CALL­ING THE STEM CELL RACE

We’ve been wait­ing 20 years for hu­man em­bry­onic stem cells to de­liver spare parts. ME­GAN MUNSIE takes a look at the win­ners com­ing down the track.

Cosmos - - Front Page - ME­GAN MUNSIE is Deputy Di­rec­tor of the Cen­tre for Stem Cell Sys­tems at the Univer­sity of Mel­bourne.

ON 6 NOVEM­BER 1998, the world woke to news of an as­ton­ish­ing dis­cov­ery. James Thom­son and his col­leagues at the Univer­sity of Wis­con­sin-madi­son had gen­er­ated stem cells from hu­man em­bryos. Un­like other types of stem cells, th­ese were ‘pluripo­tent’ – mean­ing they had the po­ten­tial to gen­er­ate any type of body tis­sue if given the right sig­nals.

FOR MANY, THIS news and the ac­com­pa­ny­ing claims that em­bry­onic stem (ES) cells could rev­o­lu­tionise medicine, ap­peared to come out of the blue. How­ever, for those of us al­ready work­ing in the stem cell space it was the vi­tal next step in ex­plor­ing the po­ten­tial of stem cell science.

Back in 1998, I was a keen PHD stu­dent, part of the stem cell re­search ef­fort at Monash Univer­sity. I was try­ing to cre­ate pluripo­tent stem cells from the skin cells of a mouse. The idea was to first clone a mouse em­bryo from its skin cell and har­vest the ES cells. In the lab next door, Ben Reu­bi­noff had been work­ing with Alan Troun­son and Martin Pera for sev­eral years to see if they could make em­bry­onic stem cells from do­nated hu­man em­bryos – ef­fec­tively in par­al­lel to their col­leagues in Wis­con­sin.

There was a lot of ex­cite­ment about how we might one day be able to use th­ese cells to make ‘re­place­ment’ body tis­sues – ef­fec­tively ‘on de­mand’– and al­le­vi­ate suf­fer­ing for many pa­tients. Al­though we all recog­nised this was go­ing to take an enor­mous amount of ef­fort – and time – to de­liver.

Out­side the lab if I men­tioned that I worked in stem cell re­search, I was met with over­whelm­ing cu­rios­ity. But peo­ple also won­dered why we couldn’t just use adult stem cells which are found in some of our or­gans. Many peo­ple I spoke to al­ready knew some­body who had been helped by a stem cell trans­plant us­ing bone mar­row or cord blood. Why did we need to use hu­man em­bryos and ES cells at all?

The rea­son was, and still is, that adult stem cells are not able to gen­er­ate any type of tis­sue be­cause they are not ‘pluripo­tent’. Bone mar­row stem cells, for in­stance, can re­gen­er­ate an immune sys­tem but they can­not re­gen­er­ate the pan­creas or brain tis­sue. The only source of pluripo­tent cells was sur­plus hu­man em­bryos – orig­i­nally cre­ated in an IVF clinic and then do­nated to re­search.

In 2007, Ja­panese sci­en­tists made a land­mark dis­cov­ery that side-stepped the need to use em­bryos. They were able to ma­nip­u­late or­di­nary hu­man skin cells to make them pluripo­tent (a much more el­e­gant and ef­fec­tive ap­proach than my at­tempts with mice skin cells dur­ing my PHD). Dubbed in­duced pluripo­tent

stem cells or IPSC, th­ese cells share the same de­sir­able fea­tures as ES cells. They can be grown in the lab and coaxed to form spe­cific types of body cells.

But both sources of pluripo­tent stem cells also carry the risk that they could form a tu­mour if we don’t fully di­rect their de­vel­op­men­tal fate. Any clin­i­cal ap­pli­ca­tion must metic­u­lously weed out the stem cells as part of the lab­o­ra­tory recipe used to make the re­place­ment cells. For me, the cru­cial chal­lenge is how to har­ness the po­ten­tial of stem cells to de­velop safe and ef­fec­tive treat­ments.

Th­ese days, as the head of the out­reach and pol­icy pro­gram for Stem Cells Aus­tralia, a na­tion­wide con­sor­tium of Aus­tralian stem cell sci­en­tists, I spend a lot of my time talk­ing to the pub­lic. To some ex­tent I’ve be­come a ‘race caller’ – fre­quently asked to pre­dict what new treat­ments are likely to come gal­lop­ing down the track. Some­times I’m asked to of­fer an opin­ion on stem cell ‘treat­ments’ that are not on the track at all. Pro­moted as a sure thing and avail­able now for a price, th­ese in­ter­ven­tions lack cred­i­ble ev­i­dence that they work or are even safe. Providers are ef­fec­tively ped­dling hope and should be viewed with cau­tion.

For­tu­nately, we do have providers com­mit­ted to re­spon­si­bly ad­vanc­ing the field with lots of bona fide con­tenders in clin­i­cal tri­als. So with my binoc­u­lars firmly in place, here is my read­ing of what’s com­ing down the track.

MAC­U­LAR DE­GEN­ER­A­TION

Lead­ing the charge to­wards the clinic is a pos­si­ble treat­ment for the most com­mon cause of age-re­lated vi­sion loss: mac­u­lar de­gen­er­a­tion. In Aus­tralia about one in seven peo­ple over the age of 50 have some ev­i­dence of this dis­ease. In this con­di­tion, dam­age to the cells at the back of the eye – the mac­ula – af­fects cen­tral vi­sion and the abil­ity to read, drive and recog­nise faces. The ac­tual ‘see­ing’ cells in the mac­ula are in­tact but sight is lost be­cause a tiny un­der­ly­ing patch of darkly pig­mented cells are dam­aged. Known as reti­nal pig­mented ep­ithe­lial cells or RPE cells, they act like a pit stop team, feed­ing and clear­ing away waste for the highly ac­tive cells of the retina.

Be­cause the num­ber of RPE cells needed is very small and pluripo­tent stem cells read­ily de­velop into this ex­act tis­sue (you can eas­ily spot a patch of darkly pig­mented cells in the dish), mac­u­lar de­gen­er­a­tion has long been a favourite. Clin­i­cal tri­als are now un­der­way in the United States, United King­dom and Ja­pan to de­ter­mine whether re­plac­ing faulty RPE cells with those made in the lab from ei­ther hu­man em­bry­onic stem cells or in­duced pluripo­tent stem cells could help.

At this early stage, safety is a key con­cern. The sur­gi­cal tech­nique to de­liver the cells car­ries the risk of de­tach­ing the retina and caus­ing fur­ther vi­sion loss. In May 2018, the Lon­don Project to Cure Blind­ness an­nounced that two pa­tients with mac­u­lar de­gen­er­a­tion – specif­i­cally what’s called the ‘wet’ form due to ex­ten­sive blood ves­sel growth un­der the retina – had im­proved their vi­sion with no sig­nif­i­cant side­ef­fects af­ter par­tic­i­pat­ing in a clin­i­cal trial.

DI­A­BETES

An­other early en­trant in the race to the clinic is type 1 di­a­betes. It’s a dis­ease caused by friendly fire: the immune sys­tem seeks and de­stroys the beta cells of the pan­creas. Th­ese re­mark­able cells can both sense ris­ing blood sugar lev­els and re­lease the ex­act amount of in­sulin needed to lower glu­cose lev­els to nor­mal. When th­ese cells are de­stroyed, which of­ten oc­curs in child­hood, the per­son is no longer able to con­trol their blood sugar lev­els.

More than 120,000 Aus­tralians man­age the dis­ease with reg­u­lar in­jec­tions of in­sulin. But they can’t reg­u­late their blood sugar lev­els as pre­cisely as beta cells do. And there are con­se­quences: high blood sugar lev­els can dam­age the blood ves­sels in the heart, eyes and kid­neys, while low lev­els can be fa­tal. Some pa­tients have been lucky enough to re­ceive a whole pan­creas trans­plant or tis­sues con­tain­ing beta cells from ca­dav­ers. But there are two prob­lems. First, trans­plant donors are in short sup­ply. Sec­ond, the do­nated tis­sue will likely suf­fer the fate of the orig­i­nal: at­tack by the immune sys­tem. En­ter pluripo­tent stem cells. Sup­ply is no longer a prob­lem. Af­ter two decades of try­ing, sci­en­tists are now able to make large quan­ti­ties of fully func­tional beta cells in the lab. And

as far as keep­ing the immune sys­tem at bay, sev­eral start-up com­pa­nies have come up with the ‘tea-bag’ ap­proach. They en­case the beta cells in a por­ous cap­sule. Like tea leaves, the beta cells are net­ted in but sol­u­ble fac­tors eas­ily move in and out across the net, in­clud­ing in­sulin and blood-borne glu­cose as well as other nutri­ents. Cru­cially, the net also stops ma­raud­ing immune cells from get­ting to the beta cells.

The Cal­i­for­nian com­pany, Vi­a­cyte, is tri­alling a ‘teabag’ about the size and shape of a credit card. Made of sur­gi­cal grade poly­mer, the cap­sule en­cases im­ma­ture beta cells (they’re more ro­bust if they ma­ture in­side the body), and is in­serted just un­der the pa­tient’s skin.

The key chal­lenge, so far, is pro­vid­ing in­ti­mate con­tact with sur­round­ing blood ves­sels so that the trans­planted cells in­crease in num­ber and sur­vive. In June this year, the com­pany re­ported its re­sults at a meet­ing of the Amer­i­can Di­a­betes As­so­ci­a­tion. Over­all, they said there was a low rate of sur­vival, but when cells did sur­vive they pro­duced in­sulin.

The com­pany is now eval­u­at­ing a sec­ond de­vice that al­lows the pa­tient’s blood ves­sels to grow through the walls of the cap­sule.

PARKIN­SON’S DIS­EASE

A strong stayer in the race to the clinic is Parkin­son’s dis­ease (PD). Pre­dom­i­nantly a dis­ease of age­ing, around 1% of peo­ple over the age of 60 suf­fer from it.

The dis­ease re­sults from the death of brain neu­rons that re­lease the neu­ro­trans­mit­ter dopamine. Like a con­duc­tor, dopamine en­sures dif­fer­ent parts of the brain act in syn­chrony to ex­e­cute rou­tine move­ments. With­out dopamine, pa­tients have trou­ble con­trol­ling their walk­ing and experience tremors in their hands and other parts of their bod­ies. Could re­plac­ing the faulty dopamine-pro­duc­ing neu­rons with healthy ones pro­vide a way to com­bat PD?

More than 20 years ago, a few dif­fer­ent re­search groups around the world gave it a try. Us­ing hu­man foetal tis­sue, they dis­sected out the dopamine­pro­duc­ing cells, and sur­gi­cally im­planted th­ese into the brains of pa­tients, specif­i­cally in a re­gion called the ‘stria­tum’. Some pa­tients im­proved, but oth­ers re­ported sig­nif­i­cant side ef­fects, par­tic­u­larly un­con­trol­lable jerky move­ments known as dysk­i­ne­sia. Ques­tions were asked about whether the cor­rect types of cells were be­ing trans­ferred to the cor­rect part of the brain and fur­ther ex­per­i­ments were put on hold. A key ques­tion was whether pluripo­tent stem cells could of­fer a more pre­cise and re­li­able source of dopamine­pro­duc­ing cells.

Jump for­ward to 2018 and sev­eral groups are on the cusp of test­ing new types of re­place­ment cells for PD in a se­ries of clin­i­cal tri­als. Years of re­search has shown that ES cells and IPS cells can be di­rected to de­velop into the cor­rect type of neu­rons and that suf­fi­ciently large num­bers can be gen­er­ated.

When tested in an­i­mals, the dopamine-pro­duc­ing cells cor­rected move­ment dis­or­ders and did not form tu­mours.

This time around, rather than work­ing in si­los, dif­fer­ent groups of re­searchers in Ja­pan, Swe­den, UK and US have banded to­gether in a coali­tion called G-force PD. Al­though each group is us­ing a slightly dif­fer­ent ap­proach for their clin­i­cal trial, by shar­ing their re­sults and ex­per­tise they hope to bring a cell­based ther­apy for PD closer to re­al­ity.

SKIN, STEM CELLS AND BUT­TER­FLY CHIL­DREN

Skin stem cells have long been solid per­form­ers for grow­ing skin grafts to treat se­vere burns. But in Novem­ber 2017, headlines ran hot with a re­port that a seven-year-old refugee Syr­ian boy, on the verge of death from a ge­netic skin con­di­tion, had been saved by a graft of skin stem cells cor­rected by gene ther­apy.

Has­san, now liv­ing with his fam­ily in Ger­many, suf­fered from a se­vere form of Epi­der­mol­y­sis Bul­losa (EB). It’s been re­ferred to as the “worst dis­ease you’ve never heard of”. It af­fects about 500,000 peo­ple world­wide, and can be caused by mu­ta­tions to 18 dif­fer­ent genes. In each case, the mu­ta­tion dis­rupts the an­chor­ing of the skin’s up­per layer, the epi­der­mis, to the un­der­ly­ing der­mis. The re­sult is skin that tears as eas­ily as a but­ter­fly’s wing. The only treat­ment is painful ban­dag­ing and re-ban­dag­ing.

Has­san’s skin had started blis­ter­ing from birth but by the time he was seven, a bac­te­rial in­fec­tion had robbed him of 80% of his skin cover. In a last ditch ef­fort to save his life, his Ger­man doc­tors con­tacted vet­eran stem cell re­searcher Michele De Luca at the Univer­sity of Mo­dena and Reg­gio Emilia in Italy. In 2006, De Luca had used skin grafts cor­rected by gene ther­apy to treat a leg wound of a wo­man who suf­fered from the same form of EB that Has­san suf­fered from. It was caused by a mu­ta­tion to a gene called LAMB3.

De Luca’s team took a tiny patch of skin con­tain­ing stem cells from Has­san’s groin. They also spliced a copy of the LAMB3 gene into a be­nign virus. Then they in­fected the skin cells with the virus which fer­ried the LAMB3 gene into their DNA. The ge­net­i­cally

SPINAL CORD IN­JURY

cor­rected skin grew into a sheet which was grafted onto Has­san’s body. Five months af­ter the first graft, Has­san was dis­charged. A month later he was back at school and play­ing soc­cer. Thanks to the ge­net­i­cally cor­rected stem cells, his grafted skin no longer blis­ters or shreds. The ex­ec­u­tive di­rec­tor of the Dys­trophic Epi­der­mol­y­sis Bul­losa Re­search As­so­ci­a­tion of Amer­ica dubbed Has­san’s treat­ment “a sea change to the world of EB”. Be­sides de Luca’s group, Peter Marinkovich and Jean Tang at Stan­ford Univer­sity School of Medicine, United States, are also tri­alling ge­net­i­cally-cor­rected skin grafts for a dif­fer­ent type of EB. One of the front run­ners at the start of the stem cell race was spinal cord in­jury. Per­haps you re­mem­ber the ac­tor Christo­pher Reeve, aka Su­per­man? Fol­low­ing a horse rid­ing ac­ci­dent that left him a quad­ri­plegic, he cam­paigned tire­lessly for re­searchers to be al­lowed to use hu­man em­bry­onic stem cells to treat spinal cord in­jury which claims about 180,000 new cases each year. Per­haps thanks to his ef­forts in 2010, the world saw the first clin­i­cal trial us­ing cells made from hu­man ES cells.

Con­ducted by the Cal­i­for­nia based biotech com­pany Geron, the re­searchers had di­rected ES cells to de­velop into pre­cur­sors of ‘oligo­den­dro­cytes’. Th­ese oc­to­pus-like cells wind their arms around neu­rons in the spinal cord to pro­vide elec­tri­cal in­su­la­tion as well as nur­tur­ing fac­tors. With a spinal cord in­jury, th­ese im­por­tant sup­port cells can be lost. Four pa­tients were in­jected with stem cell-de­rived oligo­den­dro­cyte pre­cur­sors soon af­ter their in­jury. Con­tro­ver­sially, Geron dis­con­tin­ued the study in 2011 to re­fo­cus their busi­ness. As­te­rias Bio­ther­a­peu­tics picked up the ba­ton

and last July, in a com­pany press re­lease, re­ported the re­sults of an early clin­i­cal trial on 25 ad­di­tional pa­tients who were all in­jected with oligo­den­dro­cyte pre­cur­sors three to six weeks post-in­jury. They re­ported no se­ri­ous ad­verse events and that four pa­tients re­cov­ered a de­gree of mo­tor func­tion that may in­crease their abil­ity to lead an in­de­pen­dent life. How­ever, we have to wait to see the peer re­viewed pub­lished re­sults be­fore we can as­sess the state of progress.

Beyond re­plac­ing oligo­den­dro­cytes made from ES cells, other clin­i­cal tri­als are test­ing dif­fer­ent types of cells rang­ing from neu­rons ob­tained from do­nated foetal tis­sue to us­ing the pa­tient’s own cells ob­tained from the back of the nose where they play an im­por­tant role in sup­port­ing the re­gen­er­a­tion of the ol­fac­tory neu­rons. Some types of trans­planted cells may act as paramedics, help­ing dam­aged mo­tor neu­rons to re­cover. Oth­ers are de­signed to di­rectly re­place spinal cord neu­rons.

It re­mains too early to tell which ap­proach will re­sult in long-term im­prove­ments. While many with spinal cord in­jury are ea­ger for even small im­prove­ments such as blad­der or bowel con­trol, pa­tients should be care­ful about try­ing mar­keted ex­per­i­men­tal pro­ce­dures out­side well-con­ducted clin­i­cal tri­als as they may cause fur­ther harm. In a chill­ing ex­am­ple, one young wo­man who sought treat­ment us­ing ol­fac­tory cells de­vel­oped a large, painful mu­cus-se­cret­ing tu­mour in her spine and no im­prove­ment of her para­ple­gia. Un­for­tu­nately, many stem cell ‘cures’ pro­moted on­line, es­pe­cially for spinal cord in­jury, lack cred­i­bil­ity. Seek­ing ad­vice from your med­i­cal spe­cial­ist is the best way to find out more. If they don’t know about a trial or claimed treat­ment, it is prob­a­bly a mi­rage.

KID­NEY DIS­EASE

Marked as a long shot for many years, stem cell re­search is start­ing to pay div­i­dends for kid­ney dis­ease. Though it’s not ready to pro­vide trans­plants, it is al­ready help­ing to dis­cover new treat­ments.

Kid­neys are the body’s vi­tal cleans­ing and bal­anc­ing sys­tem. They fil­ter waste prod­ucts and tox­ins from our blood into urine, main­tain the body’s wa­ter bal­ance and also make hor­mones im­por­tant for reg­u­lat­ing blood pres­sure and the pro­duc­tion of red blood cells.

Kid­ney dis­ease, which af­fects one in 10 Aus­tralians, dam­ages the fil­tra­tion units called nephrons. The ma­jor causes are di­a­betes and high blood pres­sure. Once gone, the nephrons can­not re­gen­er­ate. But wait­ing for a do­nated kid­ney can take years; close to 1,000 Aus­tralians are cur­rently on the wait­ing list for a trans­plant. This health cri­sis has cat­a­pulted re­searchers into try­ing to recre­ate kid­ney tis­sue from pluripo­tent stem cells – an im­mense chal­lenge as th­ese are com­plex bi­o­log­i­cal ma­chines com­posed of many in­ter­act­ing parts.

Melissa Lit­tle’s group, based at the Mur­doch Chil­dren’s Re­search In­sti­tute in Mel­bourne, have pi­o­neered this re­search. In 2015, they suc­cess­fully grew tiny kid­ney-like struc­tures that were show­cased on the cover of Na­ture with the headline: “Kid­ney in a dish”. While their mini-kid­neys pos­sess many of the work­ing parts of a ma­ture kid­ney, there’s a long way to go be­fore they can be used as trans­plants. The plumb­ing for ex­am­ple – bring­ing blood in and tak­ing waste out – is not yet func­tional. Also they are tiny, smaller than the tip of your fin­ger.

Nev­er­the­less th­ese mini-kid­neys are al­ready mak­ing a dif­fer­ence to our understanding of how kid­neys de­velop and what goes awry in kid­ney dis­ease, es­pe­cially the hered­i­tary form. For ex­am­ple, re­searchers were re­cently able to make mini-kid­neys from a child suf­fer­ing from a rare ge­netic con­di­tion that can cause end-stage kid­ney dis­ease. They did it by first gen­er­at­ing IPS cells from the child’s skin. In the lab they were able to ob­serve struc­tural ab­nor­mal­i­ties in the child’s cells and also showed that when the ge­netic mu­ta­tion was cor­rected, the struc­tural de­fect was cor­rected. This pro­vides a new in­sight into in­her­ited kid­ney dis­ease where pre­vi­ously we knew very lit­tle about how th­ese con­di­tions de­velop.

IL­LUS­TRA­TIONS Jef­frey Phillips

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