The A To Z Of You

OUR BOD­IES CON­TAIN SOME 30 TRIL­LION CELLS, AND A NEW PROJECT AIMS TO MAP THE MOLEC­U­LAR SIG­NA­TURE OF EV­ERY SIN­GLE ONE

BBC Earth (Asia) - - Contents - Kat Arney is a sci­ence writer and broad­caster. Her lat­est book, How To Code A Hu­man, is out now

A new project aims to map the molec­u­lar sig­na­ture of ev­ery sin­gle one of our bod­ies’ 30 tril­lion cells

Map­ping the hu­man body is one of bi­ol­ogy’s old­est en­deav­ours. By study­ing the bat­tered bod­ies of Ro­man glad­i­a­tors, the 2nd-Cen­tury philoso­pher-sur­geon Galen of Perg­a­mon wrote med­i­cal texts that stood as the pin­na­cle of anatom­i­cal knowl­edge for more than 1,000 years, un­til the Flem­ish doc­tor An­dreas Ve­sal­ius came up with more ac­cu­rate works. But it wasn’t un­til the in­ven­tion of the first prac­ti­cal mi­cro­scope in the mid-1600s, a cen­tury after Ve­sal­ius’s death, that cu­ri­ous sci­en­tists could fi­nally be­gin to study cells – the build­ing blocks that make up our tis­sues and or­gans.

Just as study­ing the tini­est subatomic par­ti­cles has helped physi­cists to un­ravel the work­ings of the cos­mos, so bi­ol­o­gists have found that zoom­ing in on our in­di­vid­ual cells can re­veal new in­sights into the hu­man body. For a long time, this has been the do­main of pathol­o­gists, study­ing the phys­i­cal ap­pear­ance of cells and tis­sues, along with a rel­a­tively lim­ited num­ber of molec­u­lar mark­ers. But, backed by the ex­cit­ing new sci­ence of sin­gle-cell ge­nomics, a project called the Hu­man Cell At­las is aim­ing to cre­ate the ul­ti­mate in­ven­tory of the hu­man body, map­ping ev­ery sin­gle one of our cells in in­tri­cate de­tail. And the re­sult­ing guide­book could rev­o­lu­tionise our un­der­stand­ing of health and dis­ease.

CEL­LU­LAR SCI­ENCE

It’s long been clear that cells in dif­fer­ent or­gans look and be­have in their own dis­tinc­tive ways. For ex­am­ple, spher­i­cal im­mune cells are primed to recog­nise in­fec­tions, while spi­dery nerve cells crackle with hun­dreds of con­nec­tions. Nev­er­the­less, each cell still has the same ba­sic set of in­struc­tions in the form of the hu­man genome, en­coded within our DNA. The thing that makes each cell type dif­fer­ent is the par­tic­u­lar set of genes ac­tive within it, pro­duc­ing molec­u­lar mes­sages called RNA. And be­cause a par­tic­u­lar pat­tern of gene ac­tiv­ity will be unique to a spe­cific cell type, the RNA made within it will be unique too, act­ing as a kind of molec­u­lar ‘fin­ger­print’.

For sev­eral decades, re­searchers have been able to mea­sure the ac­tiv­ity of genes in dif­fer­ent cell types (known as gene ex­pres­sion) by mash­ing up mil­lions of cells and analysing the dif­fer­ent RNAs, get­ting a read-out of which genes are switched on and which are off.

Yet this is only an av­er­age, and this method can’t pick up dif­fer­ences be­tween in­di­vid­ual cells. It’s like look­ing at a crowd from a dis­tance and only see­ing a colour­ful blur, rather than the ex­act hue of each per­son’s shirt. But thanks to re­cent ad­vances in tech­nol­ogy, we can now zoom right in to look at gene ac­tiv­ity in a sin­gle cell (see di­a­gram, be­low).

A typ­i­cal hu­man body con­tains around 30 tril­lion cells, but while it is of­ten said that there are around 200 dif­fer­ent types, more de­tailed molec­u­lar anal­y­sis has re­vealed that this is a mas­sive un­der­es­ti­mate. Is ev­ery cell in the liver ex­actly the same, or have we only been mea­sur­ing av­er­ages? What about the bil­lions of neu­rons in the brain, or the mul­ti­tude of dis­tinct im­mune cells? Th­ese ques­tions pro­vided the spark for the Hu­man Cell At­las, which aims to map gene ex­pres­sion pat­terns in bil­lions of in­di­vid­ual cells.

THE JOUR­NEY BEGINS

The idea flick­ered into life in 2012 when ge­neti­cist Dr Sarah Te­ich­mann came to the Well­come Trust Sanger In­sti­tute near Cam­bridge to set up a re­search group study­ing gene ac­tiv­ity in sin­gle cells in the mouse im­mune sys­tem. Over cof­fee and con­ver­sa­tion with her new col­leagues, she re­alised that her tech­niques might solve a much big­ger chal­lenge.

“De­spite cen­turies of mi­croscopy, we don’t ac­tu­ally fully un­der­stand the dif­fer­ent cell types in the body,” she says. “When I came to the Sanger In­sti­tute we started bounc­ing ideas around. It was a bit utopian be­cause the tech­nol­ogy just wasn’t there yet, but we thought what if some­day it would be pos­si­ble to atom­ise a hu­man body – take a hu­man and look at all their cells. Of course, you’re not va­por­is­ing a whole per­son, but we thought we could take tiny sam­ples from many dif­fer­ent peo­ple and stitch it all to­gether into a kind of univer­sal at­las.”

With tril­lions of cells to an­a­lyse, this isn’t the kind of task that a sin­gle lab­o­ra­tory, or even a sin­gle in­sti­tute, can han­dle alone. Te­ich­mann and her col­leagues soon re­alised that a num­ber of other re­searchers were start­ing to have the same thoughts as them – no­tably Dr Aviv Regev at the Broad In­sti­tute in Mas­sachusetts – and be­gan to build an in­ter­na­tional con­sor­tium of sin­gle-cell en­thu­si­asts rang­ing from ge­neti­cists and molec­u­lar bi­ol­o­gists to sur­geons and ma­chine learn­ing spe­cial­ists. So far, the team has com­mit­ted to study­ing four types of tis­sue: the brain, the im­mune sys­tem, ep­ithe­lial tis­sue (which lines the sur­faces of or­gans and blood ves­sels), and foetal and pla­cen­tal cells. As well as cat­a­logu­ing the cells of healthy peo­ple, a key part of the project will be to un­der­stand

how cells change their ac­tiv­ity when we get sick, so can­cer cells are on the ini­tial list, too.

RO­BOT RE­SEARCHERS

The scale of the Hu­man Cell At­las and the ac­cu­racy re­quired means that this is no longer the kind of work that can be done by hand. To find out more about the tech­nol­ogy in­volved, I vis­ited Dr Stephan Lorenz. He heads up the sin­gle-cell ge­nomics fa­cil­ity at the Sanger In­sti­tute, where a sig­nif­i­cant pro­por­tion of the work for the Hu­man Cell At­las will be car­ried out.

He shows me around sev­eral large rooms full of huge cab­i­nets con­tain­ing an army of high-tech, liq­uid-han­dling robots for pre­par­ing and pro­cess­ing sin­gle-cell sam­ples, su­per­vised by just two hu­man staff. One im­pres­sive ma­chine isn’t so much a sonic screw­driver as a sonic sam­pler, us­ing sound pulses to whack pre­cisely-mea­sured mi­cro­scopic drops of liq­uid from one plas­tic plate to another. Another can process more than 1,200 sam­ples in 90 min­utes.

“Over the last cou­ple of years there’s been an ex­plo­sion of meth­ods that al­low us to mea­sure th­ese tiny quan­ti­ties of RNA that are present in a sin­gle cell,” he says. “We can now un­der­stand how

“WE CAN NOW UN­DER­STAND HOW CELLS ‘THINK AND FEEL’ AND SEE INSIDE THE ‘MIND’ OF A CELL”

cells ‘think and feel’ and see inside the ‘mind’ of a sin­gle cell. By look­ing at the mes­sages in cells we can in­fer their func­tion and even their iden­tity.” What’s more, he ex­plains, he can even see how in­di­vid­ual cells in the im­mune sys­tem change when they are ac­ti­vated to fight in­fec­tion, or watch the genes that are switched on and off as one cell splits into two.

Yet RNA mes­sages aren’t the only thing that gives a cell its iden­tity. RNA car­ries in­struc­tions to make pro­teins, which build phys­i­cal struc­tures inside cells and carry out bi­o­log­i­cal func­tions in the body (for ex­am­ple, di­ges­tive en­zymes in the stom­ach or sturdy ker­atin pro­teins that make up our skin and hair). Lorenz and his col­leagues are now de­vel­op­ing meth­ods to an­a­lyse all the pro­teins inside a sin­gle cell.

It cur­rently takes about three weeks to an­a­lyse all the RNA in an in­di­vid­ual cell, though the process is speed­ing up all the time. Per­haps an even big­ger chal­lenge than analysing all of the cells is cop­ing with the quan­tity of data gen­er­ated. Around 850,000 mes­sages are se­quenced per cell. Mul­ti­ply that by mil­lions of cells, and it quickly adds up.

To help with this, the Hu­man Cell At­las con­sor­tium se­cured fund­ing from the Chan Zucker­berg Ini­tia­tive (set up by Face­book founder Mark Zucker­berg and his wife Priscilla Chan) to de­velop ways to process and present the tor­rent of in­for­ma­tion com­ing from the se­quenc­ing labs.

Mak­ing the At­las search­able and us­able is vi­tal if it is to be­come a mean­ing­ful re­source for sci­en­tists. Although Te­ich­mann doesn’t yet know how the data will be pre­sented, she does have one fun idea. “The re­ally fu­tur­is­tic vi­sion is that we will all be wear­ing vir­tual re­al­ity head­sets and be able to look at a vir­tual body to point out parts that we want to see,” she says.

MAP­PING THE FU­TURE

It’s still early days for this in­cred­i­bly am­bi­tious project, which of­fi­cially kicked off in Oc­to­ber 2016, but Te­ich­mann thinks it’s fea­si­ble. “I would say for a draft At­las we need to an­a­lyse be­tween ap­prox­i­mately 30 mil­lion and 1 bil­lion cells,” she ex­plains. “Over the last eight years, there has been an ex­po­nen­tial decrease in cost per cell and an ex­po­nen­tial in­crease in the num­ber of cells per ex­per­i­ment. If that trend con­tin­ues then we are in good shape.”

As well as satisfying our sci­en­tific cu­rios­ity about what we’re all made of, Te­ich­mann sees the At­las as a source of huge po­ten­tial ben­e­fits for bio­med­i­cal re­search, re­veal­ing leads for new drugs or find­ing mol­e­cules that act as biomark­ers for di­ag­nos­ing and mon­i­tor­ing dis­ease. At a deeper level, she hopes it will an­swer fun­da­men­tal ques­tions about the links be­tween genes and health. As an ex­am­ple, she men­tions the harm­ful change (mu­ta­tion) in a gene called CFTR that causes cys­tic fi­bro­sis, which af­fects the lungs and other or­gans.

“We know that CFTR is ac­tive in the lungs, but in fact is ex­pressed in other parts of the body, too. So you could in­ter­ro­gate the Hu­man Cell At­las and find those cells, to un­der­stand why things are go­ing wrong when it’s mu­tated,” she ex­plains. “Or say you want to know the side ef­fects of a drug that tar­gets the prod­uct of a par­tic­u­lar gene. You could search the At­las to see where that gene is ex­pressed – which or­gans, tis­sues and cells – and then pre­dict what the an­tic­i­pated side ef­fects might be.”

Un­der­stand­ing ex­actly what has gone wrong in a wide range of dis­eases, quickly iden­ti­fy­ing which cells and which mol­e­cules are mis­be­hav­ing, will help doc­tors to di­ag­nose con­di­tions faster and se­lect the most ap­pro­pri­ate treat­ment with less of the guess­work that goes on at the mo­ment.

Ul­ti­mately, Te­ich­mann and her team see the Hu­man Cell At­las as a fun­da­men­tal re­source that will one day have an im­pact on al­most ev­ery as­pect of bi­ol­ogy and medicine. Per­haps we could even call it Hu­man Genome 2.0.

“I like that!” she laughs. “The Hu­man Genome Project was all about de­ci­pher­ing the DNA se­quence, but the Hu­man Cell At­las is ask­ing what does that se­quence ac­tu­ally stand for? How is the ge­netic code read out to make a hu­man body? It re­ally is mind-blow­ing!”

Air­borne Event is a piece of art cre­ated by Fred To­maselli in 2003

A lab­o­ra­tory at the Sanger In­sti­tute, where a lot of the Hu­man Cell At­las re­search will be car­ried out

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