A New The­ory of Can­cer

On a dis­ease’s evo­lu­tion­ary his­tory and the im­pli­ca­tions for treat­ment

The Monthly (Australia) - - CONTENTS - by Paul Davies

When Pres­i­dent Richard Nixon de­clared war on can­cer in 1971, he set a goal for con­quer­ing the dis­ease by 1976. The US Na­tional Can­cer In­sti­tute (NCI) was em­pow­ered and ex­panded by the stroke of the pres­i­dent’s pen, and some se­ri­ous pub­lic money in­jected into a mam­moth re­search ef­fort. In the in­ter­ven­ing 47 years, in ex­cess of US$100 bil­lion of tax­payer money has been spent by the NCI alone on the search for an elu­sive “cure for can­cer”. Its 2018 fis­cal year bud­get is just shy of US$6 bil­lion. Can­cer re­search also at­tracts bil­lions from drug com­pa­nies and through char­i­ta­ble do­na­tions. Pro­por­tion­ately sim­i­lar amounts have been spent in other de­vel­oped na­tions, Aus­tralia in­cluded.

So what have we got for all the money spent? Not what was promised, clearly. Sur­vival rates for many ma­jor can­cers are lit­tle changed in sev­eral decades. Treat­ment regimes – a com­bi­na­tion of surgery, ra­di­a­tion and toxic chem­i­cals – re­main much as they were in Nixon’s day. Life ex­ten­sion is of­ten mea­sured in weeks or months rather than years, and in­ter­ven­tions are fre­quently a rear­guard ac­tion against the in­evitable. Op­ti­misti­cally touted “break­through drugs” are typ­i­cally ef­fi­ca­cious on only a few per cent of pa­tients and of­ten have dread­ful side ef­fects. Mean­while, can­cer in­ci­dence has grown re­morse­lessly as over­all life ex­pectancy has risen, mak­ing can­cer now the world’s num­ber two killer, with about 14 mil­lion new cases per year. It’s fair to say that can­cer touches ev­ery fam­ily on the planet.

Screen­ing pro­grams com­pli­cate the pic­ture. They are very ef­fec­tive for skin and colon can­cers be­cause early sur­gi­cal in­ter­ven­tion can be 100 per cent suc­cess­ful. But breast and prostate can­cer screen­ings are ex­tremely con­tro­ver­sial be­cause even though do­ing noth­ing is of­ten the best op­tion – many early-stage can­cers never progress to be life-threat­en­ing – pa­tients are un­der­stand­ably re­luc­tant to merely watch and wait when di­ag­nosed with a po­ten­tially killer dis­ease. Fur­ther­more, as screen­ing tech­nol­ogy has im­proved, tiny tu­mours are be­ing spot­ted ear­lier, which has the ef­fect of skew­ing the statistics. The med­i­cal pro­fes­sion has de­fined a “can­cer sur­vivor” as some­one re­main­ing alive five years af­ter di­ag­no­sis. Find tu­mours ear­lier and there will ap­pear to be more sur­vivors even if there was zero progress in treat­ment out­comes. So claims that we are slowly win­ning the war against can­cer have to be nu­anced. For the record, cur­rent over­all five-year sur­vival rates in Aus­tralia are still less than 70 per cent.

It is not all bad news. Some can­cers have in­deed been largely con­quered by drugs, child­hood leukaemia be­ing a fa­mous ex­am­ple. Lung can­cer, the scourge of the Nixon era, has steadily de­clined as smok­ing has be­come un­fash­ion­able. And the care­ful use of drug com­bi­na­tions has pro­gres­sively ex­tended sur­vival times for cer­tain can­cers. But oth­ers are on the rise, and the over­all pic­ture is far from rosy, as is ob­vi­ous from the con­tin­ual pleas for ad­di­tional fund­ing.

Un­for­tu­nately there is a wide­spread be­lief that if enough money is thrown at the prob­lem a so­lu­tion will be found. All sci­ence re­quires fund­ing, of course, but the truth is we have to think our way to a so­lu­tion, not spend our way to one. And we won’t out­smart can­cer un­til we un­der­stand what it is. I don’t mean un­der­stand it as a dis­ease, but un­der­stand it as a bi­o­log­i­cal phe­nom­e­non. There are more than a mil­lion pub­lished re­search pa­pers on can­cer and yet the sim­ple ques­tions, “What is can­cer?” and “Why does it ex­ist?”, have no clear an­swers in the sci­en­tific com­mu­nity. Maybe progress against can­cer is so slow be­cause we have been think­ing about the prob­lem the wrong way?

I first be­came in­volved in this sub­ject in 2008 when I re­ceived a phone call from Anna Barker, at that time deputy di­rec­tor of the NCI. She per­ceived the need for some rad­i­cal new think­ing to re­place the same­old-same-old mind­set of many can­cer re­searchers, and won­dered whether bring­ing in sci­en­tists from other dis­ci­plines, no­tably physics with its stun­ning track record of suc­cess, might pro­vide a wel­come shakeup of the field. I coun­tered that I knew noth­ing about can­cer, and she replied, “That’s per­fect!” Thus be­gan a US$35 mil­lion per an­num NCI-funded pro­gram in phys­i­cal sci­ence and on­col­ogy. In all, 12 new cen­tres were cre­ated across the US, each pair­ing a phys­i­cal sci­en­tist with an on­col­o­gist.

I was cho­sen to run the cen­tre at Ari­zona State Univer­sity (ASU), and I took se­ri­ously Dr Barker’s en­treaty to re­think can­cer from the bot­tom up. As a physi­cist and cos­mol­o­gist I am used to sidestep­ping tech­ni­cal­i­ties and search­ing for deep uni­fy­ing prin­ci­ples. A cul­ture clash was im­me­di­ately ap­par­ent. On­col­o­gists work at the sharp end of the sub­ject, and ev­ery pa­tient is dif­fer­ent. It’s nat­u­ral that physi­cians should re­gard can­cer as a baf­flingly com­plex dis­ease. But most can­cers fol­low a fairly pre­dictable pat­tern: a tu­mour grows in a spe­cific or­gan, and af­ter a while some cells leave the tu­mour and spread around the body, in­vad­ing re­mote or­gans and cre­at­ing sec­ondary tu­mours, usu­ally with fa­tal con­se­quences. As can­cer pro­gresses, it dis­plays sev­eral dis­tinc­tive hall­marks, in­clud­ing un­con­trolled pro­lif­er­a­tion, in­creased motil­ity, eva­sion of the im­mune sys­tem and or­gan­i­sa­tion of its own blood sup­ply. I wanted to know what un­der­lies this bizarre phe­nom­e­non and why it hap­pens.

What first struck me was the fact that can­cer, far from be­ing re­stricted to hu­mans, is found right across the tree of life, in most mul­ti­celled or­gan­isms. Sci­en­tists have found can­cer or can­cer-like phe­nom­ena in all mam­mals, as well as in fish, birds, worms, in­sects and corals. There are even can­cers among plants and fungi; at ASU we have just cre­ated a “can­cer gar­den” dis­play­ing strik­ing ex­am­ples of can­cer in cacti. Re­cently, cases of can­cer have been found in the hum­ble hy­dra, a tiny or­gan­ism with only seven cell types.

In bi­ol­ogy, the most wide­spread prop­er­ties of or­gan­isms are usu­ally the most an­cient, and can of­ten be traced to a com­mon an­ces­tor in the far past. Pho­to­syn­the­sis, for ex­am­ple, is used by all plants and many bac­te­ria, and dates back more than three bil­lion years. Could we use the tree of life, I won­dered, to trace the ori­gin of can­cer?

For the greater part of our planet’s his­tory, life was re­stricted to sin­gle-celled or­gan­isms: bac­te­ria and ar­chaea. The ear­li­est un­con­tentious traces of life come from the Pil­bara re­gion of West­ern Aus­tralia, and date back about 3.5 bil­lion years. Sin­gle cells have but one im­per­a­tive: repli­cate, repli­cate, repli­cate! Bac­te­ria that go on di­vid­ing and mul­ti­ply­ing are in a sense im­mor­tal. It goes with­out say­ing, how­ever, that can­cer is a dis­ease of bod­ies; it makes lit­tle sense to say a mi­crobe has can­cer. But bod­ies in the usual mean­ing of the word, in which there are dif­fer­ent tis­sue types with spe­cialised func­tions, had to await the on­set of mul­ti­cel­lu­lar­ity, which first emerged about 1.5 bil­lion years ago. By 600 mil­lion years ago, many of the ba­sic body plans we see to­day had evolved.

A mul­ti­celled or­gan­ism ex­e­cutes the life project very dif­fer­ently from a mi­crobe. Im­mor­tal­ity is out­sourced to spe­cialised germ cells (for ex­am­ple, eggs and sperm), which carry the ge­netic legacy down the gen­er­a­tions, while the rest – the so-called so­matic cells – ac­cept even­tual death. In an echo of their free-liv­ing past, so­matic cells may un­dergo quite a few rounds of di­vi­sion – skin cells, for ex­am­ple, can di­vide up to 40 times – but even­tu­ally all nor­mal so­matic cells com­mit sui­cide, a process known as apop­to­sis. In the ab­sence of the cells’ re­newal (by so-called stem cells), the or­gan­ism must fi­nally die.

To po­lice this an­cient con­tract be­tween in­di­vid­ual so­matic cells and the or­gan­ism as a whole, layer upon layer of reg­u­la­tory con­trol has evolved. As al­ways with a co­op­er­a­tive ven­ture, there is a dan­ger of cheat­ing. Just as hu­mans are tempted to ac­cept the ben­e­fits of so­ci­ety but dodge their taxes, so so­matic cells har­bour in­ner in­stincts to freeload off the ben­e­fits the or­gan­ism pro­vides but evade the apop­to­sis po­lice. The re­sult is can­cer – the un­con­trolled pro­lif­er­a­tion of a pop­u­la­tion of so­matic cells, trig­gered by a dis­rup­tion of func­tions that evolved to reg­u­late mul­ti­cel­lu­lar or­gan­i­sa­tion.

Noth­ing I have stated above is con­tro­ver­sial, but few on­col­o­gists choose to think about can­cer in this way – that is, as a bi­o­log­i­cal phe­nom­e­non with deep evo­lu­tion­ary roots stretch­ing back to the Protero­zoic era of life on Earth. But to make se­ri­ous progress we need this broader con­text.

Can­cer as a throw­back

The stan­dard ex­pla­na­tion for can­cer, known as the so­matic mu­ta­tion the­ory, is that ran­dom mu­ta­tions – ge­netic de­fects in DNA – ac­cu­mu­late in cells over time, per­haps as the re­sult of chem­i­cal dam­age or ra­di­a­tion, un­til a point is reached where a mu­tated cell em­barks on a ram­page, mul­ti­ply­ing un­con­trol­lably, form­ing a “neo­plasm”, or pop­u­la­tion of new cells, and be­hav­ing in many re­spects like a par­a­sitic in­de­pen­dent or­gan­ism. Though en­trenched, the so­matic mu­ta­tion the­ory has poor pre­dic­tive power. More­over, it strug­gles to ex­plain how ran­dom mu­ta­tions con­fer so many fit­ness-im­prov­ing gains of func­tion in a sin­gle neo­plasm in the space of weeks or months. It also seems para­dox­i­cal that in­creas­ingly dam­aged and de­fec­tive genomes en­gage in such sys­tem­atic and broadly pre­dictable be­hav­iour, ac­quir­ing the var­i­ous hall­marks I men­tioned. On top of this, it is clear that mu­ta­tions can­not be the whole story; a tu­mour’s mi­cro-en­vi­ron­ment is also crit­i­cal in de­ter­min­ing the tu­mour’s be­hav­iour. Even highly mu­tated can­cer cells can be “tamed” by sur­round­ing healthy tis­sues.

Over the past few years, my col­leagues and I have de­vel­oped a some­what dif­fer­ent ex­pla­na­tion of can­cer that seeks its ori­gins in the far past. We were struck by the fact that can­cer never in­vents any­thing new. In­stead, it merely ap­pro­pri­ates al­ready ex­ist­ing func­tions of the host or­gan­ism, many of them very ba­sic and an­cient. Lim­it­less pro­lif­er­a­tion, for ex­am­ple, has been a fun­da­men­tal fea­ture of uni­cel­lu­lar life for aeons. Af­ter all, life is in the busi­ness of repli­ca­tion, and cells have had bil­lions of years to learn how to do it well and keep go­ing in the face of all man­ner of threats and in­sults. Me­tas­ta­sis – the process whereby a neo­plasm spreads around the body – mim­ics what hap­pens dur­ing early-stage em­bryo de­vel­op­ment, when cells surge in or­gan­ised pat­terns to des­ig­nated lo­ca­tions. And the propen­sity of cir­cu­lat­ing can­cer cells to in­vade other or­gans closely par­al­lels what the im­mune sys­tem does to heal wounds. These facts, com­bined with the pre­dictable and ef­fi­cient way that can­cer pro­gresses through its var­i­ous stages of ma­lig­nancy, con­vinced us that can­cer is not a case of dam­aged cells ran­domly run­ning amok but an an­cient, sys­tem­atic and bru­tally ef­fi­cient pre-pro­grammed strat­egy that is de­ployed when cells are chal­lenged or threat­ened in some way. Cru­cially, we be­lieve that the var­i­ous dis­tinc­tive hall­marks of can­cer do not in­de­pen­dently evolve as the neo­plasm goes along, but are de­lib­er­ately switched on and de­ployed in an or­gan­ised strat­egy.

In sum­mary, our view of can­cer is that it is not a prod­uct of dam­age but a sys­tem­atic re­sponse to a dam­ag­ing en­vi­ron­ment – a prim­i­tive cel­lu­lar de­fence mech­a­nism. Can­cer is a cell’s way of cop­ing with a bad place. To be sure, it may be trig­gered by mu­ta­tions, but its root cause is the self-ac­ti­va­tion of a very old and deeply em­bed­ded tool­kit of emer­gency sur­vival pro­ce­dures. A help­ful anal­ogy is a com­puter that suf­fers an in­sult,

Few on­col­o­gists choose to think about can­cer in this way – that is, as a bi­o­log­i­cal phe­nom­e­non with deep evo­lu­tion­ary roots.

such as cor­rupted soft­ware, and starts up in safe mode. This is a de­fault pro­gram en­abling the com­puter to run on its core func­tion­al­ity even when de­fec­tive. In the same way, we think, can­cer is a de­fault state in which a cell un­der threat runs on its an­cient core func­tion­al­ity, thereby pre­serv­ing its vi­tal func­tions, of which pro­lif­er­a­tion is the most an­cient, most vi­tal and best pre­served.

Al­though el­e­ments of the can­cer de­fault pro­gram are ex­tremely an­cient, dat­ing back to the ori­gin of life it­self, some of the more so­phis­ti­cated fea­tures re­visit later stages in evo­lu­tion, es­pe­cially in the pe­riod be­tween one bil­lion and 600 mil­lion years ago, when meta­zoans (com­plex mul­ti­celled or­gan­isms) first emerged. Thus can­cer is a type of atavism – a throw­back to an ancestral form or “phe­no­type”. That es­sen­tial idea was pro­posed as long ago as 1914 by the Ger­man bi­ol­o­gist Theodor Boveri, but was side­lined un­til re­cently.

It is be­cause can­cer is so deeply in­te­grated into the fun­da­men­tal logic of mul­ti­cel­lu­lar life that com­bat­ing it proves such a for­mi­da­ble chal­lenge. Peo­ple talk about our “in­ner fish”; well, rewind­ing the evo­lu­tion­ary tape still fur­ther back in time con­nects us to our in­ner can­cer. Sadly, it seems that can­cer is an ac­ci­dent wait­ing to hap­pen.

Test­ing the new the­ory

I was lucky that when I em­barked on the NCI project sev­eral other peo­ple had been think­ing along the same lines. These in­cluded a long­stand­ing col­lab­o­ra­tor of mine in the fields of cos­mol­ogy and as­tro­bi­ol­ogy, Charles Lineweaver of the Aus­tralian Na­tional Univer­sity. Im­por­tantly, how­ever, a num­ber of clin­i­cal on­col­o­gists had ei­ther formed sim­i­lar con­clu­sions or shared our gen­eral un­ease about the in­ad­e­quacy of the so­matic mu­ta­tion the­ory. Among these were Mark Vin­cent, med­i­cal on­col­o­gist at the Lon­don Re­gional Can­cer Cen­tre in On­tario, Canada, and David Goode of the Com­pu­ta­tional Bi­ol­ogy Pro­gram at the Peter MacCal­lum Can­cer Cen­tre in Mel­bourne. In ad­di­tion, one of the more far-sighted and renowned Amer­i­can on­col­o­gists, the late Don Cof­fey of the Johns Hop­kins Univer­sity School of Medicine in Baltimore, was a strong sup­porter of our en­deav­ours. He even in­vited me to do “grand rounds” at Hop­kins to present the ba­sic ideas.

In sci­ence, for a new the­ory to be taken se­ri­ously it has to not only ex­plain the known facts but also of­fer testable pre­dic­tions. For­tu­nately our the­ory was de­vel­oped just as gene-se­quenc­ing tech­nol­ogy was ad­vanc­ing rapidly and very large ge­netic data­bases were be­ing com­piled. The key nov­elty is our em­pha­sis on the ages of genes, which is not nor­mally a con­sid­er­a­tion in can­cer re­search. It is pos­si­ble to es­ti­mate how old a gene is by com­par­ing how gene se­quences di­verge across many species. This pro­ce­dure is known as phy­lostratig­ra­phy, and it en­ables sci­en­tists to re­con­struct the tree of life, work­ing back­wards from com­mon fea­tures to­day to de­duce the con­ver­gence point in the past. Us­ing this tech­nique, we can trace the evo­lu­tion­ary ori­gin of genes

that are im­pli­cated in can­cer, a sub­set of which are called onco­genes. If the throw­back the­ory is along the right lines, one ex­pects that can­cer genes would clus­ter in age around the on­set of mul­ti­cel­lu­lar­ity.

A study by Tomis­lav Do­mazet-Lošo and Di­ethard Tautz in Ger­many used four dif­fer­ent can­cer gene datasets and con­firmed the pres­ence of a marked peak in age at around the time that meta­zoa evolved. A re­cent anal­y­sis of seven tu­mour types by Anna Tri­gos, Richard Pear­son and An­thony T. Papen­fuss in David Goode’s lab­o­ra­tory in Mel­bourne sorted genes into 16 groups by age and then com­pared how strongly the genes are ex­pressed in can­cer ver­sus nor­mal tis­sue for each group. The results were strik­ing. Can­cer over-ex­presses genes be­long­ing to the two older groups and un­der-ex­presses younger genes, much as we pre­dicted.

The Mel­bourne study also went fur­ther, sug­gest­ing that the re­gres­sion to a more prim­i­tive cel­lu­lar state was not an across-the-board af­fair, but a highly reg­u­lated and fi­nessed process. Genes rarely act in iso­la­tion; rather, they form co­op­er­a­tive net­works. Goode and Tri­gos found that the gene net­works dat­ing from the era of uni­cel­lu­lar­ity are sys­tem­at­i­cally de­cou­pled from the more re­cently evolved mul­ti­cel­lu­lar gene net­works, re­veal­ing a novel pat­tern of gene ex­pres­sion specif­i­cally tied to gene ages. They re­ported a strong as­so­ci­a­tion be­tween the evo­lu­tion of mul­ti­cel­lu­lar­ity and pat­terns of gene ex­pres­sion in can­cer. Fur­ther­more, they found that as can­cer pro­gresses to a more ag­gres­sive, dan­ger­ous stage the older genes are ex­pressed at higher lev­els, con­firm­ing our view that can­cer re­verses the evo­lu­tion­ary ar­row at high speed as it de­vel­ops in the host or­gan­ism.

Our own work at ASU, much of which was car­ried out by a ge­neti­cist, Kim­berly Bussey, in col­lab­o­ra­tion with a physi­cist, Luis Cis­neros, fo­cused on mu­ta­tion rates. The atavis­tic the­ory pre­dicts that older genes should be less mu­tated in can­cer (af­ter all, they are re­spon­si­ble for run­ning the “safe mode” pro­gram), while younger genes should be mu­tated more. My col­leagues con­sid­ered a to­tal of 19,756 hu­man genes and used an in­ven­tory of can­cer genes, com­piled by the UK’s Sanger In­sti­tute, called COS­MIC. This data was com­bined with a data­base of ge­netic se­quences from about 18,000 species across all tax­o­nomic groups, which al­lowed an es­ti­mate of the evo­lu­tion­ary ages of the genes in the hu­man genome. We found that genes younger than about 500 mil­lion years were in­deed more likely to be mu­tated in can­cer, while genes older than a bil­lion years tended to suf­fer fewer mu­ta­tions than av­er­age, as ex­pected.

The most telling re­sult came from ad­dress­ing a rather dif­fer­ent ques­tion: what are can­cer genes good for? A gene clas­si­fi­ca­tion tool called DAVID or­gan­ises genes around their func­tion. When my col­leagues fed the COS­MIC data into DAVID, what leapt out was that re­ces­sive genes older than 950 mil­lion years were strongly en­riched for two core func­tions: cell cy­cle con­trol, and DNA dam­age re­pair in­volv­ing dou­ble-strand breaks (the worst kind of dam­age DNA can suf­fer). Look­ing at the evo­lu­tion­ary his­tory of those genes in­volved re­vealed a star­tling and un­ex­pected re­sult. The can­cer genes im­pli­cated in DNA re­pair turned out to match up with genes in bac­te­ria em­ployed for a crit­i­cal sur­vival func­tion.

When bac­te­ria are stressed, for ex­am­ple from star­va­tion, they de­lib­er­ately ramp up their mu­ta­tion rates with a view to evolv­ing out of trou­ble. The mech­a­nism they em­ploy was elu­ci­dated by Su­san Rosen­berg, who holds the Ben F. Love Chair in Can­cer Re­search at the Bay­lor Col­lege of Medicine in Hous­ton, Texas. Rosen­berg found that stressed bac­te­ria cre­ate a dis­tinc­tive pat­tern of self-in­flicted mu­ta­tional dam­age around DNA dou­ble-strand breaks, ex­tend­ing ei­ther side of the re­paired break for thou­sands of DNA bases, by strate­gi­cally de­ploy­ing a sloppy re­pair mech­a­nism. Bussey and Cis­neros at ASU found iden­ti­cal pat­terns of dam­age in can­cer DNA, cre­ated by the same mech­a­nism con­trolled by es­sen­tially the same genes. This dis­cov­ery is im­por­tant be­cause the clus­ter­ing of mu­ta­tions in this man­ner is known to be as­so­ci­ated with poor pa­tient prog­no­sis.

The most telling re­sult came from ad­dress­ing a rather dif­fer­ent ques­tion: what are can­cer genes good for?

El­e­vated mu­ta­tion rates are one of the best-known hall­marks of can­cer and the main rea­son why chemo­ther­apy fal­ters when neo­plasms evolve drug-re­sis­tant vari­ants. We col­lab­o­rated with a re­search team led by Robert Austin at Prince­ton Univer­sity to in­ves­ti­gate the de­tails of drug re­sis­tance, and specif­i­cally to ad­dress the ques­tion of whether re­sis­tance is ac­quired by ran­dom mu­ta­tions plus Dar­winian se­lec­tion, as the so­matic mu­ta­tion the­ory pre­dicts, or from a more de­lib­er­ate and or­gan­ised re­sponse. The Prince­ton group sub­jected hu­man can­cer cells to a ther­a­peu­tic toxin (dox­oru­bicin) and found a highly un­even pat­tern of mu­ta­tions – hot spots of el­e­vated mu­ta­tion and cold spots that seemed to be pro­tected from dam­age. And true to the atavism the­ory, they found that the genes in the cold-spot re­gions were sig­nif­i­cantly older than av­er­age.

The Prince­ton results ex­plain why nat­u­ral se­lec­tion hasn’t elim­i­nated the scourge of can­cer. If tu­mours re­ally are a re­ver­sion to an ancestral form, then we might ex­pect that the an­cient path­ways and mech­a­nisms that drive can­cer would be among the most deeply pro­tected and con­served, as they ful­fil the most ba­sic func­tions of life. They can’t be got rid of with­out dis­as­ter be­falling the cells con­cerned. It makes sense that or­gan­isms should work hard to pro­tect key parts of their genomes, such as those an­cient genes re­spon­si­ble for run­ning the

core func­tions of the cell, and de­vote fewer re­sources to the “bells and whis­tles” as­so­ci­ated with more re­cently evolved and less crit­i­cal traits.

Fur­ther sup­port for the atavism the­ory may come from a world­wide ef­fort to en­list zoos in a com­pre­hen­sive study of can­cer across species. The ini­tia­tive is be­ing man­aged by the Ari­zona Can­cer Evo­lu­tion Cen­ter, run by my col­league Carlo Ma­ley. As part of the pro­gram, we have be­gun col­lab­o­rat­ing with Taronga Zoo in Syd­ney. I want to know whether can­cer in mar­su­pi­als dif­fers from that in pla­cen­tal mam­mals, given their widely dif­fer­ent de­vel­op­men­tal strate­gies. It has been known for decades that cer­tain onco­genes play a cru­cial role in early-stage em­bryo de­vel­op­ment. Nor­mally, these de­vel­op­men­tal genes are si­lenced in the adult form, but if some­thing reawak­ens them can­cer may re­sult; a tu­mour is, in ef­fect, a botched em­bryo de­vel­op­ing in­ap­pro­pri­ately in adult tis­sue.

The dis­rup­tion of gene reg­u­la­tory net­works that her­alds can­cer in­volves dra­matic changes in the pat­terns of in­for­ma­tion flow be­tween genes and be­tween cells, just as safe mode on a com­puter rep­re­sents a ma­jor re­or­gan­i­sa­tion of the ma­chine’s soft­ware. Our re­search group at ASU is try­ing to find “in­for­ma­tion sig­na­tures” of these gene net­work changes. We think it will prove pos­si­ble to iden­tify dis­tinct “in­for­ma­tional hall­marks” of can­cer to go along­side the phys­i­cal hall­marks I men­tioned, pro­vid­ing a soft­ware in­di­ca­tor of can­cer ini­ti­a­tion that may pre­cede the clin­i­cally no­tice­able changes in cell and tis­sue mor­phol­ogy, thus pro­vid­ing an early warn­ing of trou­ble ahead.

Im­pli­ca­tions for ther­apy

The atavis­tic the­ory of can­cer has im­por­tant im­pli­ca­tions not just for di­ag­no­sis but also for ther­apy. Most ap­proaches tar­get the strengths of can­cer. For ex­am­ple, many drugs try to block the propen­sity of can­cer cells to repli­cate rapidly. How­ever, as I have stressed, cells have had four bil­lion years to com­bat threats to their pro­lif­er­a­tive abil­ity and they usu­ally find work­arounds that ren­der the drugs in­ef­fec­tive, such as pump­ing the tox­ins out or de­fen­sively switch­ing on mu­ta­tor genes to evolve re­sis­tant strains. The stan­dard chemo­ther­apy regime of ap­ply­ing the max­i­mum tol­er­a­ble dose to hit can­cer hard there­fore seems in­trin­si­cally flawed, be­cause it risks pro­vok­ing an ag­gres­sive atavis­tic re­sponse. We sug­gest in­stead an ap­proach based on the min­i­mum ef­fi­ca­cious dose, with a view to con­tain­ing and con­trol­ling can­cer rather than try­ing to ex­ter­mi­nate it. Two clin­i­cal tri­als along these lines are cur­rently be­ing con­ducted, one by the Ari­zona Can­cer Evo­lu­tion Cen­ter in col­lab­o­ra­tion with the Mayo Clinic, and the other at the Mof­fitt Can­cer Cen­ter in Tampa, Florida.

Bet­ter still would be an al­ter­na­tive to toxic chemo­ther­apy al­to­gether. One of the more im­por­tant “bells and whis­tles” that mul­ti­cel­lu­lar life has evolved over the past few hun­dred mil­lion years is the adaptive im­mune sys­tem, in­stru­men­tal in fight­ing in­fec­tions but also in surveilling for can­cer. The atavism the­ory pre­dicts that as

can­cer pro­gresses – and hence re­gresses in evo­lu­tion­ary terms – it should sub­vert this sys­tem, and in­deed it does. A great deal of at­ten­tion has been given re­cently to im­munother­apy as a pow­er­ful new way to com­bat can­cer. The ba­sic idea is to boost the body’s im­mune sys­tem so as to strengthen the im­mune re­sponse. It is too soon to know whether im­munother­apy will prove to be the de­ci­sive break­through claimed or yet an­other ex­am­ple of can­cer out­wit­ting what­ever the physi­cian throws at it. But early results are promis­ing.

There is a cu­ri­ous back­story here. Over a hun­dred years ago, the Amer­i­can physi­cian Wil­liam Co­ley was in­trigued by the fact that some can­cer suf­fer­ers un­dergo spon­ta­neous re­mis­sion fol­low­ing an in­fec­tion. Co­ley even ex­per­i­mented with de­lib­er­ately in­fect­ing pa­tients with strep­to­coc­cus, a bold – some might say reck­less – prac­tice that soon went the way of leeches. But Co­ley may have been onto some­thing. The con­ven­tional ex­pla­na­tion is that the in­fec­tions boosted the im­mune sys­tem, which then de­stroyed the can­cer as in­ci­den­tal col­lat­eral dam­age. We con­tend, how­ever, that at least part of the rea­son for Co­ley’s results is that can­cer tu­mours are more vul­ner­a­ble to in­fec­tions than the rest of the body be­cause they have de­cou­pled from the adaptive im­mune sys­tem. In other words, by re­gress­ing to an im­muno­com­pro­mised state, tu­mours leave them­selves un­pro­tected against in­fec­tions. The se­lec­tive use of viruses and bac­te­ria against some late-stage can­cers there­fore seems a ra­tio­nal ap­proach.

An­other ther­apy idea to come from the atavism the­ory also harks back a cen­tury, to the work of Otto War­burg, a No­bel Prize–win­ning physi­cian. Nor­mal hu­man cells use oxy­gen to gen­er­ate en­ergy, but can­cer of­ten switches to fer­men­ta­tion, a low-oxy­gen, high-glu­cose process. It is less en­ergy-ef­fi­cient, but good for mak­ing biomass. War­burg dis­cov­ered that can­cer will switch to fer­men­ta­tion even in the pres­ence of nor­mal oxy­gen lev­els. It is tempt­ing to spec­u­late that, in re­vert­ing to an ancestral form, can­cer is repris­ing a life­style adapted to the state of planet Earth at the time when mul­ti­cel­lu­lar or­gan­isms first evolved. And ge­ol­o­gists have de­ter­mined that be­fore a bil­lion years ago there was in­deed far less free oxy­gen in the at­mos­phere. Some re­searchers have used this in­sight to ad­vo­cate the ap­pli­ca­tion of hy­per­baric oxy­gen ther­apy com­bined with a low-glu­cose diet to stymie the War­burg ef­fect and slow the can­cer.

I be­lieve the search for a gen­eral-pur­pose “cure” for can­cer is an ex­pen­sive di­ver­sion. Be­ing so deeply en­trenched in the na­ture of mul­ti­cel­lu­lar life it­self, can­cer is best man­aged and con­trolled (not ex­ter­mi­nated) by chal­leng­ing the can­cer with phys­i­cal con­di­tions in­im­i­cal to its an­cient atavis­tic life­style. It does, how­ever, re­quire a change in the cul­ture of can­cer care, away from Nixon’s all-out war and to­wards ac­cept­ing can­cer as a chronic dis­ease. We don’t have to de­stroy can­cer; we just have to pre­vent can­cer de­stroy­ing us. Only by fully understanding the place of can­cer in the over­all con­text of evo­lu­tion­ary his­tory will a se­ri­ous im­pact be made on hu­man life ex­pectancy. M

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