TOM IRE­LAND

BBC Earth (Asia) - - Welcome - WORDS BY TOM IRE­LAND

Tom is man­ag­ing ed­i­tor at the Royal So­ci­ety of Bi­ol­ogy where he over­sees a range of sci­ence pub­li­ca­tions and oc­ca­sion­ally ap­pears on news to of­fer ex­pert com­ments.

Here’s a stag­ger­ing statis­tic: it is es­ti­mated that up to 75 per cent of can­cer drugs do not work on the per­son they are pre­scribed for. This is be­cause medicines are de­vel­oped to work on ‘the av­er­age per­son’ when in fact all of us – and our dis­eases – are unique

Mod­ern medicine, for all its won­ders, has a rather large blind spot. Though sci­en­tific break­throughs and new mir­a­cle treat­ments are an­nounced on a seem­ingly daily ba­sis, doc­tors know that even the most ef­fec­tive drugs in their arse­nal won’t work for large sec­tions of the pop­u­la­tion.

For ex­am­ple, the drugs com­monly pre­scribed to treat dis­or­ders like de­pres­sion, asthma and di­a­betes are in­ef­fec­tive for around 30-40 per cent of peo­ple they are pre­scribed to. With hard to treat dis­eases like arthri­tis, Alzheimer’s and can­cer, the pro­por­tion of the pop­u­la­tion who see no ben­e­fit from a par­tic­u­lar treat­ment rises to 50-75 per cent.

The prob­lem stems from how treat­ments are de­vel­oped. Tra­di­tion­ally, a drug is ap­proved for use if it works for a good num­ber of peo­ple with sim­i­lar symp­toms in a drug trial – and ques­tions are not asked about those in the study who did not re­spond to the treat­ment. When the drug is then re­leased and pre­scribed to the pop­u­la­tion en masse, un­sur­pris­ingly there are plenty of peo­ple – like those in the trial – who dis­cover that the lat­est ‘mir­a­cle cure’ isn’t all that mirac­u­lous for them.

This ‘one size fits all’ sys­tem of drug dis­cov­ery – though it helped un­cover the most im­por­tant medicines of the 20th Cen­tury – is now in­creas­ingly seen as in­ef­fec­tive, out­dated and dan­ger­ous. It means medicines are de­vel­oped to work on ‘the av­er­age per­son’, when in fact all of us – even our dis­eases and our re­sponses to drugs – are unique. Not only are many drugs in­ef­fec­tive for large sub­sec­tions of the pop­u­la­tion, but they can also cause se­vere ad­verse re­ac­tions in oth­ers.

Thank­fully, a com­pletely new ap­proach to medicine is gain­ing ground. As we learn more about how peo­ple dif­fer ge­net­i­cally, med­i­cal pro­fes­sion­als are tai­lor­ing health­care ad­vice and med­i­cal treat­ment to in­di­vid­u­als, rather than pop­u­la­tions.

THE PER­SONAL TOUCH

Per­son­alised medicine (some­times known as ‘pre­ci­sion medicine’) uses a pa­tient’s ge­netic data, and other data about their health at the molec­u­lar level, to work out the best treat­ment for that in­di­vid­ual per­son and oth­ers with a sim­i­lar ge­netic pro­file.

We tend to think of our genes as de­ter­min­ing things such as our height, eye-colour, or whether we have a ge­netic dis­or­der. But the com­bi­na­tion of genes we are born with af­fects our devel­op­ment and health in many sub­tle ways over the course of our lives. The like­li­hood of us get­ting cer­tain dis­eases as we age, the way we metabolise food, and our re­ac­tion to cer­tain drugs are all in­flu­enced by the genes we have.

Given what we now know about genes, tak­ing this ap­proach may seem some­what ob­vi­ous. But it has only been made pos­si­ble in the last decade, thanks to the in­cred­i­ble progress that has been made in DNA se­quenc­ing tech­nol­ogy.

When the hu­man genome was first de­coded in 2003, it took over a decade of in­ter­na­tional col­lab­o­ra­tive ef­forts and cost $3bn. Just 15 years later, se­quenc­ing a per­son’s genome takes hours rather than years, and can be done for un­der $1,000. This means ge­netic in­for­ma­tion is more read­ily avail­able to doc­tors and re­searchers de­vel­op­ing treat­ments than ever be­fore.

The area where the new per­son­alised ap­proach to medicine has had the great­est im­pact, so far, is in on­col­ogy, or can­cer treat­ment. The treat­ment of lung can­cer, es­pe­cially, is seen as a great suc­cess story of pre­ci­sion medicine.

WAR ON CAN­CER

For years, doc­tors were puz­zled as to why only around 10 per cent of lung can­cer pa­tients re­sponded to a com­mon can­cer drug known as TKI (tyrosine ki­nase in­hibitors) that halts a tu­mour’s growth. In the late 2000s, when re­searchers were able to look at the DNA of pa­tients’ tu­mours, they found the drug ac­tu­ally only worked in peo­ple whose can­cer cells had one par­tic­u­lar mu­ta­tion in a gene known as EGFR. The mu­ta­tion causes cells to grow un­con­trol­lably, and TKI blocks this ef­fect, shrink­ing the tu­mour. But in pa­tients whose tu­mours have dif­fer­ent ge­netic ori­gins, a course of treat­ment with TKI will re­sult in a bar­rage of nasty side-ef­fects with no chance of suc­cess.

Even­tu­ally, the dif­fer­ent genes at the heart of dif­fer­ent lung can­cers were re­vealed, and the en­tire process for di­ag­nos­ing lung can­cer changed. Can­cers are no longer sim­ply clas­si­fied by where they grow and what they look like un­der the mi­cro­scope. In­stead they are tested for gene mu­ta­tions, and treat­ment op­tions are cho­sen ac­cord­ingly. Even when tu­mours mu­tate dur­ing treat­ment and de­velop re­sis­tance to gene-spe­cific drugs, doc­tors can track the ge­netic change and pick another tar­get.

Even more so­phis­ti­cated per­son­alised can­cer treat­ments are on the hori­zon, such as im­munother­apy, which takes a pa­tient’s own im­mune cells and

“A GE­NETIC TEST CAN FLAG THE KEY GENES THAT MAKE PEO­PLE HY­PER­SEN­SI­TIVE TO CER­TAIN MEDICINES”

re­pro­grams them to at­tack can­cer cells. The im­mune cells, known as CAR T-cells, are ex­tracted from the pa­tient and ge­net­i­cally mod­i­fied in the lab so they recog­nise the ex­act molec­u­lar mark­ers grow­ing on the pa­tient’s can­cer cells, then in­jected back in the body to at­tack the tu­mour. The USA’s Fed­eral Drug Ad­min­is­tra­tion (FDA) ap­proved a form of this treat­ment in Au­gust fol­low­ing im­pres­sive re­sults in clin­i­cal tri­als.

Per­son­alised medicine is also mak­ing an im­por­tant con­tri­bu­tion to the safety of drugs. Suf­fer­ing a se­ri­ous ad­verse re­ac­tion to a medicine may seem rare, but is, in­cred­i­bly, the fourth lead­ing cause of death in North Amer­ica, and ac­counts for as many as 7 per cent of all hospi­tal ad­mis­sions. Again, the prob­lem is caused by our ten­dency to try and treat large groups of very dif­fer­ent peo­ple in the same way.

A sim­ple ge­netic test can flag the key genes that make some peo­ple hy­per­sen­si­tive to cer­tain medicines, or if some­one metabolises drugs so quickly that they need a higher dose. This ap­proach, known as phar­ma­coge­nomics, is still far from com­mon­place in hos­pi­tals and GP surg­eries, but new soft­ware is in devel­op­ment that will help doc­tors make pre­scrib­ing and dosage de­ci­sions based on a pa­tient’s spe­cific ge­netic pro­file. We could one day even see phar­ma­cists check­ing your genes in-store be­fore hand­ing over your medicines.

DATA-DRIVEN

Per­son­alised medicine is not just about ge­net­ics. The medicine of the fu­ture will be driven by the gen­er­a­tion and in­ter­pre­ta­tion of many types of molec­u­lar-level data about in­di­vid­u­als, cap­tured with a level of pre­ci­sion never pos­si­ble be­fore.

“We now have tech­nol­ogy that can tell us about your genome, your pro­teomic pro­file [pro­tein lev­els], your metabolic pro­file and your in­di­vid­ual mi­cro­biome, in de­tail, at a cost that is in­creas­ingly af­ford­able,”

says Prof Pi­eter Cullis, a bio­chemist at the Univer­sity of Bri­tish Co­lum­bia and au­thor of sev­eral books on per­son­alised medicine.

“Gene anal­y­sis is in­for­ma­tive, but your genes don’t change over time and so they can’t tell you if you ac­tu­ally have a par­tic­u­lar dis­ease or if your treat­ment is work­ing. Pro­teins or me­tab­o­lites in your blood give us a real-time picture of what your body is trend­ing to­wards, or whether the drugs you have been given are do­ing what they are sup­posed to,” he adds.

From a sim­ple blood sam­ple, sci­en­tists can de­tect the first chem­i­cal clues of a huge range of com­mon dis­eases – known as ‘biomark­ers’ – long be­fore any phys­i­cal symp­toms be­come ap­par­ent. In pan­cre­atic can­cer, for ex­am­ple, many pa­tients are only di­ag­nosed when symp­toms start to show and the dis­ease is gravely

ad­vanced. But the can­cer may in fact have been grow­ing asymp­tomat­i­cally for up to 15 years, re­leas­ing tell­tale biomark­ers that could be de­tected with molec­u­lar tests.

Ac­cord­ing to Cullis, a com­bi­na­tion of pow­er­ful com­put­ing, vast data­bases of ge­netic and biomed­i­cal data, and a greater num­ber of skilled ge­neti­cists work­ing in health­care set­tings, has the power to truly rev­o­lu­tionise medicine. “We are go­ing to move from sick­ness-based health­care to pre­ven­ta­tive mea­sures,” he says, “catch­ing these dis­eases be­fore they hap­pen or while they are still at an early stage.”

Dr Elaine Mardis, a pro­fes­sor of ge­nomics and per­son­alised medicine ex­pert at the Na­tion­wide Chil­dren’s Hospi­tal in Ohio, calls this ap­proach

“pre­ci­sion preven­tion”.

“It’s about more reg­u­lar mon­i­tor­ing and screen­ing for peo­ple with high sus­cep­ti­bil­ity to cer­tain dis­eases. In its most ex­treme case, peo­ple have been found to have dis­or­ders that in­crease their DNA mu­ta­tion rate or cause de­fec­tive DNA re­pair mech­a­nisms, mak­ing them likely to de­velop mul­ti­ple can­cers over their life­time.

They are then placed on a ther­apy that can hold off the first in­stance of can­cer,” Mardis says.

Sim­i­lar treat­ments known as ‘can­cer vac­cines’ – tai­lor­made treat­ments that help peo­ple de­velop ‘immunity’ to their par­tic­u­lar can­cer – are cur­rently in devel­op­ment for a range of dif­fer­ent dis­eases in­clud­ing kid­ney, oral and ovar­ian can­cers. “That, to me, is pre­ci­sion on­col­ogy at its finest,” says Mardis.

BEYOND CAN­CER

Per­son­alised medicine is start­ing to have an im­pact in many other ar­eas of dis­ease too. Last year, re­searchers from the Well­come Trust Sanger In­sti­tute re­vealed that the most com­mon and dan­ger­ous form of leukaemia is ac­tu­ally 11 dis­tinct dis­eases that each re­spond very dif­fer­ently to treat­ment.

In HIV and hep­ati­tis C pa­tients, ge­nomic data taken from both the pa­tient and their viruses can help doc­tors de­cide on a drug com­bi­na­tion that tar­gets the spe­cific strain of the dis­ease and is less likely to cause side ef­fects in that per­son. This is im­por­tant be­cause un­pleas­ant side ef­fects can cause some pa­tients to stop tak­ing their medicines. In Canada, this two-pronged ap­proach re­duced death rates from HIV by as much as 90 per cent.

And in Alzheimer’s – a dis­ease that is no­to­ri­ously dif­fi­cult to treat – ge­netic anal­y­sis is re­veal­ing sub­types of the dis­ease that are more likely to re­spond to cer­tain treat­ments. Plus, doc­tors can ini­ti­ate treat­ment ear­lier thanks to the sub­tle chem­i­cal clues that con­firm the dis­ease be­fore symp­toms are ob­vi­ous.

But de­spite all this ex­cit­ing re­search, and some re­mark­able suc­cesses, the fact re­mains that few pa­tients en­ter­ing the health­care sys­tem in the UK will have ac­cess to the spe­cial­ist biomolec­u­lar anal­y­sis re­quired to per­son­alise their treat­ment. Out­side of on­col­ogy de­part­ments, large health sys­tems like the NHS are not set up to gather and an­a­lyse biomolec­u­lar data for ev­ery pa­tient yet. Per­son­alised medicine is too of­ten used as a last re­sort, or for the lucky few pa­tients se­lected for clin­i­cal tri­als. The pro­por­tion of the pop­u­la­tion who have had their genome se­quenced is tiny.

This is start­ing to change, how­ever. In the UK, the 100,000 Genomes Project has be­gun se­quenc­ing genomes from around 70,000 peo­ple with can­cer or a rare dis­ease, plus their fam­i­lies, and last year the NHS pub­lished its Per­son­alised Medicine Strat­egy to help drive the adop­tion of pre­ci­sion ap­proaches in more ar­eas of the health ser­vice.

In the US, the world’s largest pre­ci­sion medicine data drive was an­nounced by Barack Obama in 2015. It aims to en­rol and se­quence ge­netic data from one mil­lion vol­un­teers by 2020. Ac­cord­ing to Cullis, around

“WE ARE GO­ING TO MOVE FROM SICK­NESS-BASED HEALTH­CARE TO PRE­VEN­TA­TIVE MEA­SURES, CATCH­ING THESE DIS­EASES BE­FORE THEY HAP­PEN OR WHILE THEY ARE STILL AT AN EARLY STAGE”

40 per cent of drugs ap­proved in the US last year were ‘per­son­alised’ in some way – mean­ing the treat­ment comes with a ‘com­pan­ion ge­netic test’ to en­sure it is pre­cisely tar­geted. “In can­cer the shift is al­ready hap­pen­ing… com­pa­nies will genome se­quence a tu­mour and de­cide the best treat­ment for you,” says Cullis

DOC­TOR, DOC­TOR

How­ever, adopt­ing per­son­alised medicine across all ar­eas of health­care will re­quire ma­jor re­forms in how ser­vices are staffed and struc­tured.

“A large em­pha­sis of per­son­alised medicine is on pre­ven­ta­tive medicine and treat­ment, and health­care sys­tems have never paid for that be­fore,” says Cullis. “It will be a huge shift and will re­quire a lot of peo­ple who are not just doc­tors but trained in biomolec­u­lar anal­y­sis. The ini­tial users of this will be peo­ple who can af­ford to pay for it them­selves.”

In the next few decades, Cullis fore­sees that vis­its to the doc­tor could be re­placed by fre­quent up­dates from ‘molec­u­lar coun­sel­lors’, who track your health lev­els via reg­u­lar anal­y­sis of the biomark­ers in your blood,

“MOLEC­U­LAR ANAL­Y­SIS WILL BE SO DIS­RUP­TIVE TO DOC­TORS. IT WILL TAKE OVER THE DI­AG­NOS­TIC AND PRE­SCRIP­TION PROCESS. THE DOC­TOR WILL BE­COME YOUR HEALTH COACH, A PER­SON WHOSE JOB IT IS TO KEEP YOU HEALTHY”

sug­gest­ing treat­ments that are right for your genes. This could be done vir­tu­ally, with pa­tients up­load­ing their own blood sam­ples to the in­ter­net for anal­y­sis, and con­sul­ta­tion by Skype.

“Molec­u­lar anal­y­sis will be so dis­rup­tive to doc­tors,” says Cullis. “It will take over the di­ag­nos­tic and pre­scrip­tion process. The doc­tor will be­come your health coach, a per­son whose job it is to keep you healthy and look out for signs that you need to per­haps go for a hike more of­ten, or change your diet.”

So is it time to get your genome se­quenced? Per­haps not just yet.

“Right now it’s about $1,000 to have your genome se­quenced, or about $2,000 with the ac­com­pa­ny­ing anal­y­sis,” says Cullis. “I had mine done and I didn’t find it all that use­ful. It told me I was likely to be sus­cep­ti­ble to in­fec­tions when I’m young – but I’m not young any more.”

How­ever, as the in­fra­struc­ture in health­care sys­tems be­comes cen­tred around bioin­for­mat­ics and ge­netic medicine, it seems in­evitable that the medicine of the fu­ture will be based around your genes.

“Genome se­quenc­ing is get­ting cheaper all the time,” says Cullis, “and you only need to do it once. When the sys­tems are in place, it will pro­vide im­por­tant in­for­ma­tion about you ev­ery time you see a doc­tor, for the rest of your life.”

Tom Ire­land is a sci­ence jour­nal­ist and man­ag­ing ed­i­tor at the Royal So­ci­ety of Bi­ol­ogy

ABOVE: A can­cer cell (yel­low/green) be­ing at­tacked by CAR T-cells that have been taken from a pa­tient’s im­mune sys­tem and mod­i­fied

RIGHT: 23andMe was the first ge­netic test­ing kit that UK con­sumers could buy from a high-street phar­macy, to find out more about traits and an­ces­try

BE­LOW: The hu­man genome has been printed and bound. The 3.4 bil­lion units of DNA that com­prise the genome take up more than 100 books, each filled with

1,000 pages

ABOVE: Pi­eter Cullis be­lieves per­son­alised medicine will be­come a key way to pre­vent dis­eases like can­cer

LEFT: As US pres­i­dent, Barack Obama launched the Pre­ci­sion Medicine Ini­tia­tive to se­quence the DNA of one mil­lion vol­un­teers and track their health over many years

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