september 2008

VOL.81 NO.7 September 2008 $5.00

SAN FRANCISCO MEDICINEJ O U R N A L O F T H E S A N F R A N C I S C O M E D I C A L S O C I E T Y

DNA

MIEC reduced its already low rates in the last 15 of 18 years (1991-2008) with dividend credits on premiums for $1M/3M limits - averaging a 24.4% savings a year to its policyholders.

Which insurance carrier has distributed dividends* 15 of the last 18 years?

Has your professional liability carrier done that for you? If not, it may be time to ask why not!

Other benefits include:n We have a ZERO profit motiven MIEC is 100% owned and governed by its

policyholdersn We have provided California policyholders

continuous service for over 30 years n We have resolved over 24,000 malpractice

claims and lawsuits reported by our policyholders. Nearly 90% were closed without payment.

n We are rated A- {excellent} by AM Best’s

For more information or to apply: Go to www.miec.com or call 1-800-227-4527 and ask for our San Francisco Underwriter or email us at [email protected].* Future dividends cannot be guaranteed.

Cumulative California Dividends

0

22,000,000

44,000,000

66,000,000

88,000,000

110,000,000

1 9 9 1 — 2 0 0 8

Medical Insurance Exchange of California6250 Claremont Avenue, Oakland, California 94618 800-227-4527 www.miec.comSFmedSoc_ad_05.06.08

MIECOwned by the policyholders we protect.

SFmedSoc_ad_01.28.08.indd 1 5/6/08 9:09:16 AM

www.sfms.org september 2008San FranciSco Medicine�

conTenTS

San FranciSco Medicine September 2008 Volume 81, number 7The Mystery of dna

FEATURE ARTICLES

10 Science and the Mysteries of DNA MikeDenney,MD,PhD

12 Epigenetics VictoriaLunyak,PhD

14 The Genetics of Mental Disorders StevenP.Hamilton,MD,PhD

16 Genetics and Drug Response JaekyuShin,MS,PharmD;andRobertL.Naussbaum,MD

18 Understanding a Patient’s Genes KatiMalabed,MS,CGC

20 Cancer in the Family KathleenMcCowin,JD,MS;andMarciaMcCowin,MD

22 Coming of Age PatriciaKelly,PhD

24 Unlocking the Genetic Mystery EishaZaid

26 Darwin and Literature SteveHeilig,MPH

27 Breast Cancer Risk: An Expert Speaks EricaGoode,MD,MPH

MONTHLY COLUMNS

4 On Your Behalf

5 Upcoming SFMS Events

7 President’s Message StevenFugaro,MD

9 Editorial MikeDenney,MD,PhD

28 Hospital News

�0 Classified Ads

�0 In Memoriam

editorial and Advertising offices

1003 A o’reilly Ave, san francisco, CA 94129

phone: 415.561.0850 ext.261 fax: 415.561.0833

email: [email protected] web: www.sfms.org

subscriptions: $45 per year; $5 per issue

Advertising information is available on our website, www.sfms.org, or

can be sent upon request.

printing: sundance press p.o. box 26605 tuscon, AZ 85726-6605

The width is 3.5 by 4” highCALL Kae with any questions or concerns 415-567-5888

Fusion Diagnostic Group’s advanced technology and software bring evaluation and measurementtools to the Physician to use in the clinical setting.we also have a full time physician on staff.

High Resolution PET/CT scans

Mon - Saturday 8-5 + (flexible hours with advance request)

Positron Emission Tomography (PET)Computed Tomography (CT)

Molecular / Functional ImagingAccurate & Precise Imaging

1700 California St. #260California at Van Ness in San Francisco, CA(415) 921-7226 • 1 (800) 334-0336 • (415) 921-7225 FAXwww.fdg-inc.net

4San FranciSco Medicineseptember 2008 www.sfms.org4San FranciSco Medicineseptember 2008 www.sfms.org

on YoUr BeHaLF

aMa Helps defeat Medicare Pay-ment reduction

Despite a presidential veto,H.R.6331,the“MedicareImprovements forPatientsandProvidersActof2008,”passedwithwide,bi-partisanmajorities inboth theU.S.HouseofRepresentativesandtheU.S.Senate.TheAMAandmanyothermedicalgroupspushedveryhardfordefeatoftheproposedreimbursementcuts.This legislation replaces the10.6%paymentcutthatwentintoeffectonJuly1witha0.5%updateextensionthroughDecember31,2008.Forcalendaryear2009,theupdatewillbe1.1%.Other importantprovisionssuchasextendingtheGPCIflooronphysicianworkwerealsoin-cluded.This18-monthreprievewillalsoprovidetime forCongress toworkwithphysiciansondevelopingalong-termsolutiontoapaymentsystemthatallagreeisfatallyflawed.

Judge Blocks State’s cut in Medi-cal Fees

Afederal judgehasblockedCalifornia’s10percent cut inMedi-Cal fees fordoctors,dentists, andpharmacies, saying themoney-savingmeasuresappear toviolate federal lawandwouldworsenmedicalcareformillionsofpoorpeople.Inherruling,U.S.DistrictJudgeChristinaSnyderofLosAngeles said shewasawareofCalifornia’sgapingdeficit,butsaidthestatehasaccepted federal funds forMedi-Caland isbound touse them toprovidequalityhealthcare to low-income residents.Medicalgroups suchas theCMApresentedevidencethatmanyphysicianshadpreviously stoppedtreatingMedi-Calpatientsbecauseofthestate’slowreimbursementrates,andmanymorewouldrefusetoacceptnewMedi-Calpatientsbecauseofthe10percentcuts.Thisinjunctionhaltsthe10percentfeereductionsfordoctors,dentists,pharmacies,adultdayhealthcenters,andclin-icsreceivingMedi-Calfunds.Stateofficialsareplanningtoappealthedecision.

candidates’ night Youarecordiallyinvitedtoparticipateina

SanFranciscoBoardofSupervisorsCandidates’InterviewNightonWednesday,September24,2008,startingat5:15p.m.attheSFMSofficesat

A sampling of activities and actions of interest to SFMS members

1003AO’ReillyAvenueinthePresidio.RSVPrequired.

Asmanyofyouknow,thisisagreatwaytogettoknowthecandidatesearlyonintheirpoliticalcareers.Theformatforthiseventwillbeaseriesofinformalinterviewswitheachoftheinvitedcandidates.Candidateswillbeinter-viewedbysmallgroupsofphysicians.Wehavepreparedalistofinterviewquestionswhichwillbesentinadvancetothecandidates.

If youare interested inattending,pleaseRSVPtoPosiLyonbyphoneat(415)561-0850extension260orbye-mailatpylon@sfms.orgnolaterthanSeptember18.Makesuretoincludeyourphonenumberande-mailaddresssowecanprovideyouwithdirectionstotheevent.

Membership UpdatesThe 2008–2009 Membership Directory

has been mailed to all active members.Ifyouhavenot received this importantmember re-source,orifyouareinterestedinobtainingextracopies,contacttheMembershipDepartment.

The entire membership should have re-ceived the SFMS annual database update forms in August.Ifyouhaveanychanges,updates,orcorrectionstoyourinformationofrecord,pleasebesuretorespondtothemailingatyourearliestconvenienceifyouhavenotalreadydoneso.

Have you paid your dues online yet?Start-ingwiththe2009billing,membersareabletopaytheirduesbyvisitingtheSFMSwebsite.Detailsonthisnewandconvenientwaytorenewyourmembershipwillbeprovidedonthe2009duesstatementsthroughouttherenewalperiod.

an opportunity to reach out to the next Generation of Medicine

OnThursday,September25,membersoftheSanFranciscoMedicalSocietyareinvitedtoapizzapartymixerwithfirst-andsecond-yearmedicalstudentsattheUCSFcampus.CheckthewebsiteorcontacttheMembershipDepart-mentfortheexacttimeandlocation.Thiseventwillbe sponsoredbyEpocrates andwillbeawonderfulchancetomeetandtalkwiththenextgenerationofdoctors,whoareequallyeagertomeetthosealreadyestablishedintheprofession.Don’tmissit!Formoreinformation,ortoRSVP,

September 2008Volume 81, number 7

Editor Mike DenneyManaging Editor Amanda DenzCopy Editor Mary VanClayCover Artist Amanda Denz

Editorial Board

Chairman Mike DenneyObituarist Nancy Thomson

SFMS oFFicErS

President Steven H. FugaroPresident-Elect Charles J. Wibbelsman Secretary Gary L. ChanTreasurer Michael RokeachEditor Mike DenneyImmediate Past President Stephen E. Follansbee

SFMS Executive Staff

Executive Director Mary Lou LicwinkoDirector of Public Health & Education Steve HeiligDirector of Administration Posi LyonDirector of Membership Therese PorterDirector of Communications Amanda Denz

CMA Trustee Robert J. MargolinAMA Representatives

H. Hugh Vincent, DelegateRobert J. Margolin, Alternate Delegate

Stephen Askin Toni Brayer Linda Hawes CleverGordon Fung Erica Goode Gretchen Gooding

Shieva Khayam-BashiArthur LyonsTerri Pickering Ricki Pollycove Kathleen Unger Stephen Walsh

Board of directors

Term: Jan 2008-Dec 2010George A. FourasKeith LoringWilliam MillerJeffrey NewmanThomas J. PeitzDaniel M. RaybinMichael H. SiuTerm: Jan 2007-Dec 2009Brian T. Andrews Lucy S. CrainJane M. HightowerDonald C. Kitt

Jordan ShlainLily M. TanShannon Udovic-ConstantTerm: Jan 2006-Dec 2008Mei-Ling E. FongThomas H. LeeCarolyn D. MarRodman S. RogersJohn B. SikorskiPeter W. SullivanJohn I. Umekubo

4San FranciSco Medicineseptember 2008 www.sfms.org www.sfms.org september 2008San FranciSco Medicine54San FranciSco Medicineseptember 2008 www.sfms.org

contactTheresePorterat(415)[email protected].

SFMS Seminar ScheduleAdvance registration is required for all

SFMS seminars. Please contact Posi Lyon at [email protected] or (415) 561-0850 exten-sion 260 for more information. All seminars take place at the SFMS offices, located in the Presidio in San Francisco.

October3,2008Customer Service/Front Office Telephone TechniquesThishalf-daypracticemanagementseminarwillprovidevaluablestafftrainingtohandlephonecallsandschedulingprofessionallyandefficiently.9:00a.m.to12:00p.m.(8:40a.m.registration/continentalbreakfast)$120forSFMS/CMAmembersandtheirstaff($99eachforadditionalattendeesfromthesameoffice);$159eachfornonmembers

November4,2008“MBA” for Physicians and Office Managers9:00a.m.to5:00p.m.(8:40a.m.registration/continentalbreakfast)This one-day seminar is designed to pro-videcriticalbusiness skills in theareasoffi-nance,operations,andpersonnelmanagement.$250forSFMS/CMAmembersandtheirstaff($225eachforadditionalattendeesfromsameoffice);$325fornonmembers

other Local events

September25,2008In the Heart of the Mission GalaCathedralofSaintMaryoftheAssumption,11GoughSt.,SanFranciscoCelebratethefortiethanniversaryoftheMissionNeighborhoodHealthCenterwithchampagne,sangria,andaLatinofoodfestival.This fund-raiserwillhonorDoloresHuerta,cofounderofUnitedFarmworkers, andAntoniaSacchetti,MD, retiringmedicaldirectorof thirty-eightyears.Pleasecall(415)552-3870formorein-formation,tobuytickets,ortoreserveatableforten.

For Local Events of Interest Please Visit

Our Website, www.sfms.org.

September27,2008CMA Foundation’s Obesity Prevention Cul-tural Competency Training Symposium9:00a.m.to12:00p.m.attheAirportHiltoninOakland,CaliforniaThistrainingwillprovidephysiciansandhealthcareproviderswithcomprehensive tools, re-sources,andtipstoprovideculturallycompetentobesitypreventioneducationand services fortheirpatients.Ifyouwouldlikemoreinforma-tionabouttheproject,pleasevisitwww.calmed-foundation.org/projects/obesityProject.aspx.orcontactJenniferCaulfield,ObesityPreventionProjectAssistant,at(916)[email protected].

October2–3,2008California Primary Care Association Annual ConferenceDoubleTreeHotelOntarioAirport,OntarioContactCaroleLoebat(916)[email protected],orvisitwww.cpca.orgformoreinformation.

October4,2008Headache Cooperative of the Pacific Fall ColloquiumMission Bay Conference Center at UCSF1675OwensSt.,SanFranciscoThis conference will highlight very recentadvancesinheadachemedicineinanintimate,casual,andcreative settingwherehealthcareprofessionalscanexpandtheircollectiveknowl-edgebasesbysharingexperiences,observations,and ideas.Formore information,[email protected].

October23,2008Hope for the Uninsured: Operation Access 15 Year Anniversary and Volunteer Celebration FormedicalprofessionalswhovolunteerwithOperationAccess(OA),aSanFrancisco-basednonprofitthatprovidesdonatedoutpatientsurgi-calandspecialtycaretouninsured,low-incomeBayArearesidents.Drinks,dinnerandaprogramwithkeynotespeakersandOAsurgeonco-found-ersDrs.DougGreyandWilliamSchecter.AttheSanFranciscopresidiobetween6–8pm.Invita-tiononly.Formoreinformationpleasecontactcommunications@operationaccess.org

california debates direct to consumer Genetic Testing

Whether or not individuals shouldhaveaccesstotheirgeneticinformationisatopiccurrentlyupfordebateinCalifor-nia. In June laboratory testing regulatorsin the state sent thirteencompanies thatoffergenetictestingdirectlytoconsumers“ceaseanddesist” letters. In lateAugust,however,thetidesturnedwhenNavigenicsandGooglebacked23andMeweregrantedlicensestodobusinessinthestate.

TheceaseanddesistletterssaidthatcompaniescouldnotsolicitcustomersfromCaliforniawithoutreceivingalicensefromthe state tooperate as a laboratory andthatdoctorshadtobeinvolvedinorderinggenetictests.

According toanarticle in theNew York Times,thecompaniesarguedthattheywerenotofferingmedicaltestingbutratherpersonalgeneticinformationservices,andthatconsumershadarighttoinformationfromtheirownDNA.Thecompaniesalsosaid theydidnotneeda licensebecausetheactualtestingoftheDNAsampleswasbeingdonebyoutsidelaboratoriesthatdidhavelicenses.

“Ithinkwe’reverysatisfiedthattheyhavemettheCalifornia requirements forlicensure,”KathleenJ.Billingsley,aseniorofficialintheCaliforniapublichealthde-partment,toldtheNew York Times.

Fouroftheothercompaniestargetedbythestatehaveagreedtostopsellingtestsinthestate,whiletherest, includingthegenomictestingcompanyDeCodeGenet-ics,remaininlimbo.

Forthefullstory,seetheNew York Timeswebsite, www.nytimes.com/2008/08/20/business/20gene.html.

The Best Care -The Best CareerVeterans A�airs Medical Center San Francisco

PRIMARY CARE PHYSICIAN/BOARD CERTIFIED INTERNISTThe Department of Veterans Affairs is searching for a Primary Care Physician/Board Certified Internist for the Ukiah VA Outpatient Clinic located 100 miles north of SF on Hwy 101. The clinic serves Mendocino and Lake Counties where affordable living meets outstanding recreation with easy access to the spectacular coastline. Responsibilities include: building a manageable panel size across the adult age continuum; some administrative duties, and no call. Great supportive staff and potential for growth await the enthusiastic, self starter who values team spirit and cooperation. Full time position available.

Interested candidates please contact Linda Mulligan, MD at (707) 468-7704 and send a CV c/o Ken Browne, Ukiah Outpatient Clinic,

630 Kings Court, Ukiah, CA 95482. Fax (707) 468-7733.

US Citizenship required. Selected applicant is subject to random drug testing. Equal Opportunity Employer.

Welcome New Members!TheSanFranciscoMedicalSocietywouldliketowelcomethefollowingnewmembers:

Pamela Chan, MD, Permanente Medical Group

Louise Greenspan , MD, Permanente Medical Group, Referred by Charles Wibbelsman, MD

Josephine (Josie) Howard , MD, Referred by Ricki Pollycove, MD

Gary Huang , MD, Permanente Medical Group

Wen Jing , MD, Permanente Medical Group, Referred by Sid Boriak, MD

Kristine Lee , MD, Permanente Medical Group, Referred by Charles Wibbelsman, MD

Carolyn Y. Li , MD, Permanente Medical Group, Referred by Wen Jin, MD

STUDENTS (UCSF)

Nancy Hsu, Mara E, Horwitz, and Lacey R. Whitmire

www.sfms.org september 2008 San FranciSco Medicine7

PreSidenT’S MeSSaGe

t his issueofSan Francisco Medicine focuseson themostdramaticstoryinbiologyofthelastsixtyyears—thedis-coveryofDNAandtherapidprogressmadeoverthepast

decadesinunderstandingthecomplexinteractionofourgenomeanddisease.WhenIwasacollegestudentinthe1970s,thebreak-throughbyWatsonandCrickinidentifyingthestructureofDNAwasbarelytwentyyearsold.ResearchonrecombinantDNAandbiotechnologywas justbeginning.Sincethen,enormousstrideshavebeenmadeinunderstandingtheexactstructureandfunctionofDNAinourgenome.Indeed,thecompletionofthesequenceofthehumangenomehasbeenthestartofthegenomics“revolution,”withpromisesofnumerousdirectapplicationstopatientcare.

OneofthemostpowerfultechnologiesinthisfieldistheDNAmicroarray.DNAprobeshavebeenminiaturizedtoallowthousandsofspecificDNAorRNAsequencestobedetectedsimultaneouslyonasmallslidejustoneortwocentimeterssquare.TheseDNAmicroarraysofferunprecedentedopportunitiesforanalyzinggeneexpressionandunderstandinggene function.Thereare severalmajorapplicationsofmicroarrays,oneofwhichisgeneexpressionprofiling.Theabilitytodetecttheexpressionlevelofthousandsofgenesallowsexplorationofgenefunctiononascalepreviouslyimpossible.Inclinicalpractice,moreprecisediagnosisandriskas-sessmentbasedonexpressionprofilesareverypromising.AlreadythereisthemicroarraytechnologytoreclassifypatientswithdiffuselargeBcelllymphomaasbeinginprognosticsubgroupswithfive-yearsurvivalsrangingfrom40to80percent.

Anequallyexcitingclinicalapplicationisgenotyping,inwhichmutationsandpolymorphismscanbedetectedthatunderliesuscep-tibilitytoarangeofcommondiseases.This“geneticfingerprint,”obtainedviaDNAmicroarrays,willhopefullyenableclinicianstoassesstheriskofpatientsofdevelopingsinglegenedisordersormorecommoncomplexdiseasessuchasdiabetes,hypertension,andcoronaryarterydisease.

OneapplicationofgenotypinghasalreadybeenapprovedbytheFDAforgeneralclinicaluse.VitaminKepoxidereductase(VKORC1)isthetherapeutictargetofwarfarin.ThosepatientswithtwocopiesofthevariantalleleforVKORC1 reachatherapeuticlevelofanticoagulationtwiceasquickly(sevendaysversusfifteendays)comparedtothosepatientswithtwocopiesofthenonvariantallele.Thisfindingconfirmstheimportanceofgeneticvariationin

Steven Fugaro, MD

Discovering DNA

influencingdrugmetabolismandisanexampleoftheburgeoningfieldofpharmacogenomics.

Anotherfinding,usinggenotypingtechnology,hassomeveryinterestingconnectionswiththeMiddleAges.Inthelate1990s,Samsonidentifiedthecc-chemokinereceptor-5protein(CCR5),atransmembraneGproteinreceptorthatmediatestheinternalizationofHIVinmacrophagesandmonocytes.StudiesofindividualswhohavebeenmultiplyexposedtoHIVandyetremaindisease-freeledtotheidentificationofagenemutation.theCCR5D32allelewithmultiplebasepairdeletion.Thisshortenedproteinisconsequentlynotintegratedintothecellmembrane.ThehomozygousstateoftheCCR5D32alleleisassociatedwithahighdegreeofprotectionagainstHIVinfection.

TheCCR5D32alleleiscommoninEurope,withafrequencyof10to20percentinCaucasians.Thereisevidencethatthismuta-tionfirstarosemorethan3,000yearsago,buthowdiditbecomesoprevalentacrossEuropeinanagebeforetheHIVepidemic?Couldthisallelealsohaveboostedresistancetoanearlierepidemic,suchassmallpoxorthebubonicplague?

Answerstothesequestions,usingmedievalDNA,maycomefromoneof themost ambitious archeologicalprojects in theNetherlands.Since2002,anthropologistsandarcheologistshavebeenworkingonamassiveexcavationofa600-year-oldcemeteryinEindhovenatSt.Catherine’sChurch.Theteamhasunearthedtheskeletonsofmorethan750residentsfromtheMiddleAgeswiththeexpresspurposeofobtainingtheirDNAandcreatingamedievalEindhovenDNAbank.Studiesof thisancientDNAwillbeusedtoanswerquestionsabouttheCCR5D32alleleanditsputativeroleinenablingresistancetotheBlackDeath.Bystudyinggeneticvariationsovertime,researchershopetoadvanceknowledgeofthegeneticfactorsthatincreasetheriskofdiseaseorthatboostimmunitytoinfection.

Obviously,itisintriguingtolookbothbackwardandforwardaswebegintoreapthebenefitsofunravelingthemysteriesofDNA.Genomicsnowroutinelyusesmicroarraysforgeneexpressionpro-filing,mutationdetection,genotyping,andgenediscovery.Itwillbefascinatingtofollowthisfieldinthecomingyearsaswegaininsightsintothefunctionofthousandsofgenespreviouslyknownonlybytheirgenesequence.

2008 Northern California Conference on

Transgender Health & Wellness Jointly presented by Sutter Medical Center of Santa Rosa and

the Sonoma County Academic Foundation for Excellence in Medicine

October 10 - 11, 2008 Friday program 12:30pm-5:30pm Friday reception 5:30pm-7:00pm

Saturday program 7:30am-5:30pm

The Event Center Sonoma Mountain Village

1400 Valley House Drive Rohnert Park, CA 94928

Register Today!Take advantage of early

registration by Sept 19th.Brochure with registration

form is available at www.scafem.orgOr call (707) 527-6223

11.5 creditsfor medical and

mental health professionals Community learning track also available

Thanks to our generous sponsors Positive Images FTMsc Rykken & Scull Trust PFLAG-NB CA Office of AIDS GILEAD Sonoma Co Public Health North Coast AIDS Education & Train’g Ctr

Conference Faculty (partial list) Michael L. Brownstein, MD, FACS Jennifer A. Burnett, MD, Assistant Professor

of Community Medicine, UCSF Nicholas DeMara, PhD, Clinical Psychologist Randall Ehrbar, PsyD, Clinical Psychologist Leah M. Kelley, MD, Ob/Gyn Lori Kohler, MD, Professor, UCSF Judy D. Lively, MD, Physician-in-Chief Carol F. Milazzo, MD, FAAP Suegee Tamar-Mattis, DO Lucy Watkins, PhD, Clinical Psychologist

www.sfms.org september 2008 San FranciSco Medicine9

ediToriaL

A ftermyninety-six-year-oldmotherdiedafewyearsago,Ibeganthetediousjobofsiftingthroughdrawersandboxes,sortingouthundredsofsmallitemsshehadsquirreledaway

overtheyears—oldpostcardsandletters,rustypaperclips,canceledchecks,outdatedreceipts,frazzledspoolsofthread,andthelike.Myfavoritepieceofallsitshereonmydesk.

Idiscovereditinasmallcardboardboxthatcontainedmanykeysofdifferentshapesandsizes,eachcarefullyidentifiedinwritingonaroundwhitetagattachedbyastring.Someofthekeyswerefordoorstolong-sincevacatedhouses;onewasforadiscardedtoolbox;otherswereforabandonedcabinets,storerooms,andgarages;andstillothersmalloneswereforpadlocks, jewelryboxes,andtinystrap-locksonbooksanddiaries.Onekeyisveryspecial,andIkeephereonmydeskbecauseitseemstohavedeepmeaning.Itisagoldkey,andthereontheroundwhitetag,inMother’sdistinctivehand,thewritingsays,“Keytoanunknownlock.”

Motherisnowanancestor,and,asinthisissueofSan Francisco MedicineweponderthemysteriesofDNA,perhapsweshouldthinkofherwritingonthatwhitetagattachedtothatgoldkeyasakindofposthumousoracularmessage.Indeed,wemightdowelltoviewtherecentidentificationofthe30,000genesofthehumangenomeandthe3.1billionbasepairstobeasfar-reachingastheparadigm-shiftingdiscoveriesofsixteenth-centuryCopernicuswhotaughtusthatwearenotthecenteroftheuniverse,nineteenth-centuryDarwinwhodemonstratedthatweareonlyoneformofawholelivingweboflife,andtwentieth-centuryFreudwhoshowedthatourcognitiveawarenessisonlyafractionoftheirrationalunconsciousimagesandmotivationsthatguideourlives.

Areweinthistwenty-firstcenturyreadytoaccepttherealitythatallofourbodilyandpersonalcharacteristicscanbepreciselyidentified,andpossiblyaltered,onaspecificdouble-helixDNAmoleculethatisthesecretoflifeitself—eachofuswithourownuniquegenome?

Asaheadlineinarecentissueof The New York Times asked,“DNAChangedtheWorld.NowWhat?”

Followingthemeticulousmappingofthehumangenome,wealreadyhaveforensicgenomics,diagnosticgenomics,nutrigenom-ics,andpharmacogenomics.Weevenhaveepigenetics,throughwhichresearcherscandeterminehowtheexternalandtheinternal

environmentcanalterDNAsoastochangephenotypeswithinonegeneration.

Lookingback,wecandiscoverourancestrybyhavingtestedourmitochondrialDNAthroughourmother’slineage,andmencanhavetheYchromosomeDNAtracedthroughtheirfather’slineage.Suchdatacangiveusaccuratedataaboutourpropensitytodevelopcertaindiseases,someofthemlethal.Thisinformationcanthenleadtodecisionsaboutchildbearingandsuchprofoundquestionsaswhether tohavepreventativemeasures, includingmajorsurgeryforremovalofsusceptibleorgans.

Looking forward, some scientistspredict thatwithgeneticengineeringwemaybeabletoconstructmore“perfect”humans,not justbymodifying susceptibility todisease,butbypredeter-miningsuchcharacteristicsasIQ,height,appearance,andevenpersonality.Notonlythat,germ-linegeneticengineeringmightenablesuchalteredgenomestobepassedontofuturegenerationsthrougheggandsperm.

Otherscientists,however,urgecautionwhenmanipulatingsuchcomplexity.TheyfocusonthemysteriesofDNA,warningthateverycellthatexistsarosefromacellthatprecededit,admonish-ingthatwearejustlearninghowgenesinteractwithoneanother,warningaboutthecomplexityoftheinteractionsofgeneswiththeirenvironment,anddreadingthemonstrousindividualsandtraitsthatcouldresultfromgeneticengineeringgoneawry.NotingthatneuroscientistsarebeginningtounderstandhowparticularDNAcombinationscandeterminepersonalitytraits,psychopathologies,moodchanges,andaddictionpropensities,ethicistspointoutthatdefenselawyersmightsoonblametheirclients’crimesonDNA.

AcknowledgingthesecomplexpermutationsofthemysteriesofDNA,StanfordanthropologistandgeneticistKennethWeisswasrecentlyquotedassaying,“Ithinkweshouldreallytempermakinggeneticstheestablishedreligionofourcountry.”

Inviewofboththesephenomenalopportunitiesandpossibledireconsequences,whatwillwelearnabouthumangeneticsinthefuture?Asforme,IshalldwelluponthemysteriesofDNA,rememberingthewonderfuloracularmessageofdearMother,whodonatedto,nurtured,andgavebirthtomygenome.MotherwouldsaythatDNAisakeytoanunknownlock.

Key to an Unknown Lock

Mike Denney, MD, PhD


THe MYSTerY oF dna

I ntheyear1865,sciencewasnotreadyforanarticlepublishedinProceedings of the Scientific Society of Brno by the

AustrianbotanistandmonkGregorMen-del.Afterworkingformorethantenyearsin thegardensof theAugustinianmon-astery inBohemia, studyinghybridPisum sativum—commongardenpeas—Mendelobservedthatphysicaltraitswerenotpassedonfromgenerationtogenerationinmixedorblendedformsbutappearedordidnotappearintheoffspringindependently.Furthermore,henotedthatthenumericcountoftraitsappearedinthenextgenerationinnearlywhole-numberratiosandcouldtherebybeexpressedas“dominant”or“recessive.”

Thiswastoomuchforaworldthatwasalreadyreelinginanuproarfromthescien-tific,cultural,andreligiousimplicationsofCharlesDarwin’sbookOrigin of Species,withitslawofnaturalselection,whichhadbeenpublishedsixyearsearlierin1859.Theeccle-siasticalestablishment,includingCalvinistconservatives,highAnglicanchurchmen,andtheBishopofOxford,sidedagainstascience that seemed todisagreewith theteachingsof “creationism”as recorded inGenesis.Ontheotherhand,philosopherssuchasHerbertSpencerandJulianHuxleyusedthefindingstoattackthechurchandpromotetheirowntheoriesofsecularsocialprogress.Thisapparentdisputeof scienceversusreligion,ofevolutionversuscreation-ism,continuestothepresentday.

Meanwhile,Mendel’s lawsof inheri-tanceweredenouncedbyafewscientists,suchasthereigningleaderinbotany,KarlNaegeli,butsimplyignoredbymostothers,includingDarwinhimself.LittledidanyofthemknowthatMendel’sworkwasthekey tounderstandingDarwin’snotionofnaturalselectionbyprovidingthemissing

element to explainhowmutationscouldcontinuetomanifestthemselves in suc-ceedinggenerations.

It was in theyear1900,thirty-fiveyears afterMendel’spublication and fif-teen years after hisdeath, that the sci-entific communityfinally was ready toembrace the lawsofinheritance. It wasin that sameyearof1900 thatBertrandRusselldiscoveredtheerrorinhisPrincipia Mathematica,anerrorthatunderminedthefoundationsofmathematicsandlogic,thatlaterwasconfirmedbyGodel’sIncomplete-nessTheoremand resulted inchaosandcomplexity theory, all ofwhichdemon-stratedthatmathematicsandsciencewereforever incompletedescriptionsof reality,caughtinarecursive,self-referentialparadoxthatunderminedthepositivistic,empiricalconsistenciesoflogicitself.

Inthatparadoxicalyearof1900,HugodeVries,professorofbotanyat theUni-versityofAmsterdam,completedhisownstudiesonhybridizationusingOenothera lamarckiana—theeveningprimrose—namedafteranearlierbiologist,Jean-BaptisteLa-marck,whowasthefirsttoofferacoherenttheoryofevolution.Inhispublication,deVriespostulateddiscreteheredityentitiescalled “pangenes,”and thedata fromhisresearchontheprimroseclearlyconfirmedMendel’s work. Meanwhile, two otherbotanists,CarlCorrens,attheUniversityofTübingen,andErichTschermak,atUniver-sityofAgriculturalSciencesinVienna,also

confirmedMendel’sfindings in theirownhybridizationexperiments.Finally,theworldofsciencewasreadytoembraceMendel’slawofinheritanceandtoseeitsvitalplaceinthetheoryofevolution.

ButLamarckianandMendeliantheo-riesofevolutionwere fundamentallyop-posed. Whereas Lamarckians proposedthat thegeneticchanges in specieswere“acquired,”theresultofenvironmentactinguponthem,Mendelianthoughtconsideredthechangestobespontaneousmutations,whichthenweretestedintheenvironmentby“survivalofthefittest.”Thesetwotheoriesreachedtheiroppositionalpeak inRussiaduringthe1940sand1950swhenagrono-mistTrofimLysenko,promisingabundantcropyields throughLamarckiangenetics,becamedirectoroftheInstituteofGeneticsandpromptlyinstitutedaruthlesscampaign,declaringMendelianideastobe“decadent.”Opposition toLysenkowas formallyout-lawedin1948,andscientistswhodidopposewerecalled“enemiesoftheSovietpeople.”Theyfledthecountry,weresenttothegu-lags,ormysteriouslydisappeared.By1964,however,when theabundantcropyields

Science and the Mysteries of DNAFrom Gregor Mendel to J. Craig Venter

Mike Denney, MD, PhD


failedtomaterialize,LysenkowasdiscreditedandRussia joinedtherestof thecivilizedworldinrecognizingthevalidity,indeedthebrilliance,ofMendel’swork.

However,sciencewasnotfinishedwithJean-BaptisteLamarck.The identificationduringthefirsthalfofthetwentiethcenturyof thenatureof genes and their specificregionsonchromosomes, themappingofthechromosomesofDrosophilafruitfly,thedemonstrationthatDNAiswhattransmitsthegene’sinformation,andtheelucidationof thedouble-helix structureofDNAbyWatsonandCrickallpavedthewaytoadeeperunderstandingof justhowgenesfunction.Newerobservationsrevealedthat grandchildrenofwomensubjectedtofaminehadlowbirthratesandweresusceptibletocertaindiseases,andthatoffspringofbirdswho surviveddroughtshad longerbeaks.TheseobservationsaddedspicetoMendel’sgenetics. Then, laboratory research onmicewhowerefedlargedosesoffolicaciddemonstrated that,byachemicalprocessofmethylation,newinheritabletraits,suchasthecolorofhair,couldbepassedonbychangingthecellularchemicalenvironmentwithoutchangingtheDNAitself.Thusawholenewscienceofepigeneticsevolved,validatingLamarck’s theorythatenviron-mental factors couldproduce inheritablechangesingenetictraits.

Nowadays,understandingthe lawsofhereditymayrequirebothLamarckianandMendelian constructs.Medical researchnow focuses upon this phenomenon ofepigenetics and its influenceuponmanydiseases,includingworkbyVictoriaLunyak,PhD,attheBuckInstituteinMarinCounty,California.(Seeherarticleonpage12).

Butsuchacombinationofheredityandenvironmentbringsahighlevelofcomplex-ity, someofwhich isnotmeasurablebyordinary science.Following the report in2007ofthecompletesequencingofthehu-mangenomebyJamesWatsonandJ.CraigVenter,therelationshipbetweenDNAandscienceisheraldingnewhorizonsthatmayevenbegintoincludetherecursiveparadoxinmathematicsandlogicthatBertrandRus-selldiscoveredin1900.Indeed,theillogicalparadoxofchaosandcomplexity theory,whichthusfarhasbeenshunned,perhapsfeared,bythelogicalscientificcommunity,

maybefindingitswayintoanewsciencethroughthemysteriesofDNA.

Inadditiontocooperatingandcompet-ingwithJamesWatsonintheracetomapthehumangenome, J.CraigVenterhasbeenaleaderintheuseofsupercomputerstoexplorethecomplexitiesofhumangenetics.Heandhisteammemberswerethefirsttodecode thegenomeofawholeorganism,thebacteriumHaemophilis influenzae, andlatersequencedthefruitflyandthemousegenomes.WhenhesuccessfullycompletedthesequencingofthehumangenomeitwaswithhisownDNA,usinganewtechniquecalled“shotgunsequencing,”whichrequiressupercomputersthatcanprocessnewmath-ematicalalgorithmsuponmassiveamountsofdatawithmemorystoragemeasured inpetabytes(onequadrillionbytes).

Using this technique now in evenmorecomplexways,heiscollectingairandoceanspecimensandrunningtherandomlyharvestedDNAsequences throughsuper-computers.HehasnowdiscoveredDNAoflifeformsthathaveyettobeidentifiedbyphenotype.Ventersays,“Wehavesincediscoveredtensofthousandofnewspecies,manyof them strangeandexotic. Inallwediscoveredmorethan1.3millionnewgenesinonly200litersofwater.Toputthisnumberincontext,thefirstsamplesanalyzeddoubledthenumberofknowngenesontheplanet.”

Thisnewkindof scientificapproachrepresentsaparadigmshift,amethodologycapableofprocessingdatainhighlycomplexsystems that isbeginning to reveal someorderintheparadoxofchaos.Inhighlycom-plexsystems,suchastheweather,formationofsanddunesinthewind,andtheecosys-temsoftheplanet,spontaneousemergenceofphenomenaoccur thatarebeyondthepredictabilityofordinaryempiricalscience.Ingenetics,suchemergentphenomenacanbethoughtofasmutations.

When emergent phenomena occurin relationship to thecomplexityof thehealingofthehumanbody,wecallthem“miracles” or “spontaneous remissionofincurabledisease.”Andwecansurmisethatsuchspontaneouslyoccurringeventsmightbepresent inalldisease, includingheartdisease,immunedeficiencysyndromes,andcancer.Withmassiveamountsofdata in

supercomputers,wemaybeginto identifytheseemergentphenomena.

Chris Anderson, editor-in-chief ofWiredmagazine,notes that thepetabyteage represents anew science. Insteadofestablishinghypotheses,thensettingouttoprovethembyquantitativeandobjectivedata,thenewscience,withtheaidofsuper-computers,simplygathersmassiveamountsofdata,crunchesthem,andthenidentifieswhatemergesfromthecomplexityandchaosofpossibilities.SpeakingofVenterandthepetabyteage,Andersonsays,“Theoppor-tunityisgreat.Thenewavailabilityofhugeamountsofdata,alongwiththestatisticaltoolstocrunchthesenumbers,offersawholenewwayofunderstandingtheworld.Cor-relationsupersedescausation,andsciencecanadvanceevenwithoutcoherentmodels,unifiedtheories,orreallyanymechanisticexplanationatall.”

In thisyear2008, ismedical sciencereadytoaccepttherealityoftherecursiveparadoxinherentinmathematicsandlogic?Aremedicalresearchersreadytoexplorethemiracleofspontaneousremissionofincur-abledisease?Indeed,arewereadytoincludeinallofhealingthenotionofphenomenaemergingfromthehighlycomplexsystemofthehumanmindandbody,phenomenathatarenotexplainablebyordinaryscience?Whatmightbethefar-reachingimplicationsofshotgunsequencing,petabytetechnology,andawholenewscientificapproach?

And,asaphilosophicalandspiritualaf-terthought,whatmightthisnewparadoxicalscienceoffertotheoldyetongoingcontro-versyaboutscienceversusreligion,evolu-tionversuscreationism?Wemightnoticethattherecursiveparadoxinspontaneousemergenceoutofcomplexity,asthedrivingforceofevolution,leadsusbeyondordinarysciencetotheineffablemysteryofexistenceitself.Additionally,wemightobservethatinGenesis,anditsresultingbeliefincreation-ism, language itselfcontains therecursiveparadoxintheformofmetaphor,allegory,and the imaginal.Thus, looking throughthelensofthecomplexities,paradoxes,andunfathomablemysteriesofDNA,someofusmayevenimagineevolutionandcreationismtobeoneandthesame.


THe MYSTerY oF dna

D NAisanelegantmoleculewithmind-blowingpropertiesandanamazinginformationstorageme-

dium.AsinglecubiccentimeterofDNAholdsmoreinformationthanatrillionCDs.LivingsystemsmustsqueezetheiridentityintowhatthephysicistErwinSchrödingercalleda“codescript.”

ThehistoryofDNA(deoxyribonucleicacid)researchbeginswithFriedrichMie-scher,aSwissbiologistwho,in1868,carriedoutthefirstcarefullyconsideredchemicalstudieson thenucleiof cells.Using thenucleiofpuscellsobtainedfromdiscardedsurgicalbandages,Miescherdetectedaphos-phorus-containingsubstancethathenamednuclein.Heshowedthatnucleinconsistsofanacidicportion,whichweknowtodayasDNA,andabasicproteinportionnowrecognizedashistones,aclassofproteinsresponsibleforthepackagingofDNA.

Although Miescher separated thenucleicacidandstudieditsproperties,thestructureofDNAdidnotbecomeknownwithcertaintyuntilthelate1940s.UsinginformationderivedfromanumberofotherscientistsworkingonvariousaspectsofthechemistryandstructureofDNA,in1953JamesWatson,anAmericangeneticist,andFrancisCrick,anEnglishphysicist,wereabletoassembletheinformation-likepiecesofajigsawpuzzle,producingastructuralmodelofDNA—thedouble-strandedhelix.ThisassemblywaspossibleduetotheelegantandcomprehensiveX-raydiffractionstudiesofRosalindFranklinandMauriceWilkins.Thedoublehelixelectrifiedtheemergingdisciplineofmolecularbiology.Itelectrifiedtheworldaswell.Fortheiroutstandingworkinthediscoveryofthedouble-helicalstruc-tureofDNA,WatsonandCricksharedthe1962NobelPrizeforphysiologyandmedi-

cinewithMauriceWilkins.Sadly,RosalindFranklin,whoseworkgreatlycontributedtothiskeydiscovery,diedbeforethisdate,andtherulesdonotallowaNobelPrizetobeawardedposthumously.

SinceWatsonandCrick started themolecularbiologyrevolutioninthe1950s,culminating incataloging thehumange-nome,thousandsofcommercialtoolshavebeencreatedandmarketedformanipulatingDNAmolecules.Detailsonthenucleotidesequences for everyhumanchromosomehave been accumulated, but the secretremains a secret. DNA was introducedoriginallyasacodescriptoffournucleotides,A,T,G,C,andithasenjoyedsuccessiveincarnations as a “blueprint,” “design,”“template,”or“computerprogram.”YettheDNAparadigmhassofarfailedtoexplaincell-typeandtissuevariationsduringorgan-ismdevelopment,giventhateverycellhasthe samegenetic informationyet followsadifferentdevelopmentalpathway.TheSixty-EighthSymposiumontheGenomeofHomo sapiensatColdSpringHarbor,New

York,wasanimportantlandmarkingenet-ics;andalthoughthereisstillmuchgeneticworktobedone,thecompletesequencingofthisandothergenomessignifiedthatitwastime tomove“abovegenetics”—a literalmeaningofepigenetics.

Over theyearswehave leaned thatDNA encodes for proteins (the basicbuildingblocksofeverylivingsystem),butsomethingelseisinvolvedinthecommand,control,andcoordinationoftheirexpres-sion.WhateverthemessagecontainedinDNA,itmustsomehowbeconveyedintoavarietyoftissuesinlivingorganismsandit must be heritable upon cellular divi-sion. Cumulative research suggests thatsomething remarkablehas takenplace toproduceamultitudeofphenotypeswiththesamegeneticcontent.TheemergingfieldofepigeneticstudiespromisestotakeupthestorywhereThe Double Helixends.

Well,whatisepigenetics?Besidesbe-ingafashionablewordintensivelyusedinalmosteveryotherNIHgrantapplication,whatkindofscienceisit,and,mostimpor-tantly,whatdoesithavetooffer?Thehis-toryofepigeneticsislinkedwiththestudyofevolutionanddevelopment.Thisconcepthad itsorigins in latenineteenth-centurydevelopmentalstudiesthatlaidtheground-workforourpresentconceptualframeworkofdevelopmental-specificgeneregulation.Themeaningoftheterm“epigenetics”hasitself evolvedwithourdramaticprogressindecipheringthemolecularmechanismsunderlying regulationof geneexpressionineukaryotes.Thepresent-daydefinitionstands thus:Epigenetics isa studyofanyinheritable influence on gene activitythatdoesnot involveachange inDNAsequence.

Howisepigeneticinformationmain-

EpigeneticsNew Frontiers for DNA

Victoria Lunyak, PhD

12San FranciSco Medicineseptember 2008 www.sfms.org www.sfms.org september 2008San FranciSco Medicine1�12San FranciSco Medicineseptember 2008 www.sfms.org

tained and propagated? Is it true thatepigeneticsthrivesontheideathatthereisacodeabovethecodeembeddedintheDNAitself?Inhumans,DNAisorganizedinto23pairsconsistingofapproximately25,000genescoding forproteins.Whensummedacrossallchromosomes,theDNAmolecular inhigheukaryotes is about2meterslongandthereforeneedstobecon-densed tofit into thecell’snucleus.Thispackaging isachievedbywrappingDNAaround repeatingproteinunits (nucleo-somes).This“beads-on-a-string”template,knownas“chromatinfiber,”isadynamicpolymerexisting inmanyconfigurations,prone to remodelingand restructuringasit receivesphysiologically relevant inputfromdevelopment-specific,cell-typespecificor environmental signalingpathways. Insimplisticterms,chromatindictateswhen,where,andonwhatlevelthegeneswithinourgenomearetranscribedtoprovideforproteinproducts.Thuschromatin shouldbeviewedasmajor sourceof epigeneticinformation,providinganelegantsolutiontotheDNApackagingproblem,influencinggenomeplasticityanddefiningasourceforthecellularmemorytotransmittheregula-toryinformation.

Chromatinpackagingdesignscanbealteredthroughtheintroductionofunusualhistoneproteins (knownashistonevari-ants),localchangesinchromatinstructure(knownaschromatinremodeling),andtheadditionof chemical tags to thehistoneproteins themselves (knownas covalentmodifications).Allofthesealterationsex-pandtherepertoireoftheepigeneticcodestogovernepigeneticinfluences.Moreover,the addition of a methyl-group directlytoacytosine(C)base in theDNAtem-plate (knownasDNAmethylation)canprovidedockingsites forproteinstoalterthechromatinstateoraffectthecovalentmodifications of resident histones. TheDNAmethylationrepresentsanimportantepigeneticstrategywithnumerousapplica-tions tocancerbiologyand regenerativemedicine.Recentevidencesuggestsotherepigeneticmechanisms,postulating thatnonprotein-coding RNAs can “guide”specializedregionsofagenomeintomorecompactedchromatinstatesor“bookmark”chromosomaldomainsofdifferentialgene

function.Newstudiesindicateacritical,andprobablyprimary,rolefornoncodingRNAsin triggering epigenetic transitions andheritablymaintaining specificchromatinstatesof thechromatin template.Largelytranscribed fromendogenous transposonsandotherrepetitivesequences,thenoncod-ingRNAshaveonceagain remindedusthereisnosuchthingas“uselessgenomicjunkDNA.”

Wenowknowofcountlessexamplesofepigeneticmechanismsatwork inor-ganisms.Althoughpresented separately,allaforementionedepigeneticmechanismsshouldmoreproperlybeviewedasaseriesofparallelandinterrelatedprocessesaimedtodefineandexplainepigeneticphenom-ena.Despite the fact that contemporaryepigeneticsisarelativelyyoungdiscipline,it still addresses the century-old, funda-mental questions about mechanisms ofdevelopment.Throughtheelegantgeneticandbiochemicalstudiestotherecentge-nomewideanalysisand resolutionsat themolecular level, this fast-paceddisciplineis fullof surprises:Accountsofnewandunexpectedphenomenaalwaysholdourimagination.

Thepopularpressportraysepigeneticsas anantidote to the subjects classicge-netics stumble over as “unexplainable.”Researchersareassigning full responsibil-ityforaltruismanddepression,aggressionandeatingdisorderstoepigenetics.Someof them depart for “epigenetic shores”withwhatseemsarareurgency,promising“theepigeneticdrugs”tocuredevastatingdiseases.Othersenterthefield likequicksunburstsandthenleavethestudyofepi-geneticsdazzledbutdisappointedwhentheir

researchyieldsmorequestionsthananswers.Butepigeneticresearchcontinuestomoveforward, attracting tremendousattentionfromscientistsandcliniciansinalmostallareasofbiologyandmedicine.Morethanonethousandreviewsonepigeneticswritteninthepastfiveyearsarescholarlymilestonesandhavedeliverednewparadigms.ItisnowfiftyyearssinceWatsonandCrickinitiated“theDNAparadigm”and,understandably,claimedthatindiscoveringDNAtheyhadreallydiscoveredthesecretoflife.Andassooftenhappensinthesciences,molecularbiologyhasnot resolved themysteriesoftheelegantmolecule justyet.Epigeneticlanguageofthe“bookoflife”isunparalleled,andthetruthisthatweareonlyscratchingthetipoftheiceberginunderstandingitscomplexity.

Victoria Lunyak, PhD, currently works on the faculty at the Buck Institute for Age Research. She received her PhD in Molecular Biology from the St. Petersburg Nuclear Physics Institute, Russian Academy of Science in St. Petersburg, Russia. In addition to her position at the UCSD Department of Medicine, she has also held posts in the lab of MG Rosenfeld, a principle investigator at the Howard Hughes Medical Institute in La Jolla, CA, and in the Department of Molecular Biology, Cell Biol-ogy and Biochemistry at Brown University in Providence, RI.

“DNA is an elegant molecule with mind-blowing properties and an amazing information storage medium. A single cubic centimeter of DNA holds more information than a trillion CDs.”

SendYourMessageto2,500HealthCare

Professionals

TheSanFranciscoMedicalSocietyof-fersmultipleadvertisingopportunitiesranging from full-page,4-colordisplayads to classified ads with discountedratesformembers.PleasecontactAsh-leySkabarformoreinformation,(415)561-0850extension240or [email protected].


THe MYSTerY oF dna

I t has been five years since the an-nouncementofthecompletionofthehumangenomesequenceby theNa-

tionalHumanGenomeResearchInstituteoftheNIH.Thiswork,whichprovidestheelementalinstructionmanualforbuildingahumanbeing,isalreadycontributingtoaremarkableunderstandingofhumanevolu-tion,humanbiology,andhumandisease.A number of spin-off projects from theHumanGenomeProjectareextendingourunderstandingeven further.Withnameslike theHapMapProject, theENCODEProject, andCancerGenomeAnatomyProject, researchers are using genomicresearch toexamineDNAvariationbe-tween individuals,determine thevarietyoffunctionalrolesthatallDNAsequencesmay encode, and elucidate the geneticbasisofcancerattheDNAsequencelevel.Manyadditionalorganismshavehadtheirgenomes sequenced inparallel, includingourclosestprimaterelativesaswellasmodelorganisms(mouse,rat,dog,zebrafish),eco-nomicallyimportantorganisms(rice,honeybee,chicken,cow,pig,horse),anddiseasevectors(themosquitoA. gambiae).Theseprojectsaffordusanopportunitytodirectlycomparetheresultsofhundredsofmillionsofyearsofvertebrateevolution,aswellastounderstandtheinnerworkingoforganismsthatinflictwidespreaddisease.

The GWaS eraHasthehype fromthismonumental

forayintoBigSciencetoldusmuchabouthumandisease,andmorespecificallyaboutpsychiatric illnesses?Toanswer this,onehas toknowof threeconvergentevents:First, the InternationalHapMapProjectenabledthecataloguingofmillionsofDNAvariants called SNPs, or single nucleo-

tidepolymorphisms,thatoccuracrossthegenome (Figure 1).TheseSNPsexplaina major fraction ofthegeneticdifferenc-es among humans.Theprojectprovidedgreatlydetailedinfor-mation about thesevariants, especiallyhowtheirfrequenciesdiffer among repre-sentativepopulationsof Europe, Africa,and Eastern Asia,facilitating theiruseasmarkersorprobesof DNA variationamong individuals.Theseconddevelop-mentwasthedesignandmanufactureofmicroarrays by bio-technology compa-niesthatwouldallowresearcherstosimul-taneously examinefrom 300,000 to 1millionSNPsonasinglechip,facilitatingagenomewideassessmentofvariationattheindividuallevel.Finally,scientistsandfundingagenciesrealizedthatcooperativearrangementswererequiredthatledtotheagglomerationofthousands,oreventensofthousands,ofcasesandcontrolsfordiseasessuchas type2diabetes,Crohn’sdisease,breast andprostate cancer, obesity, andpsychiatricdisorders.The confluenceofallthreefactorshasresultedintheprolif-erationofgenomewideassociationstudies(GWAS)overthepasttwoyears(Figure

2).Forexample,regardingtype2diabetes,investigatorsfromanumberofteamshavingmorethan30,000casesandcontrolsfoundDNAvariantsinsometengenesorgenere-gionsthatwerereliablyassociatedwiththepresenceof type2diabetes. Interestingly,thegenesuncoveredwerenotpreviouslyconnectedtoanyunderstandingofdiabetes,openingthefieldtonewresearchdirections.Unfortunately,theserisk-increasingSNPswerefoundtohavesmallindividualeffects.Eachvariantincreasestheriskbylessthan20percent. Inavery largecollaborative

The Genetics of Mental DisordersAn Update of Recent Progress in Understanding the Link

Steven P. Hamilton, MD, PhD

A G T G C TG A TG C C G TA C G G TA C

A G T G C TG A TG C C A TA C G G TA C

Figure 1A single nucleotide polymorphism (SNP) is a substitution of a

single base in a DNA sequence. This leads to the presence of alternate alleles. In the figure, a homologous region of a chromosome is depicted, with the upper and lower chromosomes coming from the mother and father, respectively. In this case, the mother transmitted an “A” allele at the highlighted position (in green), while the father transmitted a “G” allele at the same position (in red). Thus this person is heterozy-gous at this SNP (“A/G”), having both possible alleles.


effort,manyoftheworld’stype2diabetesgeneticiststeamedupforameta-analysisofmorethan10,000subjects,followedbyaddi-tionalreplicationinalmost80,000subjects,and they reportedat least six additionalgenevariantsthatarecorrelatedwiththepresenceofthisdisease.Similarundertak-ingshavebeencarriedoutwithCrohn’sdisease,whereaboutthirtynovelgenesorgeneregionshavebeenidentified.Earlyin-dicationsfromthesetypesofstudiessuggestthatknowledgeofaperson’scomplementofriskvariantsmaynotexplainenoughofthesusceptibilityriskforapractical,predictivelaboratorytest.Nonetheless,knowledgeofcompletelynovel genesopensnumerousdoors forunderstandingpathophysiologyanddrugdevelopment.

Progress in Psychiatric Genetics, Too?

Giventherelativesuccessforfindingcommondisease riskalleles for commoncomplex traits suchas type2diabetes, itisreasonabletopresumeitmightworkforpsychiatricdisorders,which,similarly,arepartlydeterminedbygenetic factors andareathighprevalenceinthepopulation.Therearenumberof studies that suggestthismightbethecase,asdescribedbelow.Additionally, a number of observationscomingfromgeneticanalysesofpsychiatricdisordersraisethepossibilitythatsomecasesofschizophreniaandautismmayactuallyin-volvedramaticlarge-scalegenomicevents,manyofwhicharenot transmitted fromparentalgenomes.

Schizophrenia: The first reportedGWAS inapsychiatricdisorderwas forschizophrenia,inwhicharelativelysmallset of schizophrenia cases and matchedcontrols were genotyped for more than500,000SNPs,leadingtoanovelassocia-tiontoaregioncommontotheXandYchromosomes,termeda“pseudoautosomal”region. This curious finding, which hasnotbeen seenbyothers,was ina regionsurroundinggenesencoding receptors forcolony-stimulating factorand interleukin3.Thepotentialinvolvementofcytokine-related genes in schizophreniamay leadto additional attention to inflammatoryprocessesintheetiologyofthisdisease,forexampleinuteroviralinfection.Asecond

GWASinvolvedalargesamplecomprisedofcasesfromClinicalAntipsychoticTrialsofInterventionEffectiveness(CATIE).Thetopfindinggeneratedanassociationp-valueof0.0000017,whichwasdeterminedtobeinsignificantinthatsucharesultishighlylikely to resultbychancegiven that theauthorscarriedoutsome492,000statisticaltests.Althoughdisappointing,thisstudydidhaveanumberofintriguingfindingsofevenlesser statistical significance thatwill bepursuedinothersamples.ItwasreassuringtoseethatthisstudyfoundsomesupportforthepreviouslydescribedschizophreniariskgenesDISC1 andNRG1.ThemostrecentGWASidentifiedtwelveDNAvariantsofinterestinamodestsetofabout480casesand2,900controlsbutthensoughttorep-licatethefindingsinanadditional16,800subjects.Three regionsmaintained somesupport,withonecontaininganovelgenecalledZNF804A,which is anunstudiedgenewithunknownfunction,althoughitssequencesuggeststhatitbindstoDNAandzincions,makingitapotentialregulatoroftranscriptionofothergenes.Interestingly,thetwoothersupportedregionsliewithinregionsinwhichtherearenoknowngenes,raising thepossibility that these intervalscontainundiscoveredgenesor sequencesthatareinvolvedwithlong-rangeregulationofyetothergenes.

Bipolar Disorder: A series of

GWAS experiments involving severalthousandbipolardisordercaseshasbeenpublishedsince2007.Thefirst,astudyof2,000Britishcasesand3,000controls,wassponsoredby theWellcomeTrust.Thisstudyreportedanassociationbetweenbipo-lardisorderandaSNPwithinagenecalledPALB2,whichencodes aproteinwhosefunctionappearstobetopartnerwiththeproteinproducedbyBRCA2,ageneprevi-ouslylinkedtohighlyheritablebreastcan-cer.Ifthisfindingisindeedtrue,itmayraisequestionsabout theconnectionbetweenbipolardisorderandimportantcellularfunc-tions.AsmallergenomewideSNPscanofNorthAmericanandGermanbipolardis-ordercasesidentifiedagene(DGKH)thatencodesdiacylglycerolkinaseeta,acompo-nentofthelithium-sensitivephosphatidylinositolpathway.Investigatorsfrombothofthesestudieslookedatgenomicregionsthatscoredhighlyinbothexperiments.Interest-ingly,theyreportthatthetopfindingswerenotreplicatedinbothstudiesbutthatotherregionsthatweremodestinboth“rosetothetop”whendatawerecombined.TwosuchgenesincludeazinctransporterandJAM3,whoseproteinproductappearstobeinvolvedincellularjunctions,forexamplebetween themyelin-formingcellsof theperipheralnervoussystem.AthirdGWASofbipolardisorder, focusingprimarilyon

Continued on Page 23...

A G

A A A A

A A

A A

A A A A

A A

A A A A

A A A A

A A A A

A A

A A G G

G G G G G G

G G

G G G G

G G G G

G G A G

A G A G A G

A G A G A G

A G

A G A G A G

A G

A G A G A G A G A G A G

A G G G A G G G

C A S E S C O N TR O LS

Figure 2The design of a case-control association study is depicted. Cases and controls are genotyped

for between one to one million SNPs, and the frequencies of alleles (e.g., A versus G) or genotypes (AA, AG, or GG) is tabulated. A statistical test is performed to determine if the distribution of alleles or genotypes are significantly different between the two groups. If the statistic is significant, the SNP can be said to be “associated” with the phenotype.


THe MYSTerY oF dna

C linicianshavewonderedwhysomepatientshavegood responses toaparticulardrugandwhy some

eitherdonotrespondtothedrugordeveloptoxicityorotheradversereactions.Manyfactorsplayaroleincausingthisvariability,and genetic factors are certainly amongthem.Pharmacogenomics is the studyofhowgeneticdifferencesamongindividualsinfluence responses to a drug. Pharma-cogenomicstudieshavediscoveredgeneticvariantsthatcontributetocausingvariableresponsestodrugsthatarecommonlyusedinclinicalpractice.Infact,therearemorethanfiftydrugsthathavepharmacogenomicinformationon the label, as requiredbyFood and Drug Administration (FDA)packagingregulations.Theagencyrequires agenetictesttobeperformedbeforepre-scribingcertaindrugs,suchastrastuzumab(Herceptin)andmaraviroc(Selzentry);theFDA recommends genetictestingforothers.Warfarinisoneofthedrugsforwhichge-netictestingisrecommendedbytheFDApriortostartingtherapy.

Theanticoagulantwarfarin isadrugthatisusedtoreducetheriskofsystemicem-bolismduetocardiacarrhythmia,ventricu-lardysfunction,andtheuseofmechanicalheartvalves,aswellastopreventvenousthrombosisandthromboembolismindeepveins.Thoughwarfarinisanolddrugthatwasfirstintroducedasamedicationinthe1950s,thedrugisstillwidelyused.Nearly31millionoutpatientprescriptionsforwarfarinweredispensedin2004,upfrom21millionin1998.Thedrughasanarrowtherapeuticwindowandhasbeenassociatedwith ahigh incidenceofadversedrug reactions,particularlybleeding.Warfarin is amongthetoptendrugswiththelargestnumberofseriousadverseeventreportssubmittedto

theFDA’sAdverseEventReportingSystemduringthepasttwentyyears.Anticoagulantsrankedfirstin2003and2004inU.S.deathcertificatesfordrugscausing“adverseeffectsin therapeuticuse.”Warfarinwasassoci-

atedwithabout29,000visitsforbleedingcomplicationsperyear,anditwasamongthedrugswiththemostvisits.Thesewell-knownaspectsofwarfarintherapyledtheFDAtorequirea“blackbox”warningaboutwarfarin’sbleedingrisktobeaddedtotheU.S.productlabelingin2006.

Oneofthemainreasonsofthehighincidenceofadverseeventsbywarfarinisitsunpredictabledoserequirementsamongpatients.Thereisuptoasixteenfolddiffer-enceindoserequirements,fromaslowas1mg/daytoashighas16mg/day,amongpatients.This iswhy theuseofwarfarinrequirescarefulmonitoringofthedegreeofanticoagulationbyfrequentINRsduringtheinductionphaseof anticoagulation,withrepeateddoseadjustmentswhentheINRisfoundtobeoutofrange.Thisunpredict-

abilityincreasestheriskofbleedingcompli-cationsortreatmentfailureassociatedwithwarfarintherapy.

Studieshaveshownthatgeneticvari-ability in twogenescalledCYP2C9 andVKORC1 accountsforabout40percentoftotalvariabilityofwarfarindoserequirementamongpatients.Basedonthisinformation,theFDArecentlyrevisedthewarfarinlabelby recommendinga lower initialdoseofwarfarin forpatientswithcertaingeneticvariantsofCYP2C9and/orVKORC1.

Warfarin is mainly metabolized intheliverbythecytochromeP450enzyme2C9 (CYP2C9).TheCYP2C9 genehastwocommongeneticvariants:CYP2C9*2and CYP2C9*3 (* is used to denote ageneticvariantcomparedwithwild type,which is usually denoted as *1 for thecytochrome P450 genes). Both of thevariantsproduceaCYP2C9enzymewithreducedenzymaticactivitycomparedwithwild type (CYP2C9*1). Because of thereduced enzyme activity, patients witheitherof thesevariantsmayneedsmalleramountsofwarfarininordertoachieveatherapeutic INR,comparedwithpatientswithawildtype CYP2C9gene.Aswithallgenes(exceptthoseontheXchromosomeinamale),everypersonhastwocopiesoftheCYP2C9geneandthereforecanhaveonewildtypeandone*2or*3variant,ortheycanevenhavetwocopiesofthe*2or*3variantandrequireevenlesswarfarintoachievetherapeuticanticoagulation.Infact,studieshaveshownthatpatientswhocarryoneCYP2C9*3variant required1.5 to3mg/dayofwarfarin.Incontrast,theaveragedoseofwarfarininpatientswhodonotcarryanyCYP2C9variantwas5.5mg/day.ThefrequencyofCYP2C9geneticvariantsdif-fersbyracialbackground.ThetwoCYP2C9

“Pharmacogenomics is the study of how genetic differences among individuals influence responses to a drug. Pharmacogenomic studies have discovered genetic variants that contribute to causing variable responses to drugs that are commonly used in clinical practice.”

Genetics and Drug ResponsePharmacogenomics and Warfarin Therapy

Jaekyu Shin, MS, PharmD; and Robert L. Naussbaum, MD


variantsaremorecommoninCaucasiansthanintheothers(seeTable).

A secondgene, VKORC1, plays animportant role invariability inwarfarintherapy.ThisgenespecifiestheproductionofvitaminKepoxidereductase,anenzymeinvolvedinregeneratingvitaminKrequiredforthesynthesisofthecoagulationfactorsII, VII, IX, and X. Vitamin K epoxidereductaseinhibitionisthemajormodeofactionofwarfarin.DNAvariationinthesequences that regulate theexpressionoftheVKORC1genecausevariationintheamountofVKORC1thatismade,resultinginvariabilityinsensitivitytoagivendoseofwarfarin.ThereareanumberofDNAvariantsthatareusuallyfoundtogetherintheVKORC1gene,andwerefertothemallasavariant“haplotype.”Weonlyneedto genotype one of the variants in thehaplotype toknowwhat theothervari-antsareand,therefore,topredictwarfarindoserequirements.Forexample,VKORC1 -1639G/A,aGtoAnucleotidechangeatnucleotideposition-1639inthe VKORC1gene, is the site that ismost commonlygenotyped forVKORC1 geneticvariabil-ity.ThevariantVKORC1—for instance,VKORC1-1639A—has been shown toproduceasmalleramountofmRNAofthegenecomparedwithwildtype(VKORC1 -1639G).Compared to individualswithtwonormalVKORC1genes,whoneed6mg/dayofwarfarintoattainatherapeuticINR,individualswithoneortwovarianthaplotypesrequire5mg/dayand3mg/dayofwarfarin,respectively.Thismakessensebe-cause VKORC1variantcarriersmakelessofthewarfarintargetproteinduetoareducedamountofVKORC1mRNAand,asaresult,

theyneedsmalleramountofwarfarin.TheVKORC1varianthaplotypeismuchmorecommoninAsiansthaninotherethnicities.ItiswellknownthatAsiansneedsmallerdoseofwarfarincomparedwithotherraces.ThefrequencydifferencesintheVKORC1variantamongracesmayexplainthisclini-calobservation(seeTable).

Thereare twowarfarinpharmacoge-nomicteststhathavebeenapprovedbytheFDA.Inaddition,manyclinicallaboratoriessuchastheUCSFclinicallaboratory,QuestDiagnostics,andLaboratoryCorporationof-ferCYP2C9and VKORC1testing.Thecostisabout$300to$500,withaturnaroundofonetoseveraldays.Byincorporatingthegenetictestresultswiththepatient’sage,weight,andgenderintoadosingalgorithm,the test results should improveour abil-ity toestimatewhat theultimatecorrectmaintenancedoseofwarfarinwillbeand,therefore,helpguidetheinitialdosingdur-inginductionofanticoagulation.

Therearemanypublisheddosingalgo-rithmsavailablethattakebothgeneticandnongeneticvariables(age,weight,smokingstatus,interactingdrugs,etc.)intoaccounttopredictanindividualizedwarfarindose.One such,www.warfarindosing.org, is apubliclyavailablewarfarindosingalgorithmdevelopedbyWashingtonUniversityatSt.Louis.Thedosingalgorithmseems tobeaccurateandaccountsfor60to80percentofwarfarindosevariability.Regularmoni-toringofINRisstillimportantinwarfarintherapyevenwhengeneticinformationisusedtopredictdose,sincethegeneticinfor-mationandothervariablesdonotaccountfortheremaining20to40percentofthevariabilityindosage.Itshouldalsobenoted

thatgeneticinformationwillbemostusefulwhenitisappliedtopredictingwarfarindoseforpatientswhoare startingonwarfarintherapyandnotforpatientswhoarealreadystabilizedonadoseofwarfarin.

Robert L. Nussbaum, MD, is the Holly Smith Distinguished Professor in Medicine and the Chief of the Division of Medical Genetics at UCSF. He is a board-certified internist and medical geneticist and has served on the American College of Medical Genetics Working Group on Pharmacogenetic Testing for Warfa-rin Use and on a working group on Personalized Medicine for the Institute of Medicine as well as an advisory committee on this subject for the Secretary of Health and Human Services. Prior to coming to UCSF, he was the Chief of the Genetic Disease Research Branch at the Na-tional Human Genome Research Institute of the NIH. Dr. Nussbaum has particular interests in translational research efforts to assess the value of “personalized medicine,” the application of genetic and genomic approaches to improving patient care. Dr. Nussbaum seeks to evaluate whether individuals’ genetic and genomic infor-mation can be used effectively to improve health care by improving outcomes, reducing adverse reactions, lowering costs, and promoting health through risk education.

Jaekyu Shin, MS, PharmD, is an Assis-tant Professor of Clinical Pharmacy at UCSF and will serve as Research Coordinator of this study. He completed a three-year fellowship in Cardiovascular Pharmacogenomics under the mentorship of Dr. Julie Johnson, a leading researcher in warfarin pharmacogenetics. Along with Drs. Nussbaum, Wu, and Kayser, he is a member of the Warfarin Pharmacogenetic Consultation Service Team, which provides warfarin dosing service based on an individual patient’s CYP2C9 and VKORC1 genotype for inpatients who are receiving heart valve replacement surgery and are newly starting on warfarin.

caucasians Hispanics africanamericans

asians

cYP2c9

*2 10 8 0 0

*� 6 6 0 3-4

VKorc1

Variant 40 48 15 90


THe MYSTerY oF dna

I fyouhaveneverworkedwithageneticcounselorbefore, it’s likely that youdon’tknowmuchaboutwhatwedo.For centuries,peoplehaveobserved

that certain conditions tend to run infamiliesand“medicalgenetics”hasbeenpracticedon some level.But the formaldiscipline of genetic counseling beganmerelyfortyyearsago.Thefirstorganizedtrainingprogramwas started in1969andwasformedinpartbyhappenstance.Sincethen,manymoreprogramshavesprungupandothershavefolded.TheNationalSoci-etyofGeneticCounselors(NSGC)websitecurrentlyliststhirtyprogramsintheUnitedStatesandanadditionalsixinCanada,theU.K.,andAustralia.IntheBayArea,newgeneticcounselingprogramsatCaliforniaStateUniversityandStanfordUniversityareeachpreparingtostarttheirfirstyearofcourseworkthisfall.

TheAmericanBoardofMedicalGe-netics(ABMG)offereditsfirstexaminationstocertifygeneticcounselors,aswellastheothermedicalgeneticsspecialties,in1984.Sevenyears later, in1991, theAmericanMedicalAssociation recognizedmedicalgeneticsasitsownsubspecialty.Asaresult,genetic counselors formed theirownac-creditationgroup,theAmericanBoardofGeneticCounseling(ABGC).Despitehav-ingseparatedtheirgoverningbodies,geneticcounselorscontinue toworkverycloselywithothermedicalgenetics specialists inclinical genetics (includingdysmorphol-ogyandmetabolicgenetics)andlaboratorygenetics (cytogeneticsandmolecularandbiochemicalgenetics).

So what do we do? According theNSGC,geneticcounselorsarehealthprofes-sionalswithspecializedgraduatedegreesandexperienceintheareasofmedicalgenetics

andcounseling.Theyworkasmembersofahealthcareteam,providinginformationandsupporttofamilieswhohavememberswithbirthdefectsorgeneticdisordersandtofamilieswhomaybeatriskforavarietyofinheritedconditions.Theyidentifyfamiliesatrisk,investigatetheproblempresentinthefamily,interpretinformationaboutthedisorder,andanalyze inheritancepatternsandrisksofrecurrenceandreviewavailableoptionswiththefamily.

Geneticcounselorsalsoprovide sup-portive counseling to families, serve aspatientadvocates,andreferindividualsandfamiliestocommunityorstatesupportser-vices.Theyserveaseducatorsandresourcepeopleforotherhealthcareprofessionalsandforthegeneralpublic.

Afairly simpledescriptionofgeneticcounselingwouldbethatImeetwithpeopletodiscusstheirfamilyhistoryandprovideeducationand informedconsent aroundgenetictesting.Itdoesn’treallydojusticetoourprofession,butitworksforcasualcon-versation.Pressedformoredetail,Iwouldaddthatgeneticcounselingmelds theart

andscienceofunderstandinggeneticinfor-mationandmakingsenseof it forothers,bringingmedicalandscientificknowledgeaboutgeneticdisease—itsdiagnosis,naturalhistory,andmanagement—togetherwithcounseling skills tohelp individuals andfamiliesdigestandadapt the informationto theirowncircumstances.Asa group,geneticcounselorsareinnatelycuriousandenjoythesleuthingprocess.Elicitingperti-nentfamilyandhealthhistoryisthetypicalstartingpoint.Trackingdownandobtainingmedicalrecordsthatareoftenthoughtunat-tainableissometimesnecessary.Evaluating,interpreting,andexplaininginformationandshepherdinganindividualorfamilythroughtheprocessaretheultimategoals.

Thegeneticcounselormostcommonlyworksinamedicalcenter,andalittlemorethanhalf of genetic counselorswork inprenataldiagnosis.Thishasremainedfairlyconstantovertheyears.Adultandpediatricgeneticsaswellascancergenetics followclosely.Numerousspecialtyclinics,rangingfrombiochemicalgeneticstoskeletaldyspla-sias,cancertoneurogenetics,arealsorunbymanycenters.Manycounselorsseepatientsinmorethanasinglesetting.

Dependingupontheclinical setting,patientencounters can last a singlevisitorspanseveralyears.Inprenataldiagnosis,manyinteractionsareone-timeencountersand fairly straightforward.Manywomencome foraprenatal screening test that isnormalandrequiresnofurthervisits.Fortu-nately,uneventfulencountersarethemostlikelykindintheprenatalclinic.

Afamilyhistoryofageneticproblemora fetus identifiedwithamalformation,however,canleadtonumerousvisitsoverthecourseofapregnancyandmayinvolvefetaldiagnosticprocedures andcomplex

Understanding a Patient’s GenesGenetic Counseling for the Twenty-First Century

Kati Malabed, MS, CGC


genetictesting.Geneticcounselorsareusu-ally involvedateachsteptoprovidecasemanagementbycoordinatingappointmentsandtestingandbyconveyingresults.Often,geneticcounselorsareabletoprovidemorecontinuityofcarethanotherteammembersandinteractwiththefamilytothegreatestextent.

Inpediatricandadultclinics,therefer-ringindicationgenerallynecessitatesmul-tiplevisitsoveraperiodofmonthsorevenyears.Again, thegeneticcounseloroftencoordinatesvisitsandtestingandasactsascommunicationliaison,whileprovidingsup-portivecounselingthroughoutthistime.

Inmultispecialtyclinics,whichfocusonasingleconditionsuchasMarfansyndrome,oronagroupofconditionssuchasfamilialcancersyndromes,geneticcounselorsworkaspartof a team thatprovidesmultiplefacetsofcare.Oneexampleisacraniofacialclinic,whereaday’svisitcouldincludeap-pointmentswithageneticcounselor,clinicalgeneticist,nurse,oromaxillofacial and/orplasticsurgeon,dentist,speechpathologist,andsocialworker.Aneurometabolicclinicmightincludevisitswithacounselor,geneti-cist,neurologist,anddietician.Incancerrisk,counselorshelpidentifypatientswhoareatriskforhereditarycancersandcollaboratewithoncologistsand surgeons toprovidethebestcare.

Because genetic counselors are nottrainedtoprovidelong-termpsychologicalcounseling,wemustalsoknowourlimita-tionsandrefertoothercounselingprofes-sionalsaspartofourethicalandprofessionalresponsibilities.

In the last fewyears, themediahashighlighted the development of direct-to-consumer genetic testing. Testing athomeprovidesapersonaccesstohisorhergenetic informationwithoutnecessitatingthe involvementofadoctoror insurancecompany. Individualsmight choose thisrouteformaximumconfidentialityandlowerexpense.Somedirect-to-consumercompa-niesoffertestingforsinglegenedisorders,suchascysticfibrosisandhemochromatosis,todetermineanindividual’sstatusregardingatraitordiseaseknowntoruninthefamily.Inthelastyearanumberofcompanies,suchasNavigenicsand23&Me,haveemergedandareofferinggenomewide scans toas-

sesssusceptibilityrisksforcommondisease,complexdisease, singlegenetraits,ethnicheritage, or some combination of thesefactors.The informationmightbe soughtfortheopportunitytomodifyone’slifestyleandtoprevent,diagnose,andtherebyre-ducetheriskofdevelopingspecificdiseases.Oronemightpursuetestingoutofsimplecuriosity.

Butconcernsaboutthismodelhavesur-faced.ThestatesofNewYorkandCalifornia

havefiledcease-and-desistordersregardingofferingdirect-to-consumer testingduetoconcernsabouthowtheserviceswillbepro-vided.ThecurrentpositionoftheAmericanCollegeofMedicalGenetics(ACMG)isthatgenetictestingshouldbeprovidedonlythroughlicensedandtrainedprofessionalsandthatminimumrequirementsshouldbemetforsuchservicestoberendered.Thestoryofdirect-to-consumer testing is justnowunfolding.

The explosion of information thatcontinuestocomefromsequencingofthehumangenomeconsistently leads to thedevelopmentofnewgenetictests.Under-standingandexplainingthenuancesofthevarioustestscanbedaunting.Manyhealthprofessionalsarecapableofsuchinterpreta-tionandexplanation,andtheyprovidesomelevelofgeneticcounselingtotheirpatients.Geneticcounselors,however,trainspeciallyforthispurposeandtaketimewithfamiliestoinsuretheirunderstanding.

Naturally,Iambiasedinfavorofge-neticcounselingandthemultidisciplinarysettinginwhichitismostoftenpracticed.Theservicesofferedcanprovideinvaluableinformation inaunique fashion.Genetic

counselinghashistoricallybeennondirec-tive,whichdistinguishesitfromthetradi-tionalphysicianmodelofcare.Thesupport-iveenvironmentprovidedduringgeneticcounselingisaimedatallowingindividualstoexploretheirfeelingsandchoosethebestindividualcourseofaction.Thismayormaynotmeanhavinggenetictesting/screening,continuingorterminatingapregnancywithknownabnormalities,orchoosingprophy-lacticsurgeryormedicationforaninheritedpredispositionordisease.

Iamreassured that Idomy jobwellwheneversomeoneunderstandsallpertinentinformationandchoosesnofurthertesting.Ittellsmetheyunderstoodalltheiroptionsanddecidedtheirbestchoicewasnomoreinvestigation.Forthosewhodochoosefur-thergenetictesting,wecanserveasguidesthroughacomplexlandscape.Geneticcoun-selingmaynotbeusefulforeveryone,butitisaninvaluableinstrumentformany.

Now that theGenetic InformationNondiscriminationActof2008(GINA)hasbeensigned, federal lawprohibitsdis-criminationbasedongenetic informationwhenitcomestoestablishinghealthinsur-anceeligibilityorpremiums.Italsoprohibitsemployersfromhiring,firing,promoting,orplacingemployeesonthebasisofgeneticinformation.AfterthirteenyearsofdebateinCongress,itspassageisexcitingandoverdue.Hopefully,itwillremovebarrierstogenetictestingthatwillbenefitindividuals,aswellassimplifytheprocessforproviderstoreferpatientsforservices.

Geneticcounselingservicesareavail-ableinSanFranciscothroughtheUniversityofCalifornia,SanFrancisco,andthroughCaliforniaPacificMedicalCenterandKaiserPermanente.

Kati Malabed graduated from the genetic counseling program at U.C. Berkeley in 1996. She has been a genetic counselor at UCSF for eleven years, starting in the Sickle Cell Center at San Francisco General Hospital. She ran a quarterly pediatric genetics outreach clinic in Santa Rosa until this year. She has been with the Prenatal Diagnostic Center since 1999 and currently acts as the liaison to the Fetal Treat-ment Center.

For a full list of references, visit www.sfms.org.

“For centuries, people have observed that certain conditions tend to run in families and ‘medical genetics’ has been practiced on some level. But the formal discipline of genetic counseling began merely forty years ago.”


THe MYSTerY oF dna

A untMaewassixty-sevenwhenshewasdiagnosedwithadvancedstageIIIovariancancer.Inhertwenties,

shehadsurvivedahighlyaggressivethyroidcancer,likelycausedbythymicirradiationasachildasaresultofanunfortunateepisodeinmedicalhistorywhenchildrenwiththy-mic“enlargement”weregivenhighdosesofradiation.AlthoughAuntMaehadcheateddeathbefore,itseemedunlikelyshewouldsurvivethistime.Anditseemedunfairthatshewashittwicewithcancerwhentherestofhervoluminousfamilywashealthy.Sheistheoldestofelevenbrothersandsisters,withmorethansixtyoffspringinthenextgeneration. Amazingly, after extensivetreatment,AuntMaesurvivedthisbrushwithdeath.

Wasthiscanceracombinationofbadluckandunnecessarychildhoodradiationrather thangeneticpredisposition?Prob-ably,sincemorethan90percentofovariancancers are sporadic.Later,AuntMae’sthreesistershadtheirovariesandtubesre-movedduringotherpelvicsurgeries.Whenoneofher scoresofcousinsdiedofpan-creaticcancer, thatalsoseemedsporadic.Severalyearslater,twoofhersisterseachdevelopedpostmenopausal stage IIbreastcancer.Bothdidwellwith lumpectomiesandprophylacticchemotherapy.

We are two of Aunt Mae’s nieces:Kathleen(alicensingofficerwithamaster’sinhumangenetics)andMarcia(adiagnos-ticradiologist)werebeginningtoponderthegeneticodds.AlthoughbreastcanceraffectsoneinsevenwomenintheU.S.,postmeno-pausalbreastcancerinthetwooffoursistersappearedtobeborderlineexcessive.WhenMae’snephewdevelopedcoloncancerinhisearlyforties,itwastimetoseeageneticcounselor, anda reviewof familycancer

historywasbegun.Cousinswerefoundwithbreast cancer (a fewpremenopausal andbilateral)and,inatleasttwocases,ovar-iancancer.Therewerealsocousinsandabrotherwitholder-ageprostatecancerand

afewcousinswithcoloncancer.Bynow,manyofAuntMae’ssiblings,nieces,andnephewshadhadcolonoscopies,andsev-eralhadcolonicadenomas, theprecursortocoloncancer.

deciding Whether or not to Undergo Genetic Testing

Threegeneticsyndromesseemedthemostlikely:BRCA1,BRCA2,andLynchsyndrome II. BRCA1 and 2 are linkedtoovarian,breast, andprostate cancers;BRCA2isalsoassociatedwithpancreaticcancers;andLynchsyndromeIIhereditarynonpolyposis colorectal cancer (often

diagnosedinpatientsintheirmid-forties)is associatedwith increasedendometrial,ovarian,prostate,andothercancers.

Atfirst it seemed straightforward toproceedwithgenetictesting,nowthatthefamilydataappearedtojustifyit.However,contemplatingthisapparentlysimplenextstepledustonumerousquestions.Firstofall,whoshouldbetested—andwouldtheywanttobetested?Ifwefoundsomething,whatwould thatmean?Would that setsomefamilymembersuptobeuninsurableorunmarriageable?Wouldfamilymemberswhotestednegativehavepeaceofmindandthosewhotestedpositivebelivingwithanearlydeathsentence?

Thinking further,would identifyingageneticmarkerbeuseful to the family?Ifitwereanissueofcoloncanceronly,itmightnot.Wedon’tneedgenetictestingtoknowweshouldgetcoloncancerscreen-ing,althoughwemightstartscreeningatanearlierageandscreenmorefrequentlyif we knew our genetic status. Ovariancancerscreening,however,isnotveryeffec-tive,andtheeffectivenessofbreastcancerscreeningisgoodbutnotgreat.Ariskforovariancancerwouldposeaprophylacticsalpingo-oophorectomy,whichthesedayscanbedonewithlaparoscopy.Asignificantriskforbreastcancerwoulduptheanteonscreeningandbringup thepossibilityofbilateralprophylacticmastectomies,amuchbiggerandriskiersurgery.

Going through with itWeproceededwithgenetic testing.

Somefamilymemberswerehappyweweredoingthis,andotherswerenervousorjustplainagainstit,particularlybecauseofpo-tentialdiscriminationbylifeandhealthin-surersagainstthosefoundtobeaffected.Our

“Contemplating this apparently simple next step led us to numerous questions. First of all, who should be tested—and would they want to be tested? If we found something, what would that mean? ... Would family members who tested negative have peace of mind and those who tested positive be living with an early death sentence?”

Cancer in the FamilyA Personal Tale of Genetic Testing

Kathleen McCowin, JD, MS; and Marcia McCowin, MD


genetic counselordetermined thatAuntMaewasthekeypersontotest,sinceovar-iancancerwasthecommondenominatorofthesyndromes,andthemostsignificant.EvenAuntMae’sthyroidcancercouldberelated,sincemostpeopleofhergenerationwithchildhoodirradiationdidnotdevelopthyroidcancer,suggestingthathergeneticmakeupmayhavesetherupforcanceringeneral.

SinceAuntMaywasthemostlikelytobeacarrierofwhateveroffendinggenewemightfind,weaskedforherparticipa-tion.Beingtheoldestofaverylargefamily,AuntMaetookthisdecisionveryseriously.Shedecideditwas inthebest interestofthe family forher toget tested since,onbalance,livescouldbesaved.NowwehadyetanotherreasontobegratefulthatAuntMaehadsurvivedhercancersandwasaliveandwell!

Theinitialtestingwasnotcoveredbyinsuranceandwasveryexpensivebecausethere were so many gene abnormalitiesthatneededtobeevaluated.However, ifa geneticdefectwas found,other familymemberscouldbe tested relatively inex-pensively,sincejustonegeneneedstobetested.Eitheryou’renegativeanddon’tneedtoworry,oryoutestpositiveandcanstartscreeningproceduresand thinkingaboutpossibleprophylacticsurgery.

Getting the resultsAndtheverdictwas...inconclusive.

Testingfoundonegeneticabnormality—one thatwasnotassociatedwithknowncancers.Formanywhohopedthiswouldprovideanopportunity to rule inorouttheirsusceptibility,thiswasaseriousdisap-pointment.However,sincetheinconclusiveinformationwasknown,ourmother,AuntMae’s sisterandoneof thebreastcancersurvivors,wastestedandfoundnottocarrythatgene.

Sowhatwas theoutcomeofall thisgeneticcounselingand testing?Probablythemostimportantresultwastheincreasedknowledgeandawarenessinthefamilyofthepossibilityof inheritablecancers.AsCBSnewsanchorKatieCouricknows,thelifetimeriskforcoloncancerinthegeneralpopulationisat least5percent;thereforescreeningforcoloncancerisagoodthing,

andhopefullywewon’thaveanothercaseinthefamily.Andwehaveaheightenedawarenessaboutotherscreeningprocedures,suchasmammography.

Eventhoughwedon’tknowwhetherspecific individuals inour familyhaveanincreased riskofovariancancer,Marciadecided—basedonthelikelihoodthatweasagrouparemorepronethantheaverageperson—to get a laparoscopic salpingo-oophorectomy,whichreducesherchancesforovariancancerbyatleast80percent.Shemadethisdecisionafterweighingthefactthatscreeningtechniques(biannualexams,ultrasound,andCA-125bloodtests)arenotveryeffective,themortalityratefromovariancancerisextremelyhigh,andlaparoscopicbilateral salpingo-oophorectomy is a safeprocedurewithminimalrecoverytime.Shecontinuestobescreenedforcoloncancerwith colonoscopy alternating with CTcolonography,and forbreastcancerwithbiannualphysicalexaminationsandannualmammography.Kathleenwasconcernedthatherfamilycouldbeinseriousjeopardywereshetodevelopcancerattheagethather mother and aunts were diagnosed.Herchildrenwouldstillbeinhighschooland college when their mom, the solebreadwinner of the family, was facingmajor surgeryandchemotherapy.So shechoseprophylacticbilateralmastectomiesin addition to a salpingo-oophorectomyperformedduringthe“tummy-tuck”DIEP(deepinferiorepigastricarteryperforator)flap breast reconstruction procedure.Althoughmammographyscreeningismoreeffective thanovariancancer screening,and themortality rate for breast canceris significantlybetter,her reasoningwasthatone in sevenwomen in thegeneralpopulationwill get breast cancer,whilethe surgerywould reduceherchances toalmostnothing.Althoughshecouldhavereliedonmammographyasaworthwhilebut imperfect screeningprocedure,withprophylactic surgery up front she won’tworryaboutbreastcanceranditsassociatedissues,suchasradiation,chemotherapy,armlymphedemapostnodedissection,and soon.Shecontinuestobescreenedforcoloncancer.

Thejourneyfromawarenessofapos-siblegeneticcancerpredisposition inour

familytogenetictestinganddecidingontheappropriateactionsbasedontheinforma-tionhasbeeneye-opening.Eventhoughthetestinginourcasehasbeeninconclusive,itprovidedususeful information so thatvariousfamilymemberscouldtakeactionbasedon theirpersonalpreferences.Ourfamilywassparedthedifficultdecisionsofwhattodowithaknowngeneticdefectintermsofpossiblybecominguninsurableordecidingnot tohavechildren.Wewerecomfortedknowingthatthedecisionseachofusmadewerebasedonthebestcurrentknowledgeavailable.

Kathleen McCowin, JD, MS, studied ge-netics and is a licensing officer at the University of California, Berkeley. Marcia McCowin, MD, is a clinical professor of radiology at the University of California, San Francisco.

For Magazine Archives, Health Care News, and Local Events of

Interest Please Visit

Our Web site, www.sfms.org.

You may also order subscriptions to and single copies of San Francisco Medicine

via the Web site.


THe MYSTerY oF dna

g enetictestingforhereditarycancerrisk isavailable foran increasingnumber of cancers and cancer

syndromes.Riskassessment,inconjunctionwithgenetic testing,provides specificandrelevant information tohelpphysiciansformulatemoreprecise follow-upcareandtreatment.Forexample,amanwhocarriesamutationincreasingcoloncancerriskcanbefollowedverydifferentlyfromhissiblingwhoisnotacarrier.

Patientsbenefit fromcancer riskas-sessmentby learningabouthereditaryandnonhereditaryriskfactors,howcancercellsarise,age-specificcancerrisks,theoriginofcancercells,andearlydetectionmodalities.Withmorepreciseinformation,patientsoftenfindthatcancer’smystiqueandtheirconcernsaboutcancerriskarediminished,givingthemincreasedconfidenceinsurveillanceandtreat-ment,whichleadstoimprovedcompliance.

Cancerriskassessmentisdesignedtode-terminethelikelihoodthatgenetictestingwillbenefitagivenfamilyandpatient,thetypesofgenetictestingthatmightbeuseful,theappropriateteststoorderforpatients,andthebestwaystofullyexplaintheramificationsoftestresultstopatients.Notallmutationsthatincreasecancerriskcanbedetectedatpres-ent,sotestresultsarenotalwaysinformative,eveninthepresenceofastrongfamilyhistory.Onlywhenamutationhasbeendetectedinafamilycananegativeresultberegardedasconclusive.Therefore,wheneverpossible,geneticistsprefertofirsttestanindividualinthefamilywhowasatsomepointdiagnosedwithcancer.Informationaboutcancerriskandgenetictestingiscomplexandmustbetailoredtomeettheverydifferentinterests,educational levels,andemotionalneedsofeachpatient.Atthecompletionofthecon-sultations,acomprehensivereportissentto

patients’physicians.Age-specificrisksareanimportantcom-

ponentofthecancerriskassessmentservice.Forexample,arecentstudyfoundthatfemaleBRCA1mutationcarriershada46percentchanceofdevelopingbreastcancerbyageseventy(Chenetal2006).Theriskfromagefiftytosixtywasfarlower—13percent.Themostrelevantrisksareoftenthose forthenexttenyears, sincewithinthistimenewtreatmentsandearlydetectiontechniqueswillbedevelopedandmorepreciseinformationaboutrisksatolderageswillbecomeavailable.Unfortunately,manypatientsmakedecisionsbasedonlifetimeinsteadofage-specificrisks,notrealizingthattheycannotbeatriskforagesthroughwhichtheyhavealreadypassed.

Inadditiontorelevantinformationabouthereditaryandnonhereditaryrisks,patientsbenefitbylearningaboutcanceretiologyandrecentadvances indetectingandtreatingcancer.Somehavequestionsaboutlifestyleandotherfactorspurportedtoincreasecancerrisk.Othersbenefitbylearninghowtotalkeffectivelywithfamilyandfriendsabouttheircancerdiagnosisorincreasedcancerrisk.

Patientsmostlikelytobenefitfromcan-cerriskassessmentincludethosewith:• questionsaboutnonhereditaryrisks,earlydetection,canceretiology,orriskofasecondcancer;orthosewonderinghowtodiscussacancerdiagnosis,genetic test results,orincreasedcancerriskwithrelatives.• acancerdiagnosis,particularlyatayoungage.Caution:Asizeableproportionofstronglyinheritedbreastcancerisdiagnosedatolderages.Forexample,inonestudy,morethan20percentofBRCAmutationcarriers’breastcancerswerediagnosedatagefiftyorolder(Brekelmansetal2007).• twoormoreprimarycancers.• afamilyhistoryofcancer,including:

1) cancerdiagnosedintwoormoregenera-tions.Caution: Onlyasingleindividualmaybeaffectedinsmallfamiliesorinotherinstances.Forexample,individualswhoinheritanMYHgenemutationfrombothparentshaveasig-nificantlyincreasedcoloncancerrisk.Parentsarenotatsignificantlyincreasedrisk,soonlyasingleindividualorasinglegenerationmaybeaffected.Eachsiblingofamutationcarrierhasa25percentchanceofhavingasignificantlyincreasedcoloncancerrisk.2) twoormore relativesdiagnosedwithcancer.Caution: SomeFAPgenemutationsresultintheattenuated familialadenomatouspolyposiscoloncancersyndrome(AFAP).Mutationcarriershavesignificantlyincreasedcoloncancerrisksandareoftendiagnosedatolderages.Aboutone-thirdareduetoanewmutation,soafamilyhistoryofcancermaybeabsent.EachchildofanindividualwithAFAPhasa50percentchanceofinheritingamutationthatsignificantlyincreasesrisk.3) relative(s)diagnosedwithcanceratagefiftyoryounger.Caution: Hereditarycancersarenotinfrequentlydiagnosedafteragefifty.4) arelativewithtwoormoreprimarycan-cers.

Astheseguidelinesandcaveatssuggest,athoroughriskassessment,withorwithoutgenetictesting,maybeneededtoaccuratelydeterminecancerrisk.

Increasingly,cancerriskassessmentandgenetic testingarecoveredby insurance.Californialawandajust-signedfederallawprohibitgeneticdiscriminationbymedicalinsurancecarriers.

Dr. Kelly is a diplomat of the American Board of Medical Genetics and a founding fellow of the American College of Medical Genetics. She has authored several books, including the most recent, AssessYourTrueRiskofBreastCancer (H. Holt, NY). Her website is www.ptkelly.com.

Coming of AgeCancer Risk Assessment and Genetic Testing for Hereditary Cancer Risk

Patricia Kelly, PhD

22San FranciSco Medicineseptember 2008 www.sfms.org www.sfms.org september 2008San FranciSco Medicine2�22San FranciSco Medicineseptember 2008 www.sfms.org

theSystematicTreatmentEnhancementProgramforBipolarDisorder(STEP-BD)study,identifiedthegenesencodingatypeofmyosin(MYO5B)andatransmembraneproteinthatmaybeinvolvedincellsignal-ing(TSPAN8)aspotential riskgenes forbipolardisorder.ThesegenesdidnotconferthesameriskinaBritishbipolardisorderreplicationsample.Whentheseresearch-erscombinedtheirresultswiththatoftheWellcomeTrustexperiment,DNAvariantsin thegeneencodinganL-typevoltage-dependentcalciumchannel(CACNA1C),whosebroad functions involvemediatingneuronal calcium-dependent events andavidlybindingdihydropyridinedrugssuchasverapamil.

The lessons from these studies inschizophrenia and bipolar disorder arethattheexpected“usualsuspects,”suchasgenesencodingcomponentsof serotoninorcatecholaminepathways,arelikelynotgoingtobeprominentcontributorstothegeneticrisk,andthatmoreprogresswillbemadewhenlarge,well-characterizedsampleare jointlyanalyzed.Onemove thatwillfacilitatethelatteristheformationofthePsychiatric GWAS Consortium, whichis working to carry out a joint analysisof genomewide studies of fivedisorders,includingADHD,autism,majordepres-sivedisorder, schizophrenia, andbipolardisorder.Thisprojectwill lead toa jointanalysisofsome9,500schizophreniacasesand13,500controls,providingapowerfulsampleforidentifyinggenesexertingsmallbutpotentiallymeaningful effects.Simi-larly,analysisofsome2,800ADHDcases,5,200autismcases,7,100bipolardisordercases,and13,000depressioncaseswillbecarriedout.

rare Genomic alterations in Schizophrenia and autism

Arelativelynewapproachforidenti-fyinggeneticdeterminantsofpsychiatricdisordershasbeentoassumethatasmallnumber of cases may be largely due tolarge-scalegenomiceventsinwhichregionsoftensorhundredsofthousandsofDNAbase-pairsaredeletedfromthegenome,or

The Genetics of Mental DisordersContinued from Page 15...

evenduplicatedinmultiplecopies.Tech-nological advances have facilitated thisresearch,whichisstill inthestageofde-velopment.Nevertheless,thefirstattemptsatcarryingoutthistypeofanalysissuggestthatasmallpercentageofautismcasesarecorrelatedwithsuchgenomicchanges,alsocalled“structuralvariants”or“copynumbervariants”.Similarstudiesinschizophreniasuggestthatupto15percentofcasesharborraregenomicdeletionsorduplications,com-paredto5percentofcontrol individuals.Twocollaborativestudiesinvolvingalmost4,800casescombined foundmore subtleevidence for large-scale genomic eventsthatappeartooccurathigherratesincasesthanincontrolsinfourseparateregionsonthreedifferentchromosomes.Thesestudiesaresuretosparkfutureinvestigationintothefunctionalrelevanceofgenesintheseregionsof structuraldifferences,with theidea thathaving fewerormore than theusualnumberofcopiesofthegeneorgenesintheregionscontributestothepathophysi-ologyofthedisease.

HorizonsGiventhatmajorpsychiatricdisorders

suchasschizophrenia,autism,andbipolardisorderarehighlyheritable,itisnotsur-prising thatwearebeginning to see theidentificationofgeneticelementsthatcon-tributetothedevelopmentofthesediseases.Knowledgeofnovelriskgenesformentaldisorders results ingreaterunderstandingofthebiologyofthesedisorders.Wewilllearnhow thesegenesare regulated, thefunctionthattheproteinproductsofthesegenesperform,andhowtheirdysfunctionleadstomentalillness.Apracticalapplica-tionwillinvolvethedevelopmentofnoveltreatments targeting thesedysfunctionalproteins.

Dr. Steven Hamilton is a psychiatrist and geneticist at the University of California, San Francisco. He received his PhD in biological chemistry and his MD from the University of California, Los Angeles. He was a psychiatry resident and research fellow at Columbia University. Dr. Hamilton’s research focuses on identifying the genetic determinants of be-havior.

A full list of references is available online at www.sfms.org.

contribute to “The Greatest History Book ever Written”

National Geographic Wants Your Genetic Information From the National Geographic Web site

Wheredoyoureallycomefrom?Andhowdidyougettowhereyoulivetoday?DNAstudies suggest thatallhumanstodaydescendfromagroupof African ancestors who—about60,000years ago—begana remark-ablejourney.

TheNationalGeographicSoci-ety, IBM,geneticistSpencerWells,and the Waitt Family Foundationhave launched the GenographicProject,afive-yearefforttounderstandthehumanjourney—wherewecamefromandhowwegot towherewelivetoday.Thisunprecedentedeffortwillmaphumanity’sgeneticjourneythroughtheages.

OurgenesallowustocharttheancienthumanmigrationsfromAfricaacross thecontinents.Throughonepath,wecanseelivingevidenceofanancientAfricantrek,throughIndia,topopulateevenisolatedAustralia.

“Thegreatesthistorybookeverwritten,”Wellssays,“istheonehid-deninourDNA.”

Buttofullycompletethepicturewemustgreatlyexpand thepoolofgeneticsamplesavailablefromaroundtheworld.

The Genographic Project hasestablished ten research laboratoriesaroundtheglobeandarehopingtogetsamplesfromasmanypeopleaspos-sible.Ifyouchoosetoparticipateandaddyourdatatotheglobalresearchdatabase, you’ll help to delineateour common genetic tree, givingdetailedshapetoitsmanytwigsandbranches.

Togetherwecantelltheancientstoryofour sharedhuman journey.Visitwww3.nationalgeographic.com/genographictofindoutmoreandtolearnhowyoucanparticipate.


THe MYSTerY oF dna

D NA,deoxyribonucleic acid,hasbeen viewed as the blueprintcontainingtheinstructionstolife.

Thecolorofoureyes,ourpredispositiontodevelopingcertaindiseases,ourphysicalappearance,andourgenes—thesearejustafewofthethingsdictatedbythesequenceofA,T,C,andGinourDNA.

AftertheHumanGenomeProjectse-quencedthebasesinthegenome,scientistsdeterminedthatthereare3billionbasepairsinourgeneticcode.Interestingly,anytwoindividualsaremorethan99percentgeneti-callyidentical,meaningthatthesequencesintheirbasesmatchperfectlymorethan99percentofthetime.Itisadifferenceof3mil-lionbasesinour3billionbasepairsofgenesthatdefines thediversitywe seebetweenanytwohumanbeings.ThevariationinourDNAhasbeenusedforpracticalpurposes,including tracingancestry,understandingdiseasepathogenesis,andperformingcrimi-nalinvestigations.

Technological advancements andscientificdiscoverieshaveenabledDNAtoemergeintotheforefront,expandingtheuseofDNAbeyondthelab.Havingtransformedtoanessentialforensictool,DNAtestinghasbecomeapartofagrowingarsenalofcriminalinvestigationinstrumentscurrentlyemployedbylawenforcementofficials.

WithDNAtesting,investigationsarebecomingmoredefinitive,movingawayfromsimplyrelyingonaneyewitnessaccounttoextractingDNAtoidentifysuspects.WhiletheuseofDNAtestingcanpotentiallytakeinvestigatorsonestepclosertoprovingordisprovingguilt,DNAuseincriminalinves-tigationsrepresentsacontroversialtopicthathasseveralpracticalandethicalimplicationsthatmustbecarefullyconsidered.

***

DNAtestingisinvolvedinidentifyingsuspectsinvolvedinacrime,orthevictimsleftatacrimescene.DNAtestinghasalsobeen used to vindicate individuals whohavewrongfullyconvicted.Forthepurpose

ofaninvestigation,DNAcanbeextractedfromthecrimescenefromsamplesofblood,bone, hair, and other tissues, includingsemen fromrapekits.Fromthese tissues,theDNAisextractedandstudiedforthepresenceofparticularmarkers.Foraframeof reference,DNAfromthesuspectmustalsobeacquired.

TheSanFranciscoPoliceDepartmentcrime lab, located in theHuntersPointNavalShipyard,isastate-of-the-artfacilityequippedwiththetechnologyrequiredtohandleincreasedDNAtesting.TheForensicServicesDivisionperformstheDNAtesting,includingprocessingDNAsamples fromblood,semen,hair,andsaliva,onacase-by-casebasisaswellasanalyzingDNAtotypesexoffendersandothercriminals.

Ifadropofblood is leftatamurderscene,investigatorscanusethebloodsampletodevelopaDNAfingerprinttodetermineif thebloodbelongedto thevictimor tosomeoneelse.Todoso, investigators relyon theexistenceof stretchesofDNAin

humangenomethatareuniqueandvariablebetweenanytwoindividuals.InprocessingsamplesforDNAtesting,investigatorsusethirteenregionsofDNAthataredistinctinhumans tocreatean individualDNAfingerprint.

To create a genetic fingerprint, in-vestigatorsdevelopa seriesofprobes thatarecomposedofsmallfragmentsofDNA.Theprobesareunique,because theyarecomplementarytospecificDNAsequencesinthegenome.Oncetheprobesarecreated,aDNAfingerprintcanbedevelopedfortheunknownDNA,basedonhowmuchtheprobesbindtotheDNAacquiredfromthecrimescene.

TheDNAprofilecanthenbecomparedtotheprofileofasuspectedperpetrator.ThemoreDNAregionsthatmatch,thehigherchancethattheDNAextractedfromthecrimescenebelongstothesuspectinques-tion.Toincreasetheodds,moreprobescanbeusedtoscanmoreDNAregions.

InthecaseofDNAleftacrimescene,apositivematchcanonlyconfirmthatthesuspectedindividual’sDNAwaspresentatthecrimescene.Ultimately,thecombina-tionoffurtherinvestigationandajurywilldetermineasuspect’sfate;theDNAtestwillbecomeanotherpieceofevidence.

Nationally,DNAforensicevidenceiscataloguedonadatabasecalledtheCom-binedDNAIndexSystem(CODIS).Thedatabase containsDNAprofilesof indi-vidualswhohavebeenconvictedofviolentcrimesand sexoffenses.DNArecoveredfromcrimescenescanbecomparedtoDNAprofilescataloguedintheCODISsystem.Ifamatchisfound,thesuspectcanthenbeidentified.

WiththepassageoftheDNAIdentifi-cationActof1994,allfiftystatespassedlaws

“Having transformed to an essential forensic tool, DNA testing has become a part of a growing arsenal of criminal investigation instruments currently employed by law enforcement officials.”

Unlocking the Genetic MysteryDNA Use in Criminal Investigations

Eisha Zaid


requiring thatDNAprofilesofconvictedfelonsbecataloguedinCODIS.AsofApril2008,CongresspassedlegislationtorequireforeigndetaineestoprovideDNAsamples,regardless of whether or not they werechargedofacrime.Essentially, theseactsallowinvestigatorstocollectDNAfromanyindividualwhoisarrested.

***Ascriminalinvestigationsmovetoward

usingDNAtesting, anumberof ethicalandpractical issuesemerge.ThequestionbecomeswhethertheprosofDNAtestingoutweigh thecons incriminal investiga-tions.

Asidefromprovidingatypeofscien-tificproofthatasuspectwaspresentatthecrimescene,theadvantagesofDNAtestingincludeeaseofidentifyingrepeatoffenders,whoseDNAisstoredinthedatabase.AndifDNAisstoredandcanbeeasilyaccessed,investigationtimeandcostcanbereduced.Inaddition,postconvictionDNAtestingcanbeused toexonerate thewrongfullyaccused,providinganadditional routeofprovinginnocence.

PostconvictionDNAtestinghasbeenusedby the InnocenceProject, an inde-pendentnonprofitorganizationaffiliatedwiththeCardozoSchoolofLawatYeshivaUniversity.Theorganization,whichwasfoundedin1992,reportsthat“218peopleintheUnitedStateshavebeenexoneratedbyDNAtesting,including16whoservedtimeondeathrow.”Theorganizationreportsthatthewrongfullyaccusedwilltypicallyserveanaverageoftwelveyearsinprisonbeforebeingexoneratedandreleased.

Although the Innocence Projectaims tousepostconvictionDNAtestingtoexonerate thewrongfullyaccused, theorganizationunderstandstheimplicationsofDNAtestinginreaffirmingguilt.ClientsareadvisedthattheDNAresultsbecomepartofpublicrecord,eveniftheresultsreaffirmaguiltyverdict.

ClientsturntotheInnocenceProjectafterexhaustingmostotherroutesoflegalappeals.Thedemandfortheservicesishigh;thousandsofprisonersawaitreviewoftheircases.Forthosewhosecasesarereviewed,cli-entsundergoanextensivescreeningprocesstodetermineifDNAevidenceexistsandifitcanbeusedtoproveinnocence.

Theorganizationattributeswrongfulconvictionstoavarietyoffactors,includingeyewitnessmisidentification,unreliableorlimited science, falseconfessions, forensicscience fraudormisconduct,governmentmisconduct,andineffectivelawyering.WithincreaseduseofDNAtechnologyandagrowingnumberofexonerations,theorga-nizationisalarmedbytheinherentproblemsinthejusticesystem.InadditiontohelpingexonerateprisonersusingDNAtechnology,theorganizationaimsto introducereforminthecriminaljusticesystembypartneringwithlegislatorsandlawenforcementofficialsonthestate,local,andfederallevels.

Toaddressissuesrelatingtowrongfulconvictionsandreformthecriminaljusticesystem,theInnocenceProjectworkswithstatestodevelopreformcommissionsthataddressissuessurroundingwrongfulconvic-tions.Anumberofstateshaveimplementedreformcommissions,whicharechargedwithmakingkey recommendations geared ataddressingconcernssurroundinginvestiga-tions,laboperations,defense,prosecution,andjudicialreview.

AlthoughtheInnocenceProject,oneoftheforerunnersthatchampionstherightsofthewrongfullyaccused,hasusedDNAtestingtocorrectinjusticesthathavebeencommittedagainsttheinnocent,anumberofethical issuesmustbeconsideredwhenusingDNAtesting.ThebiggestconcernrevolvesaroundprivacyoftheindividualswhoseDNAisstoredinCODIS,includingtheconvictedand individualswhoweresuspected,eveniftheywerelaterprovedtobeinnocent.

***OurDNArepresentsmorethanjusta

seriesofA,T,C,andG;ourDNAholdsthekeytosensitivehealthinformation,includ-ingfamilyhistoryanddiseasesusceptibility.Wetake suchgreatefforts toprotectourpersonalidentity;howdoweensurethesameforprotectingourgeneticidentity?

Anumberofconcernsemergewhenconsideringwhogains access to geneticinformationandwhatwouldhappenifthedatabasewashackedandsensitivehealthinformationwassoldtoinsurancecompaniesoremployers.IfasuspectedcriminalhastoprovideDNAanditislaterdeterminedthatheorsheisinnocent,hisorherDNAwill

bekeptonrecord.Andonceanindividual’sDNA ison record, lawenforcementof-ficialscanaccess the informationwithoutan individual’sconsent.Does suchanactviolateanindividual’s rights?Searchwar-rantsarerequiredtoenterintoasuspectedindividual’sproperty.Shouldthesamerulesapplybeforeaninvestigatortrespassesintosomeone’sgeneticcode?

Anotherconsiderationwemustmakerevolvesaround the limitationsofDNAtechnology, including concerns of con-taminationormishandlingevidence.Properoversightwillbeneeded toensureDNAsamplesareprocessedproperly,especiallyastheDNAtechnologyadvancestopreventfalsepositivesandwrongfulconvictions.

Inaddition,analyzingDNAresultshasitslimitations.Forexample,doesapositiveDNAmatch,orpartialDNAmatch,meananindividualcommittedacrime?Whatifsomeone’sDNAwasleftatthecrimescenebecausetheyhadvisitedthesceneearlier?DNAtestingonlysaysthattheDNAatthescenematchesthatofanindividual.Butfur-therinvestigationwouldberequiredtolinkthecrimetothatoranyindividual.

Despite themyriadofdisadvantages,DNAtestinghasadvancedcriminalinves-tigationsbyopeninganentirenewfrontierofforensictechnologytoconvictfelonsandexoneratethewrongfullyaccused.Thedou-ble-edgedswordthatisDNAtestingrequirescareful considerationwhenDNAresultscomeintoquestionduringaninvestigation.AsmuchasDNAtestingprovidesscientificproof,thematterofinnocenceorguiltwillultimatelycomedowntoahumanprocess,including investigatorswhomustprocesstheDNAandajurywhomustunravelthemysterybehindtheevidenceanddeterminehowitfitsinthepuzzlethatdeterminesthefateofsomeone’slife.

Eisha Zaid is a second-year medical student at UCSF.


BooK reVieWSteve Heilig, MPH

Darwin and LiteratureMadame Bovary’s Ovaries: A Darwinian Look at LiteratureByDavidP.BarashandNanelleR.BarashDelacorte(2005),262pp.

w hatifCharlesDarwinwroteanovel?Whatifhewrotethemall?Well,maybehedid,inasense;thethesisofMadame Bovary’s OvariesisthatDarwin,orrather

theforcesofevolutionandnaturalselectionthatDarwindidwriteabout,underlietheplotandbehaviorofallhumancharactersinliterature.

DavidBarashisawell-knownzoologistattheUniversityofWashington,andhisdaughterNanelleisastudentatSwarthmore.Theycalltheirperspectivethatofevolutionarypsychology.Almostthirtyyearsago,amassivetomebearingthattitlebyfamedHarvardbiologistE.O.Wilsonpositedthathumanbehaviorhasastronggeneticcomponent,thussettingoffafirestormofcriticism,bothscientificand,especially,political.Anumberofsubsequentbooks,suchasRichardDawkins’sThe Selfish Gene,haveexplored thisperspectivewithsimilarlycontroversialresults.

Notsofast,replytheBarashes.Theyproceedtosurveythebestofliterature—Western,anyway—forevidenceofourDarwinianurges.Andthose, itwouldappear, largelycomedowntodoingwhateverwecantoensurethatourgenesliveonafterourbod-ies.“Whetherbatorbird,sealorspider,livingthingsreproducebecausethisisthemajorwaytheirgenespropagatethemselves,”theBarasheswrite.“Itisalsothemajorreasonforlove,includ-ing loveof adults for eachother andofparents for children.”Apparently, even love is ageneticadaptation.Thus, fromtheworksofHomer throughShakespeare toTolstoy,Dostoevsky,Dickens,Twain,Faulkner,Austen, Joyce,Nabokov,Steinbeck,andrightuptoKundera,Márquez,AliceWalker,andevenCharlesBukowski, the storylines,howeverpoetic, convoluted, steamy,orspiritual,arereallyabouttherulesofthejungle—ordesertorboardroomorbedroomoranywherethestruggleforsurvivaltakesplace—eventhoughmostauthorshavebeenlargelyunawaretheyarebeingguidedtosomedegreebythe“evolutionarybottomline.”Theprimarythemeis,apparentlyunavoidably,sex.Menwanttospreadtheirgenesfarandwideandcaneasilydoso,atleastphysically;womenmustbemorecareful.Menlookforwomenwhoappeartobegoodpotentialchildbearersbutwhowillnotcuckoldthem;women

lookforproviders,fromancientGreekmythuptoBridgetJones.Apeacock’sfeathersoraPorschearesimilarmaledisplays.Othelloisa“dominantbullelk,”driventomurderandmadnessbymalesexualjealousy—acommondynamic theBarashes then trace throughmanyofShakespeare’sotherplaysandonwardtoThe Great Gatsby.InFlaubert’sfamousnovel,whichprovidesthetitlefortheBarashes’book,poorEmmaBovaryherself,abit“loose”forhertimes,wasmerelyyieldingtodeep-setdesiresforabetter“catch”andthepos-sibilityof“marryingup,”lookingforsomeonewhowouldensurereproductivesuccess.

Themobsters inThe Godfatherputfamilyaboveallelseforthesamenepotisticreasonsthataprideoflionsonthesavannahwould.Ontheotherhand, theJoadsandotherdesperate farm-workersinThe Grapes of Wrathcleavetooneanotheroutsideoffamilytiesdueto“reciprocalaltruism,”atbottomexpectingsomesortofpayofffromhelpingothers.Thusevenfriendship,whereinreproductionshouldnotbeanissue,isunderneathitallagameofmutualback-scratching,rootedinneedsforfoodandprotection.TheBarasheshavereadwidely, thoughthard,andproducedanengrossing,provocativeworkofliteraryspeculation.Ifsomeoftheirinterpretationsseemtoocynicalintheend,theyremindus,asKath-erineHepburn’scharacterinthemovieadaptationofC.S.Forster’sThe African Queenargued,“Nature,Mr.Allnut,iswhatweareputonearthtoriseabove.”Though,asmanyclassicnovelsshow,doingsoisnotalwayseasyandsometimesnotsoentertaining.

This review originally appeared in the SanFranciscoChronicle.

26San FranciSco Medicineseptember 2008 www.sfms.org www.sfms.org september 2008 San FranciSco Medicine2726San FranciSco Medicineseptember 2008 www.sfms.org

BooK reVieWErica Goode, MD, MPH

Breast Cancer Risk: An Expert SpeaksAssess Your True Risk of Breast CancerPatriciaKelly,PhDHenryHoltandCo.(2000),253pp.

D r.PatriciaKelly,specialistincancerriskassessmentandcounseling,statesthatmanywomenwithafamilyhistoryofacancerhavecometoherfeelingthatthe“othershoe

willdrop.”However,Dr.Kellypointsout,theoppositeisthecase.Typically,anunexaminedriskisoverblownanddaughtersareseek-ingbilateralmastectomiesandoophorectomieswithoutadequateinformationofrisk.

Thisbookgivesexamplesofpeoples’issuesandwaystofindanswerstoanarrayofquestions.Dr.Kellydecodesthelanguageofgenes,oncogenes,andwhatisknownofhereditarycancers,andshediscussesBRCAgenetics,CA-125,andgenetictestingissues.

Afewchaptersaredevotedtodiscussingbenignbreastdisease,ductalcancerinsitu,andlobularcarcinomainsitu.Anothercoversthelimitedchangeinbreastcancerriskassociatedwithhormonereplacementtherapy.Yetanotherdiscussesotherfactorsthoughttoincreaserisk,suchasageatpregnancy,alcohol,anddiet.

Thebookthenshiftstoarmingthereaderwithaclearmethodofnavigatingthemedical systemtobestadvantage,proceedingthroughaseriesofbeststeps.Oneneedsaprimaryphysicianwhoisopentospendingtimeonatopicandwhoknowsandwillreferpatientstoappropriatespecialistsandsecond-opinionsourcesasneeded.

Dr.KellyprovidesaninsertregardingtheWomen’sHealthInitiativestudy,theresultshavingbeenreleasedafterthebook’spublication.Asoriginallyreported,theWHIstudy“conclusively”

showedanincreasedriskofbreastcancerinthosetakingPrempro.However,Dr.Kellyshows(asIandanumberofphysicians,notablyRickiPollycove,havethoughtallalong)thatinfacttheWHIstudydoesnotdemonstrateastatisticallysignificantincreaseinbreastcancerriskinwomentakingPrempro.Thedifferencebetweenthosetreatedandthoseuntreatedwas8/10,000women/year.Andsincethestudywasstoppedafterfiveyears,despiteourknowledgethatabreastcancertakesmorethaneightyearstoreachevenasmallsize,anddespiteintenseobjectionstotheconclusionsreleasedtothemediabyoneoftheprimaryinvestigators,theresults,fromDr.Kelly’sanalysis,arenotwhattheyseem.

Eachchapter is summarizedwitha listofkeypoints to re-member,andDr.Kellycompletes thedirectivewithachapterentitled“LivingatEasewithUncertainty,”whichistheultimatekeypoint.Theappendixincludesaglossaryandscreeningques-tionnairesforwomentousetodecideiftheyshouldseekcancerriskassessment.

Becausethisbookisinfinitelyreadableandprovidesaroadmaptothishighlychargedissueinwomen’slives,itwouldbead-visableforanyprimarycareoroncologyofficetoprovideseveralloanercopiesforthebenefitofallconcerned.Toorderthese,contactPatriciaT.Kellyat(510)[email protected].

Thisbookisawiseandpracticalguideforanyonetryingtoweighthestatementstheyhaveheardfromdoctors,readinthelaypress,andgleanedfromothermedia,friends,andrelatives.

2008-2009 SFMS Member Directory Available Now!

Directories are now available! All SFMS members receive one copy of this

valuable resource as part of their memberships. Please watch for your copy in

the mail. If you are interested in ordering additional copies please contact Carol

Nolan at (415) 561-0850 extension 0 or [email protected] for information.


KaiserRobert Mithun, MD

TheChineseCommunityHealthPlan’scolorectal screeningprogramhascontinuedtoreceivenationalattention.Infact,ithasreceivedfinalistrecognitionforthe2008CommunityLead-ershipAwardattheJunemeetingoftheAmericanHealthInsurancePlanInstitutefromitsboardofdirectors;itsposterpresentationwasdisplayedinthereceptionhalllaterthateveningatitsopeningreception.ThisprogramwillalsobepresentedattheNationalCancer Institute’sconferenceondisparitiesinWashington,D.C.,inJulyaspartofapresentationoncolorectalcancerbytheAsianAmericanNetwork forCancerResearchandTraining(AANCART).AANCARTisanNCIspecial-needsgrant,andtheSanFranciscoAAN-CARTChineseCouncilisoneoftwoAANCARTregional sites inSanFrancisco.OuresteemedCCHPMedicalDirector/IPAExecutiveDirector,Dr.EdwardChow,servesastheprincipalregionalinvestigator,andDr.JustinQuockistheclinicaldirectorforoursite.InNovember,Dr.ChowwillbepresentinghisexperienceoncolorectalscreeningattheannualmeetingoftheChineseAmericanMedicalAssociation inNewYorkCity.OurthankstoDrs.ChowandQuockfortheexcellentcommunityworktheyhavebeendoing.ChineseHospitalmedicalstaffandourIPAaremembersoftheFederationofChineseAmericanandChineseCanadianMedicalSocieties(FCMS)and,assuch,willbesupportingtheFourteenthConferenceonHealthCareoftheChineseinNorthAmericaSeptember28–29inToronto.ThisconferenceoccurseverytwoyearsandrotateshostsitesacrossNorthAmerica.Thisyear’s topic is“EmergingHealthIssuesamongNorthAmericanChinese”andtherewillbeaninauguralDr.HarryLeeMe-morialLecture.FCMSisdedicatedtopromotingthehealthofChineseinNorthAmericathrougheducation,advocacy,andcommunication.Checkoutthewebsiteatwww.fcmsdocs.org.ThecurrentpresidentofFCMSisourownDr.RandallLow,andweareproudofthegreatjobheisdoing!

ChineseJoseph Woo, MD

SaintFrancisWade Aubry, MD

ThehistoryoftheKaiserPermanenteNorth-ernCaliforniaRegionalGeneticsProgramparallelsthehistoryofmedicalgenetics.Itwasinthe1950s,adecadebeforeourgeneticsprogramhaditsbegin-nings,thatWatsonandCrickdescribedthestruc-tureofDNA.Inthe1960s,whenourprogramwaslaunched,Nierenberghadjust“crackedthegeneticcode”attheNationalInstitutesofHealth.Bythetimethehumangenomeprojectwascompletedin2003,theKaiserPermanenteRegionalGeneticsProgramhadexpandedtobecomethelargestandmostcomprehensiveclinicalandlaboratorygenet-icsprograminthecountry.TheregionalgeneticsprogramatKaiserPermanenteofferscutting-edgeservicesinallareasofmedicalgenetics,includinggeneticevaluationanddiagnosis,counseling,test-ing,andtreatment.Afullrangeofgenetictesting,includingmolecularDNA,cytogenetics,andcan-cergenetics,isavailablethrougharegionallabora-tory.Multispecialtyclinicsprovideongoingcareformanycommongeneticconditions:craniofacialproblems,spinabifida,metabolicdisorders,skeletaldisorders,neurofibromatosis,andneurogeneticproblems.KaiserPermanentealsohasextensivege-neticscreeningservicesincludingnewbornscreen-ing,hemoglobinopathyscreening,ethnicity-basedgeneticcarrierscreening,breastcancerscreeningandtracking,andinfectiousdiseasescreening.TheRegionalGeneticsEducationProgramisanewadditionthatreflectstheincreasingdemandforgeneticinformation.ThemissionoftheregionalgeneticsprogramistoprovidegeneticseducationtoKaiserPermanenteprovidersandhealthplanmembers,andtohelpbothgroupsunderstandthecontributionofgeneticstooverallhealthandwell-ness.TheSanFranciscoGeneticsDepartmentwasfoundedin1982andcoversaservicearearangingfromSantaRosatoDalyCity.Thedepartmentincludes twomedicalgeneticists,eightgeneticcounselors,andageneticsnurseavailabletoad-dressthegeneticneedsofhealthplanmembersandprovideconsultativeservices.

SaintFrancishashadaninterestinissuesrelatedtothehumangenomeforseveralyears,whichhasbeenledbymedicalgeneticistPatriciaKelly,PhD.Dr.Kellyisrecognizedasoneofthenation’sleadingexpertsinmedicalgeneticsandcancer riskassessment.She is adiplomateoftheAmericanBoardofMedicalGeneticsanda foundingfellowoftheAmericanCollegeofMedicalGenetics.Dr.Kellyhasbeenon theSaintFrancis staff foralmost tenyears, inad-ditiontoprovidingcounselingandeducationalprogramsforthecommunityoverthepastseveralyears,andshenowmaintainsaprivatepracticeincancerriskassessmentandcounselingintheBayArea.OneofherkeyareasofinteresthasbeentheuseofgenetictestingforBRCA-1and-2inthemanagementoffamilialbreastcancerandovariancancer.

PresidentandCEOTomHennessyrecentlyannouncedtheappointmentofnewChiefOp-eratingOfficerTonyJackson.Mr.Jacksonhasadoctorateofpharmacy fromFloridaA&MUniversityandamaster’sinbusinessadministra-tionfromUCLA.Hestartedinhisnewpositionon July28andbringsawealthofexperienceinoperations,strategicplanning,andcontractnegotiations to the hospital. He will workcloselywithRobertVautrain,MD,VPMA,andthemedicalstaffleadershiptobuildonthesuc-cessshownbyourfavorableJointCommissionSurveyinJune.

Andfinally,congratulationstoJohnMeyer,MD,onthepublicationofthebookheedited,IMRT, IGRT, SBRT: Advances in the Treat-ment, Planning, and Delivery of Radiotherapy. Thevolumeisacomprehensiveguidebooktonewtechnologiesinradiationoncologyandthemanyclinical treatmentprograms thatbringthemintopracticaluse,anditprovidesessentialtreatmentguidelinesforclinicalandtechnicalpractitioners.

HoSPiTaL neWS

28San FranciSco Medicineseptember 2008 www.sfms.org www.sfms.org september 2008 San FranciSco Medicine2928San FranciSco Medicineseptember 2008 www.sfms.org

St.Mary’sRichard Podolin, MD

St.Luke’sJerome Franz, MD

UCSFElena Gates, MD

WiththeBlueRibbonPanel’sJulyreportonthefutureofSt.Luke’s,therehasbeenno-ticeablymorehopeinthelunchroom,corridors,andofficesofourcampus.Wewillhaveanewhospitalmeetingseismicsafetystandards.Itwillbeadjacenttothewestsideofthe1970toweranddesignedforsixtyacute-carepatients.Out-patientserviceswillalsobeexpanded.Wewillcontinueourexcellentprogramsinobstetricsandcardiologyandplananewcenterofexcellenceforgeriatrics,whichwillbemultidisciplinary.WeawaitdetailsandtheapprovaloftheCPMCBoard.WecommendandthankthemembersoftheBlueRibbonPanelfortheircommitmenttothiscommunityanditshealthcare.

OnJuly2,thechaplaincyprovidedamemo-rialservicefortwolongtimeSt.Luke’sdoctors.PedroPintopracticedfamilymedicineat16thandMissionforfortyyearsandservedasChairofFamilyPractice.BorninEcuador,hecametoSanFranciscoin1952andalwaysmaintainedclosetieswithhishomecountry.Hewasamodelofdressanddeportment,reveredbyhispatients.Heretiredsomeyearsagotospendmoretimewithhisfamily.HepassedawayinMay.

StanleyBaer recently retired from fortyyearsoforthopedicpracticeatSt.Luke’s.Healsoservedaschairofhisdepartment.Heisremem-beredforhisexcellentcareandhiswillingnesstoworkwithunderinsuredaswell asprivatepatients.Hekeptmanyofusentertainedwithstoriesabouthisfamily,andhealwaysseemedtobeavailableforconsultation.HediedinJune.

Complextraumaticinjuriesrequiringmultipleproceduresfromseveralspecialtysurgeonscanpres-entmedicalandcaremanagementissuesforboththepatientandthephysician.Lastfall,St.Mary’sMedicalCenterrespondedtotheneedforamoreefficientcare settingbyopeninganoutpatientPlastic,Reconstructive,andOrthopedicSurgery(PROS)CenterwithateamoftopsurgeonsfromSt.Mary’s,UCSF,andtheOrthopedicTraumaInstituteatSanFranciscoGeneralHospital.Work-ingcollaboratively,surgeonsareabletoperformeventhemostcomplexreconstructiveproceduresmoreproficientlyandwith fewerprocedures.Patientsrecovermorequicklyandhaveimprovedoutcomes.

Orthopedicandplasticsurgeonsworktogeth-erfromtheverybeginningtodevelopindividualizedtreatmentplansthattakeintoaccountallaspectsofacase,whetheritisalegcrushedinanaccident,awoundthatfailstoheal,aseveredfinger,oranyotherinjurythatwouldbenefitfromthismultispe-cialtyteamapproach.Oneyoungman,whohadlosthisthumbinawoodworkingaccident,underwentatoe-to-thumbtransplantandnowhasaworkingthumbwithfullmotion.Inanothercase,amanwhohadexperiencedatibiafracturewithsubsequentinfectionhadbeentoldhewasgoingtolosehisleg.PROSCentersurgeonscleanedouttheinfectioninhisboneandperformedaskingraft—savingthelegoftheverygratefulpatient.

ThePROSCenterteamoforthopedicandplastic surgeons specializes in thetreatmentoftraumatic injuriesandposttraumaticcomplica-tions,includingacuteboneandsofttissueinjuries;brachialplexus injuries; traumacomplications;limbsalvagesurgery;pelvicandacetabularfracturesurgery;complexhand,wrist,andelbowsurgery;flapreconstructionoftheextremities,face,andbreast;chronicwoundproblems;andosteomyelitis.ThedevelopmentofthesurgicallyinnovativePROSCenterexemplifiesthemissionandpioneeringspiritofSt.Mary’sMedicalCenter.

Wewerepleased to learn recently thatUCSFMedicalCenterhas retained its rank-ingastheseventhbesthospitalinthecountry,andthebestintheBayArea,accordingtothenew2008 “America’sBestHospitals” surveyconductedbyU.S. News & World Report.ThisyearUCSFearnsaspotonthesurvey’s“honorroll,”whichrecognizesabreadthofexcellenceacrossspecialties.UCSFplacedamongthetoptenmedicalcentersinendocrinology,neurologyandneurosurgery,gynecology,urology,cancer,respiratorydisorders, rheumatology, andoph-thalmology.“Weareproudtoconsistentlyrankamongthetoptenhospitalsinthenation,”saidUCSFMedicalCenterCEOMarkLaret.

Humangeneticsisplayinganincreasinglyimportantroleacrosstherangeofspecialtyser-vicesatUCSF.IntheHelenDillerFamilyCan-cerCenter,theCancerRiskProgramprovidescounseling and testing aswell aspreventionand screening strategies.Geneticprofilingofindividualcancersnowguidestreatmentchoice.ThePrograminCardiovascularGeneticsevalu-atesandtreatspatientswithavarietyofgeneticheartdisorders, includingarrhythmiaandcar-diomyopathy.

In theneurosciences,geneticknowledgeis improving thecareofchildrenwithneuro-metabolicconditionsintheMetabolicDiseaseCenter,andfamiliesaffectedbyneurodegenera-tivediseasessuchasAlzheimer’s,intheMemoryandAgingCenter.UCSF’sPrenatalDiagnosisCenter collaborates with specialists acrossthe institutioninhelping familieswith inher-iteddiseasesmakedecisionsaboutchildbearing.ThroughoutUCSF,geneticknowledgeisbeingusedtoimprovehealth.

HoSPiTaL neWS

�0San FranciSco Medicineseptember 2008 www.sfms.org

VeteransDiana Nicoll, MD,

PhD, MPA

Representative David Obey (D - WI),ChairoftheHouseAppropriationsCommittee,recentlyvisitedtheSanFranciscoV.A.MedicalCenter.HewasaccompaniedbyHouseSpeakerNancyPelosi(D-CA),alongtimesupporteroftheMedicalCenter.

Mr.ObeyandSpeakerPelosireceivedbrief-ingsonclinicalandresearchactivities.CharlesMarmar, MD, chief of Mental Health, andThomasNeylan,MD,directorofthePosttrau-maticStressDisorder(PTSD)Program,reviewedclinicalandresearchinitiativesinthediagnosisandtreatmentofPTSD.ChiefofMedicinePaulVolberding,MD,discussedAIDS researchatSFVAMC,notingthattheV.A.systemisthelargestproviderofHIV/AIDScareintheU.S.

SpeakerPelosicommendedthehighqual-ityofhealthcareforveteransbeingprovidedatSFVAMCandobservedthattheSanFranciscoV.A.MedicalCenter’sprominentpositionasaresearchcenter“canbeattributedtothehighcaliberofcliniciansandscientistshere,whichisa resultof thestrengthof thecollaborationbetweenSFVAMCandUCSF.”

Following thebriefings, they toured thenew3-DImagingLaboratoryandheardaboutthe latest radiologicandneurologicadvancesfrom Senior Scientist Norbert Schuff, PhD;Parkinson’sCenterDirectorWilliamMarks,MD;andChiefofRadiology JudyYee,MD.Theyconcluded their tourbyvisiting severalhospitalizedpatients,includingapatientreferredfromAmericanSamoa.

Obeywas“veryimpressedbyallthegreatwork”beingdoneat theSanFranciscoV.A.MedicalCenter.“Thisiswhywe’vemadevet-erans’healthourfirstpriorityinCongress,”hesaid.“I’vebeenafanofthisplaceformanyyears,”respondedSpeakerPelosi.

robert Louis Marvin, MdRobert(Bob)Marvin,MD,wasborninLos

AngelesonJune30,1925,anddiedathomeinSanFranciscoonJune26,2008.Hebecamealong-termresidentofMarinCountyaftergrow-ingupinSouthernCaliforniaandcompletinghispsychiatrictrainingattheHarvardServicesofBostonPsychopathicandMassachusettsMe-morialHospitals.Toward theendofahighlyproductive clinical and community-orientedmedical career, Bob specialized in workers’compensation and Social Security disabilitypsychiatricassessmentsandservices.HeservedasclinicalprofessorofpsychiatryattheUniversityofCalifornia,SanFranciscoSchoolofMedicineuntilheretired.

AsayoungboyinLosAngeles,BobMarvinperformedanumberoftimesonstageasachildactor.Hewasamemberoftheprofessionalactors’union,AFTA.Fromhisyouthfulcareerissuedalifelongenthusiasmfortheatricalperformancesandmusicalevents.DuringWorldWar IIhejoinedtheNavy,andatwar’sendheenteredUCLA,whereheearnedaPhiBetaKappakeyasajuniorandqualifiedformedicalschoolatUCSF. Interning atSt.Elizabeth’sHospital,Washington,D.C.,hewentontotrainingeneralpsychiatryinBoston.HebecameadiplomateoftheAmericanBoardofPsychiatryandNeurol-ogyin1958,twoyearsafterhisultimatemovetoNorthernCalifornia.Since1956,hehasbeen

astaffmemberatMt.ZionHospital,SanFran-cisco,McAuleyPsychiatricClinicofSt.Mary’sHospital,andSt.FrancisHospitalDepartmentofPsychiatry.From1982to1985,heservedaschairmanof thepsychiatrydepartmentatSt.Francis.Healso functionedas apresidentoftheNorthernCaliforniaPsychiatricSociety.Throughoutthistime,hetaughtandsupervisedmedical students and resident physicians atUCSF.Healsotookpartinteachingpsycholo-gists-in-trainingatbothMt.ZionHospitalandUCSF.

BobservedontheEditorialBoardforSan Francisco Medicine.HechairedtheSFMSCom-mitteeonMentalHealthandwasamemberofProfessionalRelationsandtheImpairedPhysi-ciancommittee.

Bobnevergaveuphisspecialaffectionformusicandthetheater.Helovedtravel,art,andreading.Hewillberememberedfortheloveandcarehegavehisfamily,friends,andprofession;forhisboundlessenergy;hisenergizedsmile;hisattention todetails; andawillingness to takerisks.Helovedlife.

BobMarvindiedofpancreaticcancerfol-lowingaprolongedandbravefightagainstthedisease.Heissurvivedbyhiswifeoftwenty-threeyears,Connie,hisbrotherFrederick,andbyhischildren,JodyandJonathan.

HoSPiTaL neWS in MeMoriaM

cLaSSiFied adS

Seeking independent Physician to collaborate in San Francisco

Seeking young, brilliant, well-trainedfamily physician or internist to share officespace,overhead, and/orcall coverage forourfee-for-serviceprivatepracticeendeavorsinSanFrancisco.Iwouldliketodevelopacollegialandaestheticallypleasingenvironmenttopracticewherewecaneachachieveourhighestpotential.PleasesendCVanddescriptionofyourpracticeintereststophysician.search@gmail.comwww.sfodoctor.com.

Medical office Space for Lease near UcSF Mt. Zion on Sutter Street

Totallyremodelledofficespacesareavail-ableforleaseincludingparkingspace.700-960SQF.Rent$2200.00andup.Pleasecall415-342-9191oremailellie94563@yahoo.com.

�0San FranciSco Medicineseptember 2008 www.sfms.org

in MeMoriaM

1. Six out of ten employers have faced employee lawsuits within the last five years.

2. 67% of all employment cases that litigate result in a judgment for the plaintiff.

3. The median compensatory award in EPLI cases is $218,000.

4. Defense of the average EPLI case through trial costs over $45,000.

5. The average amount paid for out-of-court settlement is $40,000.

Through the San Francisco Medical Society endorsed Employment Practices LiabilityProgram, members may not only receive important coverage for judgments anddefense costs up to $1,000,000 but will also have access to risk management tools.Web-based training for you and your office managers is included as well as accessto employment attorneys for advice on how to properly handle employment issuesto mitigate potential future claims.

Contact Marsh at 800-842-3761 for information on the SFMS endorsed specialFirst-Time Buyers program.

Is that in my jobdescription?

.How was I supposed to know

I wasn’t supposed tosay that?z

I should have had that job!

If he doesn’t stop telling me

those awful jokes...

© 2008 Seabury & Smith Insurance Program Management • CA License #SL0633005777 South Figueroa Street, Los Angeles, CA 90017 • 800-842-3761 • [email protected] • www.MarshAffinity.com • 7/08

* Society for Human Resource Management – 2002

Endorsed by:

Administered by:

Neither can we. But let’s look at the facts*:

..They seem happy now, but...can you identify the one who may sue you for:

...Wrongful termination? ...Discrimination? ...Sexual harassment by a fellow employee?

Marsh is part of the family of MMC companies, including Kroll, Guy Carpenter, Mercer, and the Oliver Wyman Group (including Lippincott and NERA Economic Consulting).

www.cpmc.org

Doctors at California Pacific Medical Center have

been very successful in performing percutaneous

device closure of patent foramen ovale in patients

with cryptogenic stroke from paradoxical embolism.

The percutaneous closure procedure is performed

under local anesthesia and is extremely safe.

Patients are typically discharged within 24 hours

and are back to work the same week.

How Would You Treat A Patient After a Cryptogenic Stroke?

The California Pacific team also treats adult and pediatric patients with pulmonic stenosis, patent ductus arteriosus, aortic coarctation, hypertrophic cardiomyopathy and atrial septal defect. After you make the diagnosis with appropriate imaging studies, patient referral and/or transfer can be easily arranged with a single phone call. At CPMC, we pride ourselves on providing the best service and care for your patients, and seamless communication with you, the referring physician.

For more information, to find a specialist or to schedule a patient transfer, please call

Peter Hui, M.D. FACC, FSCAI Adult Interventional

Cardiologist

Kalyani Trivedi, M.D.Pediatric Interventional

Cardiologist

California Pacific’s Heart and Vascular Center offers quality,

comprehensive, patient-centered cardiovascular care by a team

of pioneering physicians integrating leading-edge technology.888-637-2762

september 2008

Documents

san francisco underwriter

years n

n c i s c o

s o c i e t ydnamiec

o f t h e s

e d i c

insurance carrier

time physician