variation can lead to difficulty in elimination or reduced effects of the drug in body. Environmental chemicals may also be improperly utilized by the body should variations in these proteins take place. Other substances whose metabolism can be affected include xenobiotics, drug transporters, plasma membrane, nuclear receptors and ion channels. (Orphanides and Kimber, 2003, pp 4) Thiopurine methytransferase is another system that metabolized different cancer drugs such as 6-mercaptopurine and 6- thioguanine. This system can cause increased difficulty in administration of drugs for childhood leukaemia. A hereditary TPMT deficiency can increase the drug to toxic levels within the body, who can display severe hemopoeitic toxicity. Although the deficiency of the enzyme can be as low as 1% in the white population, it is nevertheless significant given the toxicity levels of the anti cancer drugs. (Wolf et al, 2000, pp. 989) RESEARCH AREAS IN PHARMACOGENETICS: Pharmacogenetics is showing more research in certain areas than others. By utilizing the microarray technology platforms, quantitative analysis of genetic material can be carried out. There are currently many variations of microarrays available; however, all are involved in carrying out analysis of the genetic material at varying speeds. This method is being used exclusively in the new drug developing procedures, and is helping in creating drugs that do not have any toxicity issues. The application of this technology has been categorized in two broad areas; mechanistic or investigative research and predictive toxicology. (Pennie et a, 2000, pp 280) Currently the areas of research in pharmacogenetics include understanding endocrine disruption, the effect of environmental compounds that cause changes in the endocrine functions and the genetic variations that can make a person susceptible to endocrine dysfunctions and cancers. Similar line of research is in hepatology, where live liver cell models are being used for cytotoxicity and genotoxicity assays, drug-drug interactions, and mode of action studies. This is especially helpful in learning the effect of various drugs on the liver, and the genetic components that can modify or change an individual's reaction to a drug. This method can help in assessing cytotoxicity of various compounds over a range of concentrations, and predict the untoward effects of a drug. (Pennie et al, 2000, pp 281) Current research in diabetes is looking for new agents that stimulate insulin production in the body and thereby help the body in manufacturing its own insulin. Mostly this line of research is being carried out for patients with non insulin dependant diabetes mellitus. The current agents, such as thiazolidinediones, have shown toxic profiles and results, which have limited their clinical use. Among these toxic reactions is impaired hemotopoiesis, adipogenesis, and anemia. Genetic profiling and genetic assays can help in assessing and creating new compounds that have non toxic effects on the bone marrow activity. While questions about the reality and actual implications of such researches on the primary care are raised, there is hope that with more knowledge and information, these hurdles can also be overcome. (Pennie et al, 2000, pp 282) PHARMACOGENETICS IN PRIMARY CARE: The potential of use of pharmacogenetics is not so difficult to fathom now. While 10 years ago, it may have been considered a thing of the future, the recent increase in interest among the public as well as the doctors is supporting the trend. There is increased interest in utilizing DNA based testing in routine testing procedures, which means that genetic testing and its various aspects must be well known to a general physician. This field therefore is not limited to the specialists only but now includes other medical personnel as well. (Emery and Hayflick, 2001, 1028) The primary care is the only sector that follows the patient from the very beginning till the conclusion of his or her treatment. Referral to specialists is usually at a very later stage, when initial and basic screenings and testing have taken place. The use of genetic testing is especially seen in syndromic patients, and in ruling out patients who may have such damaging genes within the body. The primary care physician is now responsible to guide the patient through the correct testing and diagnostic procedures, and only till later refer the case to the specialists. The role of genetic medicine therefore is not so hard to understand, when individual prescription drugs may help in curing the patient. The most common screening procedure related to genetic testing includes prediction of risk cancers and carrier states for autosomal recessive conditions such as cystic fibrosis. (Emery and Hayflick, 2001, pp 1029) The physician in general is faced with a very tough decision when prescribing drugs to the patients. He or she cannot know for sure the results of various drugs on each individual, and cannot foresee any adverse reactions that can occur in a patient. With a rigid dosing regimes and methods used in drug therapeutics, and little regard for ethnic variations, the physicians see more than usual cases of over or under dosing, toxicity or no relief of symptoms at all. While the physician may be well aware of the pharmacokinetic aspect of the drugs, he may not be very familiar with the pharmakogenetic component, which may define the different ethnic and interracial differences in humans. The physician may even have to consider dosing of agents such as suxamethonium which can produce apnoea in certain patients. The variation of drug response due to polymorphism is of increased concern for the physician, with additional problem of not having any idea or clue about how the patient will respond to a drug. (Shah, 2005, pp 1618) GENETIC MEDICINE IN PRIMARY CARE, THE ROLE OF THE PHYSICIANS: There are two methods modifying drug therapy in patients. These include the phenotyping and genotyping respectively. Pheotyping involves administration of the drug followed by measuring its metabolic ratio. This gives the picture of an individual and consequently helps in deciding the dosing schedule for the patient. Phenotyping however, contains many risks. These include complicated methods of testing, adverse drug reactions, incorrect co-administration of drugs along with incorrect phenotype assigning and confounding effects of the disease. (Linder, Prough, and Valdes, 1997, pp 254) Genotyping defines those genetic mutations that are responsible for specific drug reaction variation. Over expression of genes, null alleles, mutant proteins or inactivating alleles all influence the genotyping of each individual. Point mutations are also recognized through this methodology. Whichever the method used, the role of genotyping is to understand the genetic influences that may be altering the activity of a drug in each patient. (Linder, Prough and Valdes, 1997, pp 255) Genetic variations and anomalies have begun to show some effect in the clinical practice, despite debates and controversies. Among these is the understanding of the genetic precursors and variations in Alzheimer's disease. The gene that is thought to increase the susceptibility to the disease is 4 allele of the gene encoding the apolipoprotein E4 (APOE4). SNP mapping has been very contributory in identifying this gene, and is hoped to increase our knowledge about other diseases as well. (Orphanides and Kimber, 2003, pp 4) Pharmacogenetics is also helping in identifying possible adverse effects of various drugs on the body. The most helpful in this regard is learning the adverse actions of abacivir used for the treatment of HIV infection. This drug shows adverse reactions in approximately 4% of the patients. Patients present with rash, fever and respiratory problems. The SNP analyses of the drug displayed approximately a 100 polymorphisms from candidate genes that influence its metabolism and adverse reactions. Among these are included polymorphisms of the tumor necrosis factor alpha as well as the genes of major histocompatibility complex. However, the small number of the patients displaying these idiosyncrasies is perhaps the main hurdle in the identification of the susceptible patients. It is here that the question of investment of time and money for such screening and evaluation begin to surface. (Orphanides and Kimber, 2003, pp 4) The physicians can play an integral role in the identification of the potential benefactors of the genetic medicine. Physicians may be able to identify patients who may have genetic disorders or those with increased risk of transmitting genetic disorders. They may be helpful in identifying features of genetic conditions, monitor their health, providing basic genetic information, help in decision making and guide them to appropriate specialists and services. The introductions of the screening programs are now introduced in primary care to assist in genetic screening and prevention of diseases. Understanding these basics of genetics can further help in pharmacogenetics, and in predicting patients who may suffer from untoward effects of the drugs. While this may not be possible to carry out in every patient, patients who have tendency to a certain disorder may be screened prior to the administration of the drug. (Emery and Hayflick, 2001, pp 1029) The racial profiling of diseases may be an area that can benefit the most from pharamacogenetics. It is now common knowledge that ethnic and race of a person can predispose him or her to certain diseases. Many new findings have been seen through the researches. For example, even within races, the chances of varied response and genetic profiling are large. While in the past, the patient disease susceptibility was divided into different racial predilections, new sub-variations are also surfacing. These differences however, can help in creating better data basis and understanding the individual variations which can help direct and improve future drug dosing. (Davies, 2006, np) The applicability of this methodology is not limited to drugs. Various environmental agents and exogenous substances are also seen to have different reactions and responses in individuals. Among these the most common example is silicosis, which shows susceptibility patterns. Allergic conditions can also be ascertained based on the genetic profiling. Polymorphisms in genes such as N-acetyltransferase 2 or (NAT2) have shown effects on the susceptibility to allergies, including food allergy.(Orphanides and Kimber, 2003, pp 5) These procedures therefore can help in identifying various susceptibilities in a patient and help in creating treatment plans and drug regimes that decrease chances of adverse effects. (Orphanides and Kimber, 2003, pp 6) Despite the wide range of applications of this therapy, the use in actual clinical practice is still very limited. Only 35% of the physicians in Europe use TPMT genotyping in some but not all cases of cancer. A further 35% of the practitioners do not use this method at all.(Davies, 2006, np) The field is now getting more complicated as more than one gene is involved in the polymorphism and in individual variation to responses in the body. This is further complicated by the fact that multiple drug therapy is usually carried out in every patient of cancer. The data so far collected is still small, and with the evolving pharmacogenomics, there is expected increase in the number of genes involved in various drug reactions and disease progressions. (Davies, 2006, np) ISSUES OF CONCERN IN PHARMACOGENETICS While pharmacogenetics opens doors to intensive discovery and understanding about individual responses to various agents and susceptibility to various diseases, it brings with it a large burden of responsibility. the ethical implications are large and there are concerns about whether the information obtained will be used with responsibility. In the US, the introduction of "ethnic drugs" is taking place. This is based on the ethnic variations in the cause of disease, and subsequent introduction of drugs that address those particular factors.(Brice and Sanderson, 2006, pp 110) While the therapy is unique and indeed beneficial, the marketing and the implications are not. The pharmacogenetics can lead to a new kind of racism, the genetic racism. This is supported by researchers claiming that inter racial differences to drug response may be much lower than intra racial differences in responses to drugs. By depending upon ethnicity and skin color as a method of racial genetic profiling is not ethically correct, and may be in fact a poor measure of genetic profiling. Another area of concern here is that by focusing purely on the genetic aspects of the disease, one may start forgetting the environmental factors and etiologies that led to the progression of the disease. Therefore, for any good treatment regime outline, the genetic as well environmental factors should be considered with due importance. (Brice and Sanderson, 2006, pp 110) These variations can also lead to favoritism among the drug companies in producing drugs. What is meant by this is that drug companies may take up manufacturing drugs that are easy to make and have simple genomic variations. At the same time, they may ignore patients, who have diseases due to complex genetic patterns and variations. The fate of such patients and their drugs may be akin to the orphan drugs, which already suffer from low production and market availability. Drugs may be difficult to introduce or test as the patients may not be interested in the pharmacogenetic method of drug testing. Similarly, such tests may not include those patients who have poor economic or social backgrounds but have the same disease.(Brice and Sanderson, 2006, pp 111) In clinical practice, the researchers argue that pharmacogenetics will increase the complexity of the disease treatment. Again the question of cost efficacy comes into light, and researchers ask which are better, preventive measures or genetic testing in the treatment regime. The lack of infrastructure in this area is also raising concerns about the standard maintenance, and who will determine the quality of the tests. (Brice and Sanderson, 2006, pp 112) CONCLUSIONS AND RECOMMENDATIONS: Pharmacogentics is currently beginning to show its efficacy in treating various diseases. By understanding and identifying the variation in each individual, it is now possible to predict the events of adverse drug reactions, drug toxicities and interactions with more confidence. Moreover, it is now possible for clinicians to dose their patients with better knowledge and therefore improved outcomes. The concern about the ethical and moral implications of the ethnic drugs is an area of immense concern to the researchers. Questions are being raised as to whether this new method of marketing and delivery of drug the best way to introduce these variations of drugs. While the future and the potential of these drugs are no doubt great, the question of the ethical dilemmas and possible ethnical discrimination in the formulation of drugs is an even greater concern. Does this mean that complex genetic cases of different diseases will be left behind, and will be treated with the same categories as are the orphan drugs by the pharmaceutical companies Who will confirm that such discrimination will not take place in pharmacy industry and that equal research and attention will be given to every genomic variations. The costs of these drugs will be high, which again raise concerns about availability to the masses and poor populations. The concern is whether genetic researches and related therapies the future for the rich only Again, there is concern that the pharmaceutical industries will only be interested in producing medicines that are functional for the ethnic groups and public of the developed countries, and may ignore the poorer nations. This can lead to an even wider divide between the health provisions. The moral implications of genetic information of the patient become a very personal and private issue. There are questions about addressing this information and whether transferring it to family members or not. The newer research field requires some time for the public and practitioners to get used to. The concern is whether the patients will be willing to undergo trials necessary for the development of the field. Last but not the least, the concerns about the implications of this technology in the primary care must be considered. While primary care is the main area where any new technology should be tested out, such institutes are under much stress, overload and work demand. The physicians are dealt with a large variety of patients with different social, economical, ethnical and religious backgrounds. They will be especially concerned about the effect of this technology in the mixed cultures and the response of these cultures. This is however, a minor concern. It is difficult to know which case will be in need of such genomic typing and which won't. Physicians also ask about how beneficial it will be in actual practice to spend large amounts of money on the genetic testing on each patient. Will it be actually conserving money for the primary care or increasing the expenditure. These and many other questions continue to raise debate about the potential role of Pharmacogenetics in primary care. For now, its implications and use in oncology, and genetics are well established and it is only a matter of time before the full effects of this field will be realized in real clinical practice. REFERENCES Philippa Brice and Simon Sanderson, 2006. Pharmacogenetics: What are the Ethical and Economic Implications The Pharmaceutical Journal Vol. 277, No. 7410 p 109-112 Darrell R Bovernhoff and Timothy R. Zacharewski, 2006. Toxicogenomics in Risk Assessment: Applications and Needs. Journal of Toxicological Sciences 2006 89(2):352-360. Stella M Davies, 2006. Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet Hematology 2006. Jon Emery and Susan Hayflick, 2001. The Challenge of Integrating Genetic Medicine in to Primary Care. 2001; 322(7293):1027-1030 Mark W Linder, Russell A Prough and Roland Valdes, Jr., 1997. Pharmacogenetics: A Laboratory Tool for Optimizing Therapeutic Efficiency. Journal of Clinical Chemistry. 43: 254-266 George Orphanides and Ian Kimber, 2003. Toxicogenetics: Applications and Oppurtunities. Journal of Toxicological Sciences. 75, 1-6. William D Pennie, Jonathan D Tugwood, Gerry J A Oliver and Ian Kimber, 2000. The Principals and Practice of Toxicogenomics: Applications and Oppurtunities. Journal of Toxicological Sciences 54, 277-283 Rashmi R Shah, 2005. Pharmacogenetics in Drug Regulation: Promise, Potential and Pitfalls. Philosophical Transactions of the Royal Society London B Biological Sciences 360(1460): 1617- 1638 C Roland Wolf and Gillian Smith, 1999. Pharmacogenetics. British Medical Bulletin 1999; 55(No. 2): 366-386 C Roland Wolf, Gillian Smith and Robert L Smith (2000) Science, Medicine and the Future, Pharmcogenetics. British Medical Journal 2000 April 8;320(7240): 987-990 Ron Zimmern, Jon Emmery, Tessa Richards, 2001. Putting Genetics in Perspective. Requires Better Understanding and More Rational Debate. BMJ, 2001; 322(7293):1005-1006 Read More