Ge­netic tool a hot tip to schizophre­nia

The study of tiny snip­pets of ge­netic ma­te­rial called mi­cro RNAs is one of the hottest ar­eas of med­i­cal re­search, writes Leigh Day­ton

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MURRAY Cairns never planned to be a schizophre­nia re­searcher. But when the lit­tle bio-tech firm for which he worked three years ago col­lapsed, the molec­u­lar bi­ol­o­gist was open to all op­tions.

‘‘ I was look­ing around and saw an ad­ver­tise­ment for the Schizophre­nia Re­search In­sti­tute,’’ he re­calls from his of­fice at the Univer­sity of New­cas­tle in NSW. ‘‘ They thought I had use­ful ex­pe­ri­ence as a molec­u­lar bi­ol­o­gist, but they didn’t have any idea that I’d come up with this branch of re­search,’’ he laughs.

It’s hardly sur­pris­ing that the SRI — a ‘‘ vir­tual’’ col­lab­o­ra­tion of Aus­tralian bio­med­i­cal re­searchers with head­quar­ters at the Gar­van In­sti­tute in Syd­ney — had no inkling of what Cairns would get up to down in the lab. Af­ter all, no­body in Aus­tralia was do­ing any­thing like it. What’s more, the ge­netic tools of Cairns’ trade, so-called mi­cro ri­bonu­cleic acids (miRNAs), were only dis­cov­ered in peo­ple in 2000.

Now, Cairns has just pub­lished re­mark­able find­ings about the in­ner work­ings of schizophre­nia. And miRNAs, tiny bits of ge­netic ma­te­rial, are hot­ter than hot in lab­o­ra­to­ries around the world. Like Cairns, re­searchers are ex­cited about the power of the ge­netic snip­pets to help them un­der­stand the mech­a­nisms of dis­eases, from schizophre­nia to can­cer, and to as­sist in the de­vel­op­ment of a brand new class of di­ag­nos­tic tools and ther­a­pies for them.

Re­al­is­ti­cally, the po­ten­tial of the emerg­ing field of miRNA ge­net­ics is huge, claims molec­u­lar bi­ol­o­gist and ge­neti­cist Greg Arndt: ‘‘ It’s enor­mous. There’s an ab­so­lutely enor­mous po­ten­tial.’’

Arndt works for the Syd­ney re­search arm of the phar­ma­ceu­ti­cal gi­ant John­son and John­son, and ‘‘ Big Pharma’’ is not known for throw­ing money around frivolously. The fact that Arndt and his J&J col­leagues over­seas are ex­plor­ing the role of miRNAs in col­orec­tal can­cer is telling.

‘‘ Col­orec­tal can­cer is one of the most prom­i­nent forms of can­cer in the world,’’ Arndt says. ‘‘ One thing that would be very use­ful for col­orec­tal can­cer would be new tech­niques for de­tect­ing the stages of the de­vel­op­ment of the dis­ease. So we un­der­took to look at miRNAs at var­i­ous stages in pa­tient tis­sue. We saw there was altered ac­tiv­ity in the miRNAs,’’ he ex­plains.

Cairns and Arndt’s work re­flects the re­al­i­sa­tion that miRNAs are very busy en­ti­ties. That’s de­spite the fact that they’re small — only 20-22 bits, or ‘‘ bases’, long — and make noth­ing. Larger RNA mol­e­cules pro­duce ‘‘ can-do’’ mol­e­cules such as pro­teins or enzymes. What miRNAs do is reg­u­late the ac­tiv­ity, or ‘‘ ex­pres­sion’’, of thou­sands of genes through­out the body.

Arndt’s find­ings about col­orec­tal can­cer are a per­fect ex­am­ple. There, the miRNAs pro­mote or sup­press the de­vel­op­ment and spread of can­cer cells.

Cairns notes an­other in­trigu­ing fact about miRNAs: ‘‘ They’re pro­mis­cu­ous.’’ One miRNA can af­fect the ex­pres­sion of many dif­fer­ent genes, and can mix-and-match with other miRNAs to reg­u­late more genes which to­gether are in­volved in a host of bio­chem­i­cal path­ways in the body. Some of those path­ways are known to play im­por­tant roles in hu­man de­vel­op­ment, stress re­sponses and vi­ral in­fec­tions.

That’s why, like Arndt, molec­u­lar bi­ol­o­gist Greg Goodall, with the In­sti­tute of Med­i­cal and Vet­eri­nary Science and the Univer­sity of Ade­laide sees ‘‘ tremen­dous scope’’ for us­ing miRNAs to un­ravel and con­trol path­ways that drive dis­eases. ‘‘ This is such a new un­ex­plored area that of­fers so many op­por­tu­ni­ties for ex­pe­ri­enc­ing the joy of dis­cov­ery,’’ says Goodall.

Cur­rently, he’s fo­cus­ing on breast can­cer. Goodall re­mains mum, but the word from ob­servers such as Ge­off Lin­de­man, a breast can­cer ex­pert at the Wal­ter and El­iza Hall In­sti­tute in Melbourne, is that Goodall’s group has publi­ca­tions in the pipe­line that will add to an im­por­tant dis­cov­ery re­vealed last month in the jour­nal Na­ture .

As re­ported in The Aus­tralian (14/1), US re­searchers iden­ti­fied three miRNAs that halt the spread of breast can­cer to the lungs and bones of women with the most dan­ger­ous forms of the dis­ease. The team leader Joan Mas­sague, head of the can­cer bi­ol­ogy and ge­net­ics pro­gram at the Me­mo­rial SloanKet­ter­ing Can­cer Cen­ter in New York, said: ‘‘ The tiny RNAs pre­vent the spread of can­cer by in­ter­fer­ing with the ex­pres­sion of genes that give can­cer cells the abil­ity to pro­lif­er­ate and mi­grate (to other parts of the body)’’.

Ac­cord­ing to Mas­sague, that makes miRNAs ‘‘ tiny tar­gets’’ for drug de­vel­op­ment: con­trol the miRNAs and con­trol the dis­ease. Arndt agrees, point­ing to two ap­proaches. The first would be to give a pa­tient a drug con­tain­ing miRNAS to boost lev­els of crit­i­cal miRNAS. That fol­lows the find­ings from Mas­sague’s team. When the three miRNAs they iden­ti­fied were low or ab­sent, the can­cer spread. But when they put them into can­cer cells im­planted in mice, the deadly cells could not spread.

Arndt says the sec­ond strat­egy is to di­rectly tar­get the miRNAs in a per­son’s body. Like more con­ven­tional ther­a­pies, drugs would boost or sup­press miRNAs which them­selves boost or sup­press the ac­tiv­ity of genes in­volved in a dis­ease or con­di­tion.

But as Arndt’s work with col­orec­tal can­cer sug­gests, miRNAs also hold huge prom­ise as di­ag­nos­tic tools, help­ing doc­tors to de­tect dis­eases early on and to mon­i­tor the ef­fec­tive­ness of treat­ment. As­ton­ish­ingly, while the en­tire field of hu­man miRNA only got rolling in 2000, the Is­raeli firm Rosettta Ge­nomics pre­dicts it will have miRNA-based di­ag­nos­tic and pre­dic­tive tests for brain can­cers on the mar­ket by the end of the year. Treat­ments for can­cers and viruses are bound to fol­low in the next few years.

All this from a left-field dis­cov­ery of an RNA ‘‘ gene’’ in a ne­ma­tode worm, first re­ported in the jour­nal Cell in 1993. At the time con­ven­tional wis­dom was that genes were found in deoxyri­bonu­cleic acid, the fa­mous dou­ble-he­lix of DNA. Genes told sin­gle-stranded RNA what to do and the RNA got onto it, syn­the­sis­ing pro­teins. But to uni­ver­sal sur­prise that’s what the weird RNA worm ‘‘ gene’’ ap­peared to do.

Fur­ther in­ves­ti­ga­tion un­cov­ered the truth. The ‘‘ gene’’ was a miRNA, says Goodall: ‘‘ It was an un­sus­pected type of ge­netic reg­u­la­tor that is re­ally just a small piece of RNA.’’ In other words, a to­tally new sys­tem of con­trol­ling what goes on in the hu­man body had been dis­cov­ered in a worm. The race is on to find out what reg­u­lates the new­found reg­u­la­tors.

That’s why Murray Cairns sus­pected that miRNAs had a role in the on­set of the dis­or­dered think­ing and hal­lu­ci­na­tions that are the hall­mark of schizophre­nia. ‘‘ I thought it could have some­thing to do with how the genes are reg­u­lated, rather than a se­ries of ge­netic mu­ta­tions,’’ he re­calls.

To find out Cairns looked at a ‘‘ think­ing’’ brain re­gion, the tem­po­ral cor­tex. He dis­cov­ered that two-thirds of genes were more ac­tive, and one-third less ac­tive, in peo­ple who died from schizophre­nia com­pared to peo­ple with­out the dis­or­der. Sig­nif­i­cantly, the Cairns and SRI col­leagues have just showed the dif­fer­ences cor­re­spond to lev­els of miRNAs in the brain, and have strong ev­i­dence that the miRNAs ‘‘ dis­reg­u­late’’ gene ac­tiv­ity in the brains of peo­ple with schizophre­nia.

Given the com­plex­ity of schizophre­nia, it’s early days yet. But Cairns has big plans for the tiny reg­u­la­tors.

Pic­ture: Amos Aik­man

Ground­breaker: Murray Cairns is fas­ci­nated by the role of ge­netic snip­pets in dis­ease — his spe­cialty is schizophre­nia

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