Neither alive nor dead: disembodied human brains put to use in medicine

By restor­ing cer­tain func­tions of intact brains taken from deceased donors, the start-up Bex­org hopes to cre­ate a more accur­ate exper­i­ment­al envir­on­ment for the devel­op­ment of drugs to treat neuro­de­gen­er­at­ive dis­eases. Only yes­ter­day, this brain was part of a liv­ing being. Barely a few hours after its owner’s death, it now sits in an air­tight jar, kept alive by a net­work of tubes infus­ing it with litres of blood sub­sti­tute, rich in oxy­gen and vital min­er­als, whilst ensur­ing the remov­al of its meta­bol­ic waste.

Almost all the essen­tial func­tions of this “isol­ated” brain without a body remain intact, even though its elec­tric­al activ­ity is reduced under the influ­ence of a power­ful anaes­thet­ic. As such, the organ hov­ers between two worlds, on the uncer­tain bor­der­line between life and death. Whilst it is sub­jec­ted to the action of chem­ic­als care­fully meas­ured out by neur­os­cient­ists, sensors record its reac­tions with metic­u­lous pre­ci­sion, gath­er­ing hun­dreds of data points on the state of its cells, its pro­teins and its physiology as a whole. After 24 hours spent in this state of organ­ic limbo, it will finally be sliced into count­less frag­ments for fur­ther study.

This brain is one of hun­dreds of spe­ci­mens stud­ied by the emer­ging bio­tech­no­logy star­tup Bex­org, foun­ded just five years ago, which has gained fame for its suite of machines known as BrainEx, cap­able of sus­tain­ing a brain removed from any liv­ing organ­ism. This tech­no­lo­gic­al plat­form offers research­ers an unpre­ced­en­ted tool for design­ing new ther­apies tar­get­ing brains rav­aged by neuro­de­gen­er­at­ive dis­eases – Parkinson’s dis­ease, Alzheimer’s dis­ease, amyotroph­ic lat­er­al scler­osis. The dis­em­bod­ied organs allow Bex­org to per­form biopsies, meas­ure how long a drug remains with­in the cells, veri­fy wheth­er it reaches its molecu­lar tar­get, and detect the early signs of any poten­tial side effects.

This sys­tem prom­ises con­di­tions for drug test­ing that are infin­itely closer to real­ity than those provided by anim­al mod­els or cells grown in Petri dishes. This is because these whole brains bear the indelible imprints of dec­ades of envir­on­ment­al expos­ure, a per­son­al his­tory of drug treat­ments and a genet­ic unique­ness that is likely to pro­foundly influ­ence the response to the molecules being tested.

The ini­tial res­ults are encour­aging, show­ing that the pre­served brains faith­fully rep­lic­ate the response of liv­ing brains to cer­tain ther­apies. Yet Bex­org has long oper­ated behind the scenes, aware that it needed to reas­sure the pub­lic: that the use of these dis­em­bod­ied brains does not cross any eth­ic­al bound­ar­ies and car­ries no risk of recov­er­ing even the slight­est frag­ment of consciousness.

Bey­ond drug tri­als, these brains could reveal new mark­ers of patho­lo­gic­al pro­cesses, such as the neuro­de­gen­er­a­tion spe­cif­ic to Alzheimer’s disease.

Before each brain is entrus­ted to the BrainEx machine, sur­geons exam­ine it metic­u­lously, then suture plastic stubs into the ves­sels that once sup­plied it with blood, thereby pre­par­ing the organ to respond to the molecules being tested and to gen­er­ate data. Once con­nec­ted to the machines, an arti­fi­cial lung and kid­ney take over the oxy­gen­a­tion and fil­tra­tion of the flu­ids flow­ing through it.

Neur­os­cient­ists had ini­tially put this approach to the test by restor­ing the func­tions of pig brains sev­er­al hours after their death at a loc­al abat­toir. Their res­ults, pub­lished in 2019 in the journ­al Nature¹, imme­di­ately sparked a wave of con­cern: did these brains retain traces of con­scious­ness, did they feel pain, did they retain frag­ments of their pre­vi­ous lives in their memory? How­ever, under the influ­ence of a power­ful anaes­thet­ic, their elec­tric­al dis­charges, which are a sine qua non of any form of con­scious­ness, are com­pletely elim­in­ated. Build­ing on this ini­tial demon­stra­tion, Bex­org now sources human brains in part­ner­ship with organ­isa­tions respons­ible for col­lect­ing organs for transplantation.

The Bex­org jour­ney began with a strik­ingly simple obser­va­tion: the obvi­ous short­com­ings of anim­al mod­els for test­ing drugs inten­ded for the human brain. There is no guar­an­tee that a molecule which eas­ily crosses the blood-brain bar­ri­er in a mouse will make the same jour­ney in humans; and a tox­ic over­dose or an inef­fect­ive under­dose is enough to doom a prom­ising ther­apy before it has even had a chance to prove itself.

Anoth­er argu­ment in favour of this approach is the grow­ing pres­sure from many gov­ern­ments, par­tic­u­larly in Europe, to encour­age research­ers and industry to move away from anim­al test­ing in favour of altern­at­ive mod­els. This is a fun­da­ment­al shift that shows no signs of abat­ing; quite the contrary.

To date, the com­pany has raised $42 mil­lion, in addi­tion to sev­er­al grants and part­ner­ships with bio­tech­no­logy firms and uni­ver­sit­ies. Bey­ond drug tri­als, these brains could reveal new mark­ers of patho­lo­gic­al pro­cesses, such as the neuro­de­gen­er­a­tion spe­cif­ic to Alzheimer’s dis­ease, whose dia­gnost­ic and pro­gnost­ic value would be invalu­able to clini­cians. This approach is par­tic­u­larly well-suited to the study of neuro­de­gen­er­at­ive dis­eases: on the one hand, because these gen­er­ally do not involve elec­tric­al brain activ­ity; on the oth­er hand, because donor brains are often affected by sev­er­al of these con­di­tions sim­ul­tan­eously, a clin­ic­al pic­ture that has proved excep­tion­ally dif­fi­cult to rep­lic­ate in the laboratory.

This “isol­ated” brain mod­el is already estab­lish­ing itself as a cred­ible altern­at­ive to brain organoids cul­tured from human stem cells, or to chips mim­ick­ing the blood-brain bar­ri­er for the study of neuro­de­gen­er­a­tion. Some point out, how­ever, that BrainEx brains may not be per­fect rep­licas of liv­ing brains: cerebrospin­al flu­id drain­age sys­tems may behave dif­fer­ently with­in an intact organ­ism, whilst the inhib­i­tion of neur­on­al fir­ing through anaes­thesia is likely to alter cereb­ral blood flow. Fur­ther­more, by depriving the brain of its elec­tric­al activ­ity, research­ers lose the abil­ity to pre­dict wheth­er a tested molecule is likely to trig­ger epi­leptic seizures.

As Bex­org expands its scope, the com­pany could turn its atten­tion to oth­er patho­lo­gic­al con­di­tions, such as psy­chi­at­ric dis­orders and cer­tain forms of brain can­cer. In the longer term, the team aims to keep brains in BrainEx for up to two weeks, hop­ing to gath­er much rich­er data on long-term pro­cesses, such as brain plas­ti­city in response to treatments.

The com­pany is also devel­op­ing a machine learn­ing mod­el called Neur­oLens, a ‘vir­tu­al brain’ trained on physiolo­gic­al read­ings, donors’ med­ic­al records, and pro­tein and micro­scop­ic data from brain tis­sue. This digit­al avatar could one day enable research­ers to test new molecules before even using a phys­ic­al brain. In this imma­ter­i­al and, in a sense, immor­tal form, the brains that Bex­org has so care­fully pre­served fol­low­ing the death of their own­ers will con­tin­ue to live long after life sup­port has been withdrawn.