McMWER McMaster's Medical Research and Health Ethics Student Journal
SARS Preparing for the next epidemic and the ethical issues encountered during ,4 the crisis „* '""*
Einstein's Brain Dr. Sandra Witelson leads investigations into the physiological basis of Albert Einstein's L% Genius
LDL & HDL The battle against heart disease
Neglected Diseases Is the developing world being left behind in the "Health Revolution"?
Microencapsulation A n inside look at the work of McMaster University's Microencapsulation G e n e Therapy Group
Issue 4 | April 2004 www.meducator.org
Issue 4 1 April 2004
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MMSIER _. Inside Scoop Presidential Address
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Med Bulletin
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Medico I. Research and. Health Ethics Articles. Ethical Issues Encountered During the SARS Crisis
Neglected Diseases The Cost of Our Health Revolution
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Jonathan M. Ng
Faizal Haji
Microencapsulated Non-Autologous Cells 8
Preparing for the Next S A R S Epidemic
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Brent Motion
The Benevolent Trojan Horse Maria-Alexandra Petre
LDL, HDL, and the Battle Against Heart Disease
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REVERSE CHOLESTEROL TRANSPOR1
Abdullah Alabousi, Waqas Kayani, Soroush Seifi, Samer Dabbo
Cover: The Mind of a Genius
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An Exploration of Albert Einstein's Brain Jayant Ramakrishna
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References
About The McMaster Meducator The McMaster Meducator adopts an educational approach to our publication. Despite The McMaster Meducator m a y be contacted our efforts to ensure correctness, w e recognize that the publication may be subject via our e-mail address: to errors and omissions. In light of these potential errors and new developments mac.meducator@learnllnk.mctnaster.ca in the medical field, w e invite you to partake in feedback and constructive or our mailing address: discussion of the content herein for the purpose of furthering your understanding B.H.Sc. (Honours) Programme of the topic - in the n a m e of education and discovery. An online discussion forum Attention: The McMaster Meducator for each article is available on our website: www.meducator.org. Students and HSC-1J11 professors alike are welcome. Please enjoy the Meducator online experience! 1 2 0 0 Main St. West Disclaimer: The views represented in the articles do not Hamilton, Ontario, L8N 3 Z 5 necessarily reflect those of the McMaster Meducator.
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President/Chief Editor G E N I U S E S LIKE ALBERT ElNSTEIN ARE OFTEN DIFFICULT TO UNDERSTAND. JONATHAN M . N G It makes it easier, however, when you can get inside their head, literally. Read Jayant Ramakrishna's article and learn about Dr. Sandra Vice President/Deputy Chief Editor Wicelson's research at McMaster on the physiology of superior intellect. Let Brent ABHISHEK R A U T Mollon's S A R S virus article infect your mind with fascinating research ideas for Managing Editor future treatment and vaccination. Then, explore the ethics of the Toronto S A R S JEANNETTE S O crisis through the eyes of bioethicist, Dr. Peter Singer, in m y o w n article. For the VP of Journal Production & Design immunology and gene therapy enthusiasts, read up on Maria-Alexandria Petre's JARON C H O N G article on microencapsulation research at McMaster. Join Abdullah Alabousi V P of Website Production & Design and colleagues as they explore the science behind lipoproteins, their link to heart THIEN H U Y N H disease and the logic behind therapeutic research strategies. If your interest is VP of Internal Affairs global medical care, read up on Faizal Haji's discussion of the health revolution NISHA SIVAGURUNATHAN and neglected diseases. After reading the articles, w e encourage you to continue VP of External Affairs the experience by joining our online discussion forum to discuss your thoughts GRACE Y. W A N G and contributions (www.meducator.org). VP/Editor of Medical Research W e extend heartfelt appreciation to our dedicated writers and post-graduate JENNIFER C. T A N G VP/Editor of Health Ethics editors w h o have selflessly donated their time and expertise to bring you these S A M M Y H. ALI high quality articles. A special thanks goes to ourfinancialsupporters, especially Director of Graphics and Images the Bachelor of Health Sciences Programme, for supporting our iniriative. This CHRISTINE ALMEIDA year, I have had the opportunity to work with a phenomenal team of executives. First Year Representatives I could not have had a better team: Abhishek Raut, Vice-President, for your FAREEN KARACHIWALLA leadership and unending enthusiasm; Jaron Chong, in layout and design, whose S O R O U S H SEIFI extraordinary skills and creative vision have made our publication rival those N A N C Y XI on the market; Jeannette So, our managing editor, for keeping pristine literary quality; Jennifer Tang and S a m m y Ali, VP's Medical Research and Health Post-Graduate Editing Ethics, for their close work with writers and keen eyes for quality conrent; Thien D R . PAT C H A N G , P H . D . Huynh, V P Website, for keeping our cyberspace image on a professional level; D R . JACK GAULDIE, P H . D . Nisha Sivagurunathan, V P Internal, for making Professor & Chairman of Pathology and Molecular collaboration and teamwork possible; Grace Medicine W a n g , V P External, for forming our secure DR. FRANK GRAHAM, PH.D. financial foundation; and Christine Almeida, DR. MARY HITT, PH.D. V P Graphics &C Images, for her attractive cover DR. MARK LOEB, M . S C , M.D. design and beautiful custom images. Finally, DR. JIM MAHONY, PH.D. to m y educational role model, inspiration and DR. ALLISON MICULAN, M.A. support from the humble beginnings: Thank
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Neglected Diseases
companies in the developed world. Alternatively, they m a y suffer from a lack of treatment all together because research into diseases that affect these populations fail to be profitable. The benefits of this global health revolution' have not been dispersed uniformly. Millions continue to die each year from preventable diseases - in 1999 communicable diseases killed 14 Faizal Haji million people worldwide, mostly in developing countries ( W H O , 2000b). IANGA HAD BEEN ILL FOR TEN MONTHS. SHE HAD The cause of this unabated tragedy lies in the fact become too weak to work in thefieldsnear her that most of the diseases affecting the developing world home in Omugo, Uganda, fetch water, or care are 'neglected'. In recent years, the term 'neglected for her six-year-old son, Lino. At first, Bianga founddiseases' has, like so m a n y other phrases involved in herself sleeping all day long, but lying ivide awake social at justice nomenclature, become a buzz word to night. Then, her behavior changed: she would run out describe all the health related ailments of developing into the street, shouting loudly at the sky. At this point, countries, even spawning further classifications of'most her husband left her. Bianga and her son went to live neglected' diseases (MSF, 2001). In fact, a disease m a y with Bianga's elderly mother in her small hut. With no be considered 'neglected' if "there is a lack of effective, one in the family able to earn money or produce food, affordable, or easy to use drug treatments" (Yamey, they were penniless. Lino became malnourished. 2002). As it is clear that most individuals suffering Finally, in despair, Bianga's mother took her to the from said diseases live in developing countries, hospital to see if something could be done. The doctorfor obvious economic reasons, the pharmaceutical discovered that she was sufferingfiomsleeping sickness. industry has traditionally ignored these diseases in She was admitted directly to the treatment center where their research and development. It is appalling that she was given a course of melarsoprol. Although the while the developing world constitutes 8 0 % of the treatment was painfid, she began to feel better. After world's the population, treatments for neglected diseases 20-day course, she was able to return home and resume account for a meager 2 0 % of worldwide medicine her life again. Afiter a month, Bianga began behaving sales (MSF, 2001). Less than 1 0 % of global spending strangely again, and Lino brought her to the hospital.on health research is devoted to diseases that account It was discovered that she had gone into relapse. Herfor 9 0 % of the global disease burden (Global F o r u m ankle had to be tied to the bed to prevent her fiom for Health Research, 2002). For individuals affected running away and getting lost. Bianga received another with these diseases, the disparity is fatal. course of melarsoprol, but this time her condition did Over the last ten years, promising efforts not show much improvement. With no other treatment from the public sector have resulted in publicavailable and little hope for recovery, she was sent home. private partnerships between the public sector and For Bianga, some of the treatments that are only now pharmaceutical companies to tackle diseases such as becoming available arrived too late (MSF, 2001). H I V / A I D S , tuberculosis, and malaria (Yamey, 2002). In the last thirty years, the Western world has At the same time, these partnerships still overlook seen unparalleled medical advances and gains in life some of the 'most-neglected' diseases, such as Chagas' expectancy of up to four months per year ( W H O , disease and sleeping sickness. Sleeping sickness alone 2000a). This health revolution has eradicated the affects 500 000 people, threatens another 60 million threat of infectious diseases from the developed in Africa, and claims thousands of lives annually (MSF, world, but has left the rest of the world behind in its 2001; Yamey, 2002). Currently, the drug of choice wake. Individuals in these underdeveloped countries for treatment of sleeping sickness is Melarsoprol, cannot afford treatment developed by pharmaceutical a n arsenic-based drug developed overfiftyyears ago
The Cost of Our Health Revolution
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Issue 4 | April 2004
funding in research and development. Without this potential market, as is often the case for diseases afflicting the poverty stricken of the developing world, the partnership deteriorates (MSF, 2001). As a result, even though these neglected diseases form 1 0 % of the disease burden in the world, only 16 of the 1393 drugs developed between 1975 and 1999 targeted these diseases (Trouiller et. al, 2002a). The major group lobbying this issue is the Nobel Prize-winning Medecins sans Frontieres (MSF). M S F Figure 1 believes that the key to resolving this issue is for the Although the developing world represents the majority of public sector to accept full responsibility for drug the world's population, only 2 0 % of worldwide medicine development, making it an issue for the public sales are devoted to these areas (MSF, 2001). s e a Q r m KSo[yc y ^ ar£ currently lobbying to test that kills up to 1 0 % of its users, and in some cases resistance to the drug results in its ineffectiveness in up to one-third of the population (Yamey, 2002). A more effective, less toxic treatment (Efiotithine) was developed; however, the company that developed it stopped production in 1995, claiming the drug was a commercial failure (Yamey, 2002). African patients were unable to afford the drug. Ironically, Eflorithine was re-introduced into the market later in the U.S. because it was found to reduce unwanted facial hair in w o m e n (MacDonald, 2001). For Chagas' disease, the story is m u c h simpler. Effective treatmentforthis disease, which thteatens one-quarter of the population of Latin America, is only available for children because no effective treatmentforadults exists (MSF, 2001). So w h y have these diseases, which have proved to be the most devastating, been ignoted? The answer lies in the nature of the contract that exists between the public and private sector. The public sectot traditionally invests m o n e y in the development of medicines for diseases, alongside the research and development that major pharmaceutical companies undertake. Unfortunately, both of these sources of funding for n e w drugs tend to focus o n diseases that affect the developed world. The public sector is influenced by politicians w h o have a responsibility to their o w n constituency and the private sector is driven by more profitable diseases than those eradicated' from the developed world (MSF, 2001;Yamey, 2002). If the private sector sees economic potential for a drug, the public sector has some leverage to lobby tor
the theory that a drug research and development network can be established in the developing world through a centralized management structure. The venture will require immense public support, but currently, there is presently little hope for the t h o u s a n d s w h o are offering and dying from curable infectious disease. h [s a caus£ for c o n c e m tha[ [he deve | oped , wQr d bdieves [he w a f agains[ infectious diseases has b e £ n w Q n W e believe [hat che b a t d e has b e e n w Q n b e a m s e w e d o nQ{. e n c o u m e r infectious diseases to the s a m e degr£e as o[her
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and biological warfare (Henderso[lj 1 9 9 8 ; Feldmann, 2002). Although w £ h a v £ b e £ n r d a d v d y f o r c u n a c e thus far, our procection againsc these threacs m a y faker Q u r i m e r v e n t i o n s to control disease m a y fail because o f increased p a c h o g e n
resistance and variance in o epidemiological surroundings (Morel, efficacvdueC 2 003). Long term, sustainable solutions tequire the effeccive a p pli c a t i o n 0 f health research to policym a k i n g (Sauerborn , 1999). They should include a m m e n d m e m s co discribution procedures and p r e v e n c a d v e p u b l i c education policies in developing c o u m r i e s Countries must unite to develop a n e w imernational pharmaceutical policv to address the c o n c e r n s ofa l[ neglected diseases (Trouiller, 2002b). 0 n l y t h e n c a n k b e said the w a f ba$ b e e n wQ^ m
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Issue 4 | April 2004
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Microencapsulated Non-Autologous Cells The Benevolent Trojan Horse into the g e n o m e of a sample of proliferating cells, like bone marrow, from the patient. These "infected" cells are inserted back into the patient where they would produce the required protein in physiologically acceptable quantities. While this appears to be an ideal Maria-Alexandra Petre treatment, there is one drawback: the patient's o w n SINGLE SUBSTITUTION OF ONE BASE PAIR OUT cells must be used in order to eliminate the need for immuno-suppressant drugs, rendering this type of gene therapy extremely costly (Campbell, 2001). T h e work of billions in our D N A can lead to horrific diseases. Millions of people afflicted with of McMaster University's Microencapsulation G e n e genetic disorders as a result of point mutations can Therapy G r o u p focuses o n a promising technique that attest to this fact. Over the past few decades m u c h bypasses the need to use autologous cells, which are research has been geared towards finding treatments or from the recipient. cures for such diseases. Recent technological advances have m a d e Diseases involving genetic mutations m a y fail microencapsulation a plausible protein delivery system. to produce necessary proteins. Intially, to treat these conditions, scientists administered the necessary The technique is elegant in its simplicity. Cells from recombinaint proteins to patients through injections. healthy individuals, or even those of another species, The problem with this, however, was that these proteins are encased in a polymeric matrix that allows diffusion were rapidly eliminated from the bloodstream. Also, of nutrients, wastes, and protein products while acting this would entail the need for costly regular injections as a barrier to the conduits of the i m m u n e system once of high dosages, which m a y have toxic effects. G e n e the cells ate implanted into the patient (Fig. 1). therapy m a y provide the solution by targeting the root The polymeric matrix usually consists of alginate, a of this problem: genetic mutation. substance extracted from seaweed and chosen for its low G e n e therapy methods can vary drastically. toxicity and its ability to maintain cell viability (Dhoot, O n e method involves the use of viruses, such as an 2002). T h e process of microencapsulation involves adenovirus, to insert a correct copy of the specific gene
A
Microcapsule Cell Recombinant Gene Product
FIGURE 1
Nutrients
Waste
Host Immune Mediators
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Cells from healthy individuals or even from other species can be encased in a polymeric matrix that allows diffusion of nutrients, wastes and protein products while acting as a barrier to the conduits of the i m m u n e system once the cells are implanted into a patient. <Source: http://www. fhs.mcmaster.ca/gene/overview. htm>
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Issue 4 | April 2004 dispensing tiny droplets of cell-alginate suspension into a solution of CaCl 2 , which provides crosslinking ions that trap the cells inside tiny beads. The entire process takes about an hour, and the product can be stored for extensive periods of time (Microencapsulation Gene Therapy Group Homepage, 1997). T h e process has a myriad of advantages, Since the microcapsules act as a barrier between the graft and the i m m u n e system, doctors can implant foreign cells into a patient without the use of immuno-supptessant drugs (Orive, 2003). T h e fact that the same cell-lines can be used for different recipients eliminates the need for customized genetic engineering of the patients' o w n cells using viruses. In addition, by changing the properties of the capsules, doctors can alter the rate at which the patient receives the protein products of the implanted cells (Dhoot, 2002).
That is not to say that microencapsulation techniques have been perfected. M u c h more research is needed to make the capsules biocompatible and stable in vivo (Orive, 2003). This necessitates collabotation with researchers from various disciplines tofindnovel substances from which to build the casing for the cells. Such substances m a y have new properties that give doctors more control over the way in which the protein products are released. In clinical trials involving diabetes patients, the capsules were found to be too large to use in the amount necessary to completely eliminate the need for insulin injections; therefore, there is an emphasis towards further miniaturization before microcapsules can be used to treat diseases. Despite the many obstacles that researchers must still overcome, microencapsulation of non-autologous cells has the potential to become synonymous with hope for many patients afflicted with genetic disorder. GJ
LDL, HDL, and the Battle Against Heart Disease Abdullah Alabousi, W a q a s Kayani, Soroush Seifi, and Samer D a b b o A
s
N O R T H AMERICANS PROGRESS INTO T H E
21st century, life has become increasingly chaotic and fast paced. T h e average North American lives in such a high-speed society that it is almost impossible to avoid fast food chains and express lines in the grocery markets. People n o w have no time to slow d o w n theit lives and adopt or maintain a healthy lifestyle. Consequently, heart disease, in particular atherosclerosis, has become the leading cause of death in North America (Ezekowitz et al., 2003). Atherosclerosis is a condition where deposits of fatty substances, cholesterol, cellular waste products, calcium, and other substances accumulate o n the inner lining of an artery and form build-ups called plaque. If a clot forms and blocks a narrowed artery, it can result in a heart attack or stroke. Recently, there have been a n u m b e r of breakthroughs in the fight against atherosclerosis, which have linked highdensity lipoprotein ( H D L ) to antiatherogenic effects. T h e latest studies have linked H D L to the reversal of cholesterol transport, a process that removes excess cholesterol from the body.
Cholesterol is a normal constituent of most body tissues, especially vital in the btain, netvous system, liver, and blood system. Cholesterol is also needed to form the sex and adrenal hormones , bile in the liver, and vitamin D ( K u m a r et al., 2 0 0 1). Unfortunately, high blood cholesterol levels increase the risk of developing health problems such as heart disease and atherosclerosis (Kumar , 2001) . T h e first major type of cholesterol is lowdensity lipoprotein ( L D L ) cholesterol; this fotm is often referred to as the "bad" cholesterol. L D L is a type of lipoprotein, which acts as a carrier for cholesterol and fats in the bloodstream. W h e n too m u c h L D L cholesterol circulates in the blood, it can slowly amass o n the inner walls of arteries that supply the heatt and brain. Togethet with other substances, plaque is formed. Evidence from observational studies suggests that higher total L D L cholesterol levels are associated with an increased risk of a variety of cardiovascular diseases, such as atherosclerosis (Anderson et al., 1994).
â&#x20AC;˘WE/UIUIO/I-
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Issue 4 | April 2004
10 High-density lipoprotein ( H D L ) cholesterol is k n o w n as the "good" cholesterol. H D L is one of the most structurally complex and functionally versatile forms of lipoproteins in the h u m a n body. This type of lipoprotein has b e c o m e a major focus of scientific and clinical investigation over the past decade. Scientific experimentation has found that H D L displays a variety of antiatherogenic effects - " H D L stimulates endothelial cell nitric oxide production, inhibits adhesion molecule expression, mediates antioxidant effects... and inhibits thrombosis and endothelial cell apoptosis a m o n g other processes" (Toth, 2003). These antiatherogenic properties act to prevent atherosclerosis. Various scientific studies have compiled a large s u m of research that indicates that H D L has the ability to clear hardened cholesterol from the arteries and aid in its removal from the body. Recent advances in atherosclerosis have led scientists to conclude that one of the most important antiatherogenic functions of H D L is its ability to drive reverse cholesterol transport, or R C T (Toth, 2003). R C T is the primary process through which excess cholesterol is extracted from peripheral tissues, delivered to the liver for conversion to bile salts, and removed from the body via secretion into bile. R C T is also critical for cholesterol delivery to other organs for conversion into steroid hormones (Toth, 2003).
Protein components of lipoproteins are called apolipoproteins (Zha, 2003). Apolipoprotein A l (apoAl) is the main protein in H D L , and is involved in the R C T pathway. A p o A l is produced by both the intestine and the liver, and once secreted, can interact with macrophages andfibroblaststo stimulate the transfer of phospholipids and cholesterol out of the cells. Th e action of apoAl results in increased cholesterol efflux (Zha, 2003). L o w levels of apoAl are associated with an increased risk for atherosclerosis in humans. The over-expression of apoAl in a n u m b er of animal species substantially reduces the risk of developing atherosclerosis in these organisms (Toth, 2003). Recent research also suggests that injection of recombinant apoAl m a y be able to reduce and/or reverse atherosclerosis, and potentially, heart disease in humans (Nissen et. al., 2003). ATP-binding m e m b r a n e cassette transport protein A l ( A B C A 1 ) plays a major role in R C T , and its activity is found to be associated with "serum levels of H D L . . . and risk for atherosclerotic disease" (Toth, 2003). A B C A 1 consumes energy to physically transport phospholipids from the cytosol into the extracellular space (Attie, 2001). Mutations in the geneforA B C A 1 in h u m a n s lead to conditions k n o w n as Tangier's disease and familial H D L deficiency, which are characterized by severely decreased levels of H D L cholesterol in the blood and increased risk for atherosclerosis and heart disease (Hayden et. al., 2000). Similarly, studies with
HDL A N D REVERSE CHOLESTEROL TRANSPORT
Bile
Nascent A B C A 1 Liver
Mature HDL
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HDL
Macrophage
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FIGURE 1 " H D L is believed to protect against atherosclerosis at least in part through the process of reverse cholesterol transport, whereby excess free cholesterol (FC) is removed from cells in peripheral tissues, such as macrophages within the arterial wall, and returned to the liver for excretion in the bile." (Ballantyne, 2000)
Issue 4 | April 2004 mice reveal that knocking out the gene for A B C A 1 gives rise to similar losses of H D L and susceptibility as in atherosclerosis, whereas over-expressing h u m a n A B C A 1 increases serum levels of H D L and protects against atherosclerosis by increasing R C T (Aiello et. al, 2003; Singaraja, 2002; Vaisman, 2001). Another enzyme, lecithin-cholesterol acyltransferase ( L C A T ) , catalyzes the esterification of cholesterol and the eventual formation of H D L molecules. In one rabbit model, L C A T over-expression was seen to decrease the risk for atherosclerosis (Hoeh, 1996). Cholesterol can also be transferred from H D L to other lipoproteins, including L D L , in the blood. This is the result of a protein called cholesteryl ester transfer protein ( C E T P ) . Since this shifts cholesterol from the "good" to the "bad" lipoprotein, researchers are testing whether blocking C E T P m a y suppress atherosclerosis by helping to divert cholesterol away from L D L and towatds pathways leading to its elimination. T h e delivery of H D L cholesterol to the liver for elimination in bile or conversion into bile salts is thefinalstep in R C T , and appears to be mediated by an H D L receptor called SR-BI (Trigatti, 2000). Studies in mice revealed that knocking out SR-BI blocks delivery of H D L cholesterol to liver and increases atherosclerosis, whereas the transfer of SR-BI gene to increase its expression in the liver increases R C T and reduces atherosclerosis (Trigatti, 2000). Various experiments have shown that it is not the absolute level of H D L that determines the risk for atherosclerotic disease, but father the overall capacity of the R C T pathway to deliver excess cholesterol from the various parts of the body to the liver for disposal. Therefore, the ability of H D L to promote R C T prevents the accumulation of excess cholesterol in the circulatory system, which in turn prevents cholesterol from building up o n the inner lining of arteties and blood vessels. Thus, the R C T pathway continues to receive a great deal of attention from researchers trying to develop strategies to prevent atherosclerosis. As scientists are still looking for a treatment for atherosclerosis, prevention remains the best w a y to combat the disease. O n e of the most effective ways to ptevent atherosclerosis is to combat the high levels of cholesterol within the population. Unhealthy diets, inactive lifestyles, and smoking also increase the risk of acquiring the condition. Subsequendy, healthy lifestyle choices play a
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11 major role in protection against atherosclerosis and heart disease. Nevertheless, pharmaceutical intervention m a y be required for individuals whose condition is very serious. Statins are a class of drugs that are typically prescribed to treat high levels of cholesterol. These drugs work by partially blocking the synthesis of cholesterol in the liver, which leads to increased removal of cholesterol from the blood. These drugs are very effective in the treatment of hypercholesterolemia and prevention of atherosclerosis. It should be noted, however, that statins are usually used in conjunction with healthy lifestyle choices. The latest statin to have received approval for treatment in Canada is Crestor9 (Rosuvastatin Calcium). In sevetal clinical trials, Rosuvastatin has been effective in significantly lowering blood cholesterol levels. In one particular trial, the n e w drug was more effective in lowering L D L cholesterol w h e n compared to 3 other c o m m o n l y used statins (Atorvastatin, Simvastatin, and Pravastatin). The most advetse side effects for statins that have been reported are pharyngitis, headaches, and diarrhea, but data regarding mortality and morbidity have not yet been m a d e available (Rosuvastain/CtestorÂŽ, 2003). A recent addition to the myriad of drugs used to combat high serum cholesterol is a drug called Ezetimibe. This drug blocks the absotption of cholesterol in the intestine, and has been shown in animal studies and h u m a n clinical trials to result in substantial reductions in L D L cholesterol and increased H D L cholesterol. M o r e importantly, because Ezetimibe and statins act o n different pathways, they can be used in combination to provide a more profound reduction in L D L cholesterol. O w i n g to m a n y years of research, the scientific community continually makes rapid progress in unravelling the m a n y biological pathways that are involved in the development of atherosclerosis. A s n e w pathways are uncovered and described, n e w targets for drug development emerge. This leads to an everincreasing arsenal of drugs and treatments to control cholesterol levels and combat atherosclerosis. T h e next several years will be a crucial period, where m a n y potential thetapies undergo clinical trials and n e w thetapies will be developed. E3
Special thanks to Dr. Bernardo Trigatti for his insightful contributions and recommendations.
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Ethical Issues Encountered During the SARS Crisis adopted. T h e idea promotes the use of minimal a m o u n t of intrusion to the individual while making proportionate sacrifices for the greater good. M o r e severe threats to public health m a y necessitate greater individual sacrifices. By Jonathan M. N g employing the m i n i m u m restrictions that succeed A summary of the ethical issues of the SARS crisis in protecting public health, a fair compromise as presented by bioethicist Dr. Peter Singer and colleagues in the article "Ethics and SARS: lessons from Toronto".
T
H E S U D D E N OUTBREAK OF SEVERE ACUTE
respiratoty syndrome (SARS) in Canada was accompanied with m a n y ethical dilemmas. Choices had to be m a d e regarding enforcement of quarantine, public identification of diseased individuals, the extent to which health care professionals were expected to provide care, resource allocation to waiting patients, and suppression of global spread. Each course of action was associated with a specific value judgement, a prioritization of one ethical value ovet another. In a recent article in the British Medical Journal, Dr. Petet Singer and colleagues explored the ethical values that were compared during this crisis. This review summarizes the insight garnered from that paper, and examines five of the majot ethical issues that the group of health care professionals and ethicists identified. 1. ETHICS OF QUARANTINE During the propagation of a deadly, contagious disease like S A R S , it is in the public's best interest to quarantine those w h o m a y have been exposed to the infectious agent. Through such an action, m a n y more lives m a y be protected from harm. However, the temptation to immediately
impose mandatory quarantine is opposed by the need to consider the rights of all the individuals w h o will be affected. Those quarantined m a y face undue threats to their individual liberty, economic status, and health if apptopriate action is not taken to consider their needs. T o balance the interests of the individual and the public, the value of proportionality must be
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between individual liberty and public interest can be reached. Furthermore, to offset the sacrifices of the quarantined, compensation should be allocated according to the principle of teciprocity. Special provisions should be m a d e to ensute that affected individuals receive the health care they require and reparation fot their economic losses.
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Issue 4 | April 2004 2. PRIVACY OF PERSONAL INFORMATION AND
PUBLIC NEED TO K N O W Under normal circumstances, individuals w h o are diagnosed with a particular disease have the right to privacy about their condition, which offers protection of their personal lives from the discriminating effects of public scrutiny. Nevertheless, w h e n disclosure of their infection status would significantly help prevent public transmission and serious h a r m to others, this
of proportionality, private information should only be disclosed as a last resort to protect public health, it n o other means are available.
3. DUTY OF CARE During the S A R S crisis, health cate workers had to m a k e important decisions about whether to protect themselves against the disease ot to fulfill their duty to care for others. O n one hand, health care workers were professionally responsible for their patients and the public relied o n their expertise to maintain the health of the community. O n the other hand, there was a limit to the extent of expected heroic c o m m i t m e n t if the duties presented setious harm to themselves and to their families. Furthermore, health cate workers were professionally responsible for maintaining theit o w n health in order to provide care for others. Currently, there is disagreement regarding h o w m u c h exposure health care providers are professionally obligated to accept. Furthet research, along with input from the public, health care providers and regulatory bodies, is required to teach a consensus decision. Fot the wotkers w h o place themselves at risk, institutions should fulfil the duty of reciprocity by providing protection, interventions to help them cope with the extreme stress, acknowledgement of their selfless acts, and suppott plans in emergency situations.
4. COLLATERAL D A M A G E In addition to the direct effects of S A R S , thousands of patients were adversely affected by the restrictions placed o n hospital admissions. Individuals with varying afflictions, sometimes as serious as heart disease and cancer, were confronted with serious barriers and delays to cate. In addition, those w h o were admitted faced the loss of contact and emotional support from family and friends as a result of the hospitals' strict isolation policies. This collatetal damage is an inevitable consequence right can be supersededforthe greater good. W h e n this of effotts to contain the spread of the disease; course of action is adopted, the benefit to the public however, determining the point at which the benefits must be balanced against the cost to the individual. of public health protection initiatives outweigh the Determination of w h e n risks to public health take costs to waiting patients that tequire care presents a precedence over personal privacy should depend o n
challenging ethical dilemma. A n analysis of the "risks,
the severity of the disease and whether or not a "welldefined public health goal can be achieved by making personal information public". According to the value
benefits, and opportunity" costs must be petformed to detetmine which "medical services to maintain and which to place o n hold".
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14 5. GLOBAL ISSUES Modern ttansportation has allowed for the rapid transmission of infectious diseases across the globe. S A R S rode halfway around the world on an airplane to reach Canada. This example illustrates the necessity forsolidarity amongst the nations to protect themselves and each other against such threats to global health. In light of the interconnected nature of today's world, it is neither ethical nor acceptable to conceal health information that can protect others. H a d China stepped forward earlier with information about the disease and its origins, the spread of S A R S m a y have been reduced. To establish effective global health protection, Dr. Peter Singer and colleagues encourage transparency, honesty, and good communication within the worldwide community.
CONCLUSION Sudden outbreaks of diseases like S A R S place enormous stress on the health care system and force health care providers to m a k e difficult ethical decisions that require the prioritization of various values. Careful consideration of the benefits and costs to patients, the public, health care providers, and other nations must be taken into account. Decisions should simultaneously respect individual liberty, personal privacy, proportionality, and reciprocity while upholding health care workers' duty to caring and protecting the public from harm. EQ For the full version of the article, read: Ethics and S A R S : lessons from Toronto (Singer et al., 2003)
Preparing for the Next SARS Epidemic Exploring Treatment Development and Vaccination Options viruses, like influenza, and m a y vary amongst patients. Detection of the virus is further complicated by the testing limitations. These tests m a y result in improper diagnosis if inaccurately conducted or incorrectly Brent Mollon analyzed. With these complications aside, the initial O N O C T O B E R I 6 , 2002 T H E FIRST C A S E O F stages of S A R S seemed to affect the health care system Severe Acute Respiratory Syndrome (SARS) more than the general public (Emanuel, 2003). Over was reported in Guangdong Province of half of the initial 60 reported cases of S A R S were health the People's Republic of China (Hawkey, Bhagani care workers. O n c e the epidemic spread to Canada, & Gillespie, 2003; Stavrinides & Guttman, 2003). The outbteak of S A R S then spread from Guangdong to more than 30 countries around the world, using air travel as a means of dissemination (Stavrinides & Guttman, 2003). As illustrated by the World Health Organization ( W H O ) in a report entitled "Sevete acute respiratory syndrome (SARS): status of the outbreak and lessonsforthe immediate future", there are several aspects of S A R S that make it particularly dangerous.
S A R S continued to subject the lives of our health care professionals at risk. From February 23, 2002 to M a y 14, 2003, 6 5 % of suspected Canadian S A R S cases were health cate workers (Emanuel, 2003). In the struggle to contain the growing epidemic, the W H O issued a global alett on March 12, 2003 (Groneberg, Zhang, Welte, Zabel & Chung, 2003). This watning, along with the quarantine of infected
individuals, face masks, and preventative measures, Thefirstand perhaps most imperative feature is that wete implemented in hospitals and on the general there is currently no vaccine or treatment for this n e w public, and allowed S A R S to be contained before it virus. The lack of medicinal tools forced doctors to
became uncontrollable. Although the 8098 cases of
resort to quarantine in attempt to halt the spread of S A R S and 774 resultant deaths (reported by the W H O SARS. Even diagnosis of the disease was difficult, as as of July 11, 2003) m a y appear minute compared the initial symptoms of S A R S are c o m m o n to other to the millions of deaths resulting from other viral
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s M Internal Core Structure HE Lipid Bilayer
FIGURE 1 A model of typical coronavirus structure: S, spike glycoprotein; M , membrane glycoprotein; E, small envelope protein; H E , hemagglutinin-esterase glycoprotein; N , nucleocapsid phosphoprotein; ICS, internal core-shell composed of M glycoprotein; N C , nucleocapsid.
infections, the novelty and high mortality rate of S A R S caught the attention of the world and challenged the world's public health systems to respond quickly to n e w health threats (Emanuel, 2003). While it m a y appear that S A R S has been contained, possibilities of a second outbreak have already been explored. As G u a n Yi, a microbiologist from the University of H o n g Kong, pointed out to Science, "The animals are the same, h u m a n activity is the same, the farms are the same, and the virus is still around. There is no reason to doubt the virus will be back" (cited from Ensetink & Normile, 2003). These fears have recently been fulfilled w h e n a Taiwanese researcher accidentally contracted S A R S while working in a high security laboratory. T o m a k e mattets worse, the scientist might also have infected his colleagues duting a conference before any symptoms had manifested. This stands as an impottant reminder that S A R S still has the potential to create another epidemic, and thus it is imperative that w e develop effective methods to prevent or treat this virus.
specialized vital fusion proteins, allowing the virus to ovetcome the phospholipid bilayer by binding to specific receptor molecules on the surface of the host cell (Bosch, van der Zee, de H a a n & Rottier, 2003). O n c e the vims and the host cell have fused, the virus will use the host cells' metabolic machinery to teplicate its o w n genome and produce the proteins necessary for the creation of additional viruses (Fig. 2) (Campbell & Reece, 2002). W h e n the genomic sequence of S A R S was completed, it was noted that the S A R S - C o V was distinct from othet coronaviridae family members (Zeng et al., 2003). This difference was observed by studying the regions of the viral genom e that code fot proteins, termed open reading frames (ORFs). The O R F that codes fot the surface glycoprotein spikes, along with a m e m b t a n e protein and a nucleocapsid protein, have nucleotide sequences that are unlike those of any other coronavitus. It is for this reason that some researchers believe S A R S - C o V should be classified as its o w n distinct group (IV) of the coronaviridae family. As well, a large O R F that codes CAUSES A N D ORIGINS O F SARS for S A R S viral enzymes is unique to S A R S , sharing less A large number of studies have concluded that SARS than 5 0 % similarity to other coronavitidae viruses. is caused by a novel coronavirus, tetmed SARS-CoV The results of this 2003 study, conducted by Zeng (Chen, Ou, Zhang & Zhang, 2003). All viruses in the et al., also found thtee u n k n o w n O R F s that ate not cotonaviridae family are positive stranded viruses named found in any other coronavirus. This confirms that for their appearance under an electron microscope. S A R S is unlike any othet virus w e have dealt with in The glycoprotein spikes covering the outet membrane the past. of the virus resemble a corona, or halo, w h e n stained Despite the establishment of the unique S A R S and viewed under exttemely high magnification (Fig. C o V genome, questions concetning the evolutionary 1) (Lai et al., 2001). These glycoprotein spikes act as pathway of this virus arestill left unanswered. Attempts
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for the S A R S - C o V . A s described in a 2003 McMastet article entitled "McMaster researchers race to S A R S vaccine development", professor Jim Mahony's work has aided greatly in the development of potential vaccines. M a h o n y cloned an important S A R S - C o V nuclear protein (SARS-N), which was then inserted into an engineered form of an adenovirus (cold virus) by a research team lead by Jack Gauldie. This team, which is composed of McMaster researchers, includes Frank Graham, M a r y Hitt, Ludvik Prevec, U m a Sankar, and Mahony. As mentioned in the article, a second engineered cold virus was constructed to contain the Spike S A R S gene (SARS-S), obtained through collaboration with the S A R S Vaccine Initiative of the British Columbia CentreforDisease Control. W h e n these modified adenovirus vectors were injected as vaccines, a strong antibody response was induced, particularly against the SARS-S protein, and provided immunity to the virus (Fig. 3). This reacrion could prevent the individual from becoming infected with S A R S - C o V , since antibodies to the Spike protein would neutralize the virus. The article also asserts that, should the virus evade the neutralization stage of protection, expression of the nucleoprotein (SARSN ) by the recombinant adenovitus vaccine would stimulate a potent lymphocyte-mediated protection that would help destroy cells infected with S A R S CoV. Animal testing is cuttently being conducted to determine whether the vaccine is safe fot h u m a n trials, but this research demonstrates that the development of a S A R S vaccine is promising. Additional investigations are being conducted in search of medications that could aid those w h o become infected with S A R S . The objective of such antiviral drugs is to disrupt viral functions by rendering important proteins or enzymes useless. However, specific antiviral medication, based upon the 3dimensional structures of the S A R S - C o V proteins cannot yet be produced (Spiga et al., 2003). Since the genome of S A R S is so unique, it is not enough to simply compate the protein products of the S A R S C o V to other members of the coronavitidae family. D E V E L O P M E N T O F S A R S VACCINES A N D ANTIThe homology of the S A R S spike glycoprotein to other VIRAL D R U G S viruses in its family range from 2 0 . 3 9 % to 27.63%. Important research is being conducted at McMaster This low percentage suggests that these proteins have University concerning the development of vaccines very different structures. Current antiviral drugs
are being m a d e to locate the particular species from which S A R S first evolved and spread to infect the citizens of Guangdong. It has been recently reported by Enserink that the S A R S virus can be isolated from masked palm civets (a cat-like animal) found in food markets (2003). However, this does not irrefutably prove that S A R S originated from civets, only that these animals are carriers of the virus. Civets m a y have been infected with the virus by anothet otganism (Enserink & Normile, 2003). With thesefindings,attempts are being m a d e to conclusively determine the species of origin. While the hunt for the vector continues, research is being conducted to determine the viral species that evolved into the S A R S virus. Studies of the S A R S C o V genome by Stavrinides and Guttman compared the S A R S O R F s with those of other viruses to find similarities in their genetic codes (2003). W h a t they found was that the S A R S virus m a y actually be a combination of mammalian and avian viruses. The m e m b r a n e and nucleocapsid proteins produced by the S A R S - C o V are similar to those produced by a coronavirus that infects birds, the avian infectious bronchitis coronavirus; however, analysis of another S A R S protein, the replicative polyprotein (PPlab), ascettains that it is mote similar to members of the coronaviridae family that infect humans. The theory that S A R S evolved from both avian and mammalian viruses is further strengthened w h e n the O R F that codes for the surface glycoprotein spikes (S) is analyzed. The S A R S S protein shares commonalities to the S proteins of both the mammalian and avian viruses mentioned above, suggesting that genetic recombination m a y have occurred between these membets of the coronaviridae family (Stavrinides & Guttman, 2003). While this research provides insight into the ancestry of the SARS-CoV, the specific species responsible for transmitting S A R S into the h u m a n population is still ambiguous. Until there is a greater understanding of this virus, S A R S will continue to be a threatforepidemics.
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Issue 4 | April 2004 -Coronavirus
Host cell
Genomic RNA (+) *^/_ Negative Strand (-) w^//Template mRNAs (+) Cytoplasm Genomic RNA (+) â&#x20AC;˘â&#x20AC;˘
FIGURE 2 The coronavirus replication cycle: (1) Virions bind to the plasma membrane by interaction of the spikes with specific receptor glycoproteins or glycans. Penetration occurs by S protein-mediated fusion or the viral envelope with the plasma membrane or endosomal membranes. (2) The gene 1 of viral genomic R N A is translated and processed to yield an RNA-depcndent R N A polymerase (Pol) and other proteins involved in viral R N A synthesis. The Pol products use the genomic R N A as a template to synthesize negative-stranded R N A s , which are, in turn, used to synthesize genomic R N A and subgenomic m R N A s . (3) With a few exceptions, each m R N A is translated to yield the sttuctural proteins N , M , E, S, and H E and sevetal non-structural proteins. (4) The N protein and newly synthesized genomic R N A assemble in the cytoplasm to form helical nucleocapsids, which bind to the M protein at the budding compartment that lies between the R E R and the Golgi. (5) Similarly, E protein is also transported through the E R to the Golgi, where E and M proteins intetact to trigger the budding of virions, enclosing the nucleocapsid. (6) The S and H E glycoproteins ate also translated on membrane-bound polysomes, inserted in the R E R , and transported to the Golgi complex. (7) Vitions are apparently released by exocytosis-like fusion of smooth-walled, virion-containing vesicles with the plasma membtane. Virions m a y remain adsorbed to the plasma membranes of infected cells (Lai, M . M . C . et al., 2001).
designed to disrupt the spike glycoprotein of one coronavirus would therefore most likely not hinder the cell recognition of a S A R S virus (Spiga et al., 2003). Development of S A R S antiviral medication that targets the S protein can only c o m m e n c e once there is a greater understanding of its structure. Along with the S protein, the main cysteine proteinase (Mpto) of the S A R S vims is seen as a likely target for antiviral drugs (Yan et al., 2003). Recent models developed for the structure of this enzyme, which is importantforthe processing of polypeptides, suggests there is a fold that can also be found in the h u m a n rhinoviral protease (3Cpro) (Anand et al., 2003; Yan et al., 2003). Although the S A R S M p t o
and thinoviral 3Cpto enzymes have very different nucleotide sequences, the c o m m o n fold places their ligand-binding sites in the same position (Yan et al., 2003). This similarity in active site implies that drugs developed to tteat the c o m m o n cold m a y be effective against S A R S (Anand et al., 2003; Yan et al., 2003). However, other research using these models have suggested that dtugs developed to treat H I V m a y be a better starting placefotthe development of S A R S M p r o inhibitots. Based on current models, it was found that HIV-1 protease inhibitors would have a greater affinity for S A R S M p r o active sites compated to h u m a n anti-thinoviral medication (Jenwitheesuk & Samudrala, 2003). Such comparisons allow
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W423
87C
FIGURE 3 Surface and ribbon representations of the tertiary structure of the SI and S2 subunits of S A R S - C o V S glycoprotein that may be used as targets for vaccines. researchers to determine the most logical starting point to develop an anti-SARS medication, but the potential for existing drugs to act on S A R S proteins is not limited to the M p r o enzyme. Othet enzymes that are crucial for the survival of this coronavirus are also being examined as prospective targets for anti-SARS drugs. The S A R S - C o V R N A polymerase, an enzyme that links R N A nucleotides together, displays slight homology to the polymerase of the hepatitis C virus (Campbell & Reece, 2002; Yan et al., 2003). This m a y imply that drugs that inhibit the H C V polymerase m a y also inhibit, to some degree, the S A R S R N A polymerase. Despite such groundbreaking research, there is cutrently no drug available for use against S A R S . Hopefully, research advances in the near future would lead to the development of an
profession, important lessons were learned. T h e W H O pointed out in a M a y 2003 outbteak report that the quick containment of S A R S demonstrated the ability of global alerts to educate the public and scientific community about n e w medical threats. However, initial cases of S A R S m a y have gone unreported, which allowed the virus to quietly infect more individuals and generate a substantial outbreak. As well, this outbreak highlighted the necessity for certain health care changes tofightfuture epidemics. A distutbingly high percentage of S A R S cases were health care workers, and hospitals were forced to impose admittance limitations, or close completely because of the epidemic. Nonetheless, the scientific community was able to respond swiftly and conducted research that could lead to the development of vaccines
anti-SARS medication.
and anti-SARS drugs. Ultimately, this would enable
Although the S A R S outbreak was a stressful, often dangerous, period of time for the health care
our health care system to be bettet prepared if there is a re-emergence of severe acute respiratory syndrome. EH
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The Mind of a Genius A n Exploration of Albert Einstein's Brain
Jayant Ramakrishna Dr. Sandra Witelson leads investigations into the physiological basis for Albert Einstein's genius. MCMASTER UNIVERSITY PROFESSOR OF
Psychiatty and Behavioural Neurosciences, Dr. Sandra Witelson, is the leading researcher o n Einstein's most vaunted possession: his brain. Witelson and colleagues study measurements, photos, and pieces of the brain that have temained undisturbed for forty-four years, stored in a jar. Albert Einstein, one of the wotld's most notable physicists, died in 1955 from a ruptured aneurysm of the abdominal aorta at the age of seventy-six (Witelson et al., 1999). In order to keep Einstein's btain for future research, Dr. T h o m a s S. Harvey, w h o removed Einstein's brain soon after his death, freely suspended it in a ten-percent formalin solution. The fresh weight and dimensional measutements were taken, and ten-percent formalin was injected into the internal carotid arteries to ensure futute preservation. Only in the last decade has access to and study of Einstein's btain been possible. Witelson's findings m a y serve to be the stepping-stone that the scientific community needs in order to reveal the mysteries and secrets of Einstein's brain and genius. BRIEF A N A T O M Y OF T H E BRAIN
Dr. Sandra Witelson is leading research on the unusual brain of Albert Einstein.
brain, which divides the frontal and temporal lobes. The postcentral sulcus is anothet surface landmark in the anterior part of the parietal lobe. Recognizing the markers of a typical h u m a n btain allows for the accutate understanding of h o w Einstein's brain differs from the brain of everyday individuals. INITIAL FINDINGS
U p o n the initial measurements of Einstein's brain, it was found that Einstein's brain weighed 1230 grams, which was within the normal range for a male of his age. T h efirstmajot study was conducted by Marian Diamond, Arnold Scheibel, Greer Murphy, and T h o m a s Harvey, w h o had removed Einstein's brain. These scientists examined tout specific ateas, labelled area 9 and area 39, of the right and left hemispheres of the cetebtal cortex (Fig. 2). Atea 9 is located in the frontal cortex and is critical in planning behaviour, attention, and
The h u m a n brain consists of four lobes or divisions, as seen in Figure 1. Each lobe, and its respective subsections, is responsible for different functions. The frontal lobe is important for reasoning, speaking, comprehension, language, musical perception, and movement. T h e temporal lobe is responsible for hearing while the parietal lobe processes spatial thought and sensory information. The occipital lobe governs visual functions (Kolb et al., 2001). T h e Sylvianfissureis a morphologic feature of the h u m a n memofy, while area 39 is located in the patietal lobe
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Frontal Lobe
Occipital Lobe
Parietal Lobe
Temporal Lobe
FIGURE 1 The four lobes of the human brain. <Source: Digital Slice of Life> and is important for language and spatial functions. The researchers analyzed these four areas for their neuron and glial cell counts, which were compared to the brains of eleven other m e n of an average age of sixty-four. By analyzing the number of neurons (excitable cells specialized fot the transmission of electrical signals over long distances) and glial cells (the supportive tissue of the brain), it was hoped that some histological differences of Einstein's brain could be uncovered (Kolb et al., 2001). It was found that in these four areas, the neuron-to-glia ratio of Einstein's btain was m u c h smaller compared to those of the specimens of the eleven normal brains (Diamond et al., 1985). The greater number of glial cells per neuron m ay be indicative of an increased metabolic requirement of Einstein's brain; his brain needed more energy than that of the average man. Thus a hypothesis was fotmed where the increased energy usage by Einstein's btain enabled him to perform a higher level of thinking, which was characteristic of m a n y of his groundbreaking theories. DISSECTING GENIUS: M C M A S T E R ' S
CONTRIBUTION
The next phase of research was led by McMaster's Dr. Sandra Witelson, w h o improved upon previous experiments in order to delve deeper and further understand the anatomy and physiology of Einstein's brain. Witelson and her team compared thirty-five normal male brains to the experimental brain and discovered major differences. Einstein's brain was found to be 1 5 % wider than the average human , roughly one centimetre wider on both parietal lobes
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Area 9
Area 39
FIGURE 2 Approximate locations of areas 9 and 39. <Source: Digital Slice of Life> (Witelson et al., 1999). His brain also had a unique pattern of sulci (grooves) on both the right and left parietal areas, because the Sylvianfissurehad a strikingly upward deflection into the postcentral sulcus and was noticeably shotter than the normal specimens (Fig. 3). Witelson theorized that this unusual parietal and fissure configuration provided more favourable connections between the neurons in this region. Since the parietal area is also involved in math and spatial reasoning, these improved connections could hypothetically account for Einstein's mastery of spatial reasoning and advanced mathematics. If it is indeed the unique organization of Einstein's brain that attributed him with such a rare intellect, then is there a specific brain configuration fot genius type individuals?
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FIGURE 3 Fissures and hemispheres of a typical control male brains (1,2, 3). Einstein's brain (4, 5, 6) has a unique pattern of sulci that includes an upward deflection of the Sylvian fissure. <Source: S. F. Witelson, Lancet, 1999>
T H E FUTURE. .. Witelson's discoveries of Einstein's brain have revealed m a n y of the mysteties surrounding brain anatomy,
of other genius individuals, such breakthroughs are the catalysts needed to determine features of 'genius-
physiology, and intelligence that have plagued the rype' btains. Until mote individuals ate studied, no scientific community. T h e differences in Einstein's concrete conclusions can be drawn. For now, only brain were critically linked to the w a y in which he inttiguing theoties can be postulated in hopes of thought, providing the possibility that superior intellect is related to specific properties of the brain, In order to fully understand the key to genius, furthet research must be conducted. A s Witelson and her team have provided clues needed for future studies
guiding future studies. If there is in fact a connection between intelligence, physiology, and anatomy of the brain, the discoveties m a d e by the M c M a s t e r team of scientists m a y be m o m e n t o u s in understanding what elements charactetize intelligence. EQ
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Ballantyne, C. (2000). H D L and reverse cholesterol transport. Retrieved February 12, 2004, from http://www.lipidsonline.org Ezekowitz, J.A., Straus, S.E., Majumdar, S.R., & McAlister, F.A. (2003). Stroke: Strategies for Primary Prevention. American Family Physician, 68(12), 2379-2380. Hayden, M.R., Clee, S.M., Brooks-Wilson, A., Genest, J. Jr., Attie, A., Kastelein, J.J. (2000). Cholesterol efflux regulatory protein, Tangier disease and familial high density lipoprotein deficiency. Current Opinion in Lipidology, 11, 117-122. Hoeg, J., Santamarina-Fojo, S„ & Berard, A. (1996). Over-expression of Lecithin: Cholesterol Acyltransferase in Transgenic Rabbits Prevents Diet-Induced Atherosclerosis, 93, 11448-11453. Iso, H , Jacobs, D.R., Wentworth, D „ Neaton, J.D., & Cohen, J.D. (1989). Serum Cholesterol Levels and Six-Year Mortality From Stroke in 350,977 M e n Screened for the Multiple Risk Factor Intervention Trial. N e w England Journal of Medicine, 320, 904-910. Kumar, R., Dahiya, J.S., Singh, D., & Nigam, P. (2001). Biotransformation of Cholesterol Using Lactobacillus Bulgaricus in a GlucoseControlled Bioreactor. Bioresource Technology, 78(2), 209-11. Nissen, S.E., Tsunoda, T., Tuzcu, E., Schoenhagen, P., Cooper, C , Yasin, M., Eaton, G., Lauer, M., Sheldon, W., Grines, C , Halpem, S., Crowe, T , Blankenship, J., & Kerensky, R. (2003). Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes: A Randomized Controlled Trial. J A M A , 290, 2292-2300. Rosuvastain/Crestor®. (2003). Retrieved January 10, 2004, from http:// www.micromedex.com/products/ptquik/samples/Rosuvastatin.htm Seidel, D. (2003). LDL-Aphaeresis in the Treatment of Coronary Heart Disease: Rationale for a Specific Adjuvant Therapy. Zeitschrift fur Kardiologie (German Journal of Cardiology), 92(3), III36-III27. Singaraja, R., Fiever, C , & Castro, G. (2002). Increased A B C A - I Activity Protects Against Atherosclerosis. Journal of Clin Invest, 110, 35-42. Strauss, S.E., Majumdar, S.R., & McAlister, F.A. (2002). N e w Evidence for Stroke Prevention. J A M A , 288, 1388-1395. Toth, P. (2003). Reverse Cholesterol Transport: High-density Lipoprotein's Magnificent Mile. Current Atherosclerosis Reports, 5(5), 386-393. Trigatti, B., Rigotti, A, & Braun, A. (2000). Cellular and Physiological Roles of SR-BI, a Lipoprotein Receptor Which Mediates Selective Lipid Uptake. Biochim Biophys Acta, 1529, 276-286. Maria-Alexandra Petre - Microencapsulated N'on-Autologous Cells: Vaisman, B., Lambert, G., & Amar, M . (2001). A B C A - I Over-expression The Benevolent Trojan Horse Leads to Hyperalphalipoproteinemia and Increased Biliary Campbell, N.A., & Reece, J.B. (2001). Biology (6th ed.). Toronto: Cholesterol Excretion in Transgenic Mice. Journal of Clin Invest, Benjamin Cummings. 180,303-309. Dhoot, N. (2002). Microencapsulation for therapeutic applications. Zha, X., Gauthier, A., & Genest, L. (2003). Secretory Vesicular Transport Retrieved January 3, 2004, from DSapce database. from the Golgi is Altered During ATP-binding Cassette Protein Al Microencapsulation Gene Therapy Group Homepage. (1997, October (ABCA-I) Mediated Cholesterol Efflux. Journal of Bio/Chem, in 23). Retrieved November 17,2003, from http://www.fhs. mcmaster. press. ca/gene/overview.htm Orive, G., Gascon, A.R., Hernandez, R.M., Igartua, M., & Pedraz, Jonathan M. Ng - Ethical Issues Encountered During the SARS L.J. (2003). Cell microencapsulation technology for biomedical Crisis purposes: novel insights and challenges. Trends in Phannacological Singer, P.A., Benatar, S.R., Bernstein, M., Daar, A.S., Dickens, B.M., Sciences, 24, 207-210. MacRae, S.K., Upshur, R.E., Wright, L., & Shaul, R.Z. (2003). Ethics and S A R S : lessons from Toronto. B M J , 327, 1342-4. Abdullah Alabousi, Waqas Kayani, Soroush Seifi, Samer Dabbo L D L , H D L , and the Battle Against Heart Disease Brent Mollon - Preparing for the Next SARS Epidemic: Exploring Aiello, R.J., Brees, D., Francone, O.L. (2003), ABCA1-deficient mice: Treatment Development and Vaccination Options insights into the role of monocyte lipid efflux in H D L formation Anand, K , Ziebuhr, J„ Wadhwani, P., Mesters, J.R., & Hilgenfeld, R. and inflammation. Arteriosclerosis Thrombosis and Vascular (2003). Coronavirus main proteinase (3CLpro) structure: basis for Biology, 23, 972-980. design of anti-SARS drugs [Electronic version]. Science, 300 1763Anderson, C.S., Jamrozik, K.D., Broadhurst, R.J., & Stewart-Wynne, 1767. E.G. (1994). Predicting Survival for One Year A m o n g Different Bosch, B.J., van der Zee, R., de Haan, C.A.M., & Rottier, P.J.M. (2003). Subtypes of Stroke. Stroke, 25, 1935-1944. The coronavirus spike protein is a class I virus fusion protein: Attie, A., Kastelein, J., & Hayden, M . (2001). Pivotal Role o f A B C A I structural and functional characterization of the fusion core complex in Reverse Cholesterol Transport Influencing H D L Levels and [Electronic Version]. Journal of Virology, 77, 8801-8811. Susceptibility to Atherosclerosis. Journal of Lipid Res, 42, 1717Campbell, N.A., & Reece, J.B. (2001). Biology (6th ed.). San Francisco: 1726. Benjamin Cummings. Faizal Haji - Neglected Diseases: The Cost of O u r Health Revolution Feldmann, H., et at. (2002). Emerging and reemerging infectious diseases. Medical microbiology and immunology, 191, 63-74. Global Forum for Health Research. (2002). The 10/90 Report on Health Research 2001-2002. Global Forum for Health Research Publication. Henderson, D.A. (1998) Bioterrorism as a public health threat. Emerging Infectious Diseases, 4, 488-492. MacDonald, R., & Yamey, G. (2001). The cost to global health of drug company profits. Western Journal of Medicine, 174, 302-303. Medecins Sans Frontieres Access to Essential Medicines Campaign, Drugs for Neglected Diseases Working Group. (2001). Fatal Imbalance: The Crisis in Research and Development for Drugs for Neglected Diseases. Publication. Morel, C M . (2003). Neglected diseases: under-funded research and inadequate health interventions. Science and Society, 4(special issue), S35-S38. Sauerborn, R., Nitayarumphong, S., Gerhardus, A. (1999) Strategies to enhance the use of health systems research for health sector reform. Tropical Medicine & International Health, 4, 827-835. Trouiller, P., et al. (2002b). Drug development for neglected diseases: a deficient market and a public-health policy failure. The Lancet, 359,2188-2194. Trouiller, P., Olliaro, P., Torreele, E., Orbinski, J., Laing, R., & Ford, N. (2002a). Drug development for neglected diseases: a deficient market and a public-health policy failure. The Lancet, 359, 21882194. World Health Organization. (2000a). Health: A precious asset. Accelerating follow-up to the World Summit for Social Development, proposal by the World Health Organization, W H O / HSD/HID/00.1. Geneva: World Health Organization Report. World Health Organization. (2000b). The World Health Report 2000 estimates for 1999, Mortality by sex, cause and W H O Regions. Geneva: World Health Organization, 2000. Yamey, G. (2002). The world's most neglected diseases Ignored by the pharmaceutical industry and by public-private partnerships. British Medical Journal, 325, 176-177.
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Chen, L.L., Ou, H.Y., Zhang, R„ & Zhang, C.T (2003). Z C U R V E _ C o V : World Health Organization. (2003). Severe acute respiratory syndrome a new system to recognize protein coding genes in coronavirus (SARS): status of the outbreak and lessons for the immediate genomes, and its applications in analyzing SARS-CoV genomes future [Electronic Version]. Retrieved December 29, 2003 from [Electronic Version]. Biochemical and Biophysical Research http://www.who.int csr media sars_wha.pdf Communications, 307, 382-388. World Health Organization. (2003). Summary of probable S A R S cases Emanuel, E.J. (2003). The lessons of SARS. Annals of Internal Medicine. with onset of illness from 1 November 2002 to 31 July 2003 139,589-591. [Electronic Version]. Retrieved December 1, 2003 from http: Enserink, M . (2003). Clues to the animal origins of S A R S [Electronic www.who.int/csr/sars/country/table2003_09_23/en' Version]. Science, 300, 1251. Yan, L., Velikanov, M., Flook, P., Zheng, W., Szalma, S„ & Kahn, S. Enserink, M., & Nonnile, D. (2003). Search for S A R S origins stalls (2003). Assessment of putative protein targets derived from the [Electronic Version]. Science, 302, 766-767. S A R S genome [Electronic Version]. FEBS Letters, 554. 257-263. Groneberg, D.A., Zhang, L., Welte, T, Zabel, P., & Chung, K.F. (2003). Zeng, F.Y, Chan, C.W.M, Chan, M.N., Chen, J.D., Chow, K.Y.C., Hon, Severe acute respiratory syndrome: global initiatives for disease C.C., et al. (2003). The complete genome sequence of severe acute diagnosis [Electronic Version]. Q J Med, 96, 845-852. respiratory syndrome coronavirus strain HKU-39849 (HK-39) Hawkey, P.M., Bhagani, S., & Gillespie, S.H. (2003). Severe acute [Electronic Version]. Experimental Biology and Medicine, 228. respiratory syndrome (SARS): breathtaking progress. Journal of 866-873. Medical Microbiology, 52, 609-613. Jenwitheesuk, E. & Samudrala, R. (2003). Identifying inhibitors of the Jayant Ramakrishna - The Mind of a Genius: An Exploration of S A R S coronavirus proteinase [Electronic Version]. Bioorganic & Albert Einstein's Brain Medicinal Chemistry Letters, 13, 3989-3992. Anderson, B. & Harvey T. (1996). Alteration in Cortical Thickness Lai, M.M.C. et al. (2001). Fields Virology (4th ed.). Pennsylvania: and Neuronal Density in the Frontal Cortex of Albert Einstein. Lippincott, Williams & Wilkins. Neurosci Lett., 210, 161-164. McMaster University Health Sciences (2003). McMaster researchers Diamond, M.C., Scheibel, A.B.. Murphy, G.M., & Harvey,T. (1985). On race to S A R S vaccine development [Electronic Version]. Retrieved the Brain of a Scientist: Albert Einstein. Experimental Neurology, November 15, 2003 from http://www.fhs.mcmaster.ca/pubrel/sars. 88, 198-204. htm Hines, T. (1998). Further on Einstein's Brain. Experimental Neurology, 150,343-344. Spiga, O , Bemini, A., Ciutti, A., Chiellini, S., Menciassi, N., Finetti, F., et al. (2003). Molecular modelling of SI and S2 subunits of S A R S Kolb, Byan, & Whishaw, I.Q. (2001). An Introduction to Brain and coronavirus spike glycoprotein [Electronic Version]. Biochemical Behavior. N e w York: Worth Publishers. and Biophysical Research Communications, 310, 78-83. Stensaas, S. & Millhouse, O.E. (n.d.). Digital Slice of Life. Retrieved Stavrinides, J. & Guttman, D.S. (2004). Mosaic evolution of the severe January 25, 2004, from http://medlib.med.utah.edu/kw/sol/sss/ acute respiratory syndrome coronavirus [Electronic Version]. Journal Witelson, S.F., Kigar, D.L..& Harvey, T. (1999). The Exceptional Brain of Albert Einstein. The Lancet, 353, 2149-2153. of Virology, 78, 76-82.
The McMaster Meducator Executive 2003-2004
Back Row (Left to Right): Christine Almeida, Jaron Chong, Grace Y. Wang, Sammy. H. Ali, Thien Huynh, Jennifer C. Tang, Nisha Sivagurunathan, Jeannette So, Soroush Seifi Front Row: Jonathan M. Ng, Albert Einstein, Abhishek Raut
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