Issue 13

McMaster’s Medical Research and Health Ethics Student Journal

IN THIS ISSUE

Cancer with Viruses?

Also in this issue: Doctor’s right to refuse patient treatment

Chaperones and protein folding

Loneliness and cardiovascular disease

Debate on Canada’s health care

All the Small Things From Science to Society

Issue 13 | November 2008

www.meducator.org

Table of Contents

Issue 13 | November 2008

Research Articles

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Presidential Address

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MedWire

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Crystal Chung

MedBulletin

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MedQuiz

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About The McMaster Meducator The McMaster Meducator is an undergraduate medical journal that publishes articles on current topics in health research and medical ethics. We aim to provide an opportunity for undergraduate students to publish their work and share information with their peers. Our protocol strives to maintain the highest standard of academic integrity by having each article edited by a postgraduate in the relevant field. We invite you to offer us your feedback by visting our website: www.meducator.org.

The McMaster Meducator may be contacted via our e-mail address: meduemail @learnlink.mcmaster.ca or our mailing address: B.H.Sc. (Honours) Program Attention: The McMaster Meducator Michael G. DeGroote Centre for Learning and Discovery Room 3308 Faculty of Health Sciences 1200 Main Street West Hamilton, Ontario L8N 3Z5 http://www.meducator.org

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Saviour Siblings Sarah Levitt

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Exploring the World of Antibiotic Resistance Kirandeep Bhullar

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November 2008

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veryday, we are engrossed by the objects that we can see and touch. We take for granted the simplest processes of life -- forgetting all the microscopic components that work vigorously to allow daily functioning. Yet, many notable discoveries and breakthroughs involve only one gene, molecule, or cell. The progression of research has stretched boundaries and magnified our field of vision. In exploring these scientific advances, we bear the responsibility of establishing rules and considering the ethical implications.

Our thirteenth issue focuses on these fundamental components, highlighting its biological roles and discussing its influence in society. For instance, the lucrative effects of genetic discovery are explored by Dan Mok, when discussing the legal and financial realities of gene patents. Ran Ran and Tiffany Chan identify epidemiological trends associated with the hygiene hypothesis, and investigate immunological mechanisms that participate in allergic responses. The concept of personalizing medicine to one’s genetic composition holds a future position in healthcare, as described by Manan Shah. Implications of genetic screening are further explored by Sarah Levitt, as she guides us through the moral and political issues of “saviour siblings.” Lastly, Kirandeep Bhullar addresses the increasing concerns of antibiotic resistance through a description of bacterial mechanisms and evolution. Together, these articles demonstrate the significant social involvement, beyond biological function, of life’s smallest components.

Likewise, this publication depends heavily on the dedication and hard work of different groups of individuals. Thank you ever so much to the writers, whose effort and enthusiasm offer us insight into important medical and health matters, and to the post-graduate editors, who ensure superior quality of our publication. I would like to extend my appreciation to Dr. Del Harnish and the Bachelor of Health Sciences Program, who continue to generously support this valuable initiative. Lastly, I am honoured and excited to work with our growing team of executives, whose patience, cooperation, and talents have made this possible. To Jacqueline Ho, thank you for your support and ability to keep everything organized. Thanks to our skilled editors: Harjot Atwal, Veronica Chan, Randall Lau, Simone Liang, Siddhi Mathur, Alexandra Perri, Navpreet Rana, Manan Shah, and Fanyu Yang; your work with the writers and post-graduate editors is exceptional and I am grateful for your collaborative efforts. Thank you to our creative team, led by Stephanie Low. Her extensive experience in layout has polished the publication to its sleek visual finish, with the help of the artistic strengths of Ran Ran and Andrew Yuen. To Avinash Ramsaroop, thank you for your development and maintenance of the website, an important channel of information. Finally, I would like to introduce our newest executives: Ahmad Al-Khatib, Alyssa Cantarutti, Randal Desouza, Keon Maleki, Hiten Naik, and Sangeeta Sutradhar. I truly thank you for all the work you have done already; with such intelligent, keen, and energetic individuals, I know that the future of the Meducator is bright.

Please visit our website, www.meducator.org, to see past issues, find information about submitting articles, and read our daily MedWire updates. The website also provides a form for inquiries and comments; we want to hear from our readers! On behalf of the writers and staff, we hope you enjoy this issue.

Sincerely,

Crystal Chung B.H.Sc. IV

Meducator Staff President Crystal Chung Vice-President Jacqueline Ho Editorial Board Veronica Chan Randall Lau Simone Liang Siddhi Mathur Alexandra Perri Navpreet Rana Manan Shah Fanyu Yang Creative Director Stephanie Low Web Master Avinash Ramsaroop Public Relations Harjot Atwal Graphics & Design Ran Ran Andrew Yuen Junior Executives Ahmad Al-Khatib Alyssa Cantarutti Randal Desouza Keon Maleki Hiten Naik Sangeeta Sutradhar

Post Graduate Editors Dr. Ronald Carter, PhD, DVM Dr. Kimberly Dej, PhD Dr. Fiona Miller, MA, PhD Dr. Ken Rosenthal, PhD Dr. Lisa Schwartz, MA, PhD www.meducator.org

Presidential Address

Dear Reader,

MedWire

4 A recent study conducted at Emory University discovered that 55% of subjects with Parkinson’s had insufficient levels of vitamin D, compared to 36% in age-matched controls.

The substantia niagra, the part of the brain inflicted in Parkinson’s, has a greater number of vitamin D receptors, suggesting that vitamin D deficiency may be associated with the disease.

The European Commission determined that 10% of the population could suffer permanent hearing loss if exposed to high volumes for longer than one hour per day, over five years. Millions of people use music players well above the safety level of about 80db in order to block out daily noises such as traffic. New safety standards are pending implementation but the trend towards high volumes continue at present.

A study in the Archives of General Psychiatry has found that children having the most protective variant of the CRHR1 gene, responsible for regulating response to stress hormones, are less likely to demonstrate long term consequences of physical or mental trauma.

Shocking health inequalities around the world have caused the World Health Organization (WHO) to criticize the universal issue of cost and access to proper healthcare.

The World Health Report 2008 drew attention to statistics

Issue 13 such as: 43% of women have no medical assistance during childbirth, 5.6 billion people pay out-of-pocket for more than half of their health care expenditures, and child mortality rate, particularly in Nairobi, varies by almost 25% depending on income.

A researcher from McGill University has discovered a “gene desert” – a stretch of DNA between two genes – that is essentially responsible for male pattern baldness.

The one out of seven men who carry this trait are seven times more likely to eventually become bald.

intricate and accurate that it is able to simulate the timing of heartbeats to within 20 milliseconds.

An interesting study by the University of Illinois’ medical school suggests that the song “Stayin’ Alive” might be the perfect rhythm for performing CPR. The American Heart Association recommends 100 chest compressions per minute; giving the 103 beats per minute disco tune a whole new meaning.

A study published in the British Medical Journal have found that women who smoke are eight times more likely than non-smoking women to die from an aortic

A British study has found that aspirin has no effect on heart disease. Current guidelines advocate use by diabetics to counter the underlying risk of heart attack and stroke. While it is shown to be beneficial in reducing the risk of future heart attacks or strokes, its use as primary prevention

aneurysm rupturing - which is characterized by the rupturing and weakening of the heart’s largest artery wall.

carries significant risks such as gastrointestinal bleeding, and poses new concerns for nondiabetics.

MED

A recent study from Nature describes the novel method used by a team of American scientists in the regeneration of prostate glands in mice.

The researchers began by isolating stem cells responsible for the development of all cells in the prostate. These cells were then transplanted back into the mice, resulting in the formation of gland replicas.

British surgeons have created one of the first threedimensional models of the human heart, which is so

Researchers at Lakehead University have found that hydrogen sulfide, the foulsmelling gas normally found in sewers, can lower blood pressure. They discovered

that it is naturally produced by cells in the body, and that it allows blood vessels to relax for improved flow.

Alberta scientists have found that after experiencing heart failure, patients are at a higher risk of fracturing bones. This is associated with an increased risk of osteoporosis. The underlying

mechanism remains unclear, but researchers are calling for more thorough and frequent screening for patients who have experienced extreme cardiac distress.

Australian scientists have discovered that shark antibodies may potentially be used to synthesize a new generation of cancer-fighting drugs. These compounds are exceptionally resilient since they are able to survive in the extreme conditions of the human gut. Through binding to cancerous cells, shark antibodies inhibit their growth, and there is evidence of their efficacy in slowing down breast cancer development.

November 2008

A new class of antibiotics is on the verge of being developed, created from compounds isolated from naturally-occurring soil organisms decades ago.

Untested as of yet on humans, researchers say that cellbased experiments suggest they are potent enough to kill even stubborn bugs such as disease-resistant TB.

The Bridge Centre of London, England has developed a test for embryos that can detect any of the 15,000 inherited diseases in the short time span of a few weeks. The test screens for genetic disorders by comparing the DNA of the embryo against that of family members to determine if the embryo has inherited DNA coding for certain genetic diseases.

Canadian researchers have determined that a typical Western diet rich in salty and fatty foods is responsible for 30% of the world’s heart attacks. The McMaster team of scientists concluded that an ideal diet consists of lots

of fresh fruits and vegetables.

This diet is even more effective than the tofu and soy oriental diet, and will lower heart attack risks better than any drug available.

A new study from the University of California Los Angeles has found that web surfing can help counteract reduced brain activity in middle and older aged individuals by stimulating brain regions responsible for reasoning and decision-making.

Baffled doctors have finally labelled a mysterious rash on people as “mobile phone dermatitis”. This condition is caused by allergic reactions to the nickel content in the phone after excessive mobile phone usage.

Australian researchers have discovered a genetic link to male transsexualism.

This gene is involved in testosterone action and was found to be longer in male-to-female transsexual volunteers. This study further

provides evidence that there is a biological basis to transsexualism.

increase standard depression measures in patients after 6 weeks of treatment.

Food allergies in young children are on the rise in North America. Since last year, the prevalence of such allergies has increased 18%.

Doctors are unsure about why this is occuring, but they note that while several years ago parents may have ignored symptoms like skin rashes, parents today are quick to take their children to specialists.

Dr. Geoffrey Hackett, a British urologist, warns that erectile dysfunction is often ignored as a sign of heart trouble.

Erectile dysfunction has been linked with a 50-per-cent higher risk of vascular disease.

Hackett is an advocate of using erectile dysfunction as a primary indicator of heart problems, suggesting that it is a better predictor of heart disease than high blood pressure or cholesterol.

A recent study in the scientific journal, Pharmacotherapy, suggests that 18% of first year university students in the United States rely on over-the-counter stimulants, such as Ritalin and Adderall, to enhance concentration during studying. Doctors fear that these students may suffer from known short term concerns, such as anxiety and insomnia, as well as unknown long term effects. The issue also presents ethical concerns for those who view the use of performance enhancing drugs as a form of cheating.

Alemtuzumab, a drug used to treat leukaemia, has been shown to reverse brain damage caused by multiple sclerosis (MS). Researchers at the University of Cambridge posit that the drug, a monoclonal antibody that acts against cancerous white immune cells, also disrupts the action of defective lymphocytes involved in MS. The U.S. government has approved a non-invasive brain stimulator that beams magnetic pulses through the skull as a therapeutic treatment for depression.

Known as transcranial magnetic stimulation, this treatment has been shown to

Dr. P. Nitschke, an euthanasia expert from Australia, is currently promoting his non-profit organization Exit International in the United Kingdom, despite many controversies regarding the ethics of assisted suicide.

Many of his workshop venues withdrew after learning the nature of his conferences. Dr. Nitscke advocates for people’s rights for a “definitive, peaceful end”, and even goes as far as providing older people with “pieces of equipment” which are sometimes dubbed as ‘Do It Yourself Suicide Kits’. www.meducator.org

MedWire

Three scientists from Hanover Medical School in Germany have developed heart valves that grow with patients.

Mechanical valves, or those from animals, prove to be problematic for children whose hearts are still growing.

To create these innovative valves, the scientists excised valves from humans or animals, removed most of the tissue, and re-engineered them with cells from the patient.

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Issue 13

The Logistics and Business Behind Gene Patenting

Dan Mok

When a patent is issued for a new invention, the inventor essentially receives a monopoly over its use for a certain amount of time, such that all who wish to use the invention may be charged a fee or even denied permission to use it.

Although this seems appropriate at first, what happens when the scope of patents broaden to include parts of the human body? Over the past decades, patents have claimed approximately one fifth of the entire human genome and have sparked considerable controversy.

The following article explores arguments both for and against the patenting of genes.

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ased on a 2005 report, approximately 20% of the human genome has been claimed as intellectual property in the United States.

This figure accounts for 4382 of the 23,688 genes in the National Centre for Biotechnology Information (NCBI) gene database.

Amongst the top ten gene patent owners, nine are based in the United States, including the University of California, Human Genome Sciences and Incyte Genomics.

Many genes have been claimed in multiple patents. The BMP7 gene coding for an osteogenic factor and the CDKN2A tumour suppressor gene have been claimed in 20 patents.

- Jensen & Murray, 2005

demonstrable utility (Nicol, 2005).

Genes are appropriate for patenting because they are not a “product of nature”. The genes are substantially different from their naturally occurring counterparts

Introduction to G ene Patenting

because they are purified, isolated, and lack intron sequences. The third requirement is fulfilled because patent laws do not differentiate between the complexity or simplicity of the method used to discover a gene (Bendekgey & Hamlet-Cox, 2002). The utility of a gene is determined in part by its function. The current method to determine a gene’s function - through homology tests with sequenced genes - is only accurate 4

Since the 1980s, ownership of the human genome has increased. Entire genes, gene fragments, and even non-coding regions of the human genome have been patented (Nicol, 2005). According to patent laws, genes are patentable if they are: 1) appropriate subject matter, 2) novel, 3) non-obvious, and 4) have

“...the ethical issues of owning human DNA notwithstanding, many see gene patenting as not conducive and even restrictive for research and patient care.”

out of 5 times. However, this method is sufficient under current patent law (Grisham, 2000).

Thus, genomic companies, universities, or hospitals are able to patent genes, thereby excluding others from using them for approximately 20 years. During this time, marketing gene-derived products, charging licensing fees and collecting royalties from licensed users generate financial profit.

The majority of gene patents claim genes either as research tools or as diagnostic tools (Thomas et. al, 2002). Thus, the ethical issues of owning human DNA notwithstanding, many see gene patenting as not conducive and even restrictive for research and patient care. The following article examines arguments both for and against gene patenting with regard to these issues.

G enes as Research Tools The use of genes as research tools is the leading reason for filing a gene patent (Thomas et. al, 2002). Its repercussions have precipitated considerable debate regarding scientific research and development.

November 2008 Points of Criticism Research and development are inhibited because gene patents create the “anticommons” effect, where multiple patentees have the right to exclude others from research on a particular DNA sequence (Heller & Eisenberg, 1998).

To this end, some genomic firms have patented thousands of Expressed Sequence Tags (ESTs) - short fragments of DNA useful for identifying genes within a chromosome.

They have also privatized their EST databases, making them inaccessible to most academic institutions (Eisenberg, 2002).

Given the competitive nature of research and development in genomics, this is evidence of the increasingly fragmented ownership of many patented genes. In this case, research and financial gain are limited to the patentee.

The anticommons effect also creates the problem of reach-through agreements, which complicates and raises the cost of research. Reach-through agreements are demands for royalties or licenses for future use of the patented gene. Mandatory royalty payments and possible future uncertainties are major deterrents for purchasing a license, thus limiting research on patented genes (Eisenberg, 2002). These disincentives are compounded when there are multiple patent holders on a single gene. According to one study, about a quarter of all patented genes have multiple rights holders (Eisenberg, 2002). The BRCA1 gene, which is linked to early onset breast cancer, is subject to 14 different patents held by 12 separate patentees (Eisenberg, 2002).

Any research performed on genes with such fragmented ownership will incur hefty fees from “royalty stacking” – paying a gene’s multiple owners for use of the gene. Repercussions include a decreased incentive to verify and investigate new findings and extended applications.

Last, critics fear that gene patents break the longstanding traditions of open science. In the past, information has been disseminated to benefit other researchers. Patents, however, prohibit other researchersfrom accessing findings, creating an environment that is counterproductive to the advancement of science.

Points of Approval Some believe that gene patents may promote innovation.

Patents constitute the right to exclude other parties from benefiting financially from the invention or discovery made, thereby granting the patentee market exclusivity. This is an incentive for innovation and discovery. In fact, the rapid growth of the American biotechnology industry in the 1980s and 1990s is attributed to the incentive patents provided for research (Klein, 2007). Without the security of patent

7 protection, investors will not be willing to provide research firms with necessary funding. This particular outcome would slow the development of gene research tools to the detriment of the greater scientific community (Bendekgey & Hamlet-Cox, 2002).

Second, proponents of gene patenting believe that patent laws should not discriminate against certain types of inventions. As long as an invention satisfies all patent criteria, it should be patentable. It is not the patenting of genes that creates problems for research, but rather the misuse of patent rights. One suggested method for addressing this problem is to rescind or amend the Bayh-Dole Act (Bendekgey & Hamlet-Cox, 2002). This law allows universities to patent inventions funded by federal research grants; however, they are not exclusively in the business of making profit off scientific developments. Hence, universities should provide non-exclusive patents.

The strongest argument may be that there is a lack of evidence that patenting genes inhibits research progress (Bendekgey & Hamlet-Cox, 2002). Many of the arguments against patenting genes are speculative. Without concrete evidence that gene patents are counter-productive for research, gene patents should continue to be granted.

Patenting G enes as Diagnostic Tools Genes with diagnostic utility are the second most common type of patented genes (Thomas et al, 2002). This raises mRNA

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separate and distinct issues compared to those raised by patenting genes as research tools.

Points of Criticism Patents on genes as diagnostic tools grant the patentee a monopoly over all methods of testing for a specific disease.

This hinders the functioning of clinical laboratories, which are faced with a limited number of options. They would have to acquire a license and pay any up-front fees and royalties that the license entails. Royalties can range from $2 to $20 per test (Merz & Cho, 2005). This can increase the cost of

“It is not the patenting of genes that creates problems for research, but rather the misuse of patent rights.” testing services preventing some patients from accessing potentially vital information. Another option for clinical laboratories is to send samples off to commercial laboratories owned by patentees and their specified licensees for testing.

Pathologists are thereby prevented from performing tests themselves (Leonard, 2002). This severely limits their ability to treat patients, remain updated in current advances, and train residents and fellows (Merz & Cho, 2005). A third option for clinical laboratories is to avoid testing on patented genes by developing in-house tests for different mutations of a disease gene. These tests run the risk of increasing costs and errors (Merz et al, 2002). The final option would be to simply stop offering tests. For example, 30% of surveyed laboratories in the US stopped performing tests for haemochromatosis because of patents (Merz et. al, 2002). This compromises health care quality by reducing patient access to testing services.

Points of Approval Proponents of gene patenting feel that patents promote disclosure and dissemination of findings in a way that provides the patentee a degree of security. Gene patents also provide security for investors. Without gene patents, there is a lack of monetary support from investors for research that may be considered risky (Bendekgey & Hamlet-Cox, 2002).

Similar to genes patented as research tools, there is little evidence that genes patented for diagnostic use have

Issue 13

compromised healthcare quality. Mertz and Cho (2005) indicate that labs have stopped offering testing services because of patent disputes, but do not provide concrete evidence that this is widespread and pervasive.

Finally, it is easy for patents to be considered negative on the basis of figures and prices. However, it is important to consider gene patents in the context of a profitcentered healthcare system, such as that in the United States (Merz & Cho, 2005). The ability to secure profit in addition to remunerating the cost of research and development is what spurs innovation.

Future Directions Despite the strong arguments for and against gene patenting, it has become a legal reality in many countries, including Canada. What remains is for the legal system and health care industry to adapt to this circumstance. The courts must determine the validity of gene patentees’ claims so that they do not have negative consequences. The health care industry would also need to implement policies to maximize the benefits provided by gene patenting and consider the well-being of patients.

References Bendekgey, L., & Hamlet-Cox, D. (2002). Gene patents and innovation. Academic Medicine, 77(12), 1373-1380.

Chavez, MA. (2003). Gene patents: do the means justify the end?

Computer Law Review and Technology Journal, 7, 255-271.

Eisenberg, R.S. (2002). Why the gene patenting controversy persists.

Academic Medicine 77(12), 1381-1387.

Grisham, J. (2000). New rules for gene patents. Nature, 18(9), 921.

Heller, MA., & Eisenberg, R.S. (1998). Can patents deter innovation?

The anticommons in biomedical research. Science, 280, 698701.

Jensen, K., & Murray, F. (2005). Intellectual property of the human genome. Science, 310, 239-240.

Klein, R.D. (2007). Gene patents and genetic testing in the United States. Nature, 25, 989-990.

Leonard, D.G.B. (2002). Medical practice and gene patents: a personal perspective. Academic Medicine, 77(12), 1388-1391.

Merz, J.F., & Cho, M.K. (2005). What are gene patents and why are people worried about them? Community Genetics, 8, 203-208.

Merz, J.F., Kriss, A.G., Leonard, D.G.B., & Cho, M.K. (2002). Diagnostic testing fails the test. Nature, (415), 577-579.

Nicol, D. (2005). On the legality of gene patents. Melbourne University Law Review, (29), 809-842.

Thomas, S.M., Hopkins, M.M., & Brady, M. (2002). Shares in the human genome – the future of patenting DNA. Nature, 20, 1185-1199.

November 2008

Canada’s Public Health Care System: A Common Misnomer

MedBulletin by Keon Maleki

Canada’s health care system is regarded as a flagship example of a publicly funded system. In every province, a non-profit entity is responsible for the provision of virtually all hospital and physician services. Advocates of the current system maintain that Canada practices “socialized medicine”; however, it is increasingly apparent that Canadians spend a greater proportion of their yearly income on drugs, dental care, and health-related transportation services.

Despite providing more comprehensive public coverage in hospital and physician services, the Canadian system is one of the least equitable public health plans among developed countries. Over the past twenty years, the cost per unit of care for Canadians has steadily increased. Innovative technologies designed to reduce costs and improve efficacy are considered part of “premium” health insurance plans only available through private payment. Accompanied by a consistent increase in the prices of drugs, medical governing bodies have chosen to increase private investment, thereby reducing public financing. The cuts in the public sector have been unbalanced, coming almost entirely from hospital budgets. The proportion of spending on hospital care has decreased from 45 percent of total health care expenditures to 30 percent over the past thirty years. This has a direct impact in the reduction of available hospital beds.

As the consequences of a growing private component in the Canadian health care system becomes increasingly more evident, the notion that Canada is a model for a purely public health care system needs to be reconsidered.

References: “Canada” Evans, R.G. Journal of Health Politics, Policy and Law, Vol. 25, No.5, 2000. Duke University Press.

“Equity” Stone, D. Policy Paradox: The Art of Political Decision-Making, Stone, D. 1997 W.W. Norton & Company Inc. “Health Care Firms: Providers, Practices and People” Evans, R.G. Strained Mercy: The Economics of Canadian Health Care, Evans, R.G. 1984 Butterworths Canada Ltd. “Hidden Overhead Costs: Is Canada’s System Really Less Expensive?” Danzon, P.M. Health Affairs, Vol. 11, No. 1, 1992. Project Hope.

No More Lying?

MedBulletin by Ahmad Al-Khatib

A judge in India recently sentenced Aditi Sharma to life in prison based on accusations of poisoning her former fiancé. The ruling has received worldwide attention because it was based on evidence from the recently developed Brain Electrical Oscillation Signature (BEOS) test. The test relies on the measurement of changes in electrical brain waves as an alleged event description is read to the accused individual. These changes are measured by an electroencephalogram (EEG), and then interpreted by a software to determine if brain regions relating to memory have been excited. The neuroscientist developer, named Champadi Raman Mukundan, claims that the BEOS test is capable of distinguishing between deeds that a person has a committed, and deeds that a person has merely observed. In the case of Aditi, the BEOS test showed large levels of brain activity in the areas responsible for memory of committing the crime, as prosecutors believed it occurred, when read to her.

While psychologists and neuroscientists are excited about this new technology’s potential, they are concerned that it was applied far too quickly. Mr. Mukundan has not published data from BEOS tests, nor has he allowed the technology to be validated by the scientific community. As a result, the ruling of the judge is being called to serious question. However, if the BEOS test does become accepted as a standardized test in future court rulings, it promises to revolutionize criminal investigations by eliminating the need for harsh interrogation techniques. However, Hank Greely, a Stanford bioethicist, asserts that this technology could cause enormous ethical and legal breaches, “implicating violations in at least the First, Fourth, Fifth, Sixth, Seventh and 14th Amendments to the U.S. Constitution.”

References: Giridharadas, Anand. “India’s Novel Use of Brain Scans in Courts is Debated”. The New York Times. 14 Sept. 2008. 10 Sept. 2008 http://www.nytimes. com/2008/09/15/world/asia/15brainscan.html?pagewanted=all.

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Issue 13

Hygiene Hypothesis: Illness as a Painful but Valuable Lesson for a High-Strung Immune System Modernity

has protected humanity from many diseases.

has also spurred the progression of allergic diseases. at alarming paces, especially in modern nations.

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popular theory that explains this paradoxical relationship as a consequence of decreased microbial exposure. Just as the immune system is necessary to

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Ran Ran & Tiffany Chan

to subdue diseases caused by the immune system. refutes this idea.

Much evidence supports and

This article provides a critical perspective on both sides of this enigma and also attempts to construe a consolidated perspective.

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ver the last two decades, a plethora of epidemiological data has emerged suggesting that the prevalence of allergic diseases is increasing at a dramatic rate, especially in developed countries. An intense debate followed over the possible causative factors and mechanisms.

In this heavily deliberated field, it seems that the idea that multifactorial determinants are responsible is the

single agreed starting point. Yet from this sea of ideologies, the hygiene hypothesis has attracted attention, generating both support and contention (Vercelli, 2006). While it has evolved greatly since conceptualization, the central tenet of this hypothesis remains unchanged: microbial exposures early in life can reduce the likelihood of developing allergic diseases and other immune hypersensitivity diseases. This

article provides a broad overview of the literature concerning the hygiene hypothesis: its evidence, mechanisms, and shortcomings.

Lessons From Epidemiology The prevalence of allergies, asthma, atopic eczema, and other diseases associated with immune dysregulation has increased dramatically.

Figure 1 Th1 and Th2 are mutually inhibitory immune responses

Th2

IL-4

Naive Helper T cell

APC IL-12

Th1

IL-4 IL-5 IL-9 IL-13 IFNy TNFa IL1B

Allergies Asthma Atopic eczema Insulin dependent diabetes mellitus

Normal immune effects can be subcategorized into several streams. The effects mediated by T-helper cell 1 (Th1) and T-helper cell 2 (Th2) are two well characterized streams that are mutually inhibitory – mediators in the Th1 stream actively suppress the Th2 stream and vice versa (Figure 1).

Mounting the appropriate immune response is pivotal in preventing and clearing disease as well as minimizing immune-mediated pathologies.

Inappropriate Th1 and Th2 responses can often have detrimental and even fatal effects. An overly strong Th2 response is often observed in atopy, allergies, and asthma.

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Limited Th1 activity Th2 activity remains high Adult is predisposed to allergic diseases

Seldom Exposure to Microbes

Baby - Constitutive Th2 Activity

Microbes spurr Th1 activity Th1 suppresses Th2 activity Adult is resistant to developing allergic diseases

Figure 2 Missing Immune Deviation in Development of Allergic Diseases

Interestingly, this trend is far from uniform pertaining to certain demographics but not others. The recent rise in epidemiological studies has identified many social factors that predispose individuals to or protect individuals from such diseases. Some of these factors include family size, socioeconomic status, and consideration for whether individuals grew up in an urban or rural environment in a developed or less developed country (Stratchan, 1989; Garn & Renz, 2007; Nowak et al., 1996; Mutius, 2007). The hygiene hypothesis tries to explain the relationship between allergic diseases and the many aforementioned social factors with one unifying concept: frequency of microbial exposures.

Family Size Dr. David Stratchan first proposed the hygiene hypothesis in 1989 when he observed that cases of hay fever were inversely related to the number of siblings in a family. He hypothesized that younger siblings were exposed to more microbes through contact with their older siblings, ultimately preventing them from developing allergies.

Socioeconomic Status More than two hundred years before Dr. Stratchan’s conjecture, scientists in the 1800s noted that hay fever seemed to only affect individuals of middle or upper classes.

Incidences of this disease were rarely found in less affluent groups such as farmers, despite their drastically increased

exposure to pollen and other pathogens (Mutius, 2007).

This strengthened the idea that exposure to microbes was inversely correlated to the risk of developing allergies.

Recent studies also show that children in families of low socioeconomic status have reduced risk of developing atopy (Garn & Renz, 2007). Presumably, these children do not have ready access to antibiotics and are also exposed to more microbes in their diet. However in the United States, AfricanAmerican and Hispanic-American children, who belong to the two main lowest socioeconomic groups, demonstrate high prevalence of asthma and allergies (Webber et al., 2002).

The hygiene hypothesis suggests that children coming from large families who live in poorer conditions are protected against allergic diseases. This does not appear to be the case, which has ultimately led scientists to believe that other factors are at work.

Developed versus Developing Countries The aforementioned observation can be expanded to a global level; individuals in developing countries display a significantly lower risk for allergic diseases (Figure 1) (The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee, 1998). However, these geographical trends are not coincidental. Less developed countries that adopt a Western lifestyle also demonstrate increased risk of allergic diseases (Nowak et al., 1996). Before the 1990s, the relatively poor and underdeveloped East Germany saw a lower prevalence of asthma and other allergic diseases as compared to West Germany, which had relatively higher standards of living (Bach, 2002). Interestingly, when Germany was reunified in 1990, scientists found that prevalence of atopic eczema and allergic sensitization increased in the children born in former East Germany (Heinrich et al., 2002). These observations led scientists to believe that factors associated with higher living standards in West Germany, which spread to East Germany after reunification, predisposed children to allergic disease. The resulting decrease in microbial exposure in East Germany is a likely explanation for the increase in allergic disease.

Farm Environments and Pets Several studies, such as the Swiss SCARPOL study, have shown that children raised in rural areas, particularly farms, are protected from hay fever, asthma, and other allergies (Garn & Renz, 2007). On the other hand, children living in the same village, but not on a farm, have a much higher prevalence of hay fever and atopic sensitization (Mutius, 2007). Arguably, children living on farms are also exposed to a wide variety of microbes in this environment. This www.meducator.org

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Th2 Response of s tion ine duccytok o r p 2 cits Th Eli and IgE

bats

Resu lt

Com

t

en

per c

gm

au Spu IL10 prrs TGF-B a ro as T-r duction as nd eg cell w activit ell y

Allergic Diseases

lud e

s in

allay

Helminths

T-reg Response

Figure 3 Pathogen Mediated Immune-Regulation in the Development of Allergic Diseases.

association provides further support for the hygiene hypothesis.

Exposure to animals seems to be another pivotal factor. Children who had a cat within the first few years of life not only had a reduced sensitization to cat allergens, but also a lowered risk of asthma later in life (Garn & Renz, 2007).

Contact with animals is thought to increase exposure to microbes. Though some exposures provide a protective effect, some bacterial products are risk factors for diseases like asthma (Mutius, 2007).

Timing as a Mediator for Microbial Exposure The type of microbe is not the only variable; the timing of exposure also plays an important role in protection.

Prenatal and early exposure in the first year of life seem to provide the strongest protective effect (Garn & Renz, 2007).

Maternal contact with stables lowered the risk of their children developing asthma. Young children who drink unpasteurized milk also demonstrate significantly reduced risk. Thus, the hygiene hypothesis seems to only apply in a certain timeframe and in regards to certain microbes (Garn & Renz, 2007).

Although there is some evidence against the range of

epidemiological evidence in support of the hygiene hypothesis, it provides important clues in deciphering the immunological mechanism behind this “lesser of two evils” ideology.

Lessons from Immunology Missing Pathogen-Mediated Immune Deviation While strong epidemiological and immunological evidence exist in support of the hygiene hypothesis, the mechanism is unclear. Some research postulates that microbial exposure “educates” the immune system, shifting it from a T helper cell 2 phenotype (Th2), which is involved in the pathogenesis of allergic diseases, to a T helper cell 1 phenotype (Th1) (Romagnani, 2004).

The observation that newborns’ T helper cell activity is constitutively Th2 while adults’ immune response is predominately Th1 grants context for this idea (Holt & Macaubas, 1997) (Figure 2). Exposure to microbes early in life is thought to mediate this shift in immune activity. Presumably with hygienic environments, this pathogenmediated immune deviation does not occur to a sufficient extent, resulting in a relatively overactive Th2 response (Romagnani, 2004).

Antigen presenting cells (APCs), crucial cells of the innate immune system, play an integral role in determining later T helper cell responses. These cells are typically first to recognize pathogens through Pattern Recognition Receptors (PRR), which are families of receptors that are capable of binding to a vast array of pathogen associated molecular patterns (PAMPs). The series of PRRs that become stimulated and their degree of activation influence the maturity of APCs. Hence, exposure to pathogens programs cells of the innate system to behave in ways that will later impact the behaviour of cells in the adaptive immune system. The details of this molecular pathway are relatively unclear, but the role of APCs and PRRs on T cell development has been firmly established (Duez, Gosset, & Tonnel, 2006).

Toll-like receptors (TLRs), a well-studied family of PRRs, has been shown to play a role in T helper cell differentiation. Thus far, ten TLRs (TLR110) have been identified. Together they are capable of recognizing and distinguishing the swath of existing pathogens, as well as eliciting more specific adaptive immune responses.

Generally, TLR activation is thought to elicit Th1 responses (Romagnani, 2004).

This is congruent with the finding that TLR agonists, which are abundant in farms and lesser developed countries, have a protective effect on allergic diseases (Patel et al., 2005). In addition to the quantity of environmental microbial products, the degree of TLR activation also depends on TLR expression. A recent study shows that maternal exposure to stables significantly upregulates their children’s expression of TLR2 and TLR4 later in life (Ege et al., 2006). Coincidentally, in utero exposure to microbial products

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also has a strong protective effect on developing allergic diseases (Ege et al., 2006). Lastly, a deleterious polymorphism in a key TLR gene, CD14, is shown to be correlated with levels of circulating IgE (Baldini et al., 1999), which is necessary in the pathogenesis of asthma and allergies (Gould & Sutton, 2008). Thus, compromised TLR recognition may contribute to the development of allergies and asthma by impeding Th1 induction.

Additional evidence supports this idea of Th1/Th2 imbalance. Illustrating the importance of Th2 responses in asthma, respiratory syncytial virus (RSV) infections - which affect young children and induce a strong Th2 response increase the risk of developing asthma (Graham, Johnson, & Peebles, 2000). Contrarily, neonatal vaccination with BCG, which protects against tuberculosis and induces a Th1 response, significantly reduces risk of developing asthma (Linehan, 2007). Considering the idea that individuals in less developed countries display a Th1 phenotype and individuals in developed countries display a Th2 phenotype, prevalence of Th1-mediated nephropathies is increasing in less developed countries while the prevalence of Th2-mediated nephropathies is increasing in developed countries (Hurtado, 2005). This association reaffirms the idea that the difference in Th1/Th2 balance between developed and developing nations may contribute to different diseases associated with immune dysregulation.

Helminths

Microbial Exposure

T-Reg

Th1

Th2

Tightly regulated Th2 Responses Figure 4 Consolidated Perspectives on Allergic Diseases.

Lack of pathogen mediated immune-regulation Despite the pervasive supporting evidence, this view of Th1/ Th2 is far from perfect. The example of RSV demonstrates that while many microbes garner a Th1 response and suppresses the Th2 response, some pathogens actually shift the immune response from Th1 to Th2. An example is the helminth, also known as a parasitic worm. They are widely prevalent in less developed countries and prime strong Th2 responses (van den Biggelaar, 2000). Despite displaying high levels of Th2 activity, frequently exposed individuals still seem to be protected from allergic diseases (The International Study of Asthma and Allergies in Childhood Steering Committee, 1998). Furthermore, there is a positive association between the occurrence of asthma, a Th2-mediated disease, and insulin dependent diabetes mellitus (IDDM), a Th1-mediated disease (Stene & Nafstad, 2001). The hygiene hypothesis predicts a negative association because Th1 and Th2 are mutually inhibitory responses.

These challenges shed scepticism regarding the explanation that microbial infections protect against allergic diseases by eliciting the expression of Th1 and suppressing Th2. Another mechanism involving general immune regulation as mediated by regulatory T cells was proposed in light of the previous model’s shortcomings.

Regulatory T cells function to modulate immune responses, prevent autoreactivity to self-antigens, and establish tolerogenic states to non-self antigens like food and other harmless substances (Figure 4). Helminth infections, which significantly raise non-specific IgE levels and Th2 cytokines, also spur high levels of IL10 and TGF-β secretion (van den Biggelaar, 2000). Therefore, although these parasites galvanize a Th2 response, they also stimulate the production of anti-inflammatory cytokines that suppress the actual response (Holt, 2000). Microbial infections also trigger IL10 and TGF-β production, especially when there is a high pathogen burden (Romagnani, 2004). Presumably, lack of exposure to pathogens will not incur such protective antiinflammatory effects. This explains the positive correlation between the occurrence of asthma and IDDM; both are assumably dependent on impaired immune suppression.

Moreover, a study on atopic individuals reveals that their regulatory T cells are less able to suppress T cell proliferation and secretion of Th2 cytokines than non-atopic individuals in the context of allergen exposure (Ling et al., 2004). The difference in suppression suggests that deficiencies in regulatory T cell activity may be a causative factor in atopic diseases. Lack of exposure to helminths and other microbes can lead to this deficiency.

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Despite the myriad of supporting evidence, this idea of missing pathogen-mediated immune suppression is also inadequate when considered alone. People in Estonia, who experience very little helminth infection, are also at decreased risk of allergic diseases (Romagnani, 2004). In addition, IL10 – despite having strong immunomodulatory effects, especially on Th1 – also contributes in driving, rather than preventing, Th2 responses to certain infections (Romagnani, 2004).

Both mechanisms possess serious flaws, but considering them together forms a more comprehensive picture (Figure 5). Different microbes have different effects.

Some shift the immune response from Th2 to Th1, while others suppress the effects of both Th2 and Th1. Some do

References Bach, F. J. (2002). The Effect of Infections on Susceptibility to Autoimmune and Allergic Disease. New England Journal of Medicine, 12(347), 911920.

Baldini, M., Lohman, I., Halonen, M., Erickson, R., Holt, P., & Martinez, F. (1999). A polymorphism in the 59-flanking region of the CD14 gene is associated with circulating soluble CD14 levels with total serum IgE. American Journal of Respiratory Cell and Molecular Biology, 20(5), 976-983.

Czeresnia, D. (2005). The hygienic hypothesis and transformations in etiological knowledge: from causal ontology to ontogenesis of the body.

Cardenos de Saúde Pública, 21(4), 1168-1176.

Devereux, G. (2006) The increase in the prevalence of asthma and allergy: food for thought. Nature Reviews Immunology, 6(11), 869-74.

Duez, C., Gosset, P., & Tonnel, A. (2006). Dendritic cells and toll-like receptors in allergy and asthma. European Journal of Dermatology, 16(1) 12-6.

Ege, M., Bieli, C., Frei, R., van Strien, R., Riedler, J., Ublagger, E., Schram-Bijkerk, D., Brunekreef, B., van Hage, M., & Scheynius, A. (2006). Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. Journal of Allergy and Clinical Immunology, 117(4), 817-823.

Garn, H. & Renz, H. (2007). Epidemiological and immunological evidence for the hygiene hypothesis. Immunobiology, 212(6) 441-452.

Gould, H., & Sutton, B. (2008). IgE in allergy and asthma today. Nature Reviews Immunology. 8(3). 205-17.

Graham, B., Johnson, T., & Peebles, R. (2000). Immune-mediated disease pathogenesis in respiratory syncytial virus infection. Immunopharmacology., 48(3), 237-47.

both, others do neither. The lack of a unifying concept in this multifarious umbrella hypothesis predisposes this conjecture to profuse debates. As it is understood now, the hygiene hypothesis is actually a large collection of imperfectly explained observations. Not enough experiments are present to safely form a generalization or a paradigm. Thus, delving deeper into this hypothesis seems to lead us back to the original concept that multifactorial determinants are responsible. However, further research on this fascinating concept of microbial exposure as both harmful and beneficial for one’s health might clarify much of the debate and issues surrounding the hygiene hypothesis today.

Linehan, M., Frank, T., Hazell, M., Francis, H., Morris, J., & Baxter, D. (2007). Is the prevalence of wheeze in children altered by neonatal BCG vaccination? Journal of Allergy and Clinical Immunology, 119, 1078-84.

Ling, E., Smith, T., Nguyen, X., Pridgeon, C., Dallman, M., Arbery, J., Carr, V., & Robinson, D. (2004). Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet, 21, 363.9409, 608-15.

Mutius, E. (2007). Allergies, infections and hygiene hypothesis – The epidemiological evidence. Immunobiology, 212, 433-39.

Patel, M., Xu, D., Kewin, P., Choo-Kang, B., McSharry, C., Thomson, N., & Liew, F. (2005). TLR2 agonist ameliorates established allergic airway inflammation by promoting Th1 response and not via regulatory T cells.

Journal of Immunology, 174, 7558-63.

Redecke, V., Hacker, H., Datta, S., Fermin, A., Pitha, P., Broide, D., & Raz, E. (2004). Activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. Journal of Immunology, 172, 2739-43.

Romagnani, S. (2004). Immunologic influence on allergy and the Th1/Th2 balance. Journal of Allergy and Clinical Immunology, 113.3, 395-400.

The International Study of Asthma and Allergies in Childhood Steering Committee. (1998). Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet, 351, 1225-32.

Schaub, B., Lauener, R., & Mutius, E. (2006). The many faces of the hygiene hypothesis. Journal of Allergy and Clinical Immunology, 117, 969-77.

Stene, L., & Nafstad, P. (2001). Relation between occurrence of type 1 diabetes and asthma. Lancet, 357, 9256, 607-8.

Stratchan, D. P. (1989). Hay fever, hygiene, and household size. British Medical Journal, 299, 1259-1260.

Heinrich, J., Hoelscher, B., Frye, C., Meyer, I., Wjst, M., & Wichmann, H. (2002) Trends in prevalence of atopic diseases and allergic sensitization in children in Eastern Germany. European Respiratory Journal., 1(4), 1040-1046.

Biggelaar, A. van den, Ree, R. van, Rodrigues, L., Lell, B., Deelder, A., Kremsner, P., & Yazdanbakhsh, M. (2000). Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. The Lancet, 356.9243, 1723-7.

Holt, P. (2000) Parasites, atopy, and the hygiene hypothesis: resolution of a paradox? Lancet. 35(9243), 1699-701.

Vercelli, D. (2006). Mechanisms of the hygiene hypothesis — molecular and otherwise. Current Opinion in Immunology 2006, 18, 733–37.

Holt, P., & Macaubas, C. (1997) Development of long term tolerance versus sensitisation to environmental allergens during the perinatal period.

Current Opinion in Immunology. 9(6), 782-87.

Webber, M.P., Carpiniello, K.E., Oruwariye, T., & Appel, D.L. (2002). Prevalence of asthma and asthma-like symptoms in inner-city elementary schoolchildren. Pediatric Pulmonology, 34, 105-11.

Hurtado, A., & Johnson, R. (2005) Hygiene hypothesis and prevalence of glomerulonephritis. Kidney International Supplement. 67(1), 62-67.

Zaccone, P., Fehervari, Z., Phillips, M. J., Dunne, W. D., & Cooke, A. (2006).

Parasitic worms and inflammatory diseases. Parasite Immunology, 28, 515-23.

November 2008

Caffeine: Harmful Drug or Healthy Boost?

MedBulletin by Alyssa Cantarutti

Trimethylxanthine is a drug consumed by Canadians daily. Most of us know it as caffeine, and it is what makes the first cup of coffee in the morning as appealing as it is. Up to 80% of adults include some sort of caffeine intake in their day. However, there are health risks associated with consumption that are often overlooked because caffeine is rarely classified in popular culture as a drug.

Health Canada recommends that adults take in a maximum daily dose of 400 to 450 mg of caffeine. A single large coffee (approximately 500 mL) contains 200 to 400 mg. As easy as it is to reach maximum recommended levels just by drinking coffee, it is important to recognize that caffeine is also found in tea, energy drinks, sodas, chocolate, and many cold medications. In September of this year, researchers called for a mandated labelling of caffeine levels in beverages - some energy drinks contain as much caffeine as 14 cans of soda! At 600 mg in a single day, an individual may start to experience symptoms of caffeine overdose, such as restlessness, nausea, headache, and irregular heartbeat.

Once caffeine is in the bloodstream, it has many of the same effects as cocaine and heroin, including a temporary sense of euphoria. Adenosine reception is blocked, which increases one’s alertness. Adrenaline production increases and changes in dopamine levels induce a sense of well-being. Unfortunately, this creates a set of extremes within the body. When caffeine is metabolized, its effects wear off and one faces fatigue and depression. Consequently, the body craves more caffeine, and this internal cycle begins again.

Caffeine isn’t entirely harmful, however, as several studies have suggested possible beneficial effects after intake.

These include helping premature babies survive the first days of life, reducing the risk of developing Parkinson’s disease, and improving memory retention in women.

Like many drugs, caffeine affects different people in different ways. Some are far more tolerant than others. Individuals who want to reduce their intake of caffeine will likely experience withdrawal symptoms for a few days, including headaches, irritability and nervousness. Carefully monitoring and gradually reducing caffeine consumption, as well as replacing caffeinated beverages with decaffeinated ones are some of the recommended strategies to minimize the effects of withdrawal.

References “Caffeine”. CBC News In Depth Health. 14 October, 2008. Retrieved 16 October 2008. http://www.cbc.ca/news/background/health/caffeine.html.

Mind Power Moves Paralyzed Limbs

MedBulletin by Hiten Naik

Researchers at the University of Washington have shown that it is possible to capture signals from the brain with a device and redirect them to innervate paralyzed limbs.

When the spinal cord is damaged, communication between the brain and limbs is prevented. However, the limbs themselves are not damaged, and recent studies have suggested that quadriplegic subjects can still exhibit conscious control over the motor cortex of the brain. Therefore, the paralysis can theoretically be relieved by developing an alternate route that connects the motor cortex to the limbs. The brain-machine interface device developed by the researchers accomplishes this by converting brain signals into electrical impulses. This cellphone-sized gadget allowed temporarily paralyzed monkeys to contract muscles in their arms, and the scientists believe it was a first step towards producing more complicated movements.

In addition to performing trials on humans, the scientists must also develop ways to integrate sensory feedback in the system. At the moment, the interface only communicates in one direction, and it may be many years before a practical model is developed. A device capable of processing sensory input and motor output would provide a convenient alternative to robotic limbs.

References “Mind power moves paralysed limbs.” BBC News. 15 October, 2008. 17 October 2008. http://news.bbc.co.uk/2/hi/health/7669159.stm

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Genetics in Healthcare The role of genetics in healthcare is expanding – the number of genetic tests available to patients continues to grow and the field of pharmacogenomics offers the enticing prospect of a more personalized approach to medicine. It is important to remember, however, that these new frontiers in medicine bring ethical and

Manan Shah

social implications along with them.

T

he field of genetics has flourished since the renewed appreciation for Gregor Mendel’s pea plant experiments in the early 1900s and the determination of DNA structure

by James D. Watson and Francis Crick in the 1950s. In particular, research developments in genetics have profoundly impacted the medical field.

Over the past 50 years, scientists and healthcare professionals have gained insight into the genetic basis of certain diseases, and have since used this knowledge to develop novel therapies, and continued research into diseases with unknown etiology. Today, genetics is revolutionizing healthcare in more ways than one.

The Human G enome Project The completion of the Human Genome Project (HGP) was a scientific milestone that allowed genetics to have a greater impact on healthcare. In 1990, the HGP set out to determine the sequence of nucleotides on each chromosome and achieved their goal by 2006 (Human Genome Project Information, 2007).

The task at hand now is the annotation of the genome, and the identification of functional elements and transcribed regions. The HGP has contributed to the

development in the field of genomics, which use various computational techniques to analyze genome sequences of organisms (Russel, 2006).

G enetic Testing Genetic testing is one area of medical genetics that has matured since the completion of the HGP. Genetic testing examines the DNA of a patient and determines that individual’s risk of being a carrier or becoming affected by a genetic disorder (Zimmern, 2007).

Table 1 describes the main categories of over 900 genetic tests available today

(Genetic Testing, 2008).

Genetic testing can prove to be extremely beneficial to patients.

Becoming aware of one’s predisposition to disease may permit lifestyle changes to help minimize the likelihood of disease onset. Furthermore, if a high familial risk of disease exists, then all members can take precautionary measures and maintain a healthy lifestyle. Newborn and prenatal genetic testing are especially important, given their ability to predict life-altering conditions for a child. Early detection along with proper treatment can ensure a better chance of normal development.

Table 1 Four major types of genetic testing (Nussbaum, 2007).

TEST

DESCRIPTION

Prenatal

Analyses the DNA of a developing fetus to determine the risk of birth defects or genetic disorders.

Newborn

Carried out after birth to determine the risk of life-threatening or developmental disorders.

Pre-symptomatic

Determines the genetic risk for an adult individual to develop a late-onset disease, such as Alzheimer’s.

Confirmational

To obtain confirmation regarding the patient’s current status with a specific inherited illness.

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Phenylketonuria (PKU) is an example of a genetic disease that if identified and treated early, can dramatically alter the course of a patient’s life. The illness is characterized by a deficiency in the enzyme phenylalanine hydroxylase.

In patients with PKU, the amino acid phenylalanine cannot be converted to tyrosine causing a build-up to high concentrations of phenylalanine in the body. Left untreated, the illness can result in mental retardation. Early recognition through genetic testing will result in the patient being placed on a very effective low phenylalanine to control its bodily concentration and high tyrosine diet (Russell, 2006).

Testing services can be obtained through a healthcare professional or from life science companies.

Companies generally offer direct-to-consumer (DTC) genetic testing, in which consumers can purchase and undergo tests independently, rather than under the supervision of a healthcare professional (Wade, 2006).

Advantages of offering this testing approach include increased access to genetic testing, greater confidentiality, and reduced testing costs for the patient (Wade, 2006).

However, there are several negative aspects to offering genetic tests in this manner that may outweigh its benefits.

For example, the methods used by life science companies to advertise their testing services are often criticized.

Critics argue that these companies provide “deterministic and simplistic explanations of genetics” to the public, and by exploiting public anxiety, convince patients to order expensive genetic tests that may not necessarily provide them with useful information (Williams-Jones, 2006). Furthermore, given that DTC marketing of genetic tests is relatively new, few governments have stipulations in place that regulate this service (Williams-Jones, 2006). Lastly, allowing consumers to obtain their personal genetic information without the supervision of a healthcare professional can lead to the possibility of patients misinterpreting information that they purchased. For these reasons, it may be necessary to involve a healthcare professional when considering a genetic test, or attempting to interpret its results.

Pharmacogenomics Perhaps one of the most intriguing proceedings in medical genetics today is the field of pharmacogenomics, originating from genomics and pharmacogenetics – the study of how a single gene can affect the body’s response to a drug.

Pharmacogenomics focuses on differences in drug response from various polymorphisms, differences in a specific phenotype, between individuals. The aim to search for the optimal drug and dosage for patients based on single genetic differences (Lindpainter, 2002).

As many illnesses involve more than one gene, pharmacogenomics can examine the impact of an individual’s genome on the body’s response to a drug, allowing an elucidation of a tailored treatment (Russehal, 2006). The differences in patients’ genomic response to a medication are often caused by single nucleotide polymorphisms (SNPs) in a multiple number of genes. SNPs can alter genes which encode proteins essential for drug metabolism. For example, Patient A may have a gene with a nucleotide sequence of A-T-G-C which produces a fully functioning protein that facilitates excretion of the drug from the body. Patient B, on the other hand, may have a SNP on the gene that results in a nucleotide sequence, A-G-G-C. This patient does not produce the functioning protein, and thus cannot excrete the drug from the body (University of Utah, 2008). Such an instance would lead to an adverse drug reaction (ADR). Many individuals experience ADRs when taking medication due to genetic predispositions to poor drug metabolism (Hood, 2007).

Utilizing a genetic profile, pharmacogenomics is used as a tool in drug discovery to examine the different effects of several medications. It identifies the best candidate from a variety of drugs based on maximum efficacy and the lowest potentials for toxicity and complications (Lindpaintner et al., 2002). www.meducator.org

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Pharmacogenomics and pharmacogenetics offer a more personalized approach to treatment. This is significant as the current ‘one-size-fits-all’ approach to treatment has its drawbacks. Both pharmacogenetics and pharmacogenomics offer the possibility of reducing ADRs, and saving crucial time by preventing the use of a drug that would be ineffective for certain individuals. Time is an especially important factor, given that delays in treating a disease could have serious implications (Hood, 2007).

However, there are obstacles that stand in the way of implementing pharmacogenomics into standard healthcare practice. First, it has been difficult for scientists to demonstrate an improvement in the quality of patient care stemming from pharmacogenomics. Many pharmacogenomic research studies have utilized small sample sizes, healthy participants as opposed to patients, and failed to consider dose-dependent effects of the studied drugs therefore decreasing the studies’ validity. Furthermore, most pharmacogenomic studies that display positive results in a laboratory setting lose their generalizability when tested against an independent patient population (Swen, 2007).

Ethical questions concerning pharmacogenomics have also arisen. The primary ethical concerns involve the wealth and availability of sensitive genetic information

and ensuring patient confidentiality. Information regarding ethnic differences in polymorpshisms is also a concern. For example, there are significant differences in the frequency of P-glycoprotein (PGP) polymorphisms among certain races.

PGP is a transporting protein employed by many drugs to enter a cell, a polymorphism in a PGP gene could thus significantly affect drug efficacy in that individual (Kim et al., 2001). The issue here is the use of the patient’s ethnicity as a variable in the prescribing process.

Conclusion Although “personalized medicine” is a long way from being integrated into everyday healthcare, the potential for the field to significantly improve healthcare holds promise. Genetic testing has already improved healthcare and will continue to do so, as the number and quality of tests available to patients increases with further genomic research. It is important to recognize; however, that the growth of medical genetics will bring new ethical, legal, and social implications into the healthcare forum. While genetics continue to revolutionize healthcare, it is imperative to maintain the patient’s privacy rights and best interests in mind.

References Genetic Testing. (2008). National Library of Medicine. Retrieved February 16 2008, from <http://www.nlm.nih.gov/medlineplus/ genetictesting.html> Hood, E. (2003). Pharmacogenomics: The Promise of Personalized Medicine. Environmental Health Perspectives. 111 (11), A 581 – A10. Retrieved February 16, 2008.

Human Genome Project Information. (2007). U.S. Department of Energy Genome Program. Retrieved February 19 2008 from <http:// www.ornl.gov/sci/techresources/Human_Genome/project/about. shtml>.

Kim, R. B., Leake, B. F. & Choo, E. F. (2001). Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clinical Pharmacology & Therapeutics. 70, 189-199.

Lindpaintner, K. (2002). The impact of pharmacogenetics and pharmacogenomics on drug discovery. Nature Reviews Drug Discovery. 6, 463-469.

Nussbaum, R. (2007). Thompson & Thompson Genetics in Medicine (7th ed.). Oxford: Saunders Book Company, 59-60.

Russel, P. (2006). iGenetics: A Molecular Approach. San Francisco: Pearson Benjamin Cummins.

Swen, J. J. (2007). Translating Pharmacogenomics: Challenges Down the Road to the Clinic. PLoS Medicine. 4 (8), 1317-1324.

Wade C. H. (2006). Ethical and clinical practice considerations for genetic counselors related to direct-to-consumer marketing of genetic tests. American Journal Medical Genetics Part C (Seminars in Medical Genetics). 142C, 284–292.

Williams-Jones, B. (2006). ‘Be ready against cancer, now’: direct-toconsumer advertising for genetic testing. New Genetics and Society, 25:(1), 89 – 107.

University of Utah: Genetics Science Learning Centre (2008).

Personalized Medicine. Retrieved October 3, 2008 from <http:// learn.genetics.utah.edu/content/health/pharma/>.

Zimmern, R. (2007). The Evaluation of Genetic Tests. Journal of Public Health. 29 (3), 246-250.

November 2008

Keeping the Red Wine Flowing Helps Cut Cancer Risks

MedBulletin by Randal DeSouza

Red wine may do more than just complement pasta. A new study showed that a glass of red wine at dinnertime, or using it to cook food, can decrease the risk of lung cancer. While the findings were restricted to men only, health benefits of theantioxidant component of red wine have been well-documented.

In addition,it is believed to protect against lung cancer particularly among smokers.

This study analyzed data from the California Men’s Health Study, which linked clinical data with self-reported data from men between 45-69 years.

Researchers pinpointed the onset of lung cancer in men and studied the effects of consumption of various alcoholic beverages such as beer, red wine, white wine and liquor with the risk of lung cancer.

Among study participants, there was a two percent lowered risk of lung cancer with each glass of red wine consumed per month. However, the most substantial risk reduction was observed among smokers who drank one to two glasses of red wine per day. The researchers reported a stunning 60 percent reduction in risk for lung cancer amongst these patients, while no such correlation between the other beverages and lung cancer were found.

Red wine contains high levels of antioxidants - substances that are extremely beneficial to general health. It is also rich in resveratrol, a compound derived from grape skins which has significant health benefits as established in preclinical studies. Despite these results, researchers cautioned that the best way to reduce the risk of lung cancer was to stop smoking, as smokers who consumed red wine were still at a higher risk than non-smokers.

References Hindustan Times (2008). Red wine can cut lung cancer risk. Retrieved October 22, 2008, from http://www.hindustantimes.com/StoryPage/StoryPage.aspx?s ectionName=LifeStyleSectionPage&id=1786f022-ca29-418d-99b3-ad51b11bbec0&&Headline=Red+wine+can+cut+lung+cancer+risk

Are Doctors Responsible for the Care of Unborn Children?

MedBulletin by Sangeeta Sutradhar

Accutane, a popular drug prescribed for acne treatment, is known to cause severe defects in fetuses. When a Toronto doctor, Dr Shaffiq Ramji prescribed this medication to expectant mother Dawn Paxton, Paxton’s child was born paralysed in portions of her face, without a right ear.

Despite such dire consequences, the Ontario Court of Appeal denied the now grown-up child’s right to sue Dr Ramji, his defence being that his primary obligation was that of the female patient, and not of her unborn child. The court’s decision reflects society’s concerns regarding similar controversial subjects, such as abortion and stem cell research. Where should the line be drawn between a mass of cells and an unborn human being?

The judge ruled that Dr Ramji’s position as a doctor in relation to an unborn fetus is remote and irrelevant, especially since adequate healthcare was ultimately provided for Mrs Paxton. This ideology questions how extensive a doctor’s obligation of care towards his patients should be. Another argument from the defence was that an unborn fetus cannot be advised or take instructions in regards to any sort of treatment.

The ethics behind the true definition of a living human has been subject to countless debates. In Jaime’s case, the court sees no way to compensate a child who becomes deformed in the womb, which in turn, resonates social concerns regarding when a fetus is ethically and legally considered a human being.

References: Makin, K. (2008, October 15). Deformed child cannot sue doctor, court rules. The Globe and Mail, p. A16.

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Issue 13

Saviour Siblings: Genetic Screening and Policy

Sarah Levitt

In the field of medicine, new technological advances and procedures require reform in health policy. During this process, ethical issues need to be examined from a variety of different points of view. For example, Pre-implantation Genetic Diagnosis (PGD) and Human Leukocyte Antigen Tissue Typing (HLA typing) are new techniques that allow for the creation of “saviour siblings,” which are embryos that are a tissue match for existing children. While certain parameters have been set up in different countries, such as the United Kingdom, these regulations are not always ethically consistent with other health policy. These new advances in medicine need to be carefully considered before they can be implemented on a broader scale.

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thical issues are intertwined with health care, as clinicians have always had to make difficult decisions surrounding patient care. Today, moral dilemmas are increasingly complex due to advances in medical technologies. The new technology that has come from reform in health policy raises ethical issues and requires legislation for regulation purposes. This process involves multiple interest groups such as government, specialists, and citizens; therefore, the writing of health policy becomes extremely difficult. Pre-implantation Genetic Diagnosis (PGD) and Human Leukocyte Antigen Tissue Typing (HLA typing) for the use of creating “saviour siblings” are examples of healthcare-related ethical issues that we must

“a ‘saviour sibling’ may only be conceived for a child whose condition is the result of a hereditary disorder” address. Currently, the United Kingdom has a controversial policy regarding these technologies. This article will address the ethical implications of this legislature, as well as assess how consistent these laws are with other UK biomedical policies.

PGD and HLA typing are used to screen embryos for genetic diseases that will affect their quality of life. This enables couples to carry a healthy baby despite a pre-disposition to a genetic disorder. These technologies can also be used to screen embryos for the benefit of a relative by testing if a person is a tissue match even before birth (Boyle and Savulescu 2004). For example, if a child has a serious blood disease for which a blood

transfusion is needed, and there are no appropriate donors, the parents may choose to conceive a second child with the ability to donate blood. Parents like Raj and Shahana Hashmi have attempted to use this procedure to save another child.

In the Hashmi’s case, their son Zain had the blood disorder β-thalassaemia and they created 14 embryos in an effort to find a blood transfusion match (Sheldon and Wilkinson, 2004). PGD and HLA typing technology create much controversy among policy-makers.

The Human Fertilisation and Embryology Authority (HFEA) in the UK has outlined parameters under which this procedure is permissible. In this criteria, it is stated that “the embryos conceived in the course of this treatment should themselves be at risk from the condition by which the existing child is affected” (HFEA, 2001). This stipulation means that a “saviour sibling” may only be conceived for a child whose condition is the result of a hereditary disorder.

The HFEA’s 2001 legislation was developed to ensure that an embryo will not be exposed to unnecessary risks from PGD and HLA typing if the child does not stand to directly benefit from such tests. If PGD and HLA typing are performed on embryos that are believed to be at risk for genetic disorders, the procedures are justified. If the disease is hereditary, one would employ PGD and HLA typing not just to select for a saviour sibling, but also to ensure that the couple’s next child does not suffer from the same condition. Therefore one can almost ignore the fact that the child will become a “saviour sibling”—an appealing thought for those who consider this issue morally compromising. This requirement ensures that the future child derives some benefit from PGD and HLA typing instead of being subjected to these technologies solely for his

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or her older sibling.

Sheldon and Wilkinson (2001) believe “the underlying principle here is that an embryo should be exposed to the risks of PGD only if it (or the person it becomes) is likely to derive enough benefit to outweigh those risks… the potential child is thought to be like an existing patient.” Since the embryo is viewed as a potential child, proponents of this reasoning afford the embryo the same moral status as that of a born child (Charo, 2001). It appears the HFEA also supports this argument because it has this condition in its guidelines for “saviour siblings”.

Those who argue for “potential” consider the embryo sacred since it will develop into a human being. Thus, they believe many acts like abortion and human embryo stem-cell research to be unethical. The HFEA’s policy is founded on a similar principle whereby PGD may only be performed on an embryo that may “benefit” from it by determining

whether or not it is healthy. Since it is considered a ‘healthy child,’ it is not just viewed as a ‘healthy embryo’. The embryo itself is neither sick nor healthy, but it does contain genetic information that will determine the well-being of the future child.

“Health policy is constantly within ethical grey areas due to the fact that there is not necessarily a right answer”

When the HFEA makes policy based on this principle, proponents for the “potential” argument will be able to appeal to this organization’s practices when discussing other embryo-related issues. Definitions of biological entities

“if the disease is hereditary, one would employ PGD and HLA typing not just to select for a saviour sibling, but also to ensure that the couple’s next child does not suffer from the same condition”

1

cannot change depending on the policy that is being written. If there is a precedent of viewing the embryo as a future child when making embryo-related policy, it must be used in all subsequent policies in order to remain ethically consistent.

In this respect, however, the UK falls short as the country passed legislature allowing human embryonic stem cell research to be performed. This decision faces disapproval from those who argue for “potential” (Deckers, 2005).

One might argue that the UK legislature regarding “saviour siblings” and the regulations regarding stem cell research differ. With “saviour siblings”, the argument from “potential” may be used because, ultimately, one is concerned with the person that results from the embryo. In stem cell research, however, one wishes to use a blastocyte, the developmental predecessor to the embryo1. By this logic, the embryos tested

by PGD and HLA typing analysis may also be used for research (Boyle & Savulescu, 2001). Using these technologies in the creation of a “saviour sibling” requires the creation of numerous embryos, but only one is implanted (Figure 1). Thus, there is an excess of embryos which couples are encouraged to donate to human embryonic stem cell research.

Under UK law, the parents may donate their embryos to research, which contradicts the present embryo policy. Furthermore, the only reason why one healthy embryo is chosen over another is based on tissue type.

In essence, this means that the only distinguishing factor between embryos is their relation to an existing person.

Therefore, the HFEA cannot truly say it is operating solely for the benefit of the embryo as this sentiment disproves the very nature of the process. If the HFEA is allowing PGD and HLA typing for the creation of a “saviour sibling,” a life that is

That stem cell research uses a blastocyte, not an embryo, is irrelevant to those who argue from potential because the blastocyte is a just a step in the process of creating a child.

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Figure 1 In-vitro fertilization. The embryo is implanted into the mother after genetic modification.

inextricably linked to the well-being of its sibling, this view should be standard in all related situations. The organization cannot shield itself by stating that the procedure may only be performed with embryos who are themselves at high risk of genetic disorder.

There is little reason to believe that PGD and HLA typing will have negative consequences for the embryo (Boyle & Savulescu, 2001). Moreover, the HFEA is not protecting the embryo with this stipulation in its policy. When the egg is fertilized, the hereditary condition may or may not be present in the subsequent embryo. PGD and HLA typing do not cure the condition but merely indicate its presence. Thus, this policy still subjects a healthy embryo to the hypothetical dangers of PGD and HLA typing (Sheldon & Wilkinson, 2001). As has been demonstrated, the HFEA’s argument is full of inconsistencies.

It is interesting to note that advocates of the argument for “potential” would disapprove of PGD and HLA typing for “saviour siblings” because it involves both the manipulation and discarding of embryos. In order to remain logically consistent, the UK, through the HFEA, must reconsider their parameters for allowing PGD and HLA typing procedures for “saviour siblings”.

There should be no distinction between testing embryos that have a higher likelihood of genetic disorder than those that are being tested solely because the embryo is meant to be a donor for his or her sibling (Sheldon & Wilkinson, 2001). Once this distinction is in place, it increases the strength of those who believe the argument for “potential” has a place in policy making — a principle which the UK has shown to disregard in certain cases.

This situation in the UK can help us to explore and maintain ethical consistency within health policy. Those who see the embryo as a potential person will be quick to condemn

Issue 13 acts such as abortion and human embryonic stem cell research.

This is where consistency becomes important. In order to have a stable policy, the legislation must maintain an unvarying opinion. The government may be swayed by one differing opinion or another, but all related policy must subsequently be rewritten in the wake of such changes in perspective.

Kurt Darr (1991) writes, “it is imperative that managers solving ethical problems, whether administrative or biomedical, be mindful of the organization’s philosophy, as well as their personal ethic… to ignore or apply these constraints arbitrarily creates inconsistencies and discontinuities that eventually cause major problems for the organization and for the manager.” In this case, the manager is the UK government and it must remain mindful of the policy it has previously put forth. If it chooses to view the embryo as a potential child, legislation must be written to reflect this sentiment.

Inconsistent legislation is vulnerable to attacks. For example, Jan Deckers’ (2005) article states that, “current UK legislation on embryo research is immoral,” thus showing one such assault based on the HFEA’s parameters.

Health policy is constantly within ethical grey areas due to the fact that there is not necessarily a ‘right answer’. In such cases, it is important for the government to take a firm and consistent stance towards the issue. The regulations on PGD and HLA typing for “saviour siblings” are an example of health policy that must be reconsidered and revised in order to achieve logical consistency. If this is neglected, all of the UK’s legislation concerning embryos is vulnerable to attack, which will create an unstable environment in their health care sector.

References Boyle, R.J., & Savulescu, J. (2001). Ethics of using pre-implantation genetic diagnosis to select a stem cell donor for an existing person. British Medical Journal, 323, 1240-1243.

Charo, R.A. (2001). Every cell is sacred: logical consequences of the argument from potential in the age of cloning. In P. Lauritzen (Ed.), Cloning and the Future of Human Embryo Research (pp.8292). Oxford: Oxford University Press.

Darr, K. (1991). Ethics in health services management. Baltimore: Health Professions Press.

Deckers, J. (2005). Why current UK legislation on embryo research is immoral. Bioethics, 19(3), 146-157.

Human Fertilisation and Embryology Authority. (2001). HFEA to allow tissue typing in conjunction with pre-implantation genetic diagnosis. Retrieved from http://www.hfea.gov.uk/forMedia/ archived/13122001.htm Sheldon, S., & Wilkinson, S. (2004). Hashmi and Whitaker: an unjustifiable and misguided distinction? Medical Law Review, 12, 127-163.

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Exploring The World of Antibiotic Resistance

Kirandeep Bhullar

Antibiotic resistance is becoming a pressing issue in the healthcare system, as multidrug resistant bacteria are resulting in more and more deaths. With various mechanisms, such as efflux pumps and Antibiotic-modifying enzymes, many bacterial strains are adapting to the effects of antibiotics. With the obstacles and ethics facing new drug discoveries it is difficult to develop new antibiotics.

However, regulated prescriptions and the understanding of resistance bacterial genes assist in the handling and understanding of antibiotic resistance. The following article will present various antibiotic mechanisms, ethical issues, and the future of drug resistance.

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ntibiotic resistance is one of the biggest challenges faced by the healthcare sector. In particular, multidrug resistance has posed problems in clinical settings.

Many species of bacteria now exhibit multidrug resistance, including Staphylococcus aureus, Enterococcus faecium and Mycobacterium tuberculosis (Wright & Sutherland, 2007).

Recent studies have shown that more people in the United States are dying from methicillin-resistant S. aureus (MRSA) than from AIDS. According to a report published in The Journal of the American Medical Association, more than 18,000 deaths in U.S. have been attributed to MRSA infections (Boyles, 2005). Discovery of new antibiotics and new therapeutic strategies are essential to help combat this challenge. This article reviews the common resistance

Figure 1 Efflux pumps expel antibiotics at a greater rate than that of drug influx, thus keeping the intracellular drug concentrations low (Walsh, 2000).

mechanisms and evolution of resistance genes while also focusing on recent progress in the development of new strategies for battling antibiotic resistance.

Mechanisms of Antibiotic Resistance Bacteria have developed numerous strategies to cope with antibiotics. For instance, some bacteria can survive antibiotic treatment by activating resistance mechanisms. The major mechanisms include active efflux of the antibiotic from the cell, transformation of the compound by specific enzymes and prevention of drug interaction through modification of its interaction site.

Pumping Out the Antibiotic Efflux pumps are transport proteins that can provide innate resistance to antibiotics by expelling toxic substances into the extracellular environment. These proteins can be associated with multiple drug resistance as they often transport antibiotics of distinct structural classes (Webber & Piddock, 2003).

A large proportion of transport genes found in bacteria encode for efflux pumps. Their expression can be part of an operon system, a genetic regulatory system found primarily in prokaryotes. These pumps alone may not be responsible for multiple drug resistance. Regardless, their elevated level of expression in highly resistant clinical strains should not be ignored (Webber & Piddock, 2003).

For example, resistance to bile salts and some antibiotics in

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A

Issue 13

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Escherichia coli has been associated with overexpression of acrAB, an energy dependent efflux mechanism found in the bacteria (Thanassi, Cheng & Nikaido, 1997).

Enzymatic Modifications Antibiotic-modifying enzymes inactivate antibiotics by chemically altering their structure. This mode of resistance is very specific in comparison to other mechanisms. A classic example is the hydrolysis of the beta-lactam ring by beta-lactamases in penicillin and cephalosporin (Wright, 2005). Another predominant example is the resistance to aminoglycoside drugs brought about by enzymatic inactivation of drug activity. Such enzymes can acetylate the amino group of an antibiotic, preventing the addition of other chemical ligands (Walsh, 2000).

Modification of the Antibiotic Target This mode of antibiotic resistance can occur through mutations, altering key binding elements, such as ribosomal RNA, or by reprogramming the target (Wright, 2005). For example, a mutation in the penicillin binding protein (PBP) can lower the affinity of penicillin towards PBPs, conferring bacterial resistance to beta-lactam antibiotics. Similar mechanisms have been observed in erythromycin resistance pathways (Walsh, 2000).

Evolution of Antibiotic Resistance Understanding the evolution of resistance and its dissemination within a population can provide valuable insights into solutions for drug resistance (Wright, 2007). It is important to consider the origin of the resistance. Some

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bacterial species exhibit intrinsic resistance; they remain unaffected without any previous exposure to an antibiotic or without further genetic modifications. Therefore, resistance proteins may have evolved as a result of selective pressures (Wright, 2007).

Bacteria can also pass on resistance genes through horizontal gene transfer. Some of the resistance genes are located on plasmids that replicate independently of the chromosomal DNA. These plasmids can be passed onto other bacterial species as well as between bacterial cells (Wright, 2007).

Mutations resulting in antibiotic resistance can have a fitness cost for an organism in the absence of antibiotics.

Mutations may cause alterations in the genetic make up and affect the natural functions of proteins. This may have implications for the survival and fitness of that species (Bjorkholm et al., 2001). Therefore, effective mutations must produce alterations that minimize the interaction of a protein with an antibiotic, while preserving its natural function. A bacterial strain with no fitness cost will have the same likelihood of survival as a bacterial strain that is not under antibiotic selective pressure (Wright, 2007).

It has been shown that resistance comes at a cost of decreased growth rate among other detrimental effects.

Therefore, evolution of compensatory mechanisms may be important in stabilizing the resistant bacterial populations.

Compensatory mechanisms become extremely important in the context of resistance mutations. A compensatory mechanism may result from another mutation that affects the active site of a protein such that it works as efficiently as the wild type protein (Bjorkholm et al., 2001).

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Future Directions

promise in the expanding field of target site recognition of antibiotics. This could help gain information on target compound pairs that can be exploited in drug designs (Wright & Sutherland, 2007).

The discussion so far alludes to the fact that there is a continuous need for the discovery of new antibiotics. Bacteria are rapidly evolving organisms that utilize strategies to minimize the effect of antibiotics. There are few antibacterial agents against which bacteria have not developed resistance.

Identification of new antibiotics presents a challenge to the drug discovery sector because it is difficult to identify new compounds with antibacterial activity. There has been a significant decline in the rate of identification of new antibacterial compounds since the 1970s. For instance, isolation of new antibiotics from soil has become more difficult as many soil bacteria produce similar range of antibiotics (Wright, 2007).

Recent advancements in the field of bacterial genomics can aid in the discovery of new bacterial targets. A genome provides useful insights into the organization of gene clusters and their regulation (Wright & Sutherland, 2007).

Gene disruption methods and chemical libraries used for testing inhibitors offer

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Antibiotic resistance challenges our current health care system. There is an urgent need to discover new drugs, but drug discovery proves difficult.

One of the biggest challenges faced

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In the last couple of years, antibiotic resistance, especially multiple drug resistance, has appeared as one of the most significant challenges in the management of infectious diseases.

The Infectious Disease Society has identified many problematic pathogens (Talbot et al.,2006). In the near future, it can be expected that this list will grow. Increasing our understanding of the genomics, origin and evolution of resistance genes and mechanisms of resistance can help us to develop new antibiotics and solve the problem of antibiotic resistance.

Ethical Implications of Antibiotic Resistance

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by drug developing companies is the production and testing of these new products in clinical trials. More importantly, regarding the clinical use of antibiotics, physicians have to decide between the risk of using antibiotic therapy and the well-being of a patient (Garau, 2008). The problem is far more complicated than it appears, and the mindful antibiotic prescription may be a method for reducing the development of antibiotic resistance.

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Figure 3 Reprogramming of the target structure in a bacterium: replacement of an amide linkage with an ester linkage causes a 1000-fold drop in the binding affinity of the drug vancomycin for the bacterial cell wall (Walsh, 2000).

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Issue 13

References Bjorkholm et al. (2001). Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori. Proceedings of National Academy of Sciences, 98, 14607-14612.

Boyles, S. (2005). More U.S. Deaths From MRSA Than AIDS. WebMD Health News. Retrieved August 18th, 2008 from Webmd Health News Database Garau,J. (2008). Impact of antibiotic restrictions: the ethical perspective. Clinical Microbiology and Infection, 12, 16-24.

Talbot et al. (2006). Bad Bugs Need Drugs: An Update on the Development Pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Anti-Infective Development Pipeline, 42, 657-668.

Thanassi, D. G., Cheng, L. W. & Nikaido, H. (1997). Active efflux of bile salts by Escherichia coli. Journal of Bacteriology, 179, 2512-2518.

Walsh, C. (2000). Molecular mechanisms that confer antibacterial drug resistance. Nature, 406, 775-781.

Webber, M.A.& Piddock, L.J.V. (2003). The important of efflux pumps in bacterial antibiotic resistance. Journal of Antimicrobial Chemotherapy, 51, 9-11.

Wright, G.D. & Sutherland, A.D. (2007). New Strategies for combating multidrug-resistant bacteria. TRENDS in Molecular Medicine, 13, 260-267.

Wright, G.D. (2007). The antibiotic resistome: the nexus of chemical and genetic diversity. Nature Reviews, 5, 175-184.

Wright, G.D. (2005). Bacterial resistance to antibiotics: Enzymatic degradation and modification. Advanced Drug Delivery Reviews, 57, 1451-1470.

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Have you read all the articles? Test yourself and see how well you understood the articles by answering the questions below.

1. The best method to gaining insight on solutions for drug resistance is by studying: a) the evolution of antibiotic resistance b) the modification of antibiotic targets c) enzymatic modifications d) the mechanisms of antibiotic resistance 2. PGD and HLA typing stand for: a) Post-implantation Genetic Diagnosis and Human Leukocyte Antigen typing b) Post-implantation Genetic Diagnosis and Histocompatibility Leukocyte Antigen typing c) Pre-implantation Genetic Diagnosis and Human Leukocyte Antigen typing d) Pre-implantation Genetic Diagnosis and Histocompatibility Leukocyte Antigen typing 3. Which of the following is not a requirement when determing if a gene is patentable? a) novelty b) non-obviousness c) appropriatness d) location of gene

4. What is pharmacogenomics? a) The study of how a gene affects an individual’s response to a drug. b) A tool for optimizing drug development c) The study of how an individual’s genome affects drug response d) B and C

MedQuiz

MedQuiz

5. Allergic diseases may result from an insufficient pathogenmediated immune deviation in early life. What is this missing immune deviation in cell mediated immunity that occurs in the development of allergic diseases? a) Exposure to microbes early in life causes equivalent levels of constitutive activation of Th1 and Th2 cells in both newborns and adults. b) Exposure to microbes early in life educates the immune system, shifting the immune response from a T helper cell 2 phenotype (Th2) to a T helper cell 1 phenotype (Th1). c) There is no missing immune deviation! Allergic diseases are thought to result from sufficient pathogen-mediated immune deviation in which exposure to microbes causes a change to constitutive Th2 activity from Th1 activity. d) This missing immune deviation is actually thought to involve components of the innate immune response and complement proteins rather than a T cell-mediated immune response.

Answers: a, c, d, a, b

Meducator Staff

McMaster’s Medical Research and Health Ethics Student Journal

Should doctors be allowed to refuse treatment?

Also in this issue: Debate on Canada’s health care Alzheimer’s drug may prevent breast cancer relapse Loneliness & cardiovascular disease Chaperones & protein folding

From Proteins to Patients Issue 11 | Nov 2007

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Back Row (Left to Right): Andrew Yuen, Stephanie Low, Keon Maleki, Randall Lau, Avinash Ramsaroop, Ahmad Al-Khatib Third Row: Veronica Chan, Ran Ran, Hiten Naik, Manan Shah, Randal DeSouza, Simone Liang, Alyssa Cantarutti Second Row: Sangeeta Sutradhar, Navpreet Rana, Fanyu Yang, Siddhi Mathur Front Row: Jacqueline Ho, Crystal Chung Absent: Harjot Atwal, Alexandra Perri

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