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Issue 3 | February 2004 www.meducator.org

Issue 3 | February 2004

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c Inside. Scoop.... o u Research Articles Presidential Address

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Med Bulletin

4 International Society for Equity in Health

Genomeceuticals as a Potential Treatment for Autism

International Health Research 10

Sammy H. Ali

4-Aminopyridine as a "Cure" for Spinal Cord Injury

8

Health Care in Uttaranchal 11

Ronald Zahoruk

Reflections on International Health Research

10

Monica Hau & John Omura

Health Care in Uttaranchal

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Abhishek Raut

Designing a Vaccine for Cancer

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Jonathan M. Ng

Tourette's Syndrome

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Jacob Kocsis

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Cover Feature: Designing Dendritic Cell-Based Cancer Vaccines 13

About The McMaster Meducator The McMaster Meducator adopts an educational approach to our publication. Despite our efforts to ensure correctness, w e recognize that The McMaster Meducator may be contacted via our e-mail address: the publication may be subject to errors and omissions. In light of these mac.meducator@learnlink.mcmaster.ca potential errors and new developments in the medical field, w e invite you • or our mailing address: to partake in feedback and constructive discussion of the content herein 8,H.Sc. (Honours) Programme for the purpose of furthering your understanding of the topic - in the n a m e Attention: The McMaster Meducator of education and discovery. An online discussion forum for each article is HSC-1J11 available on our website: www.meducator.org. Students and professors 1200 Main St. West alike are welcome. Please enjoy the Meducator online experience!

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Issue 3 | February 2004 President/Chief Editor

Dear Reader,

JONATHAN M. N G

Issue three encompasses a refreshing array of quality articles ranging from Vice President/Deputy Chief Editor genomeceuticals for autism to an inside look at Tourette's syndrome. For this issue, writers have travelled far and wide to bring you fascinating views ABHISHEK RAUT and findings. From Toronto, Monica Hau and John Omura report back from Managing Editor the bi-annual International Society for Equity in Health conference with a JEANNETTE So special report on international health research. On the other side of the world, VP of Journal Production & Design Abhishek Raut explores the unique health care situation faced by Uttaranchal, JARON C H O N G a rural region of Northern India. At McMaster, Ronald Zahoruk focuses on Dr. VP of Website Production & Design Hansebout's research on the use of 4-aminopyridine for spinal cord injury while THIEN H U Y N H my own article describes the immunological theory behind dendritic cell cancer VP of Internal Affairs vaccine research conducted locally by Dr. Ronan Foley, Dr. Jack Gauldie and Dr. NISHA SIVAGURUNATHAN Yonghong Wan. After reading the articles, we encourage you to continue the experience by joining our online discussion forum to discuss your thoughts and VP of External Affairs contributions at www.meducator.org.

G R A C E Y. W A N G The quality product that you now hold in your hands is a direct result of the VP/Editor of Medical Research quality work of the people behind it. First, we extend our heartfelt appreciation JENNIFER C. TANG to our dedicated writers who have thoroughly researched to bring you this VP/Editor of Health Ethics educational experience. W e also give our deep gratitude to our post-graduate S A M M Y H. ALI editors who have selflessly donated their time and expertise to ensure the Director of Graphics and Images highest quality content of our journal. A special thanks goes to our financial CHRISTINE ALMEIDA supporters, especially the Bachelor of Health Sciences Programme, for First Year Representatives supporting our educational initiative. This year, I have had the opportunity to FAREEN KARACHIWALLA work with a phenomenal team of executives, I am very thankful to have had you by my side: Abhishek Raut, Vice-President, for your leadership and enthusiasm S O R O U S H SEIFI in all our endeavours; Jaron Chong, in layout and design, whose extraordinary N A N C Y XI skills and creative vision have made our publication rival those on the market; Jeannette So, our managing editor, for gate-keeping literary quality; Sammy Ali Post-Graduate Editing and Jennifer Tang, VP's Medical Research and Health Ethics, for their close work DR. ROBERT HANSEBOUT M.D., M.Sc, with writers and keen eyes for quality content; Thien Huynh, VP Website, for FRCSC keeping our cyberspace image on a professional FACS Chair of the Department of Surgery level; Nisha Sivagurunathan, VP Internal, for DR. DELSWORTH HARNISH B.Sc, M.SC, making collaboration and teamwork possible; Grace Wang, VP External, for forming our secure PH.D. Professor of Biology and Pathology financial foundation; and Christine Almeida, VP Assistant Dean of the Bachelor of Health Graphics & Images, for her sleek cover design Sciences Program and beautiful custom images. Finally, as my educational role model and the man who DR. SATYENDRA K. SRIVASTAVA MBBS, Health and Family Welfare Management inspired and supported me in this endeavour from the humble beginnings, an earnest thank DR. HENRY SZECHTMAN B.SC, PH.D. you goes to Del Harnish.

Professor, Psychiatry & By picking up a copy of this publication, you Behavioural Neurosciences Senior Research Fellow, Ontario Mental Health have just embarked on a journey of discovery Foundation and exploration. May it expand your horizon of knowledge and inspire you to explore different RYAN E. WILEY, M.SC. areas of health. Welcome to the McMaster Part-time Faculty, BHSc Programme, Meducator experience.

McMaster University

Yours truly,

Meducator Header Design JAY HIGGERTY

Meducator Logo Design SHAWN MCGRATH

Meducator Website Design KAREN H O

Jonathan M. Ng

Writer Portraits: Photo Credits STASH NASTOS

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Issue 3 I February 2004 Writing for the McMaster Meducator

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Writing for the McMaster Meducator is a rewarding and valuable experience. It combines exploration of medical research and health ethics with the excitement and prestige of publishing work for the McMaster community to read. The opportunity is ideal for those consideringa future in medical research, health ethics, or any profession within the health care field. The McMaster Meducator provides quality I educational feedback and promotes in-depth exploration into a particular topic of interest. ^ i If you are interested in writing and publishing with us, please e-mail us at mac.meducator@learnlink. 1 mcmaster.ca for more information. f To access our past issues, our writers' guide or current medical research and health ethics news, | please visit our website at www.meducator.org.

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Stem Cell 'Secret of Youth' Found

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II Brivanlou and his colleagues from Rockefeller University in N e w York believe ithat they may have found a partial solution to the stem cell problem.

H u m a n embryonic stem (ES) cells have been touted as the most promisingly r\t treatment to illnesses ranging from multiple sclerosis to Parkinson's Disease.

ES cells have the ability to develop into almost any type of cell in the body, and can potentially replace damaged tissues or organs. However, there are several practical barriers to the use of E S cells in humans.

Scientists have yet to learn to control the type of cell into which the ES cells will differentiate, and more importantly, the conditions in which ES cells are cultivated require them to be contaminated with m o u s e proteins. In order to be exploited for therapies, the stem cell lines cannot have been grown in foreign proteins.

Brivanlou isolated a chemical from a sea snail, called BIO, which stops ES cells from developing into specialized adults cells by activating a set of protein signals called the W n t pathway. BIO can be used to control the timing of the development of ES cells, and might also eliminate the need for m o u s e proteins.

Although its potential is still largely uncertain, BIO brings scientists one step closer to taking stem cells into t h e Clinical setting. (Source: http://www.nature.com/nsu/031222/031222-4.html)

Emerging Medicine: Scientists Design Gold "Nanoshells" That Seek and Destroy Tumours

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ccording to Naomi Halas, an electrical engineer and chemistry Iprofessor at Rice University in Houston, the future of cancer treatment can be found in a tiny, golden capsule.

Invented by Halas, nanoshells are 100-nanometer-wide spheres with layered gold atoms surrounding a silica core that can be attached to tumours. By altering the thickness ratio between the inner glass core and outer gold layer, nanoshells can be manipulated to absorb near-infrared light, heat up, and "cook" the tumour without burning the surrounding tissues. Precision is further enhanced as nanoshells can also be employed to release drug doses directly into the bloodstream. Not only can nanoshell technology be used for early detection, but patients with early-stage, contained tumours can also be diagnosed and treated in the s a m e day. Although healthy cells in the vicinity of tumour will still die, nanoshells present a more favourable alternative to the current surgical and chemotherapy treatments.

Halas and her colleague Jennifer West was recently awarded a $ 3 million research grant by the Department of Defence to use nanoshells to develop an effective treatment for breast cancer. There are plans to begin trials on patients with breast, brain, or prostate cancer as early as next year.

(Source: http://www.popsci.com/popsci/rnedicine/article/0,12543,537964,OO.html)

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Issue 3 | February 2004

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Louisville Doctors Studying Face Transplants Weigh Ethical Issues The movie "Face/Off" brought the idea of face transplants mainstream, but it has also fuelled misconceptions about the procedure. Face transplants are often mistaken as a form of plastic or reconstructive surgery. While the latter alter the shape of facial features and repair facial skin deformities using skin from elsewhere on the individual's body, face transplants are m u c h more complex and intricate.

In Louisville, study of the procedure has been ongoing for the past decade, along with other innovative work such as hand transplant techniques, tissue rejection, and other related problems, which have all contributed to the research and work on face transplants. Doctors hope that the success of hand transplants would pave way for the acceptance of face transplants Face transplants involve removing all the layers of skin and corresponding blood vessels, nerve, muscles and tendons from the donor, positioning the "envelope" of face over the recipient's bone and cartilage structure, and painstakingly grafting it into place. Similar to other organ transplants, there is great risk of the body's immunological rejection of the new face. Even if the transplant is successful, the recipient is condemned to a life-long regimen of drugs to counter the possibility of rejection.

Although doctors claim that it is the "most careful, safest procedure", public acceptance is necessary before proceeding. Unlike other organ transplants, surgically transplanting an entire face from one person to another raises many ethical and psychological issues. The impact on friends and family of seeing the face of the deceased on another person must also be considered. Face transplants go beyond altering facial features because the face is fundamental in the constitution of identity. Doctors are adamant about educating the public on the purpose of face transplants, emphasizing that the procedure presents an option for individuals whose face has been severely disfigured from burns, cancer, or accidents, but will not be used to satisfy the narcissistic desires of the wealthy.

(Source: http://www.courier-journal.com/localnews/2003/ll/16ky/wir-front-facelll6-12650.html)

H o w Sex and Love Light Up the Brain: W e All Enjoy Sex the S a m e W a y Except W h e n W e Are in Love i [Researchers have used positron emission tomography (PET scans) to distinguish & I v t h e difference between a real and a fake orgasm, a phenomenon that is unique to w o m e n . While the ventral tegmental area (VTA), the reward centre and periaqueductal grey matter (PAG), the region of the brain that controls the fightor-flight responses are activated in both cases, the region of the cerebellum is not stimulated in a fake orgasm. Instead, a fake orgasm activates areas of the brain that are involved in control of muscles. Further research may yield new methods to treat sexual dysfunction in w o m e n .

In contrast, it w a s found that in m e n the amygdala, the area of the brain that controls fear, becomes less active and the VTA becomes active just before ejaculation. N e w studies using functional magnetic resonance imaging (fMRI) have shown that the s a m e areas of the brain are activated in heterosexual and homosexual m e n during arousal.

W h e n the emphasis of relationships shifts from the physical to the emotional, different regions of the brain are activated. Although the VTA is still activated, love also activates areas in the brain associated with attention and memory recall in w o m e n , and areas associated with vision in men. It is hypothesized that evolution has shaped the origin of passion: sex is used to find a mate, attraction conserves time and energy by focusing on one partner, and love enables couples to remain together to have and raise Offspring. (Source: http://www.thestar.ca/NASApp/cs/ContentServer?pagename=thestar/Layout/Article_Typel&c=Article&cid=106984628 5948&call_pageid=991479973472&col=991929131147)

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Issue 3 I February 2004

Genomeceuticals as a Potential Treatment for Autism: Re-establishing the Roles of Casein and Gluten often referred to as the exorphin theory of autism, originated as a result of observed similarities between the symptoms of autism and the long-term effects of morphine (Panksepp, 1979). It follows that the peptides produced through the digestion of dairy S a m m y H. Ali (casein) and wheat (gluten) are subject to incomplete A utism and Autism Spectrum Disorders are breakdown in individuals with autism. These peptides t\ characterized as mental disorders associated with have been labeled exorphins (which m e a n s exogenous self-absorption, inability to interact socially, as well as morphine) to describe both their external origin from behavioural and lingual dysfunctions. Despite these the food products as well as their resemblance to distinct impairments, very little is known about the endorphins. This results in the formation of pre-opioid aetiology of autism. In the absence of an established compounds capable of entering the bloodstream. The pathogenesis for autism, medical clinicians and exorphin, Beta-casomorphin-7 (B-CM7), a peptide researchers have proposed explanations and produced through the digestion of casein in milk, has subsequent treatments that involve regulation of received the most attention as the principal promoter diet and nutrition. One such diet that has receivedof the symptoms of autism. extraordinary attention is the casein-gluten restrictedStudies have established that B-CM7 is capable of diet. crossing the blood brain barrier -mediated, at least in part, by opioid receptors - readily activating brain cells Introduction to the Casein-Gluten Restricted Diet in m a n y areas theorized to be involved in autism (Sun Strong advocates of the casein-gluten restricted etal., 1999a). Further research, involvingthe injection diet argue that autism is the consequence of the of B-CM7 into rats in order to observe behavioural incomplete breakdown and excessive absorption of responses, has yielded astonishing results. It w a s peptides that are capable of affecting the endogenous reported that roughly seven minutes after the injection opioid system (Reichelt et al., 1990). This hypothesis, of B-CM7 the rats b e c a m e inactive, "distancing

B-CM7 Intestinal Epithelial Cell

Bloodstream

Figure 1 Damage to the tight junctions linking intestinal epithelial cells causes increased absorption of harmful exorphin as B-CM7, through the mucosal barrier of the gut into the bloodstream.

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Issue 3 | February 2004 themselves from the other rats in the s a m e cage", while showing no social interaction and very little reaction to sound (Sun et al., 1999b). These B-CM7 induced behaviours exhibit a distinct resemblance to those observed in h u m a n s with autism.

the treatment have led researchers and clinicians to explore alternate methods. This has allowed for the development of various enzyme and genomeceutical based treatments, both of which build upon the fundamental framework laid out by the casein-gluten restricted diet. Rather than prevent the ingestion of Intestinal Abnormalities casein and gluten products as in the diet, enzyme and It has been speculated that the incomplete breakdown genomeceutical treatments focus on correcting the of casein and gluten is the result of multiple intestinal dysfunctional metabolism that is the source of the abnormalities. harmful exorphins through the use of enzymes and Attenuated Genes gene promoters.

The first abnormality, present in autistics, was observed Genomeceuticals describe naturally occurring to be the result of an attenuated enzyme, dipeptyl nutrients that can affect (i) the structure of a gene, peptidase-IV (DPPIV), thought to be involved in the (ii) how well the transcribed products work and/or digestion process (Brudnak, 2001). DPPIV is typically (iii) how m u c h of it is m a d e (Brunak et al., 2001). As found in the enterocytes of the intestinal tract where previously stated, according to the exorphin theory of it is involved in the degradation of casein and gluten autism, the symptoms of autism m a y manifest due to residues. According to the exorphin theory of autism, the attenuated levels of dipeptyl peptidase-IV (DPPIV) the down-regulated levels of DPPIV could manifest as in the lumen. The genomeceutical model attempts to autistic symptoms. replenish the DPPIV levels through the use of enzyme promoters.

Increased Absorption In recent research aimed towards alleviating the The aforementioned catabolic deficiency is further symptoms of autism, galactose has demonstrated the intensified by what is referred to as the "leaky gut" potential to serve as a genomeceutical. This potential nature of autism. As the title implies, individuals surfaced from the observation that galactose increases with autism have been found to experience unusually high levels of peptide absorption through the lumen the expression of DPPIV in murine enterocytes (Smith of the gut. Past research has speculated towards the et al., 1991). The increased expression of DPPIV in nature of this abnormal permeability, suggesting that the gastrointestinal tract could m e n d the dysfunctional digestion of casein and gluten in autistics. In addition this condition is the consequence of d a m a g e to the tight junctions linking the intestinal epithelial cells to this, galactose is capable of stimulating the growth (D'Eufemia etal., 1996). These inadequate junctions of probiotic organisms. This is of extraordinary allowforthe increased absorption of harmful exorphins, importance, as probiotics are major contributors to the metabolic activity - including digestion - of their such as B-CM7, through the mucosal barrier of the gut h u m a n host. into the bloodstream (Fig. 1).

Concluding Remarks Genomeceuticals: A Potential Alternative to the Genomeceuticals have been used in conjunction Diet with various enzyme-based treatments, but have yet The casein-gluten restricted diet has received to be used on their own. Research has established extensive assessment from the scientific community that the application of galactose as a genomeceutical since the discovery of its possible effectiveness by increases the expression of an enzyme thought to be Reichelt and colleagues (1990). Despite the continual involved in the digestion of casein and gluten (DPPIV). efforts of researchers to develop this treatment, its This s a m e enzyme has been found to be attenuated ability to successfully treat the symptoms of autism in autistics and, according to the exorphin theory of is based on parent testimonials, rather than clinical autism, is the principle promoter of the symptoms of experimentation. In fact, it has been demonstrated autism. Although galactose has arisen as a prime that trying to completely eliminate all contributions of candidate in the suppression of autistic symptoms, it exorphins via the diet is neither practical nor 1 0 0 % still remains to be seen whether the application of guaranteed (Brunak, 2001).

Although the casein-gluten restricted diet has been genomeceuticals will be successful in clinical trials.M shown to yield promising results, inconsistencies in

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Issue 3 | February 2004

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4-Aminopyridine as a "Cure" for Spinal Cord

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Ronald Zahoruk "Learning to live with paralysis is a tremendous adjustment, but now there is every reason to believe it'll be a temporary one. H u m a n trials for effective therapies are already in the planning stages or actually underway."

- Christopher Reeve Chronic spinal cord injury is perhaps one of the most frightening consequences of physical trauma.

Damaging one's spinal cord generally produces a significant decrease in neurological function below the area of d a m a g e or paralysis, preventing the individual from functioning independently. The extent of disability varies from not beingable to move one's legs (paraplegia) to the inability of controlling one's limbs, with respiration often incapacitated (as in the case of actor Christopher Reeve - complete quadriplegia). There is currently no approved therapy that can improve neurological function for individuals with chronic spinal cord injuries. As a result, most afflicted individuals are destined to remain disabled for the remainder of their lives.

A new drug called Fampridrine, currently in its final stages of trials, can potentially alter this bleak outlook.

Fampridine allows for very exciting possibilities. During its clinical assessment, many patients with spinal cord d a m a g e regained sensation, and in s o m e cases even function, to limbs and areas of the body that were believed to be desensitized. This undoubtedly renews hope for those w h o have sustained chronic spinal cord injuries that have resulted in the loss of neurological function.

Fampridine (4-aminopyridine or 4-AP) is a potassium channel-blocking agent that is responsible for eliciting conduction along fibres that have been demyelinated due to a spinal cord injury (Hayes et al., 1993). Patients afflicted with such injuries retain s o m e axons. These surviving axons are often damaged and lose part of their myelin sheath. Myelin is an insulating structure that aids in the conduction of electrical impulses along the axon. W h e n the myelin portion of an axon is damaged, or when demyelination occurs, a large proportion of potassium channels are exposed and the associated potassium ions leak out, causing the affected axon

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to "short circuit" ("The mechanism", 2003). Although demyelinated axons are physically living, they are unable to transmit sensory or motor impulses from the brain to their ultimate destinations, and hence, the affected individual basically loses the sensation and movement of the particular area ("Research", 2003).

Fampridine effectively counteracts the effects of demyelination caused by spinal cord injuries (Hayes, 2002). Essentially, it restores the ability of damaged nerves to conduct electrical impulses by blocking the exposed potassium channels in the demyelinated axons, thus restoring the normal flow of potassium ions (Potter et al., 1998) (Fig. 1). This blocking ability renders the cell more excitable, and therefore amplifies the impulse signal so that it can travel along the nerve past the demyelinated area (Hansebout et al., 1993). Currently, Fampridine is given in the form of Fampridine-SR, where a sustained release (SR) mechanism allows the gradual release of 4-AP and maintains a consistent level in the blood. This ensures that the drug's effect is not an ephemeral, and that the patient will benefit for a longer period of time ("Research", 2003).

What is wonderful about 4-AP is that it is not simply a theoretical solution like m a n y trial medications - it really does work. W h e n speaking with Dr. Hansebout, Professor Emeritus of McMaster Health Sciences, w h o was one of the first people to actually participate in the drug administration in spinal cord injury patients, the response w a s clear - Fampridine w a s helping. Dr. Hansebout noted that "patients w h o could not move their legs at all noticed that, after receiving the drug, they could m o v e them up and d o w n quite substantially, relatively speaking". H e went on to add that patients with moderate (incomplete) injuries had s o m e enhancement of "sexual function, better bladder and bowel control, improved circulation [they could breathe far better], and experienced a reduction in pain and spastic movement."

Dr. Hansebout also remarked on 4-AP's interesting history. Fampridine wasapparentlydiscovered in "eastern Europe, as m a ny farmers in the area used it as bird repellant in the 1970's." After ingesting the chemical, Dr. Hansebout said "birds received an unpleasant shock to their nervous system, and never returned to the area again. Over the next decade, scientists studied the drug and eventually c a m e to the conclusion that it is a voltage enhancer, and began conducting experiments with mice.

Subsequently, its role as a conduction augmenter w a s hypothesized to alleviate the pain from conditions that reduce the transmission of electrical impulses. However, the scientists involved were not doctors and therefore

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not allowed to test on humans. Physicians were required to perform clinical trials, thus c o m m e n c e d m y own involvement."

During the first h u m a n trials, an immediate-release type of the drug w a s administered to patients. D u e to the limited trial period, only a few patients exhibited noticeable improvement in neurologic function (Hayes, 2002). In addition, the impact of Fampridine being delivered in a single, often highly concentrated dose, resulted in negative side effects such as nausea, depression, irritability and diarrhea (Hansebout et al., 1993). Once the sustained-release form (FampridineSR) w a s developed and administered to patients, it appeared that the majority of individuals suffering from moderate forms of chronic spinal cord injury enjoyed improved neurologic function below the area of injury, an effect that would never have been obtained otherwise (Hansebout et al., 1993). To date, trials have yet to give rise to noticeable improvement in neurologic function in patients suffering from severe chronic spinal cord injuries and complete paraplegia and quadriplegia (Hayes, 1993). However, Fampridine is continuously being researched, and similar cases, as well long-term usage, is also being investigated ("Research", 2003).

Fampridine is also being studied for its potential in treating people with multiple sclerosis. Thus far, the results have been incredible. In 1997, a double-blind, cross-over trial of the drug in M S patients saw that 9 0 % of those given the drug benefited noticeably compared to those w h o received the placebo (Schwid et al., 1997).

Motor function w a s substantially enhanced and M S symptoms were significantly diminished. Another similar study conducted in England in 2 0 0 0 suggested that 4-AP also improved mechanisms like potentiation of synaptic transmission, and increased skeletal muscle twitch tension, effects that do not even involve the target demyelinated axons (Smith et al., 2000). Such findings could conceivably lead to the use of Fampridine to treat other neurological disorders (Smith et al., 2000).

The effectiveness of 4-Aminopyridine in treating patients suffering from chronic spinal cord injuries and other neurological disorders is to date unparalleled.

Once it is m a d e available to the public, its application will become an important element in the concert of treatment methods used for spinal cord injury patients. These methods include spinal cord cell grafting, a technique thataidsthe regeneration of motor and sensory neurons, and implantation of AIT-082, a synthetic purine used to supplement adenosine and guanosine purine loss due to spinal cord injury. Adenosine and guanosine signal nerve cells to protect themselves from further damage, and also act as chemical messengers to signal cells like astrocytes and glia to release trophic factors ("The role of purines", 2003).

Fampridine is a truly amazing drug, and those suffering from spinal cord injury, multiple sclerosis and other neurological disorders are extremely fortunate to be on the brink of gaining access to this effective treatment. As yet, Fampridine is not a comprehensive cure because it will not allow a paraplegic individual to walk again; however, it is certainly a step in the right direction. McMaster is quite fortunate in that m u c h of the corroborative evidence obtained and groundbreaking research involved with this revolutionary treatment took place within its hospitals. As well, there are many organizations and institutions like the Canadian and American Spinal Research Organization and the Christopher Reeve Paralysis Foundation that are actively involved in ensuring that Fampridine is m a d e available to those w h o need it. Granted, m u c h research is still underway, but at least for now, there is hope for those w h o suffer from conditions and disorders that inhibit neurological function.E3

Figure 1 In many spinal cord injuries myelin surrounding nerve cells are damaged. This causes potassium ions to leak out, preventing the neuron from transmitting signals. The drug 4aminopyridine blocks the pores in the damaged myelin, thus allowing transmission when the cell becomes excited.

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Reflections on International Health Research

Monica Hau and John O m u r a In the summer of 2003, we attended the bi-annual conference of the International Society for Equity in Health (ISEqH) held at the University of Toronto. W e were interested in learning more about international health research because w e felt that although w e had s o m e background in core health research, w e hoped to see how such knowledge was applied on a global scale.

W e had previously learned about the gap that exists in health research where 9 0 % of health research funding goes towards diseases that affect only 1 0 % of the world's population. This shocked us and w e wanted to learn how the leading researchers in the international health field were addressing this problem. W e went into the conference optimistic that significant changes were occurring and that w e could be witness to them.

However, w e c a m e out confronted by the reality that such changes were slow and riddled with difficulties.

ISEqH was founded to "promote equity in health and health services internationally through education, research, publication, communication and charitable support." The conference opened with a presentation by native drummers, a reminder of the disparities that exist in health care even within our own country. The health status of Aboriginals in Canada is generally comparable to that of developing countries, largely due to inadequate quality of and access to health care.

The weekend was filled with workshops and presentations by health researchers from around the world. One of the most memorable workshops for us was "A Report Card on G 8 . Health and Development Commitmentsand the N e w Plan for African Development (NEPAD)". This workshop on African Health and Development examined past commitments of the Group of 8 (G8) countries to improve development and health research. Moreover, they discussed the impending G 8 summit in Kananaskis and its focus on African health and development as outlined in NEPAD. This was a plan m a d e by Africans for Africans to gain economic stability and independence. One topic discussed in the workshop was the brain drain from African countries to G 8 nations. For instance, the USA saved an estimated U S $ 2 6 billion in training costs because of the

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riterriational Society for E q u i t y

_ in Health 130,000 foreign physicians practicing in the US. Africa loses approximately U S $ 4 billion per a n n u m through migration of top professionals (not only health professionals). Although NEPAD made recommendations to reverse this process, the speakers criticized itforitslackofdetailanddirection. Consequently, the speakers m a d e alternative recommendations by calling upon the G 8 nations to acknowledge the economic benefits they reap from migration of health professionals. Furthermore, they suggest that the G 8 reimburse developing countries' investments in the production of health professionals. Participating in this workshop exposed us to the hardships that Africa faces and the lack of past commitment by the G 8 countries to provide assistance. It was interesting to see the dynamic and solidarity between Western and African health researchers in their commitment to improving the health in African nations.

Many of the presentations were based on public health research studies, such as "Hospitalization and recent immigration in Toronto, Canada." It was interesting for us to see the application of epidemiological concepts w e had learned in many Health Sciences classes. In particular the socio-economic determinants of health were emphasized in many of the presentations. At the time, w e had not taken Health Interventions, but it would have been interesting to apply the skills from that course to critique the studies presented at the conference. Looking back, it is possible that any flaws in these studies were due to the political, economic, or social climates of the countries that they c o m e from.

For example, civil wars or military dictatorships may restrict access to certain populations or limit funding for research. W e feel that it is important to further examine the context in which these studies were completed to gain a greater understanding of the health issues in question.

Although the emphasis of the conference was on health research, w e witnessed a heated discussion regarding the role of health researchers in advocacy.

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Issue 3 | February 2004 It w a s clear that two c a m p s existed: one that was passionate about advocating through their research and another that saw the two as separate arenas. Even within the organization's n a m e itself, the International Society for Equity in Health, the word 'for' implies an advocacy component. However, s o m e m e m b e r s shied away from advocacy for fear of undermining the legitimacy and impartiality of their research.

Researchers w h o advocated for policy change felt that they were responsible for exercising their ability to influence policy. W e feel that suggestions such as creating a coalition for global health research would be a good starting point in establishing a relationship between the research and advocacy communities. This debate brought to our attention an example of issues that we, as potential health researchers, will have to confront in the future. Moreover, it was refreshing to see research in a real world context and the power that it has to create change.

If these issues interest you, w e strongly recommend conferences of this nature. They offer an excellent opportunity to apply your knowledge, to see different types of health research and to m a k e interesting contacts. For more information on global health research, check out these links. M

International Society for Equity in Health www.iseqh.org International Development Research Centre www.idrc.ca Canadian Society for Internationa 1 Health www.csih.org

The primary communicable diseases in the region of Uttaranchal include tuberculosis, malaria, and leprosy, with TB being higher than the national average. NonThe Far Side of the World communicable diseases are also very prevalent.

Approximately 4 6 % of the population suffer from s o m e degree of anemia, while 4 % suffer from iodine deficiency. Malnutrition also plagues many, particularly w o m e n and children, causing greater vulnerability to disease and is thus strongly linked to the prevalence of Abhishek Raut the communicable diseases.

O n the first week of May 2003, twelve McMaster students representing Student International The Problem Health Initiative travelled across the globe to a newly The greatest issue that Uttaranchal faces today is its created and very rural region of Northern India known isolated population leading to a lack of resources to as Uttaranchal. Their goals were to research and properly network healthcare with those w h o require understand all aspects of health that they encountered. it. Throughout all of our conversations with villagers, Of the twelve students, Asad Moten, Abhishek Raut, doctors, and workers, the most important recurring and Jerome Waidyaratne decided to investigate the theme seemed to be infrastructure: roads, electricity, accessibility of health care to the rural populace ofand location. W e asked many of the people w e spoke Uttaranchal. This is an adaptation of their report. with what changes they would bring about if they were

Health Care in Uttaranchal

A Background into Uttaranchal It is of no wonder why Uttaranchal is natively known as "Dev Bhoomi" - a phrase which translates from Hindi to "Abode of the Gods". The state of Uttaranchal is surrounded by unparallel natural beauty, almost untouched by urbanism. But it is this very splendor, which contributes to its dilemmas of health care.

Populations are scattered with an average of 1 5 9 persons/square k m spread out in a handful of cities and 16,414 villages - each with average populations of 100.

in a position of power, and the responses were all quite similar. A villager s u m m e d it up by saying "If I were m a d e Chief Minister of the state, I would first build a roadway to m y village and secondly provide lights and electricity." The majority of people w h o shared this response felt that better health care would c o m e naturally if the infrastructure were improved. The location of health facilities as observed by us seemed to be a limiting factor in the quality of health care. For instance, a villager w h o fell sick in a remote village in that region would first have to go to Quansi (the nearest

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12 town) to receive treatment, which, on average, is a two-hour walk. If they could not get proper facilities or treatment there, they would then have to go to Chakratta (the nearest city), approximately 4 hours away from Quansi by walk. If even then they could not be helped, their next destination would be Vikasnagar (the nearest major city), six hours away by car. To rent a taxi to reach this distance, the village as a whole would have to pool money together or even borrow from other villages.

would m a k e the children infertile. M a n y villagers also do not take the child out of the house for two months because they fear that the child will be seen by the 'evil eye'. These mentalities inhibit the proper vaccination of the children during the critical times in their life.

Gender disparity is also a large issue with boys getting better nutrition and care than girls. Another politically created problem is that in the 1970s, money w a s offered for family planning methods such as sterilization.

Because of this, the people no longer listen to family planning advice unless they are offered money. All of these attitudes are a large cause of concern, since, like the physical isolation, these attitudes act as another barrier - a mental isolation, which strongly impedes any outside intervention from succeeding.

Figure 1 A picture illustrating the isolation of the villages. On average, it takes 2-3 hours to travel between villages.

The Concerns Establishing a reliable and sustained infrastructure is costly. It would also bring about a tremendous loss in cultural identity. As roads, electricity and running water bring many opportunities to the people of Uttaranchal, they will slowly urbanize, and lose their unique lifestyle and culture. W e were able to witness a sharp contrast between the people of Vikasnagar and the m a n y villages w e visited. In the villages, w e were welcomed with great warmth, as if w e were lost kin of the families while the people in the cities treated us as appointments - to be completed as soon as possible and then forgotten.

W e do acknowledge that with urbanization, the people of Uttaranchal will surely change their ways of life to suit their new environment, and the risk to the fabric of their culture is indeed great. However, w e wonder if it is significant enough an issue when people perish from grossly inadequate health care. The gains of urbanization would surely outweigh or in the very least, balance its losses.

The Attitudes The progress of Uttaranchal is greatly hampered by the attitudes of the people. Any initiatives by the government are met with strong resistance. For example, s o m e villages believed that vaccinations

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Figure 2 A picture showing poor housing in the villages.

The Solution Looking back at the challenges faced by this region, one can see that a mutual cooperation is essential between the people of Uttaranchal and the government of India.

With a variety of negative attitudes, and a potential loss of a great culture, one cannot expect tojump into change with arms wide open. Education is perhaps the key to our problem. With an illiteracy rate fluctuating from 30-40%, the focus must be on teaching and imparting knowledge, fighting the ignorance that causes children to be unvaccinated, fighting the attitudes that hinder progress. W e believe that Uttaranchal and its people have a great future ahead of them, with a compromise between the merits of urbanization and the sanctity of culture. M Special Thanks: Dr. Satendra K. Srivastava, The Furtado Family, SMTA, SIHI, and of course our beloved "Survivor India 2003" Team.

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13

Designing a Vaccine for Cancer A Look Into Dendritic Cell Cancer Vaccine Research Immune System t

Jonathan M. Ng Teach the body to fight cancer? Find out how current research may make this a reality in the coming years...

Turning the body's immune system into a weapon against cancer cells is an area that is currently brimming with breakthrough potential. Although the idea has been around since the 1890s, cumulative research findings have finally paved the way for making this idea a reality (Waldman, 2003). Scientists, many from the McMaster academic community, are now exploring the use of modified white blood cell injections as a potential therapeutic vaccine against this lethal disease. If successful, this vaccine will revolutionize the future of cancer treatment. Alone, the vaccine may cause tumour regression. Used in combination with current therapies, the fight against cancer may be won.

To help you best understand this promising new technology, this article has been divided into two parts and supplemented with several hand-made diagrams. In the first section, w e will explore the basic mechanisms of how this vaccine of the future will work.

The second section brings you to the edge of current immunological research and delves into a few of the fascinating techniques and concepts investigators are employing to overcome the remaining barriers to the vaccine's success.

I. The naiVe immune system (cop) cannot recognize the antigen (face) 2. The vaccine (wanted poster) trains the immune system to recognize it 3. The immune system can n o w recognize and kill cells that express the antigen

Figure 1 A cop-alien analogy to how a vaccine mounts an immune response against antigens. been trained to recognize their antigens specifically.

However, if the antigen is specific to cancer cells, vaccines can mount a therapeutic i m m u n e response against these cells, too (Abou-Jawde et al., 2003).

How the Dendritic Cell Cancer Vaccine Works What is a dendritic cell and why use it for a vaccine?

Dendritic cells (DCs) are potent antigen-presenting cells (APCs). One of the main roles of APCs in the body is to ingest, digest and present antigens to other cells of the i m m u n e system (Fig. 2). Presentation of antigens to other white blood cells is a crucial step in the development of an adaptive i m m u n e response; it activates 'naive' or 'inert' T cells whose T cell receptor Section 1: The Basics of Dendritic Cell-Based is specific for the particular antigen being presented Cancer Vaccines by the APC. The cytotoxic T lymphocyte (Killer T cell) adaptive i m m u n e response is the principle way in The Basic Idea which tumours can be destroyed by the body. The Vaccines work by training the body's i m m u n e system dendritic cell cancer vaccine exploits the powerful to recognize and neutralize antigens, compounds that antigen-presenting capacity of the dendritic cell and have the potential to generate i m m u n e responses. uses it to develop therapeutic immunity against cancerUsually, these are foreign proteins or peptide sequences associated antigens (Janeway, 2001). from viruses, bacteria or other unwanted interlopers How do dendritic cells 'present' antigens to the (Fig. 1). W h e n antigens are associated with cells, the immune system? Why is it important? entire cells can be destroyed by the i m m u n e reaction

as well. In the case of the c o m m o n prophylactic vaccine, infectious organisms or viruses containing this marker are destroyed by an i m m u n e system that has

After a dendritic cell has ingested and processed an antigen, it must communicate its finding to the rest of the i m m u n e system. This may be achieved by

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Issue 3 | February 2004

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The dendritic cell (DC) ingests the cancer antigen (Ag).

The D C digests the A g and presents it on an M H C class 1 molecule. The D C migrates to a lymph node.

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In the lymph node, the D C presents the Ag to a naive T cell's T cell receptor (TCR). Other binding occurs as well (not shown).

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The T cells differentiate, proliferate and become effector T cells. These enter the bloodstream.

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Figure 2 Steps in developing a cytotoxic T lymphocyte (Killer T cell) response from a dendritic cell to an activated cyto lymphocyte. physically bringing the pieces of the antigen to other How do dendritic cells cause an immune response i m m u n e cells. However, since other cells do not have against cancer-associated antigens? ready access to the engulfed particle inside the cell, After a dendritic cell has successfully presented an the antigen fragment must be presented on the cell antigen bound to an M H C I molecule on its cell surface, surface. O n e of the ways this is achieved is through it migrates to a lymph node where m a n y other white antigen binding to a special 'presenting' molecule, M H C blood cells are waiting. Here, dendritic cells interact I (Major Histocompatibility Complex - Class 1). This with C D 8 + T lymphocytes. Dendritic cell antigen/ allows the small morsel of antigen to be held in place M H C I complexes bind with T cell receptors on C D 8 + on the cell surface and gives context to other i m m u ne T lymphocytes. This contact, in conjunction with other cells, allowing them to respond properly (Janeway, co-stimulatory and adhesive processes, causes C D 8 + 2001).

T lymphocytes to multiply and mature into selective Usually, proteins that APCs ingest (exogenous cellular assassins, commonly known as killer T cells (or proteins) are presented on M H C II, not M H C I; that is, cytotoxic T lymphocytes). These cells then migrate from M H C I is reserved for fragments of proteins that cells the lymph node back into the blood and throughout produce themselves (endogenous proteins). However, the body in search of the antigen by which they were APCs have a special ability to cross-present exogenous stimulated. W h e n they find cells that express the antigens on M H C I, which allows APCs to activate cells antigen, presented with an M H C I molecule, they destroy that can recognize tumour cells expressing tumourthem. Since cells normally present bits of their internal specific antigens in the context of M H C I (Janeway, proteins on M H C I molecules, cancer cells produced 2001). antigens can be recognized and destroyed in this way (Janeway, 2001). www.meducator.org

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What are the steps to making and administering a dendritic cell-based cancer vaccine?

Section 2: Current Techniques and Concepts to Improve the Vaccine

Most dendritic cell-based vaccines are usually composed of the following four basic steps (Fig. 3): 1) Collect dendritic cells 2) Culture dendritic cells in vitro 3) Expose dendritic cells to the cancer antigen(s) of your choice 4) Administer the dendritic cells into a patient as a vaccine (Chen et al., 2000)

Currently, mild therapeutic effects of D C vaccines based on the theory in section 1 have been documented (Engleman, 1997; Hsu et al., 1996). However, with recent advances in this area, scientists are n o w looking for new ways to increase this therapeutic effect. This section discusses s o m e of the concepts and techniques that are being used to bring a curative vaccine for cancer closer to fruition.

Heteroclitic Peptides Heteroclitic peptides are those with greater ability to generate an adaptive i m m u n e response than the original peptides. By changing the amino acid sequences of existing peptides, these molecules can be generated (Dyalletal., 1998).

For the purpose of understanding this concept, it is helpful to think of the antigenic fragments that result after dendritic cell processing as having two important regions (Fig. 4): 1. The TCR binding region (TCR: T cell receptor) 2. The M H C binding region (MHC: Major Histocompatibility Complex) Heteroclitic peptides may have substituted amino acids in either or both of these regions; however, only heteroclitic peptides involving alteration to the M H C

Figure 3 The 4 basic steps in a dendritic cell cancer vaccine.

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1. The antigen is engulfed, digested and processed by an antigen presenting cell (eg. Dendritic cell) 2. The antigen fragment binds to an M H C I molecule. The affinity depends on the complementarity between M H C I and the M H C binding region.

3. The T C R binding region binds a corresponding T C R molecule. Under therightconditions, the C D 8 + T cell is activated to become a killer T cell.

4. The killer T cell then seeks to destroy cells expressing molecules similar in shape to the T C R binding region

Figure 4 After digestion, an antigen fragment has an MHC binding region and a TCR binding region that serve different functions.

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16 binding region will be discussed here (Dyall et al., 1998; Parkhurstetal., 1996).

The TCR-binding region determines the specificity of the resulting i m m u n e response. It is specific for a particular T cell receptor. Since each T cell contains a T cell receptor specific for one antigen, the TCR-binding region determines the T cell variant that is activated, and thus, the antigen to which an i m m u n e reaction will be developed (Janeway, 2001).

The MHC-binding region determines the binding affinity of the antigenic fragment to its corresponding M H C molecule. By altering the MHC-binding region, the binding affinity between antigen fragment and M H C molecule can be increased (Parkhurst et al., 1996). Stronger binding affinity for M H C I has been correlated with a greater capacity to develop of a killer T cell response. It is thought that this relationship is caused by the unstable nature of the peptide:MHC 1 complexes. Increasing binding affinity would increase the available time for presentation of the peptide to T cell receptors (Sette et al., 1994).

Therefore, altering the cancer antigen MHC-binding region to increase its MHC-binding affinity will increase the effectiveness of the vaccine by increasing the likelihood of evoking an i m m u n e response. As long as the TCR-binding region remains complementary to the s a m e T cell receptor, the specificity of the resultant i m m u n e response should be the same.

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Once the dendritic cells (DCs) have been harvested (Step 1: Figure 3), three common methods used for loading them with cancer antigens are peptide pulsing (1), cancer cell/DC fusion (2) and cell lysate co-culture (3).

Figure 5 The 3 common methods of loading dendritic cells with cancer antigens.

an opportunity for the dendritic cells to ingest all the possible antigens found in the cancer cell (Fecci et al., 2003).

Another way to create patient-specific vaccines is to meld dendritic cells with the patient's tumour cells ex vivo. This brings the antigen-presenting ability of dendritic cells together with all the antigens found in the cancer cell. As a result, dependence on A P C ingestion of the antigen is eliminated and the process of cross-presentation can be bypassed. All the important cancer antigen factors, including'MHC I/cancer antigen Patient-Specific Vaccines complexes', are combined with the i m m u n e system Cancer antigens between individuals and between stimulating properties of the dendritic cell (Fecci et al., cancer types vary substantially. Therefore, it is believed 2003). that the effectiveness of the vaccine can be increased if the chosen cancer vaccine antigens were those Polyvalent Vaccines taken for the individual patient. Tailoring the vaccine Usually lacking proper genetic repair mechanisms, to patient-specific cancer antigens ensures that the cancer cells accumulate mutations in their o w n i m m u n e response, if any, will be properly targeted to proteins at an elevated rate. This high mutation rate that person's cancer cells (Nadler & Shultze, 2002). allows cancer cells within a patient to express different There are currently three c o m m o n s methods used antigens, gaining or losing the expression of different to expose dendritic cells to antigens ex vivo (Fig. 5). proteins. This p h e n o m e n o n of ever-changing tumour Of these, all can be used to develop patient-specific antigen expression has been verified by Brasseur and vaccines (Fecci et al., 2003; Fay, 2002; Rea et al., Lehmann's studies (Renner et al., 2001). Therefore, a 2001). vaccine targeting only one antigen is more likely to allow Peptide pulsing with isolated antigens previously s o m e altered cancer cells to avoid i m m u n e surveillance. determined to be patient-specific is the most To circumvent this problem, it is beneficial to generate straightforward method of the three. It produces polyvalent vaccines that target multiple antigens. By immunity to the cancer antigens that the particular broadening the diversity of the i m m u n e response, o n e patient's tumour is expressing (Fecci et al., 2003). can minimize the probability of tumour escape due to Peptide pulsing with tumour cell lysates involves a lost antigen (Zhou et al., 2 0 0 2 ; Smith et al., 2 0 0 1 ; exposing the dendritic cells ex vivo to the dispersed cell Scanlan &Jager, 2001). contents of the individual's tumour cells. This provides

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17

A polyvalent vaccine m a y also refer to the multiple epitopes of any particular antigen (Fig. 6). An epitope refers to the region of an antigen that the T cell receptor binds. I hypothesize that targeting several epitopes on one antigen m a y increase the likelihood that cells expressing that antigen will be recognized and destroyed. Also, it m a y prevent cancer cells from escaping through random mutations as previously discussed. If the gene encoding a cancer antigen undergoes a point mutation and change in one amino acid in the peptide chain, it m a y maintain another epitope that can be recognized by the i m m u n e system.

Despite this speculation, currently I a m unaware of any research that supports this notion.

Polyvalent vaccines can be m a d e using the three techniques earlier described to introduce antigens to dendritic cells (Fig. 5): exposing dendritic cells to tumour lysates, inducing tumour cell-dendritic fusion or directly pulsing dendritic cells with multiple antigens.

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Adenoviruses can be used to insert cancer antigen genes into dendritic ceils (DCs).

1. The adenovirus containing the desired gene is used to infect DCs. This process inserts the gene into the D C 2. The foreign gene instructs the production of cancer antigens inside the D C 3. The antigens are digested by the DC and the various fragments are presented on M H C I molecules.

T w o benefits of this process are: A. Continuous production of cancer antigen for loading onto M H C I (Instead of onetime exposure as in peptide pulsing).

Cancer Antigen G e n e Continues

B. An intracellular source of antigen, easily accessible to the M H C I pathway

Figure 7 Using viral gene transduction to introduce antigen genes into a dendritic cell.

are unstable and degrade relatively rapidly with time, it is believed helpful to have constant antigen present for Multiple Epitopes (Different Antigens) Multiple Epitopes (Same Antigen) continuous loading onto M H C I (Rea et al., 2001).

Polyvalent Cancer By providing an intracellular antigenic source, gene Cancer Antigens TCR Antigen (1 epitope/each) transduction improves the access of antigen fragments I (2 epitopes) to the M H C I pathway. Exogenous antigen sources, as in peptide pulsing, are normally presented on the M H C II pathway and require cross-presentation by the dendritic cell. However, if the antigen is produced within the cell, C a n c e r Cell it will be naturally loaded onto M H C I without the need <>\/ C a n c e r Cell t for the less-efficient cross-presentation process (Rea et Killer T Cells Killer T Cells al., 2001).

Polyvalent cancer vaccines target several different cancer epitopes (instead of only one: monovalent). There are two ways polyvalency of a vaccine can be achieved.

To effect gene transduction, viruses can be used.

Mount an immune response against: Currently, one of the most effective techniques for 1. Multiple epitopes on different antigens (Left panel) dendriticcel I genetransduction make s useof genetically2. Multiple epitopes on the same antigen (Right panel) modified adenoviruses, a technology developed at Figure 6 McMaster by Dr. Frank Graham and colleagues. The There can be 2 types of polyvalency. adenoviral vector boasts high transfection rates and allows for several vectors to be introduced into the s a m e Gene Transduction D C population (Rea et al., 2001; Chen et al., 2001). In addition, this technique can also be used to transduce In addition to methods that apply the antigen to the D C genes encoding immunostimulatory cytokines that directly, it is also possible to transfer the gene encoding stimulate the killer T lymphocyte response (cytotoxic T the tumour-specific antigen into the D C (Fig. 7). Such lymphocyte response) (Chen et al., 2001). an approach can be beneficial because it provides: At McMaster University's Centre for Gene 1) A continuous production of antigenic fragments Therapeutics, gene technology has been united with 2) An intracellular source of antigen, easily dendritic cell cancer vaccine research. The results accessible to the M H C I pathway have been promising. In 2001, McMaster researchers (Okada et al., 2001; Rea et al., 2001) Continuous production of antigen allows for prolonged Dr. Ronan Foley, Dr. Jack Gauldie and Dr. Yonghong availabilityforloadingintotheMHCIpathway. Compared W a n published results in Gene Therapy showing that with peptide-pulsing techniques that provide short-term D C vaccine effectiveness could be increased by a exposure, antigen gene transduction provides long- combination of both antigen and immunostimulatory term exposure. Given that M H C l/antigen complexes cytokine gene transduction. The cytokine IL-12 w a s

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Issue 3 | February 2004

18 chosen for this experiment because of its ability to activate i m m u n e cells and strengthen the killer T cell response. Using adenoviral vectors, the team simultaneously introduced a breast cancer antigen (ErbB-2/neu) and an IL-12 gene into dendritic cells ex vivo before administering the vaccine (Fig. 8). The result w a s a significant strengthening of the protective and therapeutic immunity of mice against injected breast cancer cells (Chen et al., 2001).

known as autoimmunity and results in d a m a g e to the body's tissue. With this lingering possibility, future research must be cautious to avoid vaccines that produce i m m u n e responses that do not discriminate between self and cancer.

The Future of DC Cancer Vaccine Research

Research in the area of dendritic cell cancer vaccines is moving forward at breakneck speeds. Each month, new discoveries are m a d e that push our knowledge to Remaining Challenges for Cancer Vaccine Research greater heights, always moving closer to a cure. With an Four of the major remaining challenges for cancer increased understanding of antitumour immunity and vaccines involve identifying more cancer antigens so an enormous toolbox of i m m u n e enhancing techniques that more patients m a y be treated, developing more at our disposal, a therapeutic revolution is waiting to be effective immunization strategies, suppressing tumour had. W h e n will the cure for cancer c o m e ? Feedback escape mechanisms, and preventing autoimmunity from current and future clinical trials will begin to set the stage for the routine use of D C cancer vaccines in (Scanlan&Jager, 2001).

The hypothesis of tumour escape is one that the clinic. However, development of a highly effective or attempts to explain the current lack of robustness of curative vaccine will require the integration of carefully cancer vaccines. It is based on the concept of natural selected immunological concepts, only a few of which selection for cancer cells that can evade the i m m u n e have been discussed here. W e have only graced the tip system. Since tumour cells are highly mutagenic, of the knowledge iceberg - a vast sea of discovery still they have been known to lose or down-regulate M H C awaits you. Bon voyage! M I, cancer antigens, and other crucial molecules to the i m m u n e response. Furthermore, they m a y mutate to A special thank-you goes to Terry Ng and Deborah Leung have defective death receptors that prevent destruction for their research contributions and mind-expanding by killer T cells, secrete immunosuppressive cytokines discussions. I am also indebted to Ryan Wiley for or express death signals to cause T cell self-destruction. helping guide me into my immunological adventures Such processes, if present and selected for, would - through forests of facts I would have been otherwise greatly interfere with vaccine effectiveness (Khong & lost in.

Restifo, 2002; Vicari et al., 2002; Garcia-Lora et al., 2003).

Since cancer cells ultimately derive from self-cells, there is the risk that a killer T cell response against normal, healthy cells may develop after a cancer vaccine is administered. This phenomenon of self-reactivity is 0 IL-12 i:

ErbB-2/neu is produced, processed a n d presented o n MHC I Injection of breast cancer cells expressing ErbB-2/neu

Vaccine introduced to mouse it IL-l 2 is an immunostimulatory cytokine that helps to activate cytotoxic T tymphocytes

Protective a n d therapeutic immunity against injected breast cancer cells

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Figure 8 McMaster researchers successfully transduced breast cancer antigen, ErbB-2/neu, and IL-12 genes into dendritic cells before administering the DCs as a vaccine to induce protective and therapeutic immunity against injected breast cancer cells (Chen et al., 2001).

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19

Tourette's Syndrome A n Often Misunderstood Disorder

hile it is tempting to objectify and intellectualize any neuropsychiatric disorder, Tourette's Syndrome (TS) often defies anything beyond a descriptive, verbal-picture, painted with an experienced brush and an empathetic mind. The incredibly broad spectrum of symptoms associated with TS is, alone, a testament to the unique and fascinating aspects of what could be characterized as a model neuropsychiatric disorder. This article is not intended as a comprehensive review of TS literature or as a definitive introduction to TS. This is meant as a brief overview of TS for those w h o might be somewhat unfamiliar with the disorder. The author's own experiences with TS, as a patient and a researcher, provide for what is hoped to be a refreshing insight into this idiosyncratic disorder.

N a m e d after Georges Gilles de la Tourette, a French physician and pupil of Charcot, TS w a s also seen and described by other physicians. Sigmund Freud is thought to have seen the disorder in his practice but is said to have not really taken any notice of it. In his defense, even Charcot and Gilles de la Tourette conceded that tics and coprolalia could be symptoms of hysteria—Freud often diagnosed hysteria (Kushner, 1998). The disorder, as described by Gilles de la Tourette, is a pathological milieu in the sense that it creates a setting, a characterized mood, around itself. The disorder is, for all intents and purposes, one with the patient. Intertwined so that the person, if he/she were to be cured of TS, would cease to be themselves—almost like a personality disorder. But, relatively few diagnosed cases of TS actually fit this original description. Most people with TS have mild cases where a few facials tics and a couple of phonic tics might be their worse-case scenario. Echolalia, coprolalia, multiple motor and phonic tics, and motor incoordination are the key symptoms of Gilles de la Tourette's syndrome (Robertson, 2003). Coprolalia, though, is not c o m m o n in most cases of TS and most TS cases involve just motor and phonic tics.

The current diagnostic criteria for TS are somewhat disputed. Two governing bodies for sets of criteria are often cited: the World Health Organization ( W H O ) and the American Psychological Association (APA). The Diagnostic and Statistical Manual of Mental Disorders (DSM) of the APA includes a m a x i m u m age of onset— 18 years old in DSM-IV-TR. This version of the D S M , however, is controversial because, in addition to the presence of both motor and phonic tics, this edition of the D S M also stipulates that the patient must be experiencing impairment and distress in order for a diagnosis of TS. To s o m e physicians, this s e e m s as absurd as stating that a patient w h o deals well with their illness does not have the illness. For this reason, it is the D S M lll-R criteria, which fail to m a k e any mention of distress or impairment, which are mostoften used for TS. With an age of onset of about 7 years (Wand et al., 1992) and a male:female prevalence ratio of about 4:1 (Freeman et at, 2000), TS is most often seen in adolescent or preadolescent males. While TS can be very disturbing to children afflicted with the disorder, it is comforting to know that symptoms tend to disappear by adulthood in at least half of all cases (Robertson, 2003).

It is easy to get wrapped-up in an academic discussion of TS and m u c h harder to have an intellectual appreciation for the complexities, idiosyncrasies, and spectrum of TS. For this reason, it is important that a clinician or researcher understands TS, as best she/he can, from the patient's perspective.

While most individuals with TS tend to have mild symptoms that do not usually interfere with daily activity, both tics and behavioral problems, such as aggression, can cause social problems in individuals with TS. Tics such as head jerking, unusual vocal noises, and bouts of coprolalia can be deterrents to normal socialization in a child with TS. In adulthood, these, and similar symptoms, can m a k e it hard for an individual with TS to keep a job, m a k e friends, and have normal relationships.

The tics, from head jerking to seemingly deliberate profanities are, to the patient, m u c h like an itch that needs to be scratched. W h e n a person with TS jerks their head or blinks their eyes it is not a m o v e m e n t which they have no control over (as in Parkinson's

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20 Disease or s o m e other tic disorders) rather it is a response to an intense urge, a need that must be satisfied. The person has to jerk their head or blink their eyes - to not do so feels incredibly wrong.

Likewise, the profanity is also the result of responding to a need, an intense urge. The person m a y not m e a n to call you a bad name, she or he simply has to.

I have heard parents of children with TS remark that their child is "doing things on purpose." In one case I saw, a 9 year old girl would often call her mother a "f*cking-b*tch." Her mother w a s adamant that her daughter w a s doing this on purpose, had full control over herself, and that this offensive profanity had nothing to do with the girl having TS. In fact, neither the mother nor the father w a s convinced that their daughter actually had TS. They believed that she w a s simply a "naughty-girl" and so they would punish her, or rather try to punish her, by sending her to her room or refusing her requests for toys. Of course, the punishments did not work because the girl w a s not doing these things on purpose. She did not want to call her mother such horrible names, she had no choice, she had to, it was a tic. Imagine the torment that this little-girl must be feeling. This would be difficult enough for an adult but even more so for a

child. Confused and bewildered by her o w n behavior, she needs help, not punishment.

Unfortunately, the girl's story is all too c o m m o n . TS was once thought to be an extremely rare disorder and it is only in the past decade that it has gained any notoriety outside of the medical community. Indeed, even within the medical community knowledge of TS is growing but scarce.

Another reason why TS is often hard forthe clinician to recognize is that comorbid disorders such as Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD) can m a k e it difficult to see where the TS begins and where it ends. Indeed, one TS researcher asserts that TS begins where A D H D , OCD, tics, and behavioral problems meet (Jankovic, 2001). This brought m u c h uproar in the form of letters to the editor as TS has always been identified as a tic disorder with none of the aforementioned disorders or problems required for a TS diagnosis. However, it is entirely possible that they have a c o m m o n etiology.

Pharmacology and Current Research Foci Most studies suggest that abnormalities in dopamine and serotonin metabolism are found in TS patients.

However, just whatthose disturbances are is not known

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Figure 1 Haloperidol, dopamine, tetrahydrocannibol and nicotine have all been used with variable success to treat Touret Syndrome.

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Issue 3 [ February 2004

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and the strongest evidence towards any answers in this direction comes from the use of haloperidol in the treatment of TS. Pharmacological treatment for TS started in the early 1960s with the use of haloperidol, a dopamine receptor antagonist (Caprini, 1 9 6 1 & Seignot, 1961).

Relatively small amounts of haloperidol are needed to achieve saturation of the D 2 receptors and most TS patients do respond to it (Fitzgerald et al., 2000).

Clinical practise, though, has moved towards using atypical dopamine antagonists such as risperidone and olanzapine (Sandor, 2003). In general, dopamine receptor antagonists have been the most successful class of pharmacological agent used for the treatment of TS as they are able to reduce tic frequency and severity in about 7 0 % of cases (Shapiro and Shapiro, 1998).

Other treatments, including nicotine and tetrahydrocannabinol (marijuana) have been tried with variable success. Early nicotine studies were inefficient and the most promising study suggests that nicotine is only helpful when combined with other treatments, such as haloperidol (Silver et al., 2001).

In addition to the many clinical trials of dopamine receptor antagonists and other pharmacological interventions, there are 2 main foci in current TS research: genetics studies and brain imaging studies.

TS has, for a long time, been seen as a hereditary disorder, running in families and passed-on from parent to child. Thus, there are many international efforts to locate the gene(s) responsible (or at least partly responsible) for TS. Since 1990, 6 family studies have been completed, all of which show TS is familial and genetic linkage studies have provided enough data to suggest possible candidate genes for TS. Unfortunately, most of the studies examining candidate loci have had negative results. The c o m m o n thread a m o n g potential candidate genes which have been excluded has been their relation to dopamine metabolism with almost all of them regulating the release of dopamine or serotonin in one way or another (Pauls, 2003). Despite the negative results, segregation analysis studies have reported data sufficient to suggest that TS is due to an autosomal dominant gene. In line with most of the TS genetic work however, is that this gene has remained elusive and, if it does exist, the penetrance and variability will be an extremely interesting matter for study.

Conclusion Gilles de la Tourette's syndrome has gone from being a supposedly rare 19th century tic disorder to being a more c o m m o n neuropsychiatric spectrum disorder linked to O C D and A D H D . The psychopharmacological revolution offered the first ever effective treatment for TS, as it did for a myriad of other neuropsychiatric disorders, and the ensuing genetics revolution allowed the first-ever window into the root cause of TS, or at least w e think. Future genetics studies will likely yield promising candidate genes and, as w e work out the genetic and biochemical pathways of the h u m a n organism, these studies will probably lead to a different class of pharmacological treatment for TS - drugs that can directly alter the chemical imbalance ofTS. As for the patients, those w h o have to suffer because of their TS, those w h o fear goingtoa movie theatre so as not to disturb the peace, those w h o cannot work a job at the grocery store because they constantly tell Mrs. Smith and her daughter to "f*ck-off and have a nice day," it is for these people that w e must continue to work, learn as much as w e can, and attempt to ask questions that nobody knows the answerto.E9

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S a m m y Ali - Genomeceuticals as a Potential Treatment for Autism: Re-establishing the Roles of Casein and Gluten Brudnak, M . A. (2001). Application of genomeceuticals to the molecular and immunological aspects of autism. Medical Hypothesis, 57(2): 186-191.

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Ronald Zahoruk - Spinal Cord Injury Hansebout, R.R., Blight A.R., Fawcett, S., & Reddy, K. (1993). 4Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. Journal of Neurotramaurotrauma, 10(1):1-18.

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Jonathan M. Ng - Designing a Vaccine for Cancer: A Look Into Dendritic Cell Cancer Vaccine Research Abou-Jawde, R., Choueiri, T , Alemany, C , & Mekhail, T (2003).

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Renner, C , Kubuschok, B., Trumper, L„ & Pfreundschuh, M . (2001).

Clinical approaches to vaccination in oncology. Annals of Hematology, 80(5), 255-266.

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Jacob Kocsis - Tourette's Syndrome: A n Often Misunderstood Disorder Caprini, G.M.V. (1961). U n grave sindroma ticcosa gaurita con haloperidol. Riv Sper Freniatr, 85:191.

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The McMaster Meducator Executive 2004

Top Row (Left to Right): Christine Almeida, Jaron Chong, Soroush Seifi, Nisha Sivagurunathai, Jeannette So Bottom Row: Jennifer C. Tang, Sammy H. Ali, Jonathan M. Ng, Abhishek Raut, Grace Wang, Thien Huynh Absent: Nancy Xi, Fareen Karachiwalla

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