Issue 23 by The Meducator

APRIL 2013 | ISSUE 23

DECODING AUTISM MODELS FOR MOTOR TASK CONTROL TREATING POSTSTROKE APHASIA SOLUTIONS FOR THE SPEECHLESS INTERVIEW WITH DR. SHEILA SINGH THE COMPLEXITY OF BRAIN TUMOURS

W W W. m e d u c ato r . o r g

table of

contents

APRIL 2013 ISSUE 23 INTRO 02 MEDBULLETIN 03 FORUMSPACE 05 APHASIA TREATMENT 07 AUTISM: MOTOR CONTROL 11 OPINION: VACCINATIONS 15 INTERVIEW SPOTLIGHT 17 CONTRIBUTERS 22

ADDRESS The Meducator BHSc (Honours) Program Michael G. DeGroote Centre for Learning and Discovery Room 3308 Faculty of Health Sciences 1280 Main Street West Hamilton, Ontario L8N 3Z5

05 FORUMSPACE: Mandatory Flu Vaccines for Health Care Providers A step too far? Asha Behdinan and Crystal Chan explore the role of ethics and evidence in the enactment of a recent policy in B.C. that requires all front-line health care providers to be immunized against the flu.

07 TREATING POST-STROKE APHASIA: SOLUTIONS FOR THE SPEECHLESS Alexandra Annibale delves into the world of poststroke aphasia, a condition gaining increasing significance with Canada’s aging population. Research is suggesting that alternative therapies and pharmacological solutions may yield greater benefit than the current rehabilitative solutions being employed.

11 INTERNAL MODELS OF MOTOR CONTROL: REACH ADAPTATION AND TASK AUTISM The internal models theory proposes that the central nervous system forms neural representations of the external world, which are used to predict and adjust motor movements. Laura Zuccaro takes a look at how the “reaching task” can be viewed through this theory to examine how autistic patients differ in their motor abilities.

15 OPINION: ON VACCINES AND IRRATIONALITY

EMAIL the.meducator @learnlink.mcmaster.ca WEBSITE www.meducator.org TWITTER @TheMeducator FACEBOOK www.facebook.com /themeducator COVER ARTWORK Mark Belan

Mohsin Ali & Branavan Manoranjan investigate the role of media perception in publicizing scientific discoveries to the public. A particular focus is placed upon the MMR-autism scandal that drew headlines across the past decade.

17 INTERVIEW SPOTLIGHT: DR. SHEILA SINGH Dr. Sheila Singh, Associate Professor (Neurosurgery) and Principal Investigator at the Stem Cell and Cancer Research Institute at McMaster University, discusses her groundbreaking research on brain tumour-initiating cells and her hopes for future generations of scientists.

We are thrilled to present to you our first neuroscience-themed issue! The complex field of neuroscience is one that contemporary science is only beginning to unfold; nevertheless, the implications that neuroscience holds at both the individual and societal levels are enormous. In this issue, we highlight undergraduate research pieces that shed light on elements of this rapidly advancing discipline. In the first Critical Review, Alexandra Annibale delves into the topic of post-stroke aphasia, a neurological disorder that affects an individual’s ability to communicate and/or properly understand speech. In particular, Annibale discusses the importance of considering alternative therapies in light of the increasing number of individuals who will be affected by aphasia as a result of the aging demographic. The second Critical Review, by Laura Zuccaro, provides an in-depth exploration of how the central nervous system forms neural representations of the external world to predict and adjust motor movements. Zuccaro analyzes the “reaching task” in the context of this theory, and examines how autistic and non-autistic patients differ in their motor abilities.

The Meducator also had the opportunity to speak with Dr. Sheila Singh, a clinicianscientist working in the field of neuroscience. In her interview, Dr. Singh discusses her groundbreaking research on brain tumour-initiating cells, as well as her hopes for future generations of clinician-scientists. Finally, our ForumSpace and Opinion columns touch on some of the controversies surrounding vaccines and vaccination. Specifically, in our collaborative ForumSpace column, Asha Behdinan and Crystal Chan take a critical look at the role of ethics and evidence in a proposed policy mandating influenza vaccination for all front-line healthcare providers in B.C. Meanwhile, in our Opinion column, Mohsin Ali and Branavan Manoranjan investigate the role of media and emotional perception in the dissemination of scientific discoveries to the public. A particular focus is placed upon the autism-MMR vaccine scandal that drew headlines throughout the past decade.

introduction

INTRODUCTION ISSUE 23

dear reader,

We would like to take this opportunity to sincerely thank our entire team for their tremendous efforts and dedication to The Meducator. We are deeply honoured to have served as Editors-in-Chief this year and to have been able to work with such extraordinarily talented individuals. In particular, we want to recognize our graduating and departing staff – their continued dedication to The Meducator over the course of their undergraduate careers has helped to make the journal what it is today. We wish them all the best in their future endeavours. Yours sincerely,

A ndrew W ebster

M E D U CATO R | A P R I L 2 0 1 3

LEBEI PI

MEDBULLETIN EPIGENETICS

M E D U CATO R | A P R I L 2 0 1 3

medbulletin

INSIGHT INTO EPIGENETICS

NEURONS

A “COOL” ADVANCE IN NEUROSCIENCE

antibiotics

HUMAN FECES: NO WASTE FOR MEDICINE

HUMNA A M J A D

J O HNN Y WEI B AI

MO H SIN ALI

In 2 010 , D r. Is a b e l l e M a n s u y a n d co lleagu es at t h e U n i ve rs i ty of Z u r i c h provi de d ev i de n ce that s tress re lated i m pact ca n b e ass o c i ate d w i t h epi gen et i c c h a n g es , s u c h as the regu lat i o n of g e n e ex p ress i o n i n mice. 1, 2

The sk in is the l arg est org an i n the human b od y an d d etects e nv iron mental stimul i suc h as te mp erature an d p ain throug h s e n sory n euron s. 1 Whil e most of these n euron s are p ol ymod al (i.e., o n e n euron can d etect mul tip l e s e n sation s), sc ientists have re centl y d iscovered n euron s that s o l el y sen se col d temp erature. 2

Clostridium difficile (C. difficile) is an antib iotic -res is tant bacte rium that causes d iar rh oe al dis e as e, and is a common caus e of nos ocomial infection s. Whil e failure rates for trad ition al antib i ot ic ch e mot h e rapy r ise, recent resea rch points toward an other ap p roac h to t re at C. difficile – assoc iated d iar rh oe al illness : an ecol og ic ap p roach wh e re by ot h e r b acter ia comp ete wit h C. difficile for the n ic he of t h e gut . Such a turf war to ev ict C. difficile can b e in d uced through probiot ics (to introd uce ‘ g ood ’ bacte ria), 1 or as emp hasized in a re ce nt New England Journal of Medicine clinical t rial, fecal tran sp l antat ion from a h e alt h y host. 2

In co nt ras t to d i re ct a l te rati o n of D NA bas e p a i rs , e p i g e n eti cs invo lve ce llu lar m e c ha n i s m s that mo di fy ch ro m at i n to m o d u l ate g e n e express i o n w i t ho u t affe cti n g th e DN A s e qu e n ce i ts e l f. Thes e p r i m a r i l y in clu de D NA m ethy l ati o n , hi s to n e po s tt ran s lat i o n a l m o d i f i cati o n s , an d s m all n o n co d i n g R N As . 1 W h e n thes e ch an ges o cc u r i n g e r m ce l l s , they can be pass e d o n to th e n ext ge n erat i o n . It was fo u n d th at e a r l y life s t ress i n duce d d e p ress i ve - l i ke be h av i o u rs an d c ha n g es i n the be h av i o u ral res p o n s es i n m i ce. 2 Th es e be h av i o u ra l c h a n g es we re als o o bs e rved i n the offs p r i n g of m ales t h at we re s u b j e cte d to ea rly- li fe s t ress i n th e fo r m of matern al s e parati o n . M o re ove r, D N A met h y lat i o n was o bs e rve d n ot o n l y in t h e s perm of the fathe rs , b u t a l s o in t h e brai n an d g e r m l i n e of th e offs pri n g as wel l . H e n ce, e p i g e n eti c pro cess es i n g e r m ce l l s m ay co nt ri bu te to di s e as e he r i ta b i l i ty. 2 In t h e re cent i ss u e of Biological Psychiatry , D r. Mansuy and co lleagu es co n d u cte d a rev i ew of tran s - ge n erat i o n a l tra n s m i ss i o n i n the regu lat i o n of g e n e ex p ress i o n an d s tate d t h at “ [ a l ] th o u g h i t has be en co n s i s tentl y o bs e rve d as e a r l y as i n t h e 18 t h ce ntu ry, the ti m e has n ow co m e th at s u ff i c i e ntl y stro n g an d co nv i n c i n g ev i d e n ce has accu m u late d to f i r m l y a cce pt i t.” W i t h m an y di s e as es s u c h as ca n ce r, di abetes an d n e u ro l o g i ca l d i s o rd e rs hav i n g s t ro n g h e r i ta b l e co m p o n e nts , ep i ge n et i cs h as g a r n e re d i n c re as i n g attent i o n an d i nte res t wi thi n th e sc i e nt i fi c co m m u n i ty at l a rg e.

D r. Mc Kemy an d col l eag ues f rom the Un iversity of Souther n Cal ifor n ia d iscovered the g en e for TRPM8 , show in g that it is c hiefl y res p on sib l e for sen sation of col d te mp erature as wel l as menthol , the “c hil l in g ” in g red ient in mints. 2 I n a more recent stud y, they i nvestig ated how sp ec ific n euron s co ul d ‘ tur n off’ col d sen sation in m ice by sel ectivel y ab l atin g these n euron s usin g c hemical in jection s. 3 Th e mice were p l aced on a mul tite mp erature surface ran g in g f rom 0 -50 °C. Mice w ith intact TRPM8 -exp ressin g n euron s avoid ed extreme surface temp eratures, b ut the ab l ated mice sp ent more time o n the col d er sid e, show in g that o n l y their col d sen se was affected . A l t houg h the mice coul d n o l on g er d etect temp erature- an d col d re lated p ain , they were stil l ab l e to sen se heat, touc h, mec han ical p ain , an d d isp l ay n or mal g r ip s tren g th. This fin d in g imp l ies that i t may b e p ossib l e to shut off a s i n g l e sen sation w ithin the n ervous system. 3 D r. Mc Kemy’ s researc h may l ead to more p ain -p revention therap ies. C ur rent p ain d r ug s an d an aesthetics a re usual l y n ot sp ec ific to p ain s e n sation , l eav in g the p atient u nd esirab l y n umb to other sen ses as wel l . Throug h his researc h, Dr. M cKemy wants to “p ave the way fo r med ication s that ad d ress the p ain d irectl y in a way that d oes n ot l e ave p atients comp l etel y n umb ”. 2

The tr ial ran d om ize d pat ie nts wit h rec ur rent C. difficile infe ct ions to on e of three tre at me nt groups : stan d ard antib iot ic t h e rapy (a two-week course of vancomycin); stan d ard antib iot ic t h e rapy wit h b owel l avag e; or an init ial four-day van comyc in reg ime n, followe d by b owel l avag e an d infus ion of donor feces. The success of pat ie nts in t h e infusion g roup prompte d an e arly c l osure to the tr i al: 13 of 16 (81%) p atients had resolut ion of t h e ir C. difficile – assoc iate d diarrh oe a afte r the first infusion. Of t h e t h re e remain in g p atients , t h e diarrh oe a resol ved for two pat ie nts following an other infusion wit h fe ces from a d ifferent d on or. I n cont ras t , of t h e 13 p atients in eac h ant ibiot ic t h e rapy g roup — w ith or w it h out bowe l lavage — on l y three (2 3%) and four (31%) p atients, resp ect ive ly, ach ieve d resol ution of their diarrh oe a afte r the first infusion . Don or fecal tran splantat ion t h e refore p rov id es an effi cacious t re at me nt for rec ur rent C. difficile infe ct ion. Desig n in g therapies bas e d on an ecol og ic un d erstanding of our gut may resol ve d iseas es t h at ant ibiot ics are in cap ab l e of res olving.

1. Bohacek J, Gapp K, Saab B, Mansuy I. Transgenerational Epigenetic Effects on Brain Functions. Biological Psychiatry. 2013 Feb;73(4):313-20. Doi: 10.1016/j. biopsych.2012.08.019. 2. Franklin T, Russig H, Weiss I, Graff J, Linder N, Michalon A, et al. Epigenetic Transmission of the Impact of Early Stress Across Generations. Biological Psychiatry. 2010 Sept;68(5):408-15. Doi: 10.1016/j.biopsych.2010.05.036.

DNA TRANSFER RNA-GUIDED GENOME EDITING

TUMOURS

CANCER PREVENTION: VACCINES?

Genome e n gi n e eri n g i s the ta rg ete d modificat i o n of s pe ci f i c s e q u e n ces containe d w i t h i n ge n eti c i nfo r m ati o n . Current e u karyot i c ge n e e d i ti n g h as largely be en acco mp l i s he d u s i n g DN A nucleas es , e n zym es that ta rg et and c leave a s pe ci fi c D N A s e q u e n ce. Howeve r, i n creas i n g the DNA nuc lease’ s bi n di n g s i te s p e c i f i c i ty to fit a target s e que n ce i s ofte n laborious an d t i m e - co n s u m i n g . 1

The p u r p ose of can cer vacc in es is to g e n e rate a l on g -ter m anti-tumour res p o n s e in p atients w ho are either at r i s k for can cer or d iag n osed wi th ca n cer, in ord er to p revent i ts re c ur ren ce or sp read . 1 These va cc i n es invol ve ad min istration of p rote i n s assoc iated w ith tumours ( ca l l e d tumour -assoc iated antig en s, or TAAs), w hic h subseq uentl y p ro m pt h ost recog n ition an d immun e res p o n s e to the antig en . Sp ec ifical l y, the i m m un e system p rod uces p rotein s ca l l e d antib od ies that are sp ec ific to th at TAA. Antib od ies contr ib ute to i m m un e d efen se by n eutral iz in g p ath o g e n s an d p reventin g them from e nte r i n g cel l s, stimul atin g immun e ce l l s to d estroy antig en -p resentin g ce l l s , a nd activatin g the comp l ement p ath way to in d uce cel l l ysis. 2 H oweve r, comp l ication s may ar ise f ro m this p roced ure. For in stan ce, tu m o u r cel l s are hig hl y comp l ex, b oth g en etical l y an d in their f u n cti o n . When sel ectin g a TAA to ta rg et, it is imp ortant to sel ect on e that i s con served ac ross al l tumour ce l l s ( i .e., the cel l can n ot simp l y g et r i d of i t as a mec han ism of immun e evas i o n ). 1 B ecause tumour cel l s can eva d e an d sup p ress the immun e sys te m , comp l ementary or ad juvant sys te m s may b e n ecessary to co u nte ra ct the immun osup p ressive n atu re of tumour cel l s. 1 Desp ite al l of thes e bar r iers, sc ientists are c l ose to c re at in g a vacc in e ag ain st b reast a n d p rostate can cer that targ ets s p e c i f i c TAAs assoc iated w ith b oth ty p es of tumour cel l s. 1,3 A n othe r typ e of anti-can cer vacc in e i nvo l ves targ etin g the infectious a g e nts resp on sib l e for p artic ul ar ca n ce rs . 4 For in stan ce, Gard asil ta rg ets the human p ap il l omav ir us ( H PV ) , k n ow n to cause 70 % of cas es of cerv ical can cer. 5 I t is c l e a r th at can cer vacc in ation is a ve ry p romisin g ap p roac h to can cer p reve ntion an d treatment.

2. Glynn S. Medical News Today [Internet]. MediLexicon, Intl.; 14 Feb. 2013. Available from: http://www.medicalnewstoday. com/articles/256360.php 3. Knowlton W, Palkar R, Lippoldt E, McCoy D, Baluch F, Chen J, et al. A Sensory-Labeled Line for Cold: TRPM8Expressing Sensory Neurons Define the Cellular Basis for Cold, Cold Pain, and Cooling-Mediated Analgesia. Journal of Neuroscience. 2013 Feb 13;33(7):2837– 48. Title Unknown (WallSHQ) [image on the Internet]. 2005 [cited 2013 March 14]. Available from: http://www.wallshq.com/ uncategorized/neuron-cell-wide

1. Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO, Loeb M, Guyatt GH. Probiotics for the Prevention of Clostridium difficile–Associated Diarrhea: A Systematic Review and Meta-analysis. Ann Intern Med 2012;157(12):878–888. 2. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JFWM, Tijssen JGP, Speelman P, Dijkgraaf MGW, Keller JJ. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. NEJM 2013;368(5):407–15. Definicion de Bacteria (Concepto de, Definicion de) [image on the Internet]. 2010 [cited 2013 March 14]. Available from: http://conceptodefinicion.de/ bacteria/

1. Oost Jvd. New Tool for Genome Surgery. Science. 2013;339(6121):768-70. 2. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013. 3. Gasiunas G, Barrangou R, Horvath P, Siksnys V. Cas-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proceedings of the National Academy of Sciences. 2012;109(39):2579-86.

1. Wiedermann U, Davis AB, Zielinski CC. Vaccination for the prevention and treatment of breast cancer with special focus on Her-2/neu peptide vaccines. Breast Cancer Research and Treatment [Internet]. 2013 Jan 23 [cited 2013 Feb 17]; Available from: http://www.springerlink. com/index/10.1007/s10549-013-2410-8 2. Vergati M, Intrivici C, Huen N-Y, Schlom J, Tsang KY. Strategies for Cancer Vaccine Development. Journal of Biomedicine and Biotechnology. 2010;2010:1–14. 3. Flemming A. Cancer: Vaccine cure for prostate cancer? Nature Reviews Drug Discovery. 2011 Aug 1;10(8):575–575. 4. Umar A, Dunn BK, Greenwald P. Future directions in cancer prevention. Nature Reviews Cancer. 2012 Nov 15;12(12):835–48. 5 Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clinical Science. 2006 May 1;110(5):525. Vaccine (Financial Sense Editorials Archives) [image on the Internet]. 2004 [cited 2004 March 10]. Available from: http://www.financialsensearchive.com/ editorials/engdahl/2010/0304.html

M E D U CATO R | A P R I L 2 0 1 3

The Clu s tere d Re gu lar l y I nte rs p a ce d Short Pa li n dro m i c Re p e ats ( CRI S P R ) system, w h i ch targets a n d i n i ti ates the degradat i o n of fo re i g n n u c l e i c ac ids in bacteri al i m m u n e sys te m s , h as rece nt ly been i nves ti g ate d by researc he rs at H arva rd U n i ve rs i ty and Bos to n U n i vers i ty as a p ote nti a l n ew tool fo r ge n o m e e n g i n e e r i n g . 2 This sys tem co n s i s ts of CRI S P R RN A (crR NA ) , Cas 9 n u c l e as e, a n d trans-act i n g crR NA . Th e c r R N A guides t h e co m plex to the ta rg et (its com ple m entary D N A s e q u e n ce ) , w hile Cas 9 perfo rm s th e d o u b l e strande d cle avi n g w he n ass i s te d by the t ran s - act i n g c r R N A . 3 Th e researc h ers en gi n e ere d a CRI SP R system s i m i lar to t h at fo u n d i n bacteria , an d de m o n s trate d that the system i s able to s u ccessf u l l y perform gen o m e e di t i n g i n h u m a n embryon i c ki dn ey cell s . Th e CRI SP R system pro du ce d m e as u ra b l e res u l ts in half t h e t i m e w h en co m p a re d to TALEN s ( art i fi ci al en z y m es c u r re ntl y u sed for targete d D NA c l e av i n g ) . 2 A notable advantage of the CAS system ( s u ch as Cas 9 n u c l e as e ) over ot h e r ge n o m i c m a n i p u l ati o n tec hniqu es i s i ts ve rs ati l i ty. To target a n ew D NA s e q u e n ce, o n l y the c rR NA m u s t be c ha n g e d to b e complem entary to t hi s s e q u e n ce ; the Cas 9 protei n i ts e l f i s u n i ve rs a l . W ith furt h e r refi n e m e nt, thi s R N A guided g e n o m e m an i p u l ati o n sys te m has the pote nt i al to g re atl y i m p a ct the fut u re t re at m ent of g e n eti c disorders .

1. Schepers R, Ringkamp M. Thermoreceptors and thermosensitive afferents. Neuroscience and Biobehavioral Reviews. 2010;34:177–84.

medbulletin

G RACE ZHA NG

KIMIA SO R O UR I

Epigenetics Picture (Matt Forsythe) [image on the Internet]. 2005 [updated 2011 April 20; cited 2013 March 14]. Available from: http://comingupforair. net/2011/04/epigenetics/

FORUMSPACE

Mandatory Flu Vaccines for Asha Behdinan and Crystal Chan

forumspace

Asha Behdinan is a second year Arts & Science student and Crystal Chan is a first year Life Sciences student. Both share an interest in health-related issues and are members of the McMaster Health Forum Student Subcommittee.

Introduction

A recent debate on a new policy regarding the influenza (or flu) vaccination has garnered the attention of health care providers (HCPs), policymakers and the public alike.1 The policy, introduced in August 2012, mandated that all front-line HCPs in B.C. be vaccinated against the flu, and those who refuse must wear a mask in the vicinity of patients. An outcry from the health care community caused the full implementation of the policy to be postponed.2 However, this issue raises several key questions regarding the role of ethics and evidence in public health policy.

M E D U CATO R | A P R I L 2 0 1 3

Issues for Policymakers

conditions with mandatory vaccination policies (such as measles, mumps and rubella), the flu is often regarded as less of a threat. Hesitation to receive the vaccine has also been fuelled by evidence regarding its effectiveness. According to the Centers for Disease Control and Prevention (CDC), an effectiveness of 52% was reported for the vaccine in 2011–2012,5 which decreased to 27% (in older adults, age 65 and above) in 2012-2013.6 The risk of older adults contracting H3N2 (one of the three main circulating flu viruses) has also fallen nine percent from the previous year, which further reduces the perceived need to get vaccinated.6 Furthermore, the recent suspension of Novartis vaccines, Agriflu and Fluad,7 has led to increased uncertainty and concern regarding the availability, benefits and harms of influenza vaccines. Nonetheless, the CDC claims that vaccination is currently the best method to prevent the seasonal flu, and suggests that individuals who are more susceptible, such as HCPs, children and the elderly, would benefit from vaccination.5 However, if mandated, should the vaccination policy—which currently only applies to healthcare settings—be extended to day-care centres, nursing homes and other venues alike?

In light of recent policies mandating influenza vaccination, it is essential to consider both the evidence available to inform the policy and the public’s response Duty to Care to such legislation. Current research evidence indicates The role of HCPs must also be evaluated in order to a lower-than-desired success rate for the vaccination,3 understand issues of adherence. Despite expectations despite HCPs promoting the vaccine as the only effective for HCPs to receive their flu shot owing to their risk of preventative measure against influenza, productivity loss flu exposure in the health care setting, only 60% of U.S. and death.4 If policies mandating influenza vaccination doctors and nurses were vaccinated in the 2010-2011 for HCPs are passed, this coercive mechanism may flu season, and the figures are less than 50% for other successfully increase vaccination rates. However, HCPs.7 The lack of adherence from HCPs may lead to policymakers should consider how the use of coercion difficulty in gaining support from the public for this would impact the public’s perception towards public policy. However, in accordance with the vows made by health officials in the future. HCPs, their duty to care includes the promise to do no harm.8 By allowing HCPs to refuse the influenza vaccine, Evidence HCPs may unknowingly harm patients by transmitting Strong opposition to the new policy mandating the flu to them. The question then is whether adding the vaccination suggests the need for a review of the evidence annual influenza vaccine to the list of mandatory vaccines about the flu and flu vaccines. In comparison to other is the best way to approach this issue.

Health Care Providers:

A STEP TOO FAR?

Ethics

Conclusion

It is important to consider the evidence base and the ethical perspectives regarding mandatory vaccination policies. Currently, the lack of evidence supporting the efficacy of flu vaccinations seems to constrain adherence rates among HCPs and the public. However, mandating that HCPs receive the influenza vaccination in order to benefit the larger patient population may in turn disregard their individual autonomy and rights. Thus, a suitable middle ground between the opposing ethical and efficacy arguments must be met.

B.C. backs off on flu-shot policy for nurses. CBC News [Internet]. 2012 November 30 [cited 2013 Feb 10]. Available from: www.cbc.ca/ news/canada/british-columbia/story/2012/11/30/bc-flu-shots-nurses. html 2. Theodore T. BC flu shot requirement for health workers suspended. Huffington Post Canada [Internet]. 2012 December 04 [cited 2013 Feb 10]. Available from Huffpost British Columbia: www. huffingtonpost.ca/2012/12/04/ bc-mandatory-flu-shot-requirementsuspended_n_2238054.html 3. Wilde JA, McMillan JA, Serwint J, Butta J, O’Riordan MA, Steinhoff MC. Effectiveness of influenza vaccine in health care professionals: a randomized trial. JAMA 1999;281(10):908– 913. 4. Centers for Disease Control and Prevention. Influenza Vaccination Coverage among Health-Care Personnel – United States, 2010–2011 Influenza Season. Morbidity and Mortality Weekly Report (MMWR) 2011:60(32):1073–1077 5. Centers for Disease Control and Prevention. 2011–2012 Influenza Season [Internet]. 2012 Dec 28 [cited 2013 Feb 10]. Available from: www.cdc. gov/flu/pastseasons/1112season. htm 6. Branswell H. This year’s flu shot offered little protection to 65s and older, new data reveal. The Vancouver Sun [Internet]. 2012 Dec 04 [cited 2013 Feb 10]. Available from: www2.macleans.ca/2013/02/21/ this-years-flu-shot-offered-littleprotection-to-65s-and-older-newdata-reveal/ 7. Novartis Suspends Distribution of Seasonal Flu Vaccines Agriflu and Fluad in Canada as a Precaution. Health Canada [Internet]. 2012 Oct 26 [cited 2013 Feb 10]. Available from: www.hc-sc. gc.ca/ahc-asc/media/advisoriesavis/_2012/2012_162-eng.php 8. U.S. Department of Health & Human Services. National Action Plan to Prevent Healthcare-Associated Infections: Roadmap to Elimination [Internet]. No date [cited 2013 Feb 10]. Available from: www.hhs.gov/ ash/initiatives/hai/hcpflu.html 9. Centers for Disease Control and Prevention. Prevention Strategies for Seasonal Influenza in Healthcare Settings [Internet]. 2013 Jan 9 [cited 2013 Feb 10]. Available from: http://www.cdc.gov/flu/professionals/infectioncontrol/healthcaresettings.htm 10. Tilburt JC, Mueller PS, Ottenberg AL, Polan GA, Koenig BA. Facing the challenges of influenza in healthcare settings: the ethical rationale for mandatory seasonal influenza vaccination and its implications for future pandemics. Vaccine 2008;26(4):D27–D30. 11. Selgelid MJ. Pandethics. Public Health 2009;123(3):255–259. 12. Theodore T. B.C. government suspends mandatory flu shots for health workers for one year. The Vancouver Sun [Internet]. 2012 December 04 [cited 2013 Feb 10]. Available from: www.vancouversun. com/health/government+suspends +mandatory+shots+health+workers +year/7650399/story.html 13. Backer H. Counterpoint: in favour of mandatory influenza vaccine for all health care workers. Clin Infect Dis 2006;42(8):1144–1147.

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The duty of beneficence and non-maleficence is a defining aspect of HCPs’ roles. Therefore, patients can reasonably expect HCPs to take appropriate precautions to ensure patient safety.9 One such measure would be to reduce the risk of flu transmission through mandatory worker vaccination. However, the B.C. Nurses Union has actively opposed this policy. Deb McPherson, union president, stated: “Given the clearly conflicting evidence about the effectiveness of the [flu] shot, we were very much opposed to policies aimed at forcing workers to get it.” The Health Sciences Association, another union against this movement, also feels the policy is “coercive” and a “violation of people’s privacy.”11 Based on these claims, and the inconclusive evidence on the effectiveness of the vaccine, it can be argued that violation of HCP autonomy is not morally justified from

Nonetheless, others argue that this policy is morally permissible. Hospitals and public health officials strongly advocate for HCPs to receive the flu shot as part of a safety and prevention plan for patients.12 There have been objections concerning whether resources put towards this initiative could be more efficiently allocated. However, such objections based on resource allocation and the opportunity cost of producing and distributing the vaccinations do not provide sufficient basis to reject mandatory flu vaccines. Backer,13 for instance, claims that the flu vaccine is the most cost-effective of all preventative vaccinations administered to adults. The production costs incurred by this policy, then, are minimal, especially when compared to other mandatory vaccination policies currently in place. Therefore, based on evidence on the efficacy of similar policies (such as the MMR vaccine), many individuals support the policy of mandatory HCP influenza vaccination.

forumspace

A key ethical issue pertaining to this policy is autonomy. While HCPs have the prima facie duties of beneficence, nonmaleficence, justice and fidelity to patients,9 their autonomy must also be safeguarded in new policies and legislation. Yet to what extent does their autonomy outweigh their duty to care and their duty of beneficence towards patients and coworkers? During pandemics, it may be ethical to infringe on citizens’ autonomy when sufficient evidence is provided in support of the policy – such as restriction of freedom of movement during mandated patient isolation and quarantine.10 However, in order for a mandatory vaccination policy to be implemented, it must be supported by appropriate evidence to justify violation of HCP autonomy.

the beneficence/non-maleficence standpoint.

ARTIST ANNIE ZHU

CRITICAL REVIEW

Solutions for the Speechless

N e w D i r e ct i o n s i n Po s t- S t ro k e A p h a s i a T r e at m e n t

Alexandra Annibale Bachelor of Health Sciences (Honours) Program, Class of 2015 Correspondence should be addressed to: alexandra.annibale@learnlink.mcmaster.ca ABSTRACT An increasing number of Canadians will be affected by aphasia and other post-stroke communication disorders as the nation’s population continues to age. Recent studies have expressed concern in the face of this reality; the rehabilitative services being provided to post-stroke aphasia patients are often based on correlative evidence, and important quantitative benefits evoked from this form of therapy remain unclear. A new body of research is emerging, and is giving greater consideration to alternative forms of treatment for post-stroke aphasia—including novel therapy techniques and pharmacological interventions. Perhaps the findings of these studies will have an impact on the way Canada administers care to those suffering from this disorder.

suggests, this disorder typically involves damage to Wernicke’s area, located in the posterior region of the superior temporal gyrus.5

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Broca’s and Wernicke’s aphasia are the two most common forms of the disorder, but there are many more— some of which are easier to treat than others. At present, the standard practice for post-stroke aphasia rehabilitation is one-on-one speech-language therapy (SLT) administered by a Aphasia, alternatively referred to as dysphasia, is qualified speech-language pathologist.6 SAMPLE SENTENCE an acquired neurological disorder affecting an Patients typically undergo a battery “Yesterday was very sunny and individual’s linguistic performance and overall of neurological tests to assess their the sky was blue.” communication abilities.1 It is highly prevalent baseline skills in verbal reasoning, their among individuals who have suffered an ischemic capability to utter speech sounds (i.e., BROCA’S APHASIA stroke affecting various language centres in the “phonetic range”), and their perception of “Yesterday...sunny...blue” brain. When blockage to the middle cerebral artery sentence structure and interpretation— WERNICKE’S occurs in the brain’s left hemisphere, the extent and referred to by linguists as syntactic APHASIA location of the resulting tissue damage can have a and semantic comprehension (Figure 1,6 “Yesterday was very sunsily and wide array of detrimental effects on one’s ability to 1). The primary intent of this 2 the sky was green” read, write or verbally externalize thoughts. communication therapy is to augment the patient’s communication skills The two most common forms of aphasia are through repetitive “impairment Broca’s and Wernicke’s aphasia.2 While no two reduction” exercises.7 The end goal is to maximize FIGURE 1: An example of manifestations of the disorder are exactly alike, the patient’s ability to participate in social activities, typical speech tendencies that the symptoms of each form of aphasia generally be it by means of skill restoration or developing may occur in individuals with Broca’s and Wernicke’s aphasia. correspond with damage to the cortical regions compensation techniques for skills that cannot be Broca’s aphasia is characterized after which they are named. Broca’s aphasia, for recovered.1,6,8 by very sparse speech that omits ‘function words’ in example, involves a functional deficit of Broca’s area. This region is located at the left inferior A recent study published by the U.K.’s National between principle nouns and verbs. Meanwhile, Wernicke’s frontal gyrus, and is responsible for the motor Institute for Health Research (the “ACT NoW” aphasia does not affect movements necessary to initiate speech. A defining study) performed a thorough evaluation of the utterance of speech, but instead characteristic of Broca’s aphasia is that while speech clinical effectiveness of the U.K.’s National Health causes words to be scrambled one is slow and effortful, receptive audio comprehension Services’ post-stroke communication therapy or incorrectly substituted for 2 that is functionally similar. is still intact; this classifies the disorder as a “non- services.10 These researchers were unable to find fluent” aphasia.2 It is also common for individuals evidence that early communication therapy from with this disorder to speak in a manner that is a speech-language pathologist provided additional described as “telegraphic,” often omitting smaller benefit above natural recovery and “attention control” inflectional affixes and “function words” between trials.10 This expressed concern is not an isolated key nouns and verbs.1,3 There is speculation that finding, either; an emergence of randomized these traits are related to peripheral damage in control studies have further demonstrated that the the temporal and parietal regions posterior to the reported benefits associated with communication central sulcus.1,4 therapy remain largely correlative.11,12,13 The specific elements of cognitive rehabilitation resulting from Wernicke’s aphasia, by contrast, is a “fluent” SLT remain unidentified at this time. aphasia. Individuals with this form of the disorder have no trouble with the utterance of words, but This emerging body of scepticism may carry experience difficulty with comprehension and some interesting implications for the Canadian word perception.2 Their speech, while spoken population in the years to come. Statistics Canada with ease, tends to be nonsensical—often riddled reports that Canadians above the age of 65 are with jumbled or misused words. As the name indeed the fastest growing demographic.14 This is

CORE COMPONENTS OF THE INTERVENTION

1. ASSESSMENT – Initial and ongoing, standardised, functional, case history, goal setting

2. INFORMATION PROVISION – Communication problem, strategies or equipment to assist communication, intervention plan, therapist opinion of progress, available information resources and support networks

Pharmacological Interventions

3. PROVISION OF COMMUNICATION MATERIALS – Communication book for recording activities, an “alternative and augmentative communication device” if required

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4. CARER CONTACT – Discussion and provision of information, observation and participation in therapy, conversation training for patient’s partner, preparation for the end of the research intervention

therefore challenges the conventional belief that significant restoration of communicative abilities is not possible past one year following a stroke.17 Remarkably, this intensive form of therapy has resulted in a variety of improvements for patients in a short timeframe, including expanded vocabulary and increased utterance of words (among many other linguistic measures of speech quality).17,18

5. INDIRECT CONTACT – Written descriptions of needs, abilities, and strengths; discussions with clinical teams; goal planning with multidisciplinary team

In the past, pharmacological supplements have been explored as a possible treatment method for aphasia, often to be administered in conjunction with traditional SLT. While viable improvements among patients have been reported, numerous drug trial methodologies have undergone criticism.6 Thus, no pharmacological agents are currently recommended for the purposes of language recovery.

One such drug is a cyclic derivative of γ-aminobutiric acid (GABA), known as “piracetam.” It was initially prescribed for 6. DIRECT CONTACT – Therapy to improve language skills at all levels of vertigo and several cognitive disorders in the the World Health Organisation ICF model: Impairment (improving language skills), Activity (compensatory strategies), Participation (developing 1970s, and current research is investigating confidence, accessible information) the nootropic effects of this drug on individuals who have experienced aphasia FIGURE 2: Current postfollowing ischemic stroke.19,20 Piracetam stroke aphasia treatment. A also the age bracket with which the onset of post- has demonstrated positive effects in randomized typical sequence of intervention stroke aphasia is most positively correlated.15 With placebo-controlled trials, particularly in the acute measures applied in the 50,000 Canadians experiencing a stroke each year, stages of recovery; the drug’s efficacy also increased provision of speech-language therapy (SLT).9 and thirty-five percent of those affected developing when prescribed in conjunction with SLT.21,22 some form of aphasia, post-stroke communication Localized increases in blood flow were also reported disorders are likely to become a rising concern in key language regions of the brain, including the among older Canadian adults.15,16 left transverse temporal gyrus, Broca’s area and Wernicke’s area.22,23 Despite this initial success, the In an effort to meet the needs of this burgeoning specific mechanism of action of piracetam has not vulnerable demographic, post-stroke therapy been investigated further, and therefore remains research has been expanding, over the past few unclear.24 It is known that piracetam facilitates years, to explore the viability of alternatives to excitatory neurotransmission in cholinergic and SLT. Not only are different methods of one-on- glutamatergic pathways.26 However, other bodies one therapies being developed, but there is also of research suggest that its structural similarity to a growing consideration for pharmacological GABA indicates the involvement of GABAergic supplements. pathways, which are typically inhibitory in nature.26

Constraint-Induced Aphasia Therapy Constraint-induced aphasia therapy (CIAT) is a novel, intensive take on SLT It requires patients to perform typical SLT exercises performed in longer sessions over a few consecutive days.17 CIAT is typically performed on individuals with chronic aphasia. The theory behind this method of practice

Ultimately, piracetam has never emerged as a mainstream treatment supplement for communication therapies. The results that piracetam has produced in research trials, while appearing promising, have also been subject to criticism due to flawed methodologies.27,28 The drug provided few definitive benefits for long-term recovery of communication skills.26 The shortterm therapeutic effects of piracetam described

previously, however, should not be overlooked. It includes a wide array of intervention styles, including has been acknowledged that, if fine-tuned control “group programs, training conversation partners, trials were pursued with greater vigour and detail, computer-based instruction, as well as deficit-specific then it would not be unreasonable to revisit the rehabilitation.”31 consideration of piracetam as a pharmacological supplement to SLT.27 Research Context Within

Canadian Geriatric Health Issues

A 2009 Senate special report entitled “Canada’s Aging Population: Seizing the Opportunity” highlights the benchmarks and upcoming goals of the Special Senate Committee on Aging. The committee’s primary aim is to provide a higher standard of living to Canada’s older adults. With regard to health care research, the committee identified a need to increase funding for longitudinal studies on aging processes in order to provide better-informed care to this demographic.32 While longitudinal studies are valuable resources in assessing variable changes over long periods of time, they provide only correlational data that, in isolation, may not be enough to ensure the provision of thorough, evidence-based therapies. Greater consideration for research into alternative therapies and pharmacological supplements, may also be valuable avenues.

Current and Future Options for Ontarians

It will be intriguing to see whether Canadian research efforts shift in the coming years in response to these emerging therapeutic alternatives to traditional There are many exciting evidence-based interventions methods of SLT. The recent findings and sentiments that are currently offered in Ontario, with expressed by the researchers of the ACT NoW other innovations still on the horizon for future study in the U.K. represent a more critical outlook consideration. For a broader summary of current on the treatments currently available for individuals and future provincial aphasia rehabilitation strategies, suffering from post-stroke communication disorders. interested readers are directed to the Evidence-Based Dialogue of this nature may become more frequent Review of Stroke Rehabilitation website, www.ebrsr. as researchers and health care professionals seek costcom. This review website provides a “comprehensive effective, evidence-based solutions for health concerns review of [post-stroke] aphasia that includes both pertinent to Canada’s fastest-growing demographic. therapy-based and drug-based interventions.”31 It 1.

The reviewer for this article wishes to remain anonymous

10.

11.

2012, Issue 5. Art. No.: CD000425. DOI: 10.1002/14651858.CD000425. pub3. Farrajota et al.: Speech Therapy in Primary Progressive Aphasia: A Pilot Study. Dement Geriatr Cogn Disord Extra 2012;2:321–331. Canadian Association of SpeechLanguage Pathologists and Audiologists (CASLPA). Scope of Practice for Speech-Language Pathology. 2011. Available from: http://www.caslpa.ca/ PDF/Scope_of%20Practice_SLP_ english_2008.pdf. Bowen A et al. Effectiveness of enhanced communication therapy in the first four months after stroke for aphasia and dysarthria: a randomised controlled trial. BMJ 2012;345:e4407 doi: 10.1136/bmj.e4407. Bowen A, Hesketh A, Patchick E, Young A, Davies L, Vail A, et al. Clinical effectiveness, cost- effectiveness and service users’ perceptions of early, well-resourced communication therapy following a stroke: a randomised controlled trial (the ACT NoW Study). Health Technol Assess 2012;16(26). Laska et al.: Very Early SLT in Acute Stroke Patients with Aphasia. Cerebrovasc Dis Extra 2011;1:66–74. DOI:

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O’Grady W, Archibald J. Contemporary Linguistic Analysis- An Introduction. 7th edition, Toronto: Pearson-Longman, 2011. Ropper AH, Samuels MA. Chapter 23. Disorders of Speech and Language. Adams and Victor’s Principles of Neurology. 9th edition, New York: McGraw-Hill; 2009. Available from: http://www.accessmedicine.com/ content.aspx?aID=3633872. Penke M, Westermann G. Broca’s Area and Inflectional Morphology: Evidence from Broca’s Aphasia and Computer Modeling. Cortex, 2006. 42, 563576. Keller SS et al. Broca’s area: Nomenclature, anatomy, typology and asymmetry. Brain & Language. 109 (2009) 29–48. Waxman SG. Higher Cortical Functions. Clinical Neuroanatomy. 26th edition. New York: McGraw-Hill, 2010. Available from: http://www. accessmedicine.com/content. aspx?aID=5275278. Accessed January 27, 2013. Brady MC, Kelly H, Godwin J, Enderby P. Speech and language therapy for aphasia following stroke. Cochrane Database of Systematic Reviews

critical review

A more recent pharmacological intervention that is being explored for the purpose of post-stroke communication treatment is an acetylcholinesterase inhibitor and vasodilator known as “donepezil.” Donepezil acts to ameliorate cerebral cholinergic connections to language processing centres, which are particularly susceptible to damage during ischemic stroke.29 By inhibiting acetylcholinesterase in these regions, acetylcholine function is potentiated, thereby improving cholinergic projections important for language, learning and memory.29 Donepezil has also demonstrated vasodilating properties in cerebral arterioles, increasing blood flow to these regions.17,30 Research relating donepezil to poststroke aphasia treatment has identified significant benefits in both acute and chronic forms of the disorders. Notable improvements were observed in subjects’ ability to produce speech spontaneously, which could conceivably bring about improvements for individuals with nonfluent aphasia.30

10.1159/000329835. 12. Young A, Gomersall T, Bowen A on behalf of the ACT NoW investigators Clin Rehabil. Published online 26 July 2012. DOI: 10.1177/0269215512450042. 13. Bakheit AMO et al. A prospective, randomized, parallel group, controlled study of the effect of intensity of speech and language therapy on early recovery from poststroke aphasia. Clin Rehabil 2007 21: 885. DOI: 10.1177/0269215507078486. 14. Statistics Canada. Canada’s population estimates: Age and sex, July 1, 2012. The Daily. 2012: 11-001-X. 15. Dickey L, Kagan A, Lindsay MP, Fang J, Rowland A, Black S. Incidence and profile of inpatient stroke-induced aphasia in Ontario, Canada. Arch Phys Med Rehabil 2010;91:196-202. 16. Canadian Stroke Network. About Stroke. [Online]. 2011. Available from: http://www.canadianstrokenetwork. ca/index.php/about/about-stroke. 17. Pulvermüller F et al. ConstraintInduced Therapy of Chronic Aphasia After Stroke Stroke.2001; 32: 16211626doi: 10.1161/01.STR.32.7.1621. 18. Jerzy P. et al. Constraint-induced aphasia therapy stimulates language recovery in patients with chronic aphasia after ischemic stroke. Med Sci Monit. 2008 May; 14(5): CR243– CR250 Available from: http://www. n c b i . n l m . n i h . g ov / p m c / a rt i c l e s / PMC2553559. 19. Malykh AG, Sadaie MR. Piracetam and piracetam like drugs: From basic science to novel Clinical Applications. Drugs 2012; 70 (3): 287-312. 20. Berthier ML. Poststroke Aphasia Epidemiology, Pathophysiology and Treatment. Drugs Aging 2005; 22 (2): 163-182. 21. Pulvermüller F, Berthier ML. Aphasia therapy on a neuroscience basis. Aphasiology, 2008, 22 (6), 563–599. DOI: 10.1080/02687030701612213. 22. Liepert J. Pharmacotherapy in restorative neurology. Current Opinion in Neurology, 2008 21(6), 639-643. DOI: 10.1097/ WCO.0b013e32831897a3. 23. Kessler J, Thiel A, Karbe H and Heiss WD. Piracetam Improves Activated Blood Flow and Facilitates Rehabilitation of Poststroke Aphasic Patients. Stroke. 2000;31:2112-2116. DOI: 10.1161/01.STR.31.9.2112. 24. Güngör L et al. Does long term use of piracetam improve speech disturbances due to ischemic cerebrovascular diseases? Elsevier. 2011 Apr;117(1):23-7. DOI: 10.1016/j. bandl.2010.11.003. 25. Malykh AG et al. Piracetam and Piracetam-Like Drugs From Basic Science to Novel Clinical Applications to CNS Disorders. Drugs. 2010 Feb 12;70(3):287-312. DOI: 10.2165/11319230-00000000000000. 26. Greener J, Enderby P, Whurr R. Pharmacological treatment for aphasia following stroke. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD000424. DOI: 10.1002/14651858.CD000424. 27. Ricci S, Celani MG, Cantisani TA, Righetti E. Piracetam for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD000419. DOI: 10.1002/14651858.CD000419.pub3. 28. Berthier et al. A randomized, placebo-controlled study of donepezil in poststroke aphasia. Neurology Nov 14 2006 67:9 16871 6 8 9 d o i : 1 0 . 1 2 1 2 / 01 . wnl.0000242626.69666.e2. 29. Berthier et al. Drug Therapy of Post-Stroke Aphasia: A Review of Current Evidence. Neurology. Apr 8 2003. 60:7 12181219. DOI:10.1212/01. WNL.0000055871.82308.41. 30. Salter K et al. Aphasia. EvidenceBased Review of Stroke Rehabilitation. 2012;15. Available from: http:// www.ebrsr.com/uploads/AphasiaSREBR-SREBR-15_1.pdf. 31. Carstairs S, Keon WJ.Deputy Chair. Canada’s Aging Population: Seizing the Opportunity. Special Senate Committee on Aging, 2009. Available from: http://www.parl.gc.ca/ Co nte nt / S E N / Co m m i tte e / 4 0 2 / agei/rep/AgingFinalReport-e.pdf.

ARTIST MARK BELAN

CRITICAL REVIEW

Internal Models of Motor Control RE ACH A DA PTATIO N TA SK A N D A U TISM

LAURA ZUCCARO Bachelor of Health Sciences (Honours) Program, Class of 2013 Correspondence should be addressed to: laura.zuccaro@learnlink.mcmaster.ca

ABSTRACT

(e.g., position of one’s Golgi tendon organs). The output, or prediction, from the forward model is then compared with the actual position of the body following movement. The actual and predicted body positions may differ due to noise introduced F or e x ample , when tickling into the system by either oneself , an efference copy of the tickling internal sources (e.g., motor command is sent from sensory systems) or to the forward model to external sources (i.e., forces predict the likely sensory acting on the body).1,5 outcome one would Efference copies enable e x pect . 10 If this sensory the forward model to distinguish prediction matches the between these external and internal actual sensory feedback signals by comparing the outgoing ( which it usually does predictive signals to post-movement when tickling oneself) , the feedback is attenuated feedback.5

The internal models theory is one of many hypotheses that aim to explain the mechanism of motor control in humans. The theory proposes that the central nervous system (CNS) forms neural representations of the external world, which are used to predict and adjust movements.1,2 Internal models have been well-studied, and this paper provides a general insight into the internal models theory before examining how subjects adapt during a reaching task.3 This reaching task, as explained via the internal models theory, will be compared between normal and disease states, specifically autism, a disorder of neural development. Through this comparison, it will be possible to determine how autistic patients differ in their motor abilities.

THE THEORY OF INTERNAL MODELS

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An early theory of how humans control their movements is the feedback learning theory. and the tickling is less The feedback learning theory suggests that intense . If another person when a motor instruction is given, the brain The inverse model determines the is tickling you , there is receives sensory feedback outlining the motor commands needed to achieve no accurate prediction effects of that movement, to which it bases a desired movement trajectory of the sensory outcome future decisions (Figure 1a).1 However, the (Figure 1c).1,2,5 It uses the desired and no match to be made, sole reliance on post-movement feedback to and actual body positions as inputs resulting in greater make future motor decisions is too slow and to estimate the necessary motor tickling sensation . 2 6 cannot predict outcomes. For these reasons, commands that would transform it fails to explain how humans make fast the current position into the desired and coordinated movements.1,4 The internal one.2,5 For example, in an arm reaching task, models theory accounts for these limitations, the desired position of the arm is inputted making it the front-runner in the explanation into the inverse model, which generates of complex motor movements. the motor commands necessary to control the arm and bring it to the desired position. Internal models of motor control are neural Motor command signals generated by the representations of the external world used controller can reflect feedback errors, as to predict and adjust movements.1,2 Internal any discrepancies between the limb motor models are formed in the cerebellum through output and instruction signals indicate a learning and are adjusted as movement is malfunctioning internal model.1 repeated.1,2,5 The internal models theory includes two components: a forward and It is suggested that proprioception helps build an inverse model. The forward model is a an internal representation of one’s arm and its feed-forward system whose goal is to predict dynamical properties.9 In the internal model, the consequences of a motor command error comparison between the proposed and (Figure 1b).1,2,5 Forward models are stored actual sensory feedback usually involves in the cerebellum and predict the likely multiple sensory modalities (e.g., visual, sensory feedback that would result from a proprioceptive, somatosensory).5 The relative movement.1,6 They make these predictions importance of proprioceptive versus visual using the body’s current state, a model of feedback in forming an internal model is still the system, and an efference copy of the being explored, though one thesis dissertation motor command.7,8 An efference copy is a found that the process primarily depends on duplicate of the motor command, containing proprioceptive cues from the limb (although a motor command’s predicted movement visual information did provide additional and resulting sensations.5 For example, if the benefits to learning).10 Other research also motor command was to move one’s arm, the suggests a distinction between kinematic and efference copy would contain the predicted dynamic internal models, which are mediated sensations resulting from the movement by vision and proprioception respectively.2

com Input

output

Feedback

B Internal Feedback

(cerebellum)

b a

Input

com

(motor cortex or prefrontal cortex)

(Physical part of mental model)

output

Feedback

(cerebellum)

prN Io

Input

(motor cortex or prefrontal cortex)

(Physical part of mental model)

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FIGURE 1: The Feedback, Forward, and Inverse Models.1 A) The feedback control system. An instructor (P) gives an instruction to the controller (CT) that provides a command (COM) to manipulate a controlled object (CO). The sensory system (SS) provides feedback to the controller (dashed line). B) The forward model control system. The outputs of the CT and CO (via SS) are compared with the forward model’s predictions to derive an error signal. This realtime comparison happens in the inferior olive (IO) and is sent to the forward model to modify it. C) The inverse model control system. Feedback errors are derived from the CT-generated COM signal and tune the dynamics of the IM. The paraventricular red nucleus (pRN) acts as a relay. 1.

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Ito, M. Control of mental activities by internal models in the cerebellum. Nature Reviews Neuroscience. 2008;9:304-313. Kawato, M. Internal models for motor control and trajectory planning. Current Opinion in Neurobiology. 1999;9:718-727. Wolpert, DM, Diedrichsen, J, Flanagan, JR. Principles of sensorimotor learning. Nature Reviews Neuroscience. 2011;12:739-51. Galea, V. Seminar 1B 2012: Motor Control Theories and Models. [unpublished lecture notes]. HTH SCI 4PP3; McMaster University; lecture given 2012 Jan 13. Wolpert, DM, Miall, RC, Kawato, M. Internal models in the cerebellum. Trends in Cognitive Sciences. 1998;2(9):338-47.

output

Feedback

Localized U-fiber connections between adjacent brain regions contain proprioceptive inputs to the internal models, whereas distant cortical and subcortical connectivity contains visual feedback inputs.11

LEARNING TO CONTROL A NOVEL TOOL: REACH ADAPTATION

The evidence for internal models in a reaching task relies on the concept of error-based learning. After one establishes a goal and begins to reach (e.g., to pick up a cup), the sensorimotor system compares the movement outcome to the desired outcome, producing a sensory prediction error.3,12,13 This error tells the system if, and in what way, the hand missed the target—allowing the forward internal model to make real-time movement corrections to ensure the target is reached.3 The body’s adaptation of reaching movements has been studied by exposing subjects to novel force fields or visual perturbations. To do this, subjects move their arms towards a target that they see on a computer screen, while grasping a handle hooked up to a robotic arm. The robotic arm can apply different forces, and visual perturbations are introduced by changing the target image the subject sees on the computer screen.16 Initial movements under the perturbed conditions are error-ridden, but gradually straighten with adaptation. The CNS adapts quickly, and it can learn from error on a single trial.16 For example, Gidley Larson et al.17 examined children’s learning ability in manipulating a robotic arm (exerting a novel force) to aim for targets projected on a screen.17 The catch trials (random, unperturbed trials within a series of perturbed trials, or field trials) illustrated mirror-image aftereffects. These aftereffects indicate that subjects learned and formed a predictive internal model to anticipate the effects of the force field on the reaching task.17

The goal of reaching is to transport the hand to a specific environmental location for meaningful object manipulation.12 Reaching begins early AUTISM AND THE REACH in post-natal development – as early as at the ADAPTATION TASK age of 3 to 12 weeks (although movement may be poorly coordinated and jerky).12 Through Autism is a pervasive developmental disorder error learning, infants develop smoother hand with a strong genetic basis.18 Symptoms must paths, greater hand speed, less inter-trial be noticed before 3 years of age and typically variability, and improved accuracy. 12 Kinematic include: impaired social interaction, behavioural improvements during the development of stereotypes (e.g., repetitive behavior such as reaching reflect an increasing ability of the hand flapping), delays in motor milestones, and child to rely on their internal model of the limb a large range of cognitive deficits.18,19 Motor when organizing the movement.12,13 Research impairments are not part of the formal diagnosis supports the involvement of internal models of autism, though they are among the earliest in reaching. Clifton et al.14 found that infants symptoms.20 Motor signs commonly include develop reaching at similar ages in both light poor muscle tone, incoordination, poor balance and dark conditions.14 Since the dark provides and dexterity, the presence of motor stereotypes, no visual feedback, an internal representation imitation impairments, and a lack of anticipatory of the limb must be available at the onset of postural adjustments.20,21,22 Although the reaching behaviours.14 Further, as a child ages, specific cortical abnormalities in autism are still errors decrease and fewer experimental trials being elucidated, it has been shown that the are needed to attain complete adaptation during cerebellum is a constant site of neuroanatomic motor tasks—indicative of a more developed abnormality—more than 95% of cases show internal model.15 cerebellar pathology.20,21 This is commonly

caused by a decrease in Purkinje neurons (the inhibitory output cell), although reductions in Purkinje cell size and molecular and receptor abnormalities have also been reported.20,21 The cortex of autistic patients also has altered nerve cell synapse connections and organization.20,11 This usually presents as overgrowth in localized cortical connections.11,23

sample due to the sole participation of high functioning autistics).

Sean Rasmussen is a M.D./P.h.D. candidate in the MINDS program at McMaster University working in the lab of Dr. Michael Mazurek. His research makes use of rat models to study the monoaminergic effects of various drugs used for the treatment of schizophrenia, depression, and bipolar disorder.

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Reviewed by SEAN RASMUSSEN

critical review

Autistic patients’ reliance on proprioceptive signals also provides some explanation for the observation that autistic children are ‘blind while seeing and deaf while hearing’.24 Increased proprioception may suppress other sensory information, limiting visual and auditory The reach adaptation task in autistic children processing.24 This likely affects an autistic child’s can be compared to controls. Gidley Larson et observational learning and their success in al.17 assessed learning ability in manipulating social situations. Other research also suggests a robotic arm in typically developing and a distinction between kinematic and dynamic autistic children.17 Despite the usual cerebellar internal models, which are mediated by vision abnormalities in autistic patients, both autistic and proprioception respectively.2 Besides the and normal children adapted and formed internal large range in autistic symptoms, this could models. This was demonstrated through reduced also explain why some studies show differences errors in field trials (the regular, perturbed trials) between autistic participants and controls in and increased errors in catch trials over time.17 internal model formation and other studies do Thus, autistic subjects are able to form internal not. Studies where visual feedback is preferred models, and the anomalous pattern of motor would likely show worse performance in autistic learning must result from an error in the process, children, since they rely on proprioceptive such as the balance in the use of proprioceptive information. The opposite would be true when or visual feedback. proprioceptive information is preferred. Future research should examine the autistic patient’s Haswell et al.23 used a similar task to investigate error comparison and the role of proprioception this phenomenon and concluded that children in both kinematic and dynamic internal models. with autism spectrum disorder (ASD) have a stronger-than-normal reliance on CONCLUSION proprioceptive feedback when generating motor commands.23 This reliance on proprioception According to the internal models theory, the may result from the typical overgrowth in CNS develops an internal representation of the localized cortical connections seen in autistic body in reference to a task. Forward and inverse brains.11,23 Alternatively, autistic patients may be models are used to predict sensations and forced to rely on proprioceptive information due correct movements without delay. These models to deficits in visually-guided action—causing can be combined to facilitate more complex a localized cortical overgrowth. Regardless, movements. Internal model formation is typically Haswell et al.23 further demonstrated that a demonstrated through the adaptation that greater use of proprioceptive feedback correlated occurs during an arm-reaching task. Conflicting with greater impairments in social interactions results have emerged with regards to autistic and observational learning, which rely on visual patients’ performance when reaching, likely due cues.23 Interestingly, one study found that to the great variability of symptoms in patients. autistic patients, and not controls, transferred However, strong evidence suggests that autistic adaptation to perturbed conditions to a non- patients rely more heavily on proprioceptive adapted hand.24 This further demonstrates a feedback when generating movements. This is focus on proprioceptive information instead of supported by neuroanatomical abnormalities real-time visual feedback to execute movements (increased localized connections), and can during the adaptation phase.24 Increased ultimately influence their error comparison proprioceptive feedback relative to other and internal model function. A greater sensory modalities could result in an abnormal understanding of the autistic brain and internal error comparison.17 This would likely change models is necessary to determine where exactly how the internal model is fine-tuned (though deficits arise. Continued study will likely provide changes were not observed in Gidley Larson et improved diagnostic and clinical treatments for al.’s17 study, possibly due to an unrepresentative autism.

6. Kawato, M, Kuroda, T, Imamizu, H, Nakano, E, Miyauchi, S, Yoshioka, T. Internal Forward Models in the Cerebellum: fMRI Study on Grip Force and Load Force Coupling. Progress in Brain Research. 2003;142:171-88. 7. Miall, RC, Wolpert, DM. Forward Models for Physiological Motor Control. Neural Networks. 1996;9(8):12651279. 8. Todorov, E, Jordan, M. Optimal feedback control as a theory of motor coordination. Nature Neuroscience. 2002;5(11):1226-35. 9. Vercher, JL, Sares, F, Blouin, J, Bourdin, C, Gauthier, G. Role of sensory information in updating internal models of the effector during arm tracking. Progress in Brain Research. 2003;142:203-22. 10. Hwang, EJ. Representations of proprioceptive information for generation of arm dynamics [thesis]. John Hopkins University; 2004. 11. Izawa, J, Pekny, SE, Marko, MK, Haswell, CC, Shadmehr, R, Mostofsky, SH. Motor learning relies on integrated sensory inputs in ADHD, but over-selectivity on proprioception in autism spectrum conditions. Autism Research. 2012; doi: 10.1002/aur.1222. 12. Choe, NN. The coordination of multijoint reaching movements: a developmental profile [thesis]. School of Rehabilitation Science, Queen’s University. 2009 Nov. 13. Krakauer, JW, Ghilardi, MF, Ghez, C. Independent learning of internal models for kinematic and dynamic control of reaching. Nature Neuroscience. 1999;2(11):1026-31. 14. Clifton, RK, Muir, DW, Ashmead, DH, Clarkson, MG. Is visually guided reaching in early infancy a myth? Child Development. 1993;64(4):1099-1110. 15. Konczak, J, Jansen-Osmann, P, Kalveram, K. Development of force adaptation during childhood. Journal of Motor Behavior. 2003;35(1):41-52. 16. Kluzik, J, Diedrichsen, J, Shadmehr, R, Bastian, AJ. Reach Adaptation : What determines whether we learn an internal model of the tool or adapt the model of our arm? Journal of Neurophysiology. 2008;100:14551464. 17. Gidley Larson, JC, Bastian, AJ, Donchin, O, Shadmehr, R, Mostofsky, SH. Acquisition of internal models of motor tasks in children with autism. Brain. 2008;131:2894-2903. 18. Caronna, EB, Milunsky, JM, TagerFlusberg, H. Autism Spectrum Disorders: clinical and research frontiers. Archives of Disease in Childhood. 2008;93:518-523. 19. American Psychiatric Association. Diagnostic criteria for 299.00 Autistic Disorder. Diagnostic and Statistical Manual of Mental Disorders. 4th, text revision (DSM-IV-TR); 2000. 20. Allen, G, Muller, RA, Courchesne, E. Cerebellar Function in Autism: Functional Magnetic Resonance Image Activation During a Simple Motor Task. Society of Biological Psychiatry. 2004;56:269-278. 21. Lee, M, Martin-Ruiz, C, Graham, A, Court, J, Perry, JR, Iversen, P, Bauman, M, Perry, E. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain. 2002;125:148395. 22. Schmitz, C, Martineau, J, Barthelemy, C, Assainte, C. Motor control and children with autism: deficit of anticipatory function? Neuroscience Letters. 2003;348:17-20. 23. Haswell, CC, Izawa, J, Dowell, LR, Mostofsky, SH, Shadmehr, R. Representation of internal models of action in the autistic brain. Nature Neuroscience. 2009;12(8):970-2. 24. Masterson, BA, Biederman, GB. Proprioceptive versus Visual Control in Autistic Children. Journal of Autism and Developmental Disorders. 1983;13(2):141-52. 25. Bernier, PM, Chua, R, Bard, C, Franks, IM. Updating of an internal model without proprioception: a deafferentation study. Neuro Report. 2006;17(13):1421-5. 26. Davidson, PR, Wolpert, DM. Widespread access to predictive models in the motor system: a short review. Journal of Neural Engineering. 2005;2:S313-S319.

OPINION

On Vaccines & Irrationality: LEVERAGING EMOTION FOR THE GREATER GOOD MOHSIN ALI

Bachelor of Health Sciences (Honours) Continuing Student, Class of 2012

Branavan Manoranjan

opinion

Bachelor of Health Sciences (Honours) Alumni, Class of 2011 M.D./Ph.D. Candidate, Michael G. DeGroote School of Medicine

Consider the rhetorical difference between two camps: those for and against vaccinations. The pro-vaccination group, backed by much of the scientific community, argue that vaccinations are safe and save lives.1 They often couch their assertions in the facts.2 For example, in biologist Steven Salzberg’s July 2012 Forbes article, entitled “Anti-vaccine movement causes the worst whooping cough epidemic in 70 years,” he warns that the U.S. has already had 17,000 cases of whooping cough that year.3 Of these cases, ten died, mostly infants too young to be vaccinated. Contrast this with celebrity Jenny McCarthy, of the anti-vaccination group, who asserts the MMR vaccine causes autism.4 She made the following statement on Oprah in 2007 about her son receiving the vaccine: “and soon [after he got the shot]—boom—the soul’s gone from his eyes.”5

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ARTIST YASMEEN MANSOOR

University of Pennsylvania paediatrician Paul Offit recognizes the power of the latter rhetoric. “Anecdote trumps epidemiology every time,” he says.2 He describes, for instance, the struggle to vaccinate the workers of his hospital against influenza.2 In 2002, the year when two five-year-old girls contracted the flu in the hospital and died, the voluntary vaccination rate among the 10,000 staff of the Children’s Hospital of Philadelphia was 35%. For several years afterward, the hospital’s senior administrators pushed for 100% staff vaccination. They offered the vaccine free of charge, an approach complemented by an extensive effort to educate the healthcare workers. While the rate doubled, still one in three staff chose not to get vaccinated. Seven years later, the hospital made the vaccine compulsory. Nine workers still refused. They were fired. Dr. Offit notes: “It is very easy to scare people; it is much harder to unscare them.”2

Some vaccine proponents—Dr.Offit included— blame the media. He describes the media as paralyzed by the mantra of balance, despite only one side of the story being supported by science.2 The media do influence vaccination rates, apparent in the 2003–04 flu season, when more than one in four parents vaccinated their children following media coverage or re c o m m e n d a t i o n from a friend.6 However, the media are not at fault—they may feel obligated to present both sides of the story. The onus is on the reader, who decides with whom she will side.

System 1. Kahneman’s book highlights how humans are surprisingly susceptible to many fallacies, and he emphasizes that, “In the picture that emerges from recent research, the intuitive System 1 is more influential than your experience tells you, and it is the secret author of many of the choices and judgments you make.”7

What is important for vaccine proponents, therefore, is to compel the reader. Highlighting the numbers and appealing to logic works. But they must also appeal more to emotion.

Such an approach is not unscientific. Nobel Laureate Daniel Kahneman describes in his best-selling book, Thinking, Fast and Slow, the fdsfdsLinda is 31 understands years old, single, The BBC the outspoken, importance of two modes of thinking that govern decisionand very bright. She News majored in philosophy. stories. Their making:7 System 1 is automatic, emotional, and Styleguide has a As section a student, was deeply issues they subconscious; System 2 is effortful, logical, and on she numbers and concerned measures, with in which of discrimination and social and and alsomany conscious. Consider this classic question posed caution journalists aboutjustice, using large participated in9 anti-nuclear demonstrations. by Kahneman and his fellow psychologist numbers: Which is more probable? Amos Tversky from the early 1980s:8 The brain struggles to take in millions Linda a bank teller.They are difficult Linda is 31 years old, single, A. andis thousands. B. Linda is a bank teller and is active in the outspoken, and very bright. She to visualise. Even smaller numbers feminist movement. majored in philosophy. As a student, are a problem if there are too many she was deeply concerned with issues of them. . . . A story with too many of discrimination and social justice, figures numbs the listener. Simplify and also participated in anti-nuclear wherever you can, round up or down, demonstrations. Which is more and try to tell the story without probable? getting bogged down in numbers. A. Linda is a bank teller. B. Linda is a bank teller and is active in the feminist movement.

Vaccine proponents, therefore, should not shy away from inciting emotions—whether it is sorrow, anger, or fear—to bolster their arguments. They should weave strands of facts into the fabric of stories. Not doing so would be irrational.

2. Roehr B. Media induced antivaccination sentiment can even affect health workers, vaccine researcher says. British Medical Journal. [Online] March 1 2012. Available from: http://www.bmj. com/content/344/bmj.e1563 [Accessed 8th December 2012]. 3. Salzberg S. Anti-vaccine movement causes the worst whooping cough epidemic In 70 years. Forbes. [Online] July 23 2012. Available from: http://www.forbes.com/ sites/stevensalzberg/2012/07/23/ anti-vaccine-movement-causes-theworst-whooping-cough-epidemic-in70-years/ [Accessed 8th December 2012]. 4. Dawn F. After vaccine–autism case settlement, MDs urged to continue recommending vaccines. Neurology Today 2008;8(11):1,8. 5. Generation Rescue. Jenny: Evan’s Story. [Online]. Available from: http://web.archive.org/ web/20080405214005/http:// generationrescue.org/evan.html [Accessed 7th December 2012]. 6. Ma KK, Schaffner W, Colmenares C, Howser J, Jones J, Poehling KA. Influenza vaccinations of young children increased with media coverage in 2003. Pediatrics 2006;117(2):e157–63. 7. Kahneman D. Thinking, Fast and Slow. Toronto: Doubleday Canada; 2011. 8. Tversky A, Kahneman D. Judgments of and by representativeness. In: Kahneman D, Slovic P, Tversky A. (eds.) Judgment Under Uncertainty: Heuristics and Biases. Cambridge, UK: Cambridge University Press; 1982. pp. 84–98. 9. Allen J. The BBC News Styleguide. British Broadcasting Corporation. 2003. Available from: http://www. wsscc.org/resources/resourcepublications/bbc-news-styleguide [Accessed 7th December 2012].

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About 85 percent of respondents—142 undergraduate students at the University of British Columbia—chose the latter, falling prey to the conjunctive fallacy. The correct answer is A, which you would have arrived at through System 2. However, for many people, option B seems intuitively right—a consequence of

It is clear that the anti-vaccination camp understands this message. Stories work, echoed in the apocryphal quote attributed to Joseph Stalin: “A single death is a tragedy; a million deaths is a statistic.”

Nield LS. Anti-vaccine media: Its impact—and strategies to combat it. Consultant for Pediatricians 2008;7(9):S4–S7.

opinion

It is clear that vaccine proponents opt for the System 2 approach. This is likely because in science we are taught to abhor anecdotal evidence. While such an approach helps to design and interpret studies and communicate results with scientific colleagues, story telling—because it appeals to System 1—needs to be employed more by the pro-vaccine camp. Dr. Salzberg, for instance, could have chronicled one of those 10 deaths he mentions in his whooping cough article, depicting the tragic death of a child and the unnecessary suffering of the family.

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dr.sheila singh

Could you tell us about your education and research, specifically about the brain tumour-initiating cells?

I started my program here just over five years ago, in August 2007. Prior to that, I completed my undergraduate degree in neurobiology at McGill University and came to McMaster University for medical school. I was then accepted into the neurosurgery residency at the University of Toronto, where during the course of my residency I undertook my Ph.D. within the Surgeon Scientist Program at the Hospital for Sick Children, in the Arthur and Sonia Labatt Brain Tumour Research Centre. I then worked in the lab of Dr. Peter Dirks. In his lab, we made a discovery in 2003 that there were abnormal stem cells that seemed to drive the formation of brain tumours. This was the first published description of the finding, so it opened up a new field of the cancer-stem cell The Meducator recently sat down with Dr. Sheila Singh, hypothesis. After that discovery our work gained a lot Associate Professor and scientist at the Stem Cell and of recognition, and now many people around the world Cancer Research Institute at McMaster University, to discuss her ground-breaking research on brain tumour-initiating cells use our model. I wanted to build on that momentum and her hopes for future generations of scientists. Dr. Singh of discovery by opening my own laboratory here and explained to us how she was able to make her discovery and following up on the work done in my Ph.D. When I why the science of tumours is such an intricate one. She also finished my Ph.D., I did a paediatric neurosurgery shared her insights about the long road ahead for clinicianfellowship at the Hospital for Sick Children, before scientists and described why students should take their time finally coming here.

The complexity of brain tumours

with their careers.

and grew these cells ourselves, under Sam Weiss’s culture conditions. I remember plating the cells on the dish and wondering what would happen after I put them into the incubator. Neural stem cells grow as these beautiful floating colonies called neurospheres. A single stem cell will give rise to a whole colony of cells in one sphere. You then conduct a clonal assay by dissociating these spheres and plating them at singlecell density, then Dr. Sheila Singh, M.D., Ph.D., F.R.C.S.(C) figuring out how Neurosurgery, is currently the Canada many spheres Research Chair in Human Cancer are formed. This Stem Cell Biology gives you a way of estimating clonal frequency of stem cells in your cell population. When you see a sphere, you know you have one stem cell because it has to have arisen from a single stem cell. I remember taking the dishes out of the incubator and looking at them under the microscope, and there in the dish were these spheres. That’s when I knew there was a stem cell population in brain tumours. It was really a true moment of scientific epiphany.

In your Technology, Education and Design Talk, you mentioned your discovery of the interconversion between CD133+ and CD133-. Could you elaborate on that? Most of the Cluster Differentiation (CD) markers are exclusively cell-surface receptors. CD133 is a fivetransmembrane cell surface receptor. The utility of CD receptors is that they’re expressed on the cell surface, so you can literally just use them to mark a cell population. One of the problems with these markers is that when you mark a cell population, you cannot make the assumption that the CD133+ cells you’ve sorted are all stable. Going back to the principles of physics, we know that everything is constantly in motion; the concept of Schrodinger’s Cat is very relevant to our field. No more than whether we know

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That’s an excellent question because we did have a classic epiphany moment. Generally, when people study brain tumours, they use cell lines or study the expression of markers and other proteins of interest. There aren’t many other models to study how cancers form, so we went to a famous Canadian scientist, Sam Weiss, who discovered neural stem cells back in 1992. He cultured cells from the subventricular zone of the mouse brain and put them into specific culture conditions. Keep in mind that the majority of cell lines require serum. Dr. Weiss developed these interesting conditions in which he knew that the only type of cell that could survive without serum is a stem cell, due to their unique resilience and ability to grow. In this culture method, you can place cells in serum-free media with specific growth factors, such as epidermal growth factor and fibroblast growth factor, and 99% of the cells in the dish will die because most differentiated cells cannot survive without serum. What you get rising from the ashes is the neural stem cells, which will thrive in those conditions, leaving you with a beautiful selective method of growing only stem cells. Peter Dirks and I used these culture methods. We took some brain tumour tissue from the operating room

interview spotlight

When did you first get a hint of this important hypothesis that came out of your research?

From that, the idea emerged that tumours are made of cells that histologically all look the same, but not every cell in a tumour is capable of initiating a tumour, especially in a tumour with a variety of cells in it, like a glioblastoma multiforme (GBM). They all serve different functions within the tumour; some cells may form the support network. However, the model doesn’t apply to tumours that are monoclonal. For example, B-cell lymphoma is not a good model for the cancer-stem cell hypothesis because that probably is a tumour that forms when one cell goes wrong and generates every other cell in a clonal manner. Similarly, melanoma may not be a cancer-stem cell type of tumour. But tumours that have that complexity, that are heterogeneous, that have multiple different lineages of cells within the same tumour, probably originate from a stem cell. So this model system gives you a way to study tumour heterogeneity, to order cells and figure out what they are.

the cat is dead or alive in the box, we really don’t know whether a CD133+ cell will stay positive or if it fluctuates between different states. In all likelihood, we are not studying stable environments; cells are dynamic. So the complexity in science comes from our inability to study proteins or receptors in isolation. I think all scientists are studying one piece of the puzzle. The challenge for the next generation of scientists is going to be putting all these puzzle pieces together.

Keeping in mind the dynamic nature of cells, what are the implications of these findings for technical feasibility of potential treatments?

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Everything we know about the tumours we study is gathered from an initial pre-treatment biopsy. We take out a tumour and then we subject the patient to a million different treatments, but we’re basing all this on one sampling time point of the tumour. There’s an evolutionary biologist named Charles Swanton from London, England who applies evolutionary biology theory to the study of cellular populations. He published this breakthrough study in the New England Journal of Medicine last year, which showed that if you take ten different samples from a renal tumour you’ll see ten totally distinct gene expression profiles. He went back to characterize the tumour and showed that it was a patchwork quilt of different grades within the same tumour. So depending on where the surgeon samples the tumour, that’s how the patient will be treated; it’s almost random. It shows the problem with cancer treatment. Cancer is a dynamic disease unfolding in a patient but all of our treatments are based on samples taken at the beginning.

Dr. Sheila Singh was the first researcher to identify the presence of stem cells in brain tumours in 2003 while completing her PH . D. during her surgical residency . Dr. Singh ’s research has served as the basis for the formation of the cancer- STEM CELL hypothesis that has led the way to an entirely new framework for understanding select cancers and ultimately greatly impacting the development of cancer drugs and therapies .

What we realize more and more is that we need experimental models that capture how tumours evolve with time. Something we’re doing in the lab right now is developing therapy models for our human tumours. We implant human tumours into mice and profile the stem cell population as they evolve through therapy. We treat the mice with chemotherapy and radiation therapy, then conduct a time point analysis at each state to see how the tumours change with treatments, which stem cell populations are responding to the treatments we’re giving, which ones are resistant, and which are arising after the therapy. So, one way that developmental biology is applied to cancer is through this method of clonal tracking. We can figure out how the cancer cells are evolving through therapy by labelling a cell population at the beginning, then treating the cancer in the mouse with all the different treatments we use in humans and tracking that cell population over time.

Do the cancer cells that metastasize to the brain differ in any way from primary brain cancers? Yes and that is what we are currently studying. We are looking for some signature that would indicate migratory homing to the brain, so that we can identify which cells seek brain metastases and understand how and why they are able to form a secondary tumour in the brain. This project is important because, ultimately, these secondary tumours are fatal. We currently have no adequate treatment for such tumours. We do not have answers yet, but we are close to discovering what distinguishes tumour cells that migrate to the brain from tumour cells that originate and develop within the brain. It is important to understand how these cells migrate to the brain and how they evade the normal protective mechanisms like the blood-brain barrier and the immune system. There are many theories in

oncology that try to understand the molecular mechanisms of immune surveillance to explain how cancer cells escape the immune system.

Do you think there will be a cure for cancer, or will this field of medicine remain treatment-oriented?

Are there any scientific controversies in your field?

Balancing basic research and clinical practice is a constant challenge. Often you feel as if you are walking on a high wire. The only advice I have, which I give my trainees in the Surgeon Scientist program at McMaster University, is that the more continuity and feedback you have between the clinical practice and the research practice, the better. In the past, people would often study things that had nothing to do with the focus of their clinical practice, but the more similarities there are between the two, the better your work will be. When trying to work in two different fields, you have to be even more vigilant and recognize when something is outside your expertise. For example, I focus on brain tumours in my laboratory, and my work has focused and honed my brain tumour clinical practice, giving me more power to become an expert in one thing. If a patient presents with an aneurysm, which is outside my expertise, I will not hesitate to ask for help from my vascular surgeon colleague or even refer the case; it is very important for patients that you are staying within the realm of your expertise. The best advice I have is that if you are trying to work in two different fields in your practise and your research, you must maintain a very tight focus on both, so that you never endanger anyone on the clinical side nor will you claim to be able to do something outside your capacity on the research side. If you do stay tightly focused on one area, you will be able to approach a problem like brain tumours using all of the tools in your tool box. I have clinical ways and laboratory ways to study brain tumours, but it is all one research focus.

What advice would you give to undergraduate students who are potentially hesitant about this longterm journey? I would say that the only way to be able to serve your patients the best that you possibly can is to become an absolute expert in the area. And the only way to become an absolute expert in anything is to devote long hours and to work hard. My residency program was one of the toughest residency programs. When I came here and started as a staff paediatric neurosurgeon, Dr. Hollenberg, my senior partner, threw my pager at me and said, “I’m going to the lake for three weeks – bye!”, leaving me on my own. The only way you can become equipped to handle those first weeks is through your training. I fell back on

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Huge! One controversy exists regarding which cancers the cancer-stem cell hypothesis is relevant to and which cancers it does not apply to at all, because it is certainly not going to explain the bulk of cancers. We have controversies in our field about which markers actually identify brain tumour-initiating cells, and which sub-populations can be identified. We even have controversies about culture methods. There are so many controversies, and there always will be. You just have to figure out what works in your hands for your program and which methods result in models that are the most similar to the patient’s disease course. If the findings in your dish recapitulate what the disease process is in humans, then you know it is a good model. We navigate those decisions everyday in science,

What have been the challenges of balancing both research and clinical practice?

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I do not think there will be one cure for cancer. What we realize now is that there is not one GBM; every case of GBM is a different beast. A brain tumour that evolves in the brain of a 45 year-old male will be distinct from a similar tumour that evolves in that of an 85 year-old woman because of differences in the microenvironment. This is why patienttargeted and individualized therapy is becoming such a popular topic. I think the only way that we will ever be able to cure cancer will be on a case-by-case basis. You will have to be able to profile the patient’s tumour by extracting the cells and conducting quick multi-level analyses to figure out what gene expression is present in each cell population of the tumour. Only then will you be able to determine which drug to give that patient. Another patient may present with the exact same tumour but we may find that a different cell population is causing trouble. Then we will target that cell population with another drug. I think that treating each patient with an individualized cancer therapy is the only way we will ever be able to manage cancer; it will not be a matter of curing it, but more so managing it. Part of successful individualized therapy will be based on detecting these populations at an earlier stage. The dream would be to detect these populations before they turn cancerous and prevent it from transforming ahead of time. But that is down the road as well. I am worried about the amount of money that will be necessary to profile at this level, because such procedures are still very expensive. This will not be sufficiently funded by the Ontario Health Insurance Plan unless the technology can catch up to the point that it can be incorporated into everyday diagnosis. The government should be investing their money into making these technologies high-throughput and affordable.

trying to decide “Is this right?” or “Is this modelling what is happening in the patient?” If it is not, we do not bother with it. That is another reason for why it is beneficial to be a physician as well. I actually know whether a model is appropriate or not, which is very useful.

everything from my training to succeed: every long night, experience, and difficult struggle to stay awake. That is what made me competent in the end. Sometimes I think we do not emphasize enough that those struggles are what make you the best physician. My advice to those students would be to not be afraid of struggle and a large workload. Do not worry if it will get you anywhere, or if it is really worth it. Do not think about that. If you love something and want to study it, then commit to it and become the best at it. The hard work will not pay off in the short run, but it pays off in the long run.

interview spotlight opinion

Do you think you would be able to have that connection to the research if you were not practicing? No, I do not think I would be so deeply invested in it. That is another big benefit of being a clinician-scientist – it is hard not to be invested in what you do. You walk across that bridge to the hospital where you treat patients with brain tumours, then come here to sit in your office and work on your research. I am very lucky to have that direct connection. A lot of people study a topic in a lab simply because they are part of that lab and the supervisor chose to. But these people do not really know why they are studying it or what future benefit it will have. In my lab, I think my students do feel very lucky because they know exactly whom they are working to benefit. They are working for all of those patients in the hospital and they have a direct connection to the practise.

With the help of bioinformation and collaboration between experts that were not previously as involved, what do you think the next big breakthrough is? Well, just ten years ago we were all looking at the human genome and profiling individual genomes; that was a big breakthrough. I think we are really advancing to the level where we need to take all of that information and translate it into targeted therapies for patients. That is going to be the next big breakthrough. If there were a team of scientists that could collaboratively work on every cancer patient, maybe we could improve survival. Right now, the

solutions are not financially feasible because we need the technology sector to help us work on making the tools accessible and cheap. It is about making the new wave of scientific discoveries accessible and trying to figure out how to generalize that technology to the population. In fact, it will take economists as well to work on this kind of problem – to understand how to deliver that degree of technological diagnostic care to the general population. It is all about translating technologies to patients. It will require a lot more people than just scientists in a laboratory. It will require bioinformaticians, health care economists, people in the technology sector, and more. The question is how to get these people to work together to deal with the disease? Just twenty to thirty years ago, science was such a different field. It was all about, “I am a scientist, I study sarcomas and my model is mice and my laboratory is in this building and I work by myself.” That mindset does not exist anymore. Science is evolving into a team game. I hope I am going to be able to stay youthful enough in my philosophy to change with the times, and stay up to date with the new technology and new ideas.

Your career has spanned a very short period of time, and you still have a great deal of time remaining in your career. What do you hope your legacy to be when all is said and done? I hope to be an active participant in this revolution of how therapies are administered to cancer patients, helping to shape how brain tumours are treated and managed in the future. I think that at the end of my career, I would like to have been able to contribute to advancing brain tumour therapy to a point where people survive things that they never would have been able to survive and are able to have a better quality of life. These are some of my patients who have not made it [she points to pictures of young children behind her monitor], so at the end my career, I would like to know that patients with those same tumours are now surviving. That is what drives me and my laboratory program. We are working not towards a cure but to better outcomes and survival, and ways of managing things that we are not able to manage right now. It is bound to happen, so I just want to play a role and participate.

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interview conductors

ILIA OSTROVSKI

Bachelor of Health Sciences (Honours) Program, Class of 2014

Bernard HO

Bachelor of Health Sciences (Honours) Program, Class of 2014

Kimia Sorouri

Bachelor of Health Sciences (Honours) Program, Class of 2015

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