Anaemia one more mys­tery of the blood

Re­searchers hope that un­lock­ing some mys­ter­ies of blood will put them on the path to bet­ter treat­ments for anaemia, writes Amanda Saun­ders

The Weekend Australian - Travel - - Health -

BLOOD has fas­ci­nated peo­ple for cen­turies and images of blood­shed con­tinue to per­me­ate all facets of cul­ture, from pop­u­lar art and lit­er­a­ture to re­li­gion and even psy­cho­anal­y­sis. Through­out his­tory, an­cient rit­u­als and re­li­gious cer­e­monies have cel­e­brated blood as the liq­uid of life and used it as an im­por­tant sym­bol of sac­ri­fi­cial rites.

But blood holds a place of com­pa­ra­ble mys­tery in a sci­en­tific set­ting and re­searchers con­tinue to try and un­cover more of its prop­er­ties.

One of the most com­mon blood disor­ders is anaemia, and re­searchers hope that new find­ings will lead to bet­ter and more tar­geted treat­ments for the con­di­tion.

Peo­ple with anaemia ei­ther have an in­suf­fi­cient red blood cell sup­ply or a low level of the blood pro­tein haemoglobin, which is nec­es­sary to move oxy­gen through the body.

Un­lock­ing the path to new anaemia treat­ments is a key part of bio­chemist Peter Klinken’s re­search. Klinken, head of the West­ern Aus­tralian In­sti­tute of Med­i­cal Re­search (WAIMR), hopes that his ef­forts to de­ci­pher the in­tri­ca­cies of red blood cell pro­duc­tion will trans­late into treat­ments that clin­i­cians can give to their pa­tients.

Klinken was in­spired to ex­plore the power of red blood cells dur­ing his three-year stint do­ing post-doc­toral re­search at the Na­tional In­sti­tutes of Health (NIH) in Wash­ing­ton.

Un­der the lights of his su­per­vi­sor’s lab, his imag­i­na­tion was set on fire as he watched his su­pe­rior work on im­ma­ture red blood cells and can­cer-caus­ing genes that had only just been dis­cov­ered. The idea that one faulty gene could de­stroy some­one’s health amazed Klinken.

‘‘ I was look­ing at all this and say­ing, oh boy, how does a blood stem cell make de­ci­sions so it turns into a red blood cell rather than a white blood cell,’’ he says.

Klinken com­pares de­cod­ing the an­swers to such ques­tions with the task of the early ex­plor­ers. ‘‘ Let’s go back 400 or 500 years to the ex­plor­ers, who were sup­ported by wealthy no­ble­men to dis­cover won­der­ful trea­sures,’’ he says. ‘‘ I think we are do­ing much the same thing now. So­ci­ety is say­ing to us, ‘ go out and seek new worlds’.’’

Break­ing new ground in anaemia re­search can be dif­fi­cult be­cause the causes of the dis­ease are var­ied, rang­ing from iron or vi­ta­min de­fi­ciency, blood loss, chronic ill­ness, a ge­netic or ac­quired de­fect and the use of some med­i­ca­tions.

Wol­lon­gong Hospi­tal haema­tol­o­gist Peter Pres­grave says that while anaemia caused by iron or vi­ta­min de­fi­ciency can be treated by tak­ing sup­ple­ments, other more se­ri­ous forms of the dis­ease can be hard to treat.

‘‘ One of the prob­lems with dis­eases of the red cells lead­ing to anaemia is that there is lit­tle that can be done un­less there is a sim­ple cause such as a vi­ta­min de­fi­ciency,’’ Pres­grave ex­plains. ‘‘ The only other so­lu­tions are to give reg­u­lar blood trans­fu­sions, at a time when there is a deal of strain on the blood sup­ply, or treat­ment with ery­thro­poi­etin (EPO).’’

EPO treat­ment is used on anaemia pa­tients be­cause it stim­u­lates pro­duc­tion of their miss­ing blood cells. Al­though it held early prom­ise, EPO is not suit­able for all types of anaemia and its suc­cess rate varies, says Klinken.

Pres­grave says EPO’s ca­pac­ity to treat pa­tients who have de­vel­oped anaemia due to bone mar­row fail­ure is lim­ited. ‘‘ In a con­di­tion called myelodys­pla­sia, a form of bone mar­row fail­ure, EPO works in only 20-50 per cent of pa­tients and has to be used in very high doses on a con­tin­u­ous ba­sis,’’ he ex­plains.

EPO also has cost prob­lems and pa­tients only qual­ify for gov­ern­ment sub­si­dies if their anaemia is the re­sult of re­nal (kid­ney) fail­ure, he says. ‘‘ If you take the ‘ av­er­age’ re­nal fail­ure pa­tient, they may need about $8000 worth of EPO per year — po­ten­tially for the rest of their life,’’ says Pres­grave. ‘‘ In pa­tients with mar­row dis­eases, not el­i­gi­ble for sub­si­dies, the doses are of­ten con­sid­er­ably higher — pos­si­bly three times this, if not more.’’

David Joske, head of haema­tol­ogy at Sir Charles Gar­diner Hospi­tal in Perth, says EPO works on the vast ma­jor­ity of pa­tients who have anaemia as­so­ci­ated with re­nal fail­ure. ‘‘ How­ever, EPO, when it is used ther­a­peu­ti­cally, is as­so­ci­ated with an in­creased risk of blood clots in some pa­tient groups, such as those on dial­y­sis,’’ he ex­plains.

One of Klinken’s latest sig­nif­i­cant dis­cov­er­ies is set against the back­drop of im­per­fect treat­ments such as EPO, and prom­ises the pos­si­bil­ity of al­ter­na­tive treat­ments.

Bas­ing its work on mice, his WAIMR team dis­cov­ered a link be­tween EPO and the thy­roid hor­mone, which was re­ported in the March edi­tion of the Amer­i­can haema­tol­ogy jour­nal Blood (2008;111(6):3245-3248).

The re­search shows that the thy­roid hor­mone, al­ready known to af­fect me­tab­o­lism, also con­trib­utes to red blood cell for­ma­tion. How­ever, the ex­act ef­fect of thy­roid on blood pro­duc­tion has not yet been es­tab­lished.

‘‘ We knew there was a link be­tween the me­tab­o­lism and thy­roid hor­mone lev­els and so we sud­denly thought: for your me­tab­o­lism to work you re­ally need oxy­gen, and what car­ries oxy­gen?’’ says Klinken. ‘‘ Red blood cells do.’’

Joske says such un­der­stand­ing could ul­ti­mately lead to a cure for anaemia.

‘‘ If the dif­fer­ent path­ways that lead to anaemia can be iden­ti­fied, then they can be blocked,’’ he says. ‘‘ So we can then not only treat anaemia — we can pre­vent it.’’

Joske be­lieves the re­search may also lead to new treat­ments for anaemia pa­tients with hy­pothy­roidism, or un­der­func­tion­ing thy­roid glands.

Klinken’s find­ing oc­curred by chance and coin­ci­den­tally came shortly af­ter Blood re­ported an­other of his team’s im­por­tant dis­cov­er­ies. They un­earthed a can­cer-caus­ing gene and ex­posed its role in reg­u­lat­ing red blood cell pro­duc­tion.

A study on the gene, known as Hls5, ap­peared in the jour­nal in Fe­bru­ary (2008;111(4):1946-50) and of­fers hope of new re­search av­enues that po­ten­tially could lead to new treat­ments for con­di­tions such as anaemia, leukaemia and can­cer.

Klinken was sur­prised to find that Hls5 con­trols how genes are switched on and off, and stunts the growth of de­vel­op­ing red blood cells. He be­lieves there are con­sid­er­able prospects of al­ter­ing the gene, as even mi­nor changes in Hls5 were shown to have a large im­pact. ‘‘ By know­ing what the func­tion of this Hls5 gene we dis­cov­ered is, we have a bet­ter un­der­stand­ing of its role in can­cer,’’ says Klinken.

Joske thinks the re­search will lead to more tar­geted treat­ments for leukaemia and anaemia. ‘‘ The key mes­sage of this re­search is that we can get as clever about a com­mon prob­lem like anaemia as we have about rarer prob­lems like leukaemia, and that prom­ises much more spe­cific and ef­fec­tive treat­ments in the years to come,’’ he says.

Joske also points out that more tar­geted treat­ments may mean fewer or no side ef­fects. ‘‘ For leukaemias, what we are in­creas­ingly go­ing to be able to do is iden­tify the ab­nor­mal genes or mol­e­cules and tar­get a treat­ment that just works against them,’’ ex­plains Joske. ‘‘ That treat­ment then won’t af­fect nor­mal cells.’’

How­ever, Pres­grave is not so sure that Klinken’s re­search will lead di­rectly to new treat­ments, and says its role will re­late more to in­creas­ing the un­der­stand­ing of pro­cesses that lead to red cell dis­eases and blood can­cers.

‘‘ My un­der­stand­ing is that this re­search may be of ben­e­fit in blood and mar­row dis­eases pa­tients, who do not cur­rently get EPO un­less they pay for it, but who re­quire reg­u­lar blood trans­fu­sions,’’ he says.

Jill Fin­layson, the head of haema­tol­ogy at PathWest in Perth, thinks the find­ings are im­por­tant in build­ing knowl­edge of the fun­da­men­tal pro­cesses in­volved in cell de­vel­op­ment.

‘‘ This knowl­edge lays the foun­da­tion for un­der­stand­ing the in­ter­ac­tions at a cel­lu­lar level re­quired for nor­mal de­vel­op­ment, and may pro­vide a key to un­rav­el­ling the pro­cesses which are af­fected in malig­nan­cies,’’ she ex­plains. ‘‘ This type of un­der­stand­ing may well lead to tar­geted ther­a­pies in the fu­ture.’’

Klinken will con­tinue to at­tempt to ful­fil his self-as­cribed role as a mod­ern day ex­plorer. ‘‘ So­ci­ety is in­vest­ing in us to go forth and do good things,’’ he says. ‘‘ So we have a re­spon­si­bil­ity to come up with won­der­ful new dis­cov­er­ies.’’

Pic­ture: Colin Murty

Re­search: David Joske per­forms a bone mar­row biopsy. Peter Klinken looks on

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