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ust who is SiddharthaMukherjee? Thisis thequestionmanyveteransof thecan-cer community asked as a book by thisunknown author began to win criticalaccolades and prizes last year, including

the Pulitzer Prize for non-Fiction and the GuardianFirst BookAward, earningMukherjee a place amongTIMEmagazine’s 100most influential people.Less than two years since publication, The

Emperor ofAll Maladies:A Biography of Cancer hassold between half a million and a million copies, isbeing translated into20 languages, andcontinues togenerate around50emails to the author aday. “Iwascompletely overwhelmed by the generosity of theresponse,” says Mukherjee, currently a practisingoncologist specialising in haematological cancers atthe Columbia University Medical Center in NewYorkCity. “By thesizeof it, byhowdiverse it is, byhowdiffuse it is. From students and general lay readerswho said ‘I was never interested in this question tillI read thebook,’to scientists at theNational Institutes

of Health who write thanking me for providing anoverview. Different people come at it in differentways.For somepeople it gives themsolace, for someit activates them.Youngmen andwomenwrite andsay ‘I nowwant tobea scientist, a cancer researcher’.This happens literally everyday.”His celebrity statusis such thathewasevenapproachedbyagroupof stu-dents while on a trip with his kids toDisneyland.ReadingMukherjee’s ownbiographical noteswill

tell you that he reached his current position as assis-tant professor ofmedicine atColumbiaUniversity, inchargeof a translational research labat theUniversity’sIrvingCancerResearchCenter, throughanacademicresearch route,with the clinical practice comingonlylater.Bornandeducated inNewDelhi, India,hewenton tomajor in biology at StanfordUniversity,Califor-nia, where he worked in Nobel Laureate Paul Berg’slaboratory defining cellular genes that change thebehaviours of cancer cells. A Rhodes Scholarshiptook him to Oxford, where he earned a DPhil inimmunology. Only then did he train as an MD at

With our new-found understanding of cancer biology comes the opportunity to explain

a disease that for centuries has confounded doctors and engendered stigma and

superstition. Siddhartha Mukherjee took that opportunity and turned it into a best seller.

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HarvardMedicalSchool,wherehecompletedhis res-idency in internal medicine followed by an oncologyfellowship atMassachusettsGeneralHospital.His research focuseson the linksbetweennormal

stem cells and cancer cells, specifically probing themicroenvironmentof stemcells –particularly blood-forming stemcells. It has attractedgrants frommanysources including a coveted Challenge Grant fromthe National Institutes for Health, and generatedpapers published in journals includingNature,Neu-ron and the Journal of Clinical Investigation.Mukherjee, then, couldbe summedupasoneof

the newgeneration of translational researcherswho

is exploringoneofmany interestingavenues thatmayoffer newopportunities for intervening in processesthat generate and fuel certain typesof cancer growth.None of this, however, offers a clue as to why he

ended up being the first person to explain to a massgeneral readership thenatureof this frightening,mad-deningly elusive,multifacetedenemy that formillen-niahashaddoctors, cancerpatientsandsocietyat large P

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asking: what is this thingwe are up against?For Mukherjee, however, the real question is

why no one else had already done it. “When I wastraining as a fellow in cancer medicine what wasamazing tomewas that suchabookdidn’t exist.Hereis a family of diseases that will affect one in two orthree of us, and we don’t have a sense of whatbrought us to this point andwhatwemight bedoingnext.So that ishowthebookbegan tobewritten.Butmyapproach to thiswasn’t towrite a600-pagebook.Really Ibegan tokeepa journal; itwas a verypersonaljourney forme to start with.”It didn’t take him long to realise that his need to

understandwas shared, evenmoreurgently, bymanyofhispatients, and thebook thenalso tookon the taskof trying to respond to their needs.“Every time you treat a patient in the hospital,

onceyou’ve allowed themtogetused to themadnessthatmodernmedicine is, the first question patientswant to know is:Why do I have this?What is goingon?Whatdo Idonext?That is their firstmechanismof grapplingwith the disease, long before diagnostictests and therapeutics kick in.”If people don’t get an answer they can make

sense of, says Mukherjee, they reach out forother explanations,whichcan range fromnihilism–

cancer is too complex, too evasive; nothing can bedone – to conspiracy theories. He recalls a talk hegave at a healing retreat for womenwith breast can-cer, involvingyogaandmeditation, as “oneof themosthostile environments” he has ever been in. “Theconversation went like this: ‘Is it not obviously clearto you that there are abundant environmental car-cinogens that you knowand that I knoware causingbreast cancer?And if youknowandIknow,whyhavewe not been able to change the world and removethese environmental carcinogens?’”Heoftenencounterspatientswhoare convinced

that pharmaceutical companies are hiding the realcureandare incahootswith thegovernment, or therearealternative therapies thatwill cureall cancers, butno one wants to invest in them and refine them.“These theories really aboundacross a swatheof thisand other countries.”Understandably, saysMukherjee, these percep-

tions corrode the relationship between doctors andpatients that is so essential to practicemedicine. “AsI point out in my book, there is reason to be suspi-cious.The relationshiphasbeencorroded in thepast.But Ihope thebookprovides aperspective across thecenturies about the complexity of theproblem, howit has been tackled, correctly and incorrectly, what

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beendecoded.The virologistswhosediscovery of theso-called “Rous sarcoma virus” in chickens lent cre-dence to the theory thatcancer is an infectiousdisease,leading to a fruitless decadeof fevered searching for asingle viral cause, which made little sense given thewider evidence.Mukherjeedescribeshis book as ‘amanifesto for

humility’, and says he wanted to show that sciencedoesn’t exist in “some kind of anArcadian realm ofperfect truth and honesty”, but is in fact a veryhuman project, “and therefore susceptible to thesamefoibles that anyhumanproject is susceptible to:egos andmistakes and attachments to theories thatthen don’t get unattached from your brain.”Every character in the book is real, he says, and

shares the benefits, but also the paralysis, of being avisionary. “Thevisionbecomesanobstruction. Imadea point of trying to identify, to isolate, thosemomentsin which the vision occurs and then the vision itselfbecomes ablock. It’s true ofmost of the characters ofthis book. They have the simultaneity of humangenius andhuman flaws. It becamea story of humanbeings trying very hard, and sometimes failing veryhard, to work their way aroundwhat is clearly one ofthe seminal problems of the 20th century.”Thebook is notwithout critics.Many researchers

question the choice of what to include and what toleaveoutof thebook. “The lodestonewasanything thatmadeadifferencedirectly in the livesofpatients,” saysMukherjee. “Someoneaskedme:What about telom-eres? I said that is a very interesting theory and it willmake itself into this book when you findme the firstmedicine that canmodify telomeres in a real humanbeing andmake adifference in their lives.Evenwhatabout Avastin? If you were writing about maculardegeneration, that bookwould have to have a centralrole for a drug like Avastin. But has Avastin reallychanged thewaywe thinkaboutand treat cancer?Notreally. Itwasawonderful theory, and thenmet theuglyfacts. Does it make a huge difference? No. Not inbreast cancer and barely in colorectal cancer.”Mukherjee has also faced criticism for choosing

wrong roads we went down, and how we workedourselves back.”Thechallengeof explaining suchcomplexities to

a lay audience may be one reason why no one hasattempted such a book before, and this one cer-tainly does not lack ambition. It took Mukherjeeseven years from start to finish and it is no ‘Idiot’sGuide’. Among its more scientific passages, forinstance, is a highly accessible, but nonethelessdemanding, description of themechanism of retro-viral transcription. But by that point in the book thereaderhas alreadybeendrawn into adramatisedhis-toryof thebreakthroughsand false trailsbywhich thetrue nature of cancer was being revealed, in fits andstarts, glimpse by glimpse, through a diverse paradeof protagonists from specialisms ranging from epi-demiology tobiology, pathology, surgery,haematology,internalmedicine, radiology, virology and genetics.These individual stories arewoven together into

a tragic-heroic detective story, an odysseywhere thetrail frequently diverts up blind alleys, led there bygifted, dedicated and courageous specialists whoareoften toocertainof their ownvision topickupandinterpret clues that should have turned them inanother direction.The surgeonswho insisted for decades, andwith-

out evidence, that theonly reason for recurrences andmetastatic spread following breast cancer surgerymustbe that theyhadused too small amargin, and theonly remedywas tochopoutever largerchunksof theirpatients’ upper torsos. Themedical oncologists who,after the great initial breakthroughs using multidrugregimens to treat acute leukaemia andHodgkin’s dis-easewenton toapply the sameprinciples to advancedbreast cancer, treating up to 40,000 women withextremely toxic therapies before discovering that theonly evidence of benefit was generated from a fraud-ulent trial in Johannesburg. The geneticists who dis-covered the structure of DNA, which was to provesuchan important part of thepuzzle, but insisted thatNixon’s proposedwar against cancerwouldbea futileexerciseuntil every last geneof thehumangenomehad

“I made a point of trying to identify moments in which

the vision occurs and then the vision becomes a block”

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to call the book a biography, on the grounds that itanthropomorphises cancer, attributing to it charac-teristics of ananimateenemy rather thanabiologicalphenomenon. “It’s createdquite abacklash,” he says,“though there isnosentence in thebook thatdoesanyof thatexceptwhenquotingpeople talkingabout theirillnesses in very human and personal terms.”And while the book has certainly been widely

welcomed by the oncology and science community,there may also be a hint of regret among some whowere centre stage during many of the most excitingyears, that this extraordinary tale ofhumanendeavourended up being told by someone who had not beenthere at the time. “My take on this is that you had tobeanon-expert towrite thisbook. It is crucial.Youhavetohave the vulnerability towritewithouthaving to sayyouare thebig expert.”Hepoints out thatmanyof themostmoving and seminal books inmedicine recentlywerewrittenbypeoplewhoare relatively young to thefield. “AtulGawande,writing in theNewYorker aboutsurgical error,wrote that as a young resident in surgery,just after his fellowship, because he could see thatworld for what it was, with fresh eyes.”Ironically, perhaps, thebookMukherjeewrote as

a ‘non-expert’haspropelledhimonto theA-list of invi-tees to speakat countless seminars andconferences.Havingoutlined soelegantly thehumanobstacles tomakingprogress, surelyhecanoffer somesolutions?He does not duck the challenge. The big issue

rightnow, saysMukherjee, is converting the tremen-dous gains of scientific research into human medi-cines. “The level of diversity that has been revealedevenwithinonecancer let aloneacross cancers, andthe level of evolutionarypressures that are operatingin a single cancer cellwouldhave left someone fromthe 1950s shocked. So we have all this knowledge,

and thepublic is asking, andweare all asking:whereare themedicines that come out of this knowledge?“I talk in the book about this metaphor that sci-

ence inevitably produces a boil that lets itself out assteamthrough technology.But if youare living in theworld of cancer, there is a lot of boil, especially fromthe basic science world, but there is little steamwhichwouldmake theenginemove.So thequestionwe are asking ourselves is:Where is it?Howcanwetransformbreast cancer so thatwecan treat, say, triplenegativebreast cancer inaway thatwecouldnotevenhave imagined four or five years ago.”One problem, he argues, is a lack of innovation

from the pharmaceutical industry. “I’m waiting forgood exemplars of this change in which the drugemerges from research performed primarily bybiotechorpharmacompanies. I’veyet to see that.Thereality typically still remains investigator-initiatedtrials or protocols. The drug company possessessome IP [intellectual property rights] around amol-ecule and investigators around the world go to thecompanyand say, look youhave thismolecule, allowus to test it in a particular disease. Then if there issomething real there it catches fire.But the initiativestill lies with the clinicians and translationalresearchers, even today.”Comparisons that have been made with other

industries with a similar focus on turning academicknowledge into marketable technologies – the ITindustry for example – Mukherjee finds unillumi-nating. “It reduces theproblemofcancer toa systemsanalysis and information systems problem, which itisn’t. It is vastly more complex.”And he doesn’t buyinto the idea that progress is being strangledbecausecommercial secrecy is tying up vital information. “Itwould be possibly if therewere dozens of things out

“My take on this is that you had to be a

non-expert to write this book. It is crucial.”

“We have all this knowledge, and the public is asking:

where are the medicines that come out of it?”

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looks stable. There’s something there.’ In the olddays of chemotherapy, youwould say, ‘This is a non-sense intuition.’Thiswouldbeprecisely thedrug thatyouwould discard.”The BOLERO trial of Afinitor used in patients

with advanced hormone-receptive breast cancer,who are resistant to endocrine therapy alone, is oneof the few thatMukherjee admits could turn out tobe ‘transformative’.Callingupagraphcomparing pro-gression-free survival between thoseonanendocrineinhibitor aloneand those additionally given themTor

there tobesecretiveabout. It’snot clear tomethatwehave that level of innovation yet. Pharma keepstelling us it has things up its sleeve that are deeplytransformative. I haven’t seen them.”He concedes, however, that these things can

take time. “The claim is that a lot of innovation isgoingonwithin thepharmauniverse,butwecan’t seeit becauseby its verynature it’s hidden.Fair enough.Let’s say it happens in about adecade.Theclockhasjust begun.Wewill find out if it is true or not.”Moreanddeeperunderstandingof cancerbiology

will of course continue tobe important, but this is notwhere the blockage lies. What is needed now, saysMukherjee, is tobringmore talentedchemists into thefield to help answer the question of how to intervenein the potential targets that have already been identi-fied.Heexpects a strongcontribution to this effortwillcome from the pool of expertise that is developing inIndia andChina, among other emerging economies.“Hopefully they will bring a whole new wealth ofideas, chemical ideas.”Ironically perhaps, theother areaof expertise that

Mukherjee argues is becoming increasingly impor-tant in developing newdrugs comes from the tradi-tional skills of the clinical practitioner. “You needbetter old medicine to understand new drugs. Yourclinical skills have to be more astute than ever,because the variables have become so complex.That was not the case when you were giving cyto-toxics.Nowyouare interveningonextremely specificaspects of humanphysiology and youneed to knowhow to follow those.” He cites the example of thedoctors who first began to notice a correlationbetween rash and response in the EGFR-inhibitorErbitux (cetuximab). “Youneed a very astute physi-cian to pick that up and say, ‘There is somethinghere. This rash out of the hundreds of rashesthat happen to people on chemotherapy,seems to have something to do withresponse.’This has initiated awhole newfield of understanding.”Thedevelopmentpathof themTor

inhibitor everolimus (Afinitor) isanother good example, he says. “Thephase Ipeoplewho first tested thedrugonpatientswithkidneycancer said ‘It’snotas if thedrugweremelting the tumouraway,butwesee thesepatients comingback,they feelbetter, they lookbetterandtheirdisease

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from now we will conclude that this is not the bestway to go. But you cannot go somewhere else with-out being here now.”Mukherjeehimself seems to accept no limits on

his intellectual curiosity. In midApril theNewYorkTimesmagazine carried a feature piece he wrote onthe science andhistory of treating depression, titled‘Post-ProzacNation’, where he applies his detectivewriting skills to trying tomake senseof another jour-ney of scientific discovery that has beenmarked bygreat hopes of a magic bullet followed by disap-pointment, conspiracy theories and distrust.At the same time, hehas taken great care to sus-

tain his hands-on clinical practice, though this hasbeen tricky in thewakeofhisnew-found fame, to theextent thathe finds it veryhard tokeephisclinical andresearch agendaon track.Overloadedwith requestsfrom people wanting second, third, fourth or evenfifth referrals, he tookapragmaticdecision to removethat pressure. While he takes his turn caring forpatients on the ward, he hasmoved his entire clini-calpractice to the ‘fellows’clinic’,which is run forpeo-ple with no medical insurance and often no properlegal status. “Not because I’m a saint,” hehastens toadd, “but because it wipes the slate clean of all theaccess issues.”Mukherjeedoesnot encouragediscussionof his

backgroundor family, though thewideuseof literaryallusionsand thegeneral accessibility of the structureand style of his writing has, rightly or wrongly, beenat least partially credited to the influenceofhis artistwife Sarah Sze, and he clearly revels in intellectualstimulus fromalmost anydirection.He talks of him-self as having multiple lives, “or at least dual lives,”centred around patients. “Every time I think aboutanything that is relevant, for instance trying tounder-stand how we ended up with this hypothesis ofdepression in2012, andwhat thenext steps are, I goback topatients. So this life is very important forme.It keepsmealive and it keepsmybrain alive in awayIhave toprotect, otherwise I cannotkeepworkingonothermore abstract things.”

Remembering the lessons of his own book,

Mukherjee is careful not to get too carried away

inhibitor, heputs his finger between the twocurves.“It fits the famous ‘BobMayer rule’[namedafter theeponymous Harvard professor at the Dana-FarberCancer Institute]: if youcanput a fingerbetween thetwo arms it is real, if not youmight aswell discard it.Weneedmore of these things that reallymake a bigdifference in survival.”He is also excited about GlaxoSmithKline’s trial

combiningBRAF therapywith immunological ther-apy againstmelanoma. “This is anobvious idea, see-ing what will happen if you can combine targetedtherapy andmicro-environment-directed therapy orimmunology-directed therapy. Presumably theimmunology-directed therapy will have completelydifferent pathways and be non-redundant with tar-geted therapies that are autonomous to the cancercell. This is the kind of stuff that really excitesme.”Remembering the lessons ofhis ownbook, how-

ever, Mukherjee is careful not to get too carriedaway. As he says, the reality is that there are morewomen who have been cured or benefited from“boring old chemotherapy” for early breast cancerthanany targeted therapy for any cancer. “Theques-tion is: where are we going?Havewemade anothermistake?Arewewrong in thinking that theway for-ward is to target the cancer cell? Maybe five years

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