Bring­ing back the Ne­an­derthal

Sci­en­tists are grow­ing ‘mini-brains’ con­tain­ing Ne­an­derthal genes. Could they re­veal what made mod­ern hu­mans such a suc­cess­ful species?

Focus-Science and Technology - - CONTENTS - WORDS: JV CHAMARY

How putting our an­ces­tors’ brains in ro­bots will re­veal the ori­gins of our in­tel­li­gence.

Hu­mans are the only liv­ing species of ho­minin, a tribe of great apes that also in­cludes our shorter, stock­ier, stronger – and ex­tinct – cousins, the Ne­an­derthals. Th­ese pre­his­toric rel­a­tives orig­i­nated in Europe, colonised Asia and were suc­cess­ful for al­most 250,000 years. But within 10,000 years of ‘anatom­i­cally mod­ern hu­mans’ ap­pear­ing in Eura­sia, fol­low­ing our last mi­gra­tion out of Africa over 50,000 years ago, Ne­an­derthals had dis­ap­peared.

While the cause of ex­tinc­tion re­mains con­tro­ver­sial, many aca­demics be­lieve our an­ces­tors out­com­peted Ne­an­derthals by be­ing smarter. Ar­chae­o­log­i­cal ev­i­dence tells us that we had burial rit­u­als, cave art and tools that sur­passed any­thing cre­ated by the Ne­an­derthals – all thanks to an abil­ity to in­no­vate. “We could solve novel prob­lems bet­ter,” says Prof Fred Coolidge, a psy­chol­o­gist at the Univer­sity of Colorado, Colorado Springs, and co-au­thor of How To Think Like A Ne­an­der­tal.

Un­for­tu­nately, we can’t go back in time to meet the Ne­an­derthals and find out what made them tick. But new lab tech­niques are al­low­ing us to do the pre­vi­ously unimag­in­able: recre­ate the Ne­an­derthal mind in the lab. And it could give us the best chance yet of find­ing out why Homo sapi­ens sur­vived while Homo ne­an­derthalen­sis died out.

THE SO­CIAL APE

The lead­ing the­ory for why nat­u­ral se­lec­tion has favoured in­tel­li­gence is the ‘so­cial brain’ hy­poth­e­sis: be­ing in­tel­li­gent is an adap­ta­tion for deal­ing with the com­plex in­ter­ac­tions as­so­ci­ated with liv­ing in groups. Hu­mans man­age 150-200 peo­ple, for ex­am­ple, whereas av­er­age group size in chim­panzees is 50. That fig­ure can dou­ble, but ten­sions soon cause the chim­panzee troop to split. “Ne­an­derthals couldn’t han­dle groups of more than 20-30,” says Coolidge. More re­la­tion­ships re­quire more brain power and, in mam­mals, the size of a so­cial group is cor­re­lated with the size of the cere­bral cor­tex – the folded, outer lay­ers of the brain, which are in­volved in higher thought pro­cesses such as lan­guage and de­ci­sion mak­ing.

Larger groups en­abled ideas to spread. “We are able to col­lab­o­rate, to co­op­er­ate, and to share tech­nol­ogy in a way no other species has done,” says Dr Alysson Muotri at the Univer­sity of Cal­i­for­nia, San Diego. “Part of that is due to the abil­ity to com­mu­ni­cate and in­ter­act among our­selves – and most of that seems to have evolved from the front of the cor­tex.”

To find out more about the brains of mod­ern hu­mans and Ne­an­derthals, Muotri is grow­ing or­gan-like 2

“Many aca­demics be­lieve our an­ces­tors out­com­peted Ne­an­derthals by be­ing smarter”

2 struc­tures made from cells from the frontal cor­tex. Could th­ese organoids, or ‘mini-brains’, help ex­plain what makes hu­mans unique?

NEW GE­NET­ICS, OLD DNA

Grow­ing organoids based on an ex­tinct species is pos­si­ble due to break­throughs in sev­eral tech­niques: gen­er­at­ing stem cells, ex­tract­ing DNA from fos­silised bones, and gene edit­ing. Muotri is mak­ing organoids through a process that he calls ‘Ne­an­der-thal­i­sa­tion’. Here, he ed­its genes in hu­man cells, re­plac­ing one let­ter of DNA with an­other – the ge­netic vari­ant car­ried by Ne­an­derthals – then prompts those cells to de­velop into pea-sized balls of cor­tex tis­sue. The Ne­an­derthal vari­ant is iden­ti­fied by com­par­ing hu­man DNA to the Ne­an­derthal genome, which was first se­quenced in 2010 by a team led by Prof Svante Pääbo of the Max Planck In­sti­tute for Evo­lu­tion­ary An­thro­pol­ogy in Leipzig, Ger­many. In­ci­den­tally, Pääbo’s lab is also cre­at­ing Ne­an­derthalised organoids.

One of the first hu­man genes Muotri edited is NOVA1, a ‘master reg­u­la­tor’ which en­codes a pro­tein that con­trols when other genes are switched on or off. NOVA1 is known to be in­volved in early brain de­vel­op­ment be­cause its mu­ta­tions are linked to autism and schizophre­nia. As organoids with the Ne­an­derthal vari­ant of NOVA1 ma­ture, they de­velop de­fects in the synap­tic con­nec­tions be­tween cells, scram­bling their neu­ral net­works. Ne­an­derthalised cells within the ball also mi­grate in a man­ner that ends up pro­duc­ing unexpected ex­tra fold­ing, says Muotri. “They look like pop­corn.”

But some sci­en­tists are scep­ti­cal that organoids will re­veal much about our ex­tinct cousins. “Hu­man-type be­hav­iour, and I in­clude Ne­an­derthals, is af­fected by much more than just the cor­tex,” says Coolidge, who points out that many daily ac­tiv­i­ties, like walk­ing and talk­ing, are as­so­ci­ated with ‘pro­ce­dural mem­ory’. This in­volves un­con­scious pro­cesses oc­cur­ring in re­gions be­low the cor­tex, like the cere­bel­lum, which is re­spon­si­ble for co­or­di­nat­ing move­ment and is also linked to autism.

Ac­knowl­edg­ing the lim­i­ta­tions of study­ing the cor­tex alone, Muotri is hop­ing to grow a true mini-brain, 2

“Maybe in the fu­ture we will learn how to make all the brain re­gions and put them to­gether”

2 or ‘cere­bral organoid’. “Maybe in the fu­ture we will learn how to make all the brain re­gions and put them to­gether,” he says. Edit­ing a sin­gle gene – NOVA1 – tech­ni­cally pro­duces ‘par­tially Ne­an­derthalised’ cells, so he’s now work­ing to make a ‘fully Ne­an­derthalised’ organoid, which re­quires re­plac­ing DNA letters in thou­sands of genes. “We are re­plac­ing chunks of the en­tire chro­mo­some in th­ese cells.”

The best model to study the hu­man brain is in a liv­ing per­son, but so­ci­ety con­sid­ers such ex­per­i­ments un­eth­i­cal, so sci­en­tists use sur­ro­gates – any­thing from a few cells in a Petri dish to graft­ing tis­sue onto a mouse brain. So where do mini-brains lie on the eth­i­cal scale? Ac­cord­ing to Prof Hank Greely, a bioethi­cist at Stan­ford Law School, they’re cur­rently too small and sim­ple to cause con­cern. “If organoids be­come larger and more com­pli­cated, then I think you’re a lot closer to hav­ing to worry about what’s in the dish.”

Re­gard­less of which sur­ro­gate is used as the model for a liv­ing brain – hu­man or Ne­an­derthal – Greely says the key eth­i­cal ques­tion is the same: would it be en­ti­tled to spe­cial treat­ment? The answer isn’t based on whether it de­serves ‘hu­man’ rights, but on con­sid­er­a­tions that al­ready ap­ply to lab­o­ra­tory an­i­mals, like the ca­pac­ity to feel pain (as de­tected through char­ac­ter­is­tic pat­terns of neu­ral ac­tiv­ity). Such bar­ri­ers would prob­a­bly pre­vent sci­en­tists from cre­at­ing mini-brains ca­pa­ble of con­scious­ness or be­com­ing sen­tient.

But even if tech­ni­cal hur­dles can be over­come and the re­search is passed by an eth­i­cal re­view panel, grow­ing an en­tire Ne­an­derthal brain may not of­fer enough in­sight into the lives of our ex­tinct rel­a­tives, as it would be dif­fi­cult to un­der­stand the be­havioural im­pacts of any Ne­an­derthal-hu­man DNA dif­fer­ences in a brain that’s iso­lated from its en­vi­ron­ment. So if the aim is to un­der­stand the Ne­an­derthal mind, why not grow a whole body too, by cloning?

Cloning a Ne­an­derthal has been sug­gested by renowned ge­neti­cist Prof Ge­orge Church. It would in­volve ex­ten­sive gene edit­ing to gen­er­ate a fully Ne­an­derthalised em­bryo, im­planted into a hu­man mother. Bring­ing a Ne­an­derthal baby kick­ing and scream­ing into the 21st Cen­tury means de-ex­tinc­tion of the species, and Greely says the eth­i­cal im­pli­ca­tions run deeper, as he sus­pects peo­ple wouldn’t be civilised enough to treat clones with re­spect, partly due to racism il­lus­trated by the out­dated ‘stupid cave­man’ stereo­type. “Even if we didn’t have that im­age, just know­ing that they were not fully hu­man would lead to dis­crim­i­na­tion,” he says.

MEN­TAL TRADE-OFFS

Views on our ex­tinct rel­a­tives have shifted re­cently. While this shift can be ex­plained by ar­chae­o­log­i­cal finds that show a more so­phis­ti­cated Ne­an­derthal cul­ture than once as­sumed, the cyn­i­cal ex­pla­na­tion

“The small echoes of Ne­an­derthal DNA that we all har­bour are ac­tive in mod­ern hu­mans”

is that the shift has only hap­pened since present-day Euro­peans dis­cov­ered that in­ter­breed­ing oc­curred be­tween the two species. To­day, non-Africans carry about 2 per cent Ne­an­derthal DNA.

The legacy of mat­ing can still be heard in our anatomy. “Even the small echoes of Ne­an­derthal DNA that we all har­bour are very much ac­tive in mod­ern hu­mans,” says Dr Karen Ber­man, chief of the neu­roimag­ing sec­tion at the US Na­tional In­sti­tute of Men­tal Health. In 2017, Ber­man and her col­league Dr Michael Gregory per­formed MRI scans on 221 healthy hu­mans to con­struct 3D mod­els of their heads. The work re­vealed that peo­ple with a greater num­ber of an­cient ge­netic vari­ants – a higher ‘Ne­an­der Score’ – have skull shapes that more closely match our ex­tinct cousins, whose skulls were elon­gated at the back. (Although we as­so­ciate size with smarts, the Ne­an­derthal brain was ac­tu­ally 10 per cent larger.)

Af­ter se­quenc­ing DNA from the par­tic­i­pants’ blood sam­ples, Ber­man and Gregory found that a higher Ne­an­der Score also meant the cor­tex had more grey mat­ter (brain cells) and white mat­ter (mostly branch­ing fi­bres from cells). Fold­ing of the cor­tex was greater too, mir­ror­ing Muotri’s pop­corn-like organoids. The most af­fected ar­eas were be­neath the back of the skull: the oc­cip­i­tal and pari­etal lobes of the cor­tex – re­gions that are in­volved in pro­cess­ing vis­ual and spa­tial in­for­ma­tion.

The brain has lim­ited re­sources, so al­lo­cat­ing more to vis­ual and spa­tial pro­cess­ing comes at the ex­pense of other abil­i­ties, lead­ing to a trade-off. Those ge­netic vari­ants that in­flu­ence how a brain’s re­sources are al­lo­cated seem to have given Ne­an­derthals su­pe­rior vis­ual and spa­tial skills (prob­a­bly for hunt­ing), driven by eco­log­i­cal pres­sures to find calorific 2

RIGHT: Ne­an­derthals looked af­ter their sick and their dead, as this re­con­struc­tion shows. They lived in small fam­ily groups and are thought to have had lan­guageBE­LOW RIGHT: The de­mands of manag­ing life in a wide so­cial group is one ex­pla­na­tion for the de­vel­op­ment of in­tel­li­gence. Chimps can han­dle a big­ger group than Ne­an­derthals, while hu­mans can han­dle big­ger groups than chimps

ABOVE: DNA can per­sist in­side bones for thou­sands of years. By drilling into the bone, you can ex­tract the DNA. This is how Ne­an­derthal DNA was first ob­tainedRIGHT: Mini-brains grown from hu­man cells (left) and with a Ne­an­derthal vari­ant (right). The ones with the Ne­an­derthal vari­ant pro­duce ex­tra ‘pop­corn-like’ fold­ing

ABOVE: Tiny Ne­an­derthalised mini-brains, grown in Alysson Muotri’s lab

ABOVE LEFT: Neu­ro­sci­en­tist Alysson Muotri is putting Ne­an­derthal gene vari­ants into hu­man cells

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