THE IN­CRED­I­BLES:

Can we teach our most com­plex or­gan to heal it­self? Jac­que­line Detwiler re­ports.

Popular Mechanics (South Africa) - - Contents - BY JAC­QUE­LINE DETWILER PHO­TOG­RA­PHY BY BRIAN FINKE

AL GARD­NER and his brother-in-law built the house in Mount Kisco, New York, back in 1984 – two sto­ries, three bed­rooms, with a sweet lit­tle porch over­look­ing a sunny back­yard. At the time, Gard­ner had worked in con­struc­tion man­age­ment for years. He had, in fact, been me­chan­i­cally in­clined ever since he was a kid, when he helped re­fur­bish a Beaver trac­tor his dad bought from a neigh­bour. But the house was the first he ever built from scratch, and he was proud of it. Not many peo­ple can say they’ve built a house for their fam­ily. Al Gard­ner could.

Al has a hard time walk­ing up the stairs to his home’s sec­ond floor these days, so he lives on the first. In a lounge chair, sur­rounded by pic­tures of his fam­ily and the homes he’s built, he slowly, care­fully crosses one knee at the an­kle as though he’s in a busi­ness meet­ing. His legs are thin and pale and pa­pery. His face, too, has taken on a gaunt­ness since the photo of his daugh­ter’s wed­ding, mounted on the wall right in front of him, was taken back in 2009. Al lunges for­ward as if he might stand. But then, when he tries to say hello, all that comes out is a gut­tural moan.

When Al, who is 68, was di­ag­nosed with pro­gres­sive supranu­clear palsy (PSP) in 2012, he was not guar­an­teed even this. The dis­ease is caused by de­gen­er­a­tion of cells in ar­eas of the brain as­so­ci­ated with move­ment, balance, and thought. On av­er­age, life ex­pectancy is about seven years af­ter di­ag­no­sis. It has no known cause and no cure. Think of it as Parkin­son’s dis­ease, but faster, and more hor­ri­ble. L-DOPA, a drug that can re­duce symp­toms in Parkin­son’s pa­tients and help them move, usu­ally has no ef­fect on PSP. Apart from an as­pirin, an antacid, and some­thing for blad­der con­trol, Al doesn’t even take any drugs. There aren’t any to give him.

Al’s wife, Fran, ruf­fles his hair. He stares straight ahead. Al can no longer blink or move his eyes, which Fran says is the worst of it. He has to wear sun­glasses just to go up­stairs. For now, Al can still com­mu­ni­cate in writ­ing: Last week he had a si­nus in­fec­tion, and hadn’t been able to make it out of the house for his usual ap­point­ments. On the white­board he uses to com­mu­ni­cate, he wrote a sin­gle word: Bored.

As the losses mount, Fran has writ­ten out an af­fir­ma­tion she can re­cite when she needs it. She has joined sup­port groups, and is ac­tive in the PSP com­mu­nity. She smiles as if mak­ing the mo­tion is all that’s keep­ing her afloat. ‘We’ve been for­tu­nate to have this time,’ she says, up­stairs, in the kitchen, where Al will not hear. ‘It could be a lot worse.’

The neu­ro­sci­en­tist who wants to turn sup­port cells into neu­rons WASH­ING­TON, DC

A DI­SHEV­ELLED GUEST emerges from the lift of the Wash­ing­ton Plaza Ho­tel in Wash­ing­ton, DC, car­ry­ing a bag of laun­dry to drop off at the front desk. He looks out the win­dow, where a gi­ant pic­ture of a brain lum­bers past on the side of a city bus.

‘Are you here for the neu­ro­science con­fer­ence?’ the man asks a stranger stand­ing next to him. The bus de­parts, re­veal­ing packs of neu­ro­sci­en­tists mak­ing their way around Thomas Cir­cle, black poster tubes for pre­sen­ta­tions slung across their shoul­ders like quiv­ers. ‘It just seems as though ev­ery­one is here for this thing,’ the man says. ‘I’m just try­ing to fig­ure out how far it goes.’

Far. This week­end marks the be­gin­ning of the So­ci­ety for Neu­ro­science’s an­nual meet­ing, which at­tracts more than 30 000 pro­fes­sors, doc­tors, grad­u­ate stu­dents, and post­doc­toral re­searchers from more than 80 coun­tries to dis­cuss the fu­ture of the hu­man brain. SFN, as the con­fer­ence is called, is so enor­mous that only seven cities in the United States can even ac­com­mo­date it.

In­side the Wal­ter E. Wash­ing­ton Con­ven­tion Cen­ter, the fea­tured lec­tures have al­ready be­gun in the au­di­to­rium, which is so ca­pa­cious (and dark) you could play a game of Marco Polo in it with your eyes open. Up next is Mag­dalena Götz, a pro­fes­sor who has flown in from Lud­wig Max­i­m­il­ian Univer­sity of Mu­nich to give a talk about treat­ing brain in­juries in mice. Her face, com­plete with blunt Ger­manic bangs, is briefly du­pli­cated on a gi­ant screen like an evan­gel­i­cal preacher’s.

There are many rea­sons that pro­gres­sive supranu­clear palsy, the dis­ease Al Gard­ner has, is hell on Earth, but they can all be traced to one thing: Gen­er­ally speak­ing, neu­rons don’t grow back. With a few ex­cep­tions, when the brain’s pri­mary in­for­ma­tion-pro­cess­ing cells die, they’re dead. So to­day, when a doc­tor en­coun­ters a neu­rode­gen­er­a­tive dis­ease or a brain in­jury, the strate­gies are lim­ited: One, do your best to keep the rest of the neu­rons alive; and two, en­cour­age the brain to work around any sec­tions that are dam­aged. If some­one could some­how per­suade neu­rons in hu­man pa­tients to spon­ta­neously re­gen­er­ate, it would be one of the most in­cred­i­ble achieve­ments in neu­ro­science. For now, it re­mains im­pos­si­ble.

Götz doesn’t study neu­rons. Or, at least, not at first. She works on an­other type of cells, called glia. Glia (Greek for ‘glue’) com­prise at least half of the cells in the brain, but sci­en­tists thought they were just a sup­port­ing frame­work for neu­rons for more than a cen­tury. Then, in 1990, a Stan­ford re­searcher named Stephen J Smith dis­cov­ered that a par­tic­u­lar type of glia, star-shaped cells called as­tro­cytes, could com­mu­ni­cate with each other. It started a race to fig­ure out what these strange cells did. The list keeps grow­ing.

‘When an in­jury strikes, as­tro­cytes be­come ac­ti­vated,’ says Götz. They can kill more neu­rons, or they can help keep them alive. They can reg­u­late in­flam­ma­tion and con­trol how neu­rons re­con­nect af­ter their net­works have been dec­i­mated. Some stick around and form a scar. As­tro­cytes are im­por­tant all the time, but af­ter a brain in­jury, the scaf­fold­ing runs the asy­lum.

Here’s why any of this mat­ters: By in­ject­ing cer­tain pro­teins (called tran­scrip­tion fac­tors) in­volved in de­vel­op­ment di­rectly into the brain, Götz and her team in Mu­nich have fig­ured out how to al­ter the func­tion of as­tro­cytes af­ter an in­jury. Like re­ally al­ter it. In­stead of build­ing use­less scar tis­sue, Götz’s as­tro­cytes trans­form into brand-new neu­rons to re­place the ones that were lost. Götz has done this to hu­man cells in a dish, and she’s done it in liv­ing mice. Her team has even con­vinced the re­pro­grammed neu­rons to send lit­tle feeler pro­jec­tions out to the places they should go. Now, nearly a year af­ter her talk in Wash­ing­ton, DC, she has part­nered on a re­view ar­ti­cle with a doc­tor who sees Parkin­son’s pa­tients, and is work­ing on ways to de­liver the tran­scrip­tion fac­tors to mice through oral drugs rather than brain in­jec­tions.

‘Pre­dic­tions about how long some­thing will take [to be avail­able for hu­mans] are no­to­ri­ously wrong,’ Götz says. ‘ This is how much I can say: We did this for the first time in a liv­ing an­i­mal in 2005, and that was con­sid­ered a com­plete blue-sky ap­proach. Only 15 years later we’ve reached a stage where clin­i­cians are in­ter­ested.’ That doesn’t mean that 15 years from now doc­tors will be able to pre­scribe a course of tran­scrip­tion fac­tors to cure PSP. But then again … The au­di­to­rium is only about half full for Götz’s talk, which seems in­cred­i­ble when you con­sider the po­ten­tial im­pact of her work. Re­pro­gram­ming sup­port cells to cure brain dis­ease! But SFN is host­ing thou­sands of pre­sen­ta­tions over the next five days. It’s a hal­cyon Satur­day in Wash­ing­ton, DC. And in neu­ro­science, amaz­ing things are hap­pen­ing ev­ery­where you look.

The phi­lan­thropist who wants to fig­ure out how the brain works S E AT TLE

THE YEL­LOW-BRICK HAR­BORVIEW Med­i­cal Cen­ter, dec­o­rated in places with white chevrons and pocked with doll­house win­dows, is a gor­geous build­ing, an early 20th-cen­tury san­i­tar­ium over­look­ing Seat­tle’s in­fi­nite har­bour. But in­side the base­ment, it looks much like any other hospi­tal – a labyrinth of tiled cor­ri­dors bro­ken only by the oc­ca­sional set of dou­ble doors. Out­side one such set, un­der a red ban­ner that reads ‘Op­er­at­ing Room Staff Only,’ a re­search as­so­ciate named Tamara Casper leans on a black in­dus­trial kitchen cart, wait­ing. For 45 min­utes, she was wait­ing in a lab down the hall, but now she’s moved here to wait some more.

Past the dou­ble doors, Jef­frey Oje­mann, a brain sur­geon from a fam­ily of them (his fa­ther, un­cle, and brother are neu­ro­sur­geons, and his mother is a neu­rol­o­gist), stands over the ex­posed cere­bral cor­tex of a 23-year-old woman whose epilepsy has be­come un­man­age­able. It’s likely that the woman is awake: Oje­mann of­ten wakes up pa­tients at this point in the pro­ce­dure, to ap­ply elec­tri­cal cur­rent to the brain while the pa­tient names pic­tures. He wouldn’t want to ac­ci­den­tally re­move an ir­re­place­able chunk of neu­rons on his way to the knob of tis­sue that has been caus­ing the woman’s seizures – a spot known as an epilep­tic fo­cus.

Oje­mann makes a cut in the side of the woman’s tem­po­ral lobe, which is above the ear, avoid­ing what’s known as the elo­quent cor­tex, parts of the brain that are gen­er­ally un­der­stood to al­low peo­ple to move, hear, speak, and see. He tun­nels in to reach the fo­cus. He will do his best to re­move as lit­tle as pos­si­ble.

About 20 min­utes later, a young woman wear­ing dark-blue scrubs with a mask drawn down around her neck emerges from the dou­ble doors with a lurid pink and white mar­ble in a jar. It’s the man­hole cover Oje­mann cut from the outer lay­ers of the woman’s brain to get down to the epilep­tic fo­cus. The mar­ble is healthy, nor­mal brain tis­sue.

Un­for­tu­nately, once it was sev­ered from the neu­rons sur­round­ing it, there was no putting it back. ‘Sorry it took a lit­tle while,’ the woman says, hand­ing over the jar. ‘But it’s lit­er­ally brain surgery.’

Tamara Casper places the jar in a sty­ro­foam cooler packed with ice and rolls her cart out into the street. She loads it into the back of an anony­mous white courier van, which slips into Seat­tle’s af­ter­noon traf­fic. Within 15 min­utes, the mar­ble has been re­ceived at the Allen In­sti­tute for Brain Sci­ence – founded by ec­cen­tric Mi­crosoft co-founder and Seat­tle-based phi­lan­thropist Paul Allen – where it will be­come a per­ma­nent part of the first-ever cel­lu­lar map of the hu­man brain.

Many peo­ple think that be­cause neu­ro­sur­geons are able to op­er­ate on the brain, there must al­ready be a map of how it works, and that is true, to an ex­tent. A struc­tural di­a­gram of the brain has ex­isted since the early 1900s, out­lin­ing the re­gions where cells ap­pear dif­fer­ent un­der a mi­cro­scope. But most of what doc­tors know about the func­tion of each of those pieces comes from presur­gi­cal elec­tri­cal record­ings, such as the ones Oje­mann takes; or func­tional mag­netic res­o­nance imag­ing (FMRI) stud­ies, which show how blood flow changes while peo­ple do tasks; as well as from a whole lot of doc­tors ac­ci­den­tally re­mov­ing parts they shouldn’t. There is still a lot of empty space on the map. Es­pe­cially when com­pared to the rest of the hu­man body, the brain is vir­tu­ally un­charted.

In 2003, Paul Allen learned that his mother had Alzheimer’s dis­ease. Al­ready ob­sessed with com­put­ers, and de­ter­mined to do­nate most of his for­tune to char­ity, he be­came fas­ci­nated with the brain, ear­mark­ing an ini­tial $100 mil­lion to found an in­sti­tute that could do the com­pre­hen­sive, labour-in­ten­sive work that would be re­quired to fig­ure out how it works. It would be like Great Bri­tain’s Royal Geo­graph­i­cal So­ci­ety – the world’s first shared ob­ser­va­tory for brains.

Over the years, the Allen In­sti­tute has used mice and the brains of ca­dav­ers to cre­ate at­lases of where var­i­ous genes are ex­pressed in the brain. They’ve mapped the spinal cord. They’ve mapped pri­mate brains. In ac­cor­dance with Allen’s in­struc­tions, all of the di­a­grams and data are avail­able to the en­tire neu­ro­science com­mu­nity for free. But even that hasn’t been enough to ex­plain how an or­gan can process in­for­ma­tion. Even­tu­ally, the Allen In­sti­tute’s staff started to won­der if de­vel­op­ing a pe­ri­odic ta­ble of brain cells would help re­searchers fig­ure it out. Just how many dif­fer­ent kinds were there?

The short an­swer: prob­a­bly more than a thou­sand. Since 2015, the in­sti­tute has been work­ing on the first-ever tax­on­omy of brain cells, sort­ing them by their elec­tri­cal ac­tiv­ity, the genes they ex­press, and their mor­phol­ogy (how they look). They started with liv­ing cells from mouse brains, which are eas­ier to get, but have re­cently moved over to hu­mans, part­ner­ing with six lo­cal doc­tors to pick up left­over cells from surg­eries that would oth­er­wise be thrown away or kept in hospi­tal tis­sue banks. Christof Koch, the Allen In­sti­tute’s chief sci­en­tist and pres­i­dent, com­pares the work to map­ping the genome, which has rad­i­cally trans­formed medicine since it was com­pleted in 2003. ‘ To­day, noth­ing in bi­ol­ogy makes sense any­more with­out know­ing the in­volve­ment of genes,’ he says. ‘ The same thing is true of cell types. It is go­ing to be an ab­so­lute, nec­es­sary next step to un­der­stand who we are.’

Af­ter the sam­ple Tamara Casper col­lected from Har­borview Med­i­cal Cen­ter ar­rives at the Allen In­sti­tute in the white courier van, she and a team of tech­ni­cians metic­u­lously slice it and hand it off to re­searchers who will probe the cells be­fore they die, which can take any­where from sev­eral hours to three days at the out­side. It’s an all-hands-on-deck sit­u­a­tion. Some of the staff will re­main at the cen­tre un­til one or two in the morn­ing, painstak­ingly se­lect­ing cells that look hardy, and pok­ing them with van­ish­ingly tiny glass pipettes to zap them with elec­tric­ity and record their re­sponse.

Thank­fully for the tech­ni­cians who per­form this work, hu­man cell sam­ples aren’t an ev­ery­day oc­cur­rence. The Allen In­sti­tute’s

part­ner­ships net them only about 40 a year, each of which is por­tioned for a half-dozen teams.

But even dur­ing the hu­man-sam­ple frenzy, the cell cen­sus is not the only am­bi­tious project un­der­way at the Allen In­sti­tute. On the first floor, a group known as the elec­tron mi­croscopy team is dis­as­sem­bling a cu­bic mil­lime­tre of mouse brain (the size of a grain of sand) into 25 thou­sand slices, tak­ing 250 mil­lion mi­cro­scopic pho­tographs of those slices, and then re­assem­bling the pho­tos into an in­ter­ac­tive Google Earth-style street view that will al­low re­searchers to trace a bil­lion con­nec­tions be­tween roughly 100 00 neu­rons.

Al­ready, the crew has com­pleted an early pro­to­type, and it is in­cred­i­ble, like the first map scrib­bled by a team of con­quis­ta­dors re­turn­ing from South Amer­ica. Click on one neu­ron and the soft­ware zooms in, show­ing you ev­ery­thing it is con­nected to and how. As­tro­cytes, it turns out, ac­tu­ally look more like sea sponges than pointed stars. Neu­rons called chan­de­lier cells con­nect axon to axon, which is weird. Pyra­mi­dal cells shoot one thick den­drite up to the brain’s sur­face, like a periscope. Look­ing at it, you can see a fu­ture

in which the cell cen­sus, com­bined with an in­ter­ac­tive map­ping tool such as this, could lead to the kinds of sci­ence-fic­tion tools cur­ing brain dis­eases will re­quire – cel­lu­lar surgery, remap­ping the cor­tex, even rewiring a dam­aged brain us­ing Götz’s as­tro­cyte-neu­rons.

The name of this sec­ond project is MI­CRONS, short for Ma­chine In­tel­li­gence from Cor­ti­cal Net­works, and, in ad­di­tion to Paul Allen’s gen­er­ous grant, it is sup­ported by $18.7 mil­lion from IARPA, the US in­tel­li­gence agen­cies’ high-risk, high-re­ward re­search pro­gramme. It is also work­ing with ma­chine-learn­ing re­searchers from Google. Cer­tainly, IARPA and Google find the med­i­cal ap­pli­ca­tions of MI­CRONS com­pelling, but their pri­mary in­ter­est is in re­verse en­gi­neer­ing the brain’s in­for­ma­tion-pro­cess­ing set-up to de­velop ever more pow­er­ful ma­chine-learn­ing al­go­rithms. These could, in turn, help the Allen In­sti­tute de­code more com­plex strate­gies the brain uses to process in­for­ma­tion, form­ing a feed­back loop of com­pu­ta­tional progress that either ends in an ex­haus­tive study of hu­man in­tel­li­gence and the end of brain dis­ease … or the rise of sen­tient death ma­chines.

The video-game de­sign­ers who want to im­prove stroke care B A LT I M O R E

IT IS IM­POS­SI­BLE to eat the darn fish. I rock my right hand for­ward and back­ward and the dol­phin on the screen, mim­ick­ing me by way of a hacked Xbox Kinect, half­heart­edly starts for­ward and then flops over on its back. I swing my fore­arm around in a cir­cle, which makes it swim away from me, but up­side down, in a way no real dol­phin would deign to move. Fi­nally, by un­du­lat­ing my shoul­der as though I’m play­ing an oc­to­pus in a modern-dance piece, I man­age to get the dol­phin to swim up to a fish, open his mouth, and chomp it. And this is as easy as this game gets.

‘ There are about 110 lev­els in here,’ says Promit Roy, the be­spec­ta­cled soft­ware ar­chi­tect who built this game from scratch on a pro­gram­ming en­gine he also built from scratch. ‘As you start to get up there, the fish get faster and smarter. And there are sharks.’ Sharks? ‘ They’re go­ing to start to at­tack you.’

Roy, who used to work for Mi­crosoft and Nvidia, and helped ship the game Frac­ture for Xbox 360 and Playsta­tion 3, is one of three found­ing mem­bers of the Kata De­sign Stu­dio at Johns Hop­kins Stroke Cen­ter in Bal­ti­more. Along with Omar Ah­mad, who has a PHD in com­puter sci­ence, and John Krakauer, di­rec­tor of the Brain, Learn­ing, An­i­ma­tion, and Move­ment Lab at the Johns Hop­kins Univer­sity School of Medicine, he has cre­ated one of the most ad­vanced ther­a­peu­tic video games in the world.

While the neu­ro­science com­mu­nity painstak­ingly re­searches treat­ments that may be able to phys­i­cally re­pair brain in­juries and neu­rode­gen­er­a­tive dis­eases, most of the cur­rent ther­apy en­cour­ages the brain to re­wire it­self af­ter it has been dam­aged, which can be re­mark­ably ef­fec­tive. But it takes time, and an enor­mous amount of ef­fort. Over­all, re­ha­bil­i­ta­tion is a dev­as­tat­ingly bor­ing af­fair. ‘ There is se­vere de­pres­sion across much of the pa­tient pop­u­la­tion. There’s the big ques­tion of: “Do you even want to do your ther­apy?” No one wants to do their ther­apy,’ says Roy. Many pa­tients regis­ter the par­tic­u­lars of their bi­o­log­i­cal catas­tro­phe – the alarm­ing

brain scans, the bleak re­cov­ery time­lines – and then men­tally check out.

Roy, Ah­mad, and Krakauer iden­ti­fied the main prob­lem as one of mo­ti­va­tion. If pa­tients be­lieved they were doomed to a life of ap­prox­i­ma­tions – of strug­gling to lift a cup to their face over and over again, which is what some pa­tients do in oc­cu­pa­tional ther­apy – why would they in­vest the ef­fort re­quired to re­cover to the best of their abil­ity? What stroke pa­tients needed was a trick – a ther­apy so en­ter­tain­ing that they would do it un­til they beat it, no mat­ter how hard it was, or how long it took.

‘ They’re told to eat the fish. That’s the only in­struc­tion they get,’ ex­plains Roy, demon­strat­ing the first round of the game the team even­tu­ally cre­ated. Called I Am Dol­phin, it al­lows the pa­tient to in­habit a sea crea­ture named Ban­dit, mov­ing and twist­ing the dam­aged side of her body (stroke is a dis­rup­tion of blood flow that of­ten af­fects just one side of the brain, caus­ing dif­fi­culty mov­ing the op­po­site side of the body) to make the dol­phin flip and glide. ‘I don’t know how a dol­phin moves if I’m com­ing into this. I don’t know what I’m sup­posed to do. So I have to fig­ure it out,’ says Roy. ‘I’m not think­ing about my dis­abil­ity. I’m not think­ing about the fact that I’m in a hospi­tal. It’s just: How do I eat these guys?’

Some­thing about re­learn­ing to move this way – by pre­tend­ing to be a car­toon that isn’t re­stricted to mov­ing in stan­dard, hu­man ways – is ex­tremely ef­fec­tive in help­ing stroke pa­tients re­cover. Kata’s pilot pa­tient, a man named David Steven­son, was paral­ysed in his left arm and leg by a stroke a few years ago at the age of just 47. Af­ter play­ing I Am Dol­phin us­ing an ad­di­tional grav­ity-as­sis­tance sys­tem, he left with move­ment qual­ity in his arm that was prac­ti­cally in­dis­tin­guish­able from that of a per­son who had never had a brain in­jury. Although the team is still analysing the data from their first fully en­rolled study, pre­lim­i­nary re­sults sug­gest that an in­tense reg­i­men us­ing the dol­phin game is sig­nif­i­cantly more ef­fec­tive than tra­di­tional meth­ods of ther­apy.

Jar­reau Wim­berly, an il­lus­tra­tor and graphic de­signer given to whim­si­cal ties and mis­matched prints, re­cently joined the Kata team af­ter 15 years of draw­ing il­lus­tra­tions for places such as Mar­vel, Has­bro, and Bl­iz­zard. Now, his il­lus­tra­tor’s touch­screen is cov­ered in mock-ups of Mad Max- style aquatic space are­nas, squids with ten­ta­cle fists, and a tiny gold­fish driv­ing a ro­bot great white. He adores his new gig – in­stead of toil­ing away at some task in a pri­vate-in­dus­try prod­uct pipe­line, he’s ac­tively de­sign­ing I Am Dol­phin 2.0, which is likely to in­clude a mul­ti­player aquatic soc­cer ex­trav­a­ganza that could al­low re­cov­er­ing stroke pa­tients to play with their friends and fam­ily when they come in on vis­its.

Imag­ine: the long-term hospi­tal slog trans­formed into a fam­ily game of Wii dol­phin. Vir­tual touch foot­ball with laser sharks. Stroke pa­tients be­liev­ing that – if they ap­ply ev­ery ounce of their en­ergy to a goal – there is still some­thing they can win. The in­crease in joy alone could ex­plain why the game has been so ef­fec­tive.

To­ward the end of the demon­stra­tion, Roy shows me an ad­vanced level of I Am Dol­phin, one that a pa­tient would reach only af­ter weeks of ded­i­cated prac­tice. Waves of an­gry fish and

sharks swarm Ban­dit to the sounds of heavy drums. To es­cape them, the dol­phin can at­tack, he can swim away, or, as one pa­tient fig­ured out, he can flip out of the wa­ter into the night sky, soar­ing end over end in the moon­light. The stage is berserk, high-fly­ing, as tough as a video game a healthy teenager might fail and curse at.

‘I hon­estly don’t know if I can beat this,’ says the man who built this game from noth­ing. ‘But pa­tients can.’

The bio­physi­cist who wants to un­ravel a prob­lem pro­tein NEW YORK CITY

BE­FORE AN­THONY FITZ­PATRICK en­ters this story with his su­per­mi­cro­scope, it is first im­por­tant to know a strange fact about neu­rode­gen­er­a­tive dis­eases. Most of them – in­clud­ing PSP, Parkin­son’s, Hunt­ing­ton’s, Alzheimer’s, Pick’s dis­ease, fron­totem­po­ral de­men­tia, amy­otrophic lat­eral scle­ro­sis (ALS), and chronic trau­matic en­cephalopa­thy (CTE, the post-con­cus­sive disor­der that strikes NFL play­ers and box­ers), among oth­ers – in­volve pro­teins in the brain fold­ing them­selves into clumps.

No one knows why this hap­pens, or how it gets started, or even whether the pro­teins cause the dis­eases or are a side ef­fect of some­thing else that does, but the phe­nom­e­non shows up of­ten enough that it clearly means some­thing. In Parkin­son’s dis­ease, a pro­tein called al­pha-synu­clein origamis it­self into a mess. In other dis­eases, it’s a pro­tein called amy­loid-beta, or one called tau. Re­gard­less of the pro­tein’s name and nor­mal func­tion, the out­come is the same: a brain rid­dled with tan­gles of use­less pro­teins.

In con­trast to many other neu­rode­gen­er­a­tive dis­eases, Alzheimer’s dis­ease shows up in the brain as two mis­folded pro­teins, which makes it one of the more com­pli­cated dis­eases to fight, at least on a molec­u­lar level. If you’ve heard doc­tors talk about ‘plaques and tan­gles’ in ref­er­ence to Alzheimer’s dis­ease, this

is what they mean: The plaques are made of a mis­folded pro­tein called amy­loid-beta. The tan­gles are tau.

In the early 1990s, drug mak­ers seized on amy­loid-beta as the main tar­get for Alzheimer’s drugs, be­cause it could cause prob­lems if it started fold­ing it­self all screwy else­where in the body (in the heart, for ex­am­ple), and be­cause genes that coded for amy­loid-beta were mu­tated in pa­tients who had fam­ily his­to­ries of Alzheimer’s. Amy­loid-beta also ap­pears to start de­gen­er­at­ing be­fore tau, which made drug de­vel­op­ers think that if you stopped it, you could halt the dis­ease en­tirely.

For the next 25 years, phar­ma­ceu­ti­cal com­pa­nies tar­geted mis­folded amy­loid-beta with more than 200 drugs. Nearly all failed. So many amy­loid-beta drugs failed, in fact, that most of Big Pharma has quit de­vel­op­ing drugs for Alzheimer’s dis­ease al­to­gether, ced­ing the mar­ket to smaller, nim­bler start-ups, such as De­nali and Aquin­nah, with newer ideas. In Jan­uary, Pfizer pulled its en­tire neu­ro­science di­vi­sion, set­ting aside $150 mil­lion in­stead to fund start-ups. ‘I don’t think it means that these com­pa­nies are go­ing to stay out for­ever,’ says Cara Al­timus, as­so­ciate di­rec­tor at the Milken In­sti­tute’s Cen­ter for Strate­gic Phi­lan­thropy. ‘It’s that they don’t see a path­way to­day to run a drug through the Food and Drug Ad­min­is­tra­tion.’ (At press time, an amy­loid-based drug from Bio­gen and Ja­pan­based com­pany Ei­sai called BAN2401 had man­aged to sig­nif­i­cantly re­duce amy­loid lev­els and slow cog­ni­tive de­cline by 30 per cent in a Phase 2 trial.)

So now: An­thony Fitz­patrick. An English bio­physi­cist at Columbia Univer­sity’s new in­ter­dis­ci­pli­nary Zuck­er­man In­sti­tute in New York City who has the ideal back­ground to sort out the ques­tion of pro­tein mis­fold­ing. He works with an elec­tron mi­cro­scope, which is the ma­chine that makes those pic­tures of bac­te­ria blown up as big as cheese curls from high-school text­books. In short, he freezes mis­folded pro­teins, takes pic­tures of them from mul­ti­ple an­gles, then uses com­put­ers and his own for­mi­da­ble knowl­edge of chem­istry to fig­ure out ex­actly how they’re folded, and why, and how they could be tar­geted with drugs. Re­cently, Fitz­patrick achieved a huge coup for Alzheimer’s dis­ease re­search: He be­came the first per­son to freeze a pro­tein that came di­rectly from the brain of a woman who died from the disor­der and map its struc­ture. Only he didn’t start with amy­loid-beta. He started with tau.

Fitz­patrick flips his com­puter around to show me his work, the mul­ti­coloured loops and squig­gles form­ing a shape like the sym­bol for Pisces. When tau folds cor­rectly, it joins other tau pro­teins to sup­port the long hol­low cylin­ders that func­tion as skele­tons for the ax­ons of neu­rons. When it doesn’t, it makes a mess like this, and is fright­en­ingly adept at con­vinc­ing other tau pro­teins to join it.

Here’s the in­ter­est­ing thing about tau: The lat­est re­search shows that the spread of mis­folded tau, not amy­loid-beta, more closely cor­re­lates with cog­ni­tive deficits in Alzheimer’s dis­ease. Maybe amy­loid-beta gets the process go­ing, goes the most re­cent the­ory, but it’s tau that goes around mur­der­ing neu­rons. Tau is cer­tainly ca­pa­ble of do­ing it all by it­self in other dis­or­ders. PSP, the dis­ease Al Gard­ner has, is as­so­ci­ated with the build-up of tau in the brain stem, frontal lobes, and basal gan­glia. It’s con­sid­ered a ‘pure tauopa­thy,’ and stands out as one of the first Fitz­patrick be­lieves his re­search could cure.

The ques­tion he would most like to an­swer is whether tau is the same pro­tein in all the dis­eases where it ap­pears, be­cause it might not be. ‘You have six dif­fer­ent forms of the tau mol­e­cule that are slightly dif­fer­ent length and slightly dif­fer­ent be­hav­iour,’ he says. There are at least nine dif­fer­ent tauopathies. Some com­bi­na­tion of tau type and the type of cell it ac­cu­mu­lates in could ex­plain why the var­i­ous neu­rode­gen­er­a­tive dis­eases have dif­fer­ent symp­toms. Al­ready, the tau Fitz­patrick iso­lated from the Alzheimer’s brain was folded dif­fer­ently than tau that has been stud­ied in labs be­fore. Is the dif­fer­ence be­tween Alzheimer’s dis­ease, PSP, and CTE as sim­ple as which type of tau goes bad? If you un­lock one dis­ease, can you get all of them?

The only way to find out is for some­one like Fitz­patrick to map mis­folded tau from brains of peo­ple who’ve suc­cumbed to var­i­ous

The en­gi­neer who wants to build bet­ter brain-in­ter­face de­vices CAM­BRIDGE, MAS­SACHUSETTS

ONE REA­SON IT’S SO DIF­FI­CULT to re­port a story such as this is that, with tens of thou­sands of neu­ro­sci­en­tists all spe­cial­is­ing in their own mi­crofields and try­ing to make a dif­fer­ence as if their very own lives de­pended on it, the cor­nu­copia of po­ten­tially promis­ing treat­ments is bound­less. By the time neu­ro­sci­en­tists fig­ure out how the brain works, and why it goes wrong, and how to fix it when it is in­jured or dis­eased, they’ll have their choice of meth­ods for de­liv­er­ing so­lu­tions. One of those meth­ods will be the fi­bres Polina Ani­keeva has made.

She’s 1.6 m tall and com­pact as a gazelle. Ani­keeva is a marathon run­ner, a rock climber, and one heck of a sci­en­tist. She was born to a pair of me­chan­i­cal en­gi­neers in the for­mer Soviet Union, where she so ex­celled at aca­demics that she was moved to an elite high school, then ma­jored in physics in col­lege. Af­ter stints at Cold Spring Har­bor Lab­o­ra­tory, the Swiss Fed­eral In­sti­tute of Tech­nol­ogy in Zurich, Switzer­land, and Los Alamos Na­tional Lab­o­ra­tory, she got a PHD (at MIT) in a field called op­to­elec­tron­ics, where she worked on a light-emit­ting nano­ma­te­rial tech­nol­ogy called quan­tum dots that was li­censed to a start-up that was later bought by Sam­sung. Also: She has a habit of bar­rel­ing down the halls like a tiny cruise mis­sile, flut­ter­ing the fly­ers on the bul­letin boards. You al­most want to flat­ten your­self against the wall.

Un­sur­pris­ingly, af­ter five and a half years of study­ing nanoop­to­elec­tron­ics, light-emit­ting quan­tum dots started to bore Ani­keeva. Im­prove­ments in the field came slowly and in­cre­men­tally, while she wanted to in­vent fan­tas­ti­cal things that didn’t ex­ist. There were few sci­en­tific ar­eas where that was a pos­si­bil­ity any­more. Neu­ro­science, though, was a field in its tod­dler­hood, where it was still pos­si­ble for a sci­en­tist to do big, ex­cit­ing work. So Ani­keeva se­cured a two-year post­doc in a neu­ro­science lab at Stan­ford. She started to think about open­ing her own lab.

And then: On a climb in Cal­i­for­nia, one of Ani­keeva’s friends fell 16 me­tres and sev­ered her lower spinal cord. She was left with min­i­mal nerve func­tion on one side of her body. The doc­tors had to bolt a cou­ple of her ver­te­brae to­gether with gi­ant ti­ta­nium screws.

‘ They weren’t even do­ing any kind of func­tional stim­u­la­tion or try­ing to re­con­nect any of the nerves,’ Ani­keeva says of her friend’s treat­ment. Ther­apy went the same way it al­ways does: phys­i­cal re­hab, oc­cu­pa­tional re­hab, sit and watch and wait. It seemed to Ani­keeva, who had spent years per­fect­ing semi­con­duct­ing nanocrys­tals that were be­ing used in tele­vi­sion dis­plays, as though we should be able to do bet­ter for some­one who was fight­ing to walk again.

Af­ter Ani­keeva saw a brain-stim­u­la­tion de­vice, which she found bar­baric, she knew how she could help. Brain stim­u­la­tion, which has been used as a ther­apy for pain and mo­tor dis­or­ders since the 1970s, has vastly im­proved over the last few decades, most no­tably with the ad­di­tion of feed­back mech­a­nisms that train the sys­tems al­go­rith­mi­cally. But the in­ter­face is still aw­ful: With ev­ery heart­beat, the brain, which has the con­sis­tency of pud­ding, moves in the skull. Stick­ing a metal wire into it is ba­si­cally like con­tin­u­ously scrap­ing it with a knife.

And so Ani­keeva be­came de­ter­mined to de­sign flex­i­ble fi­bres that could in­ter­face with the ner­vous sys­tem with­out dam­ag­ing it, trans­mit­ting sig­nals to re­con­nect nerves or stim­u­late neu­rons. Her lat­est piece of equip­ment in­cludes a con­duc­tive wire that can send elec­tric­ity; a tiny tube that can move liq­uid drugs or chem­i­cals; and a re­flec­tive duct that can trans­mit light, the ba­sis of a new field called op­to­ge­net­ics, which in­volves ge­net­i­cally al­ter­ing groups of neu­rons so that they can be turned on and off us­ing pho­tons.

Cre­at­ing a minia­ture pipe­line out of a ma­te­rial that has all of these prop­er­ties is in­cred­i­bly dif­fi­cult. So Ani­keeva and her team built bi­o­log­i­cal tele­com ca­bles, bun­dles of sep­a­rate chan­nels (for light, fluid, and elec­tric­ity) sur­rounded by a clear com­pos­ite. They also built them huge – plas­tic pa­per­weights the size of a fist with the chan­nels glit­ter­ing in the mid­dle. To turn these into ca­bles, she heats up the pa­per­weight (called a pre­form), at­taches a weight to it, and draws it out like Play-doh pasta un­til it gets thin enough. ‘ The whole thing will be­come the size of your hair,’ she says. ‘But in­side they will have the same cross sec­tion.’ She has even de­vised a wa­ter-sol­u­ble coat­ing that will tem­po­rar­ily stiffen the fi­bres so that they can be im­planted into the cor­rect lo­ca­tion.

In the fu­ture, Ani­keeva’s fi­bres could be­come a plat­form for de­vices that pro­vide hy­per-spe­cific brain ther­a­pies. Al­ready, Ani­keeva’s col­leagues at the Univer­sity of Wash­ing­ton are test­ing them on mouse mod­els of spinal-cord in­jury. Fi­bres such as Ani­keeva’s could even con­nect com­pu­ta­tional in­ter­faces that would be the brain’s ver­sion of the ar­ti­fi­cial heart valve – for ex­am­ple, a fake set of basal gan­glia that could op­er­ate a Parkin­son’s pa­tient’s body for her. ‘From a tech­ni­cal per­spec­tive, I could make this avail­able right now,’ she says. But much more re­mains to be done: due dili­gence on safety, the im­prove­ment of al­go­rithms that can ap­prox­i­mate neu­ral ac­tiv­ity,

and, in many cases, know­ing what needs to be fixed in the first place. Even think­ing op­ti­misti­cally, Ani­keeva says, it will be at the very least a decade be­fore the fi­bres she de­vises can help pa­tients.

Ani­keeva usu­ally has a box of sam­ples on her desk to show to vis­i­tors, but to­day it is in front of Con­gress to con­vince law­mak­ers of the ben­e­fits of gov­ern­ment fund­ing for sci­ence. What re­main are the pre­forms that failed, about ten twisted hunks of plas­tic that are too fat, too short, un­even or bro­ken, and had to be stopped in the mid­dle of spool­ing. They nar­row as they rise into wispy tails, like pointy smoke­stacks.

Ani­keeva’s climb­ing friend made a mirac­u­lous re­cov­ery, by the way. She came to Ani­keeva’s lab three years af­ter her in­jury – on

foot – to give an in­spi­ra­tional talk to the staff.

The doc­tors who want to help sol­diers re­turn­ing from the Mid­dle East BETHESDA, MARY­LAND

PAST THE WELL–DE­FENDED GATES of Wal­ter Reed Na­tional Mil­i­tary Med­i­cal Cen­ter in Bethesda, Mary­land, the Na­tional In­trepid Cen­ter of Ex­cel­lence (NICOE) rises up, peace­ful and mono­lithic, out of a broad, steam­ing lawn, like a neo­clas­si­cal artists’ colony. In a way, that’s what it is. NICOE, paid for by do­na­tions to the In­trepid Fallen He­roes Fund, was first de­signed to of­fer a sooth­ing respite to the peo­ple who visit. The en­tire staff whis­pers as they walk through the cor­ri­dors.

‘Eighty-some per­cent of the peo­ple in­jured in the over­seas con­flicts in the last 15 years have been in­jured through ex­plo­sive de­vices,’ says Louis French, NICOE’S deputy di­rec­tor for op­er­a­tions, at a ta­ble in his of­fice. ‘ The sad re­al­ity is, if you’re close to some­thing that blows up, you can quite lit­er­ally get hurt head to toe.’

It’s the head, in par­tic­u­lar, that’s the prob­lem. Trau­matic brain in­jury has been called the sig­na­ture ca­su­alty of the wars in Iraq and Afghanistan: When a ser­vice mem­ber is struck by an im­pro­vised ex­plo­sive de­vice, the blast can twist or stretch the ax­ons that neu­rons use to send in­for­ma­tion to each other in ways that aren’t nec­es­sar­ily vis­i­ble on an MRI. Many sol­diers ex­pe­ri­ence in­ex­pli­ca­ble neu­ro­log­i­cal or psy­chi­atric prob­lems that con­tinue when they re­turn home.

A con­gres­sional man­date in 2007 in­sisted that these peo­ple de­served a place that would re­search their con­di­tions and

pro­vide ad­di­tional treat­ment as and when nec­es­sary. That place is NICOE.

French, along with his col­league, neu­rol­o­gist and chief in­no­va­tions of­fi­cer Thomas De­graba, both wear Amer­i­can flag pins on their lapels. They are very proud of what NICOE is able to pro­vide to ser­vice mem­bers – a holis­tic re­cov­ery pro­gramme that ex­tends to the pa­tient’s im­me­di­ate fam­ily. But they are also both very hon­est about what is cur­rently pos­si­ble in the realm of brain in­juries. ‘We treat symp­toms right now,’ says French, his voice car­ry­ing all the heav­i­ness that state­ment sug­gests.

Even though neu­rons them­selves do not spon­ta­neously re­gen­er­ate, train­ing the brain to com­pen­sate for deficits works, as the Kata team at Johns Hop­kins has proved. Down the road in Bethesda, NICOE is do­ing some­thing sim­i­lar: In its sig­na­ture treat­ment, a four-week out­pa­tient pro­gramme, pa­tients have an ini­tial as­sess­ment, then a cur­ricu­lum of ther­apy so in­tense it ri­vals a camp sched­ule. There are neu­ro­feed­back ex­perts, phys­i­cal ther­a­pists, neu­rol­o­gists, psy­chi­a­trists, art and mu­sic ther­apy, acupunc­ture. There’s an im­mer­sive 3D tread­mill en­vi­ron­ment the size of a swim­ming pool that can re­train mo­tion sen­si­tiv­ity and vis­ual in­te­gra­tion. Over­all, 71 per cent of pa­tients who go through the pro­gramme re­port an im­prove­ment in their qual­ity of life, and that’s among the sub­set of pa­tients who end up at Wal­ter Reed, which gen­er­ally in­cludes the most chal­leng­ing cases.

Still, De­graba says, if he could have one tool that would make his job eas­ier, it would be a way to re­veal ex­actly which cir­cuits have been scram­bled by ex­plo­sive de­vices in each pa­tient. Most times, peo­ple come to NICOE with some sub­tly warped be­hav­iour that could be caused by sev­eral dif­fer­ent phys­i­cal prob­lems. Is it psy­cho­log­i­cal? Is it neu­ro­log­i­cal? Is it dam­age to the vis­ual or au­di­tory sys­tem? How do you re­pair an or­gan when you can’t see what’s wrong with it?

MEG, which is short for mag­ne­toen­cephalo­graph, is the clos­est thing De­graba has to his dream ma­chine. It looks like a cross be­tween a Pixar ro­bot and a beauty-sa­lon hairdryer, hulk­ing shyly be­hind a 28 cm-thick mag­net­i­cally shielded door. One of just nine such ma­chines in clin­i­cal use in the United States, it works by mea­sur­ing the mi­cro­scopic mag­netic fields that are cre­ated as elec­tri­cal im­pulses travel down ax­ons. The MEG does this in real, mil­lisec­ond, think­ing-speed time, us­ing sen­sors su­per­cooled by liq­uid he­lium. De­graba is un­der­stand­ably proud of it.

‘It’s a game changer for neu­rol­o­gists,’ he says. ‘Up un­til this point, all we had to look at brain-wave ac­tiv­ity in a non-in­va­sive way was to put elec­trodes on peo­ple’s scalps.’ MEG, in con­trast, can map the whole brain’s ac­tiv­ity, show­ing how ar­eas as­so­ci­ated with emo­tion, lan­guage, vi­sion and move­ment com­mu­ni­cate with each other in real time as pa­tients per­form tasks.

In his of­fice, De­graba pulls up a set of slides to show me what this means for pa­tients. A few years ago, a sol­dier came back from the Mid­dle East with a trau­matic brain in­jury from a mor­tar blast that left him un­able to per­form his du­ties. The prob­lem, in par­tic­u­lar, was mak­ing de­ci­sions based on writ­ten com­mu­ni­ca­tions. It sure looked like an ex­ec­u­tive func­tion­ing is­sue, which could re­sult from dam­age to the front of the brain.

De­graba hits play on the slide, and waves of ac­tiv­ity sweep across the side of the man’s brain. Com­pared to a nor­mal ex­am­ple, it’s as clear as day – a de­lay and de­crease in sig­nal be­tween two ar­eas known to af­fect the vis­ual pro­cess­ing of words. As it turned out, the man didn’t have a prob­lem with ex­ec­u­tive func­tion at all. His in­jury had dis­rupted his brain’s pro­cess­ing of let­ters. He couldn’t read quickly enough to make de­ci­sions. The sol­dier was as­signed to an in­cre­men­tal pro­gramme that would help him re­learn, start­ing with just min­utes a day. Within

a few months, the man got bet­ter.

De­graba had done the im­pos­si­ble: He had looked in­side a liv­ing per­son’s brain and seen where and how its ex­ceed­ingly in­tri­cate cir­cuitry was misfiring.

And then he had fixed it.

The fu­ture

HOLD­ING A HU­MAN BRAIN is not like hold­ing any other body part. Any­one who has spent time in a bi­ol­ogy lab un­der­stands the re­spon­si­bil­ity of work­ing on a formerly liv­ing be­ing. But the brain is dif­fer­ent. It’s more. Hold­ing a brain is the clos­est you can get to hold­ing a per­son’s soul. If you’re the kind of per­son in­clined to such feel­ings, you can al­most feel the ad­di­tional weight of ev­ery­thing you’re re­spon­si­ble for when you pick it up – the mem­o­ries and soc­cer skills and boat­ing tal­ent and love af­fairs. Peo­ple used to think that the soul resided in the heart, but when you pick up a brain, you are hold­ing a per­son. It is im­pos­si­ble not to no­tice.

There is no way of know­ing how much longer Al Gard­ner has left, but he has al­ready made it clear where his brain will go when he dies. He wants it to go to re­search. Ideally the Mayo Clinic, which main­tains a bank of brains rav­aged by neu­rode­gen­er­a­tive dis­eases down in Jack­sonville, Florida. But if that won’t work out, cost-wise, a lab closer to home would be fine. Al made this wish clear to Fran a long time ago, when they were still talk­ing wishes. PSP, this strange, rare ill­ness, could be the door to a dozen brain dis­eases. Al wants his brain to have a shot at be­ing the key.

For now, Fran can still take Al to doc­tor’s ap­point­ments at North­ern Westch­ester Hospi­tal. She can bring him to his box­ing class at the lo­cal gym. But when there’s noth­ing else left to do for him, when she can’t shred his chicken so he can swal­low it or put on his sun­glasses to go up­stairs, she’ll be able to help him give the phys­i­cal em­bod­i­ment of his soul to re­search. One day, she hopes, no one else will have to try so hard to re­main op­ti­mistic, be­cause the doc­tors and neu­ro­sci­en­tists and en­gi­neers and phi­lan­thropists will have found some­thing bet­ter: a cure.

44

Nick Dee and Her­man Tung, two other mem­bers of the Allen In­sti­tute’s tis­sue­pro­cess­ing team, use a vi­bratome to slice the hu­man brain sam­ple.

Re­searchers at the Allen In­sti­tute in Seat­tle are us­ing pre­cious sam­ples of hu­man brain tis­sue, such as these taken from the cere­bral cor­tex, to cre­ate a kind of pe­ri­odic ta­ble of all the cells in the brain.

I Am Dol­phin, a video game de­vel­oped at Johns Hop­kins Univer­sity School of Medicine, re­trains stroke pa­tients to move their arms. The ma­chine above helps coun­ter­act grav­ity’s ef­fect.

Jar­reau Wim­berly de­signs video games that can re­train stroke vic­tims to move their limbs. He wants to make the games as en­ter­tain­ing as pos­si­ble.

MIT ma­te­ri­als sci­en­tist Polina Ani­keeva next to the 4 m tower that draws her pre­forms into ca­bles that could in­ter­face with the brain.

At Wal­ter Reed, hospi­tal corps­man Luke E Wi­ele­chowski demon­strates the MEG, a ma­chine that can track how dif­fer­ent parts of the brain com­mu­ni­cate in real time as a pa­tient per­forms tasks.

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