So I'm a neurosurgeon. And like most of my colleagues, I have to deal, every day, with human tragedies. I realize how your life can change from one second to the other after a major stroke or after a car accident. And what is very frustrating for us neurosurgeons is to realize that unlike other organs of the body, the brain has very little ability for self-repair. And after a major injury of your central nervous system, the patients often remain with a severe handicap. And that's probably the reason why I've chosen to be a functional neurosurgeon.
Ja sam neurokirurg. I kao većina mojih kolega, svaki sam dan suočena s ljudskim tragedijama. Razumijem kako se život može promijeniti iz sekunde u sekundu nakon teškog moždanog udara ili nakon prometne nesreće. Vrlo je frustrirajuće nama neurokirurzima shvatiti da za razliku od ostalih organa u tijelu, mozak ima jako male mogućnosti samostalnog popravka. Nakon teže ozlijede središnjeg živčanog sustava, pacijentima često ostaju trajne posljedice. To je vjerojatno razlog zašto sam odlučila biti funkcionalni neurokirurg.
What is a functional neurosurgeon? It's a doctor who is trying to improve a neurological function through different surgical strategies. You've certainly heard of one of the famous ones called deep brain stimulation, where you implant an electrode in the depths of the brain in order to modulate a circuit of neurons to improve a neurological function. It's really an amazing technology in that it has improved the destiny of patients with Parkinson's disease, with severe tremor, with severe pain. However, neuromodulation does not mean neuro-repair. And the dream of functional neurosurgeons is to repair the brain. I think that we are approaching this dream.
Što je funkcionalni neurokirurg? To je liječnik koji pokušava poboljšati neurološke funkcije uz pomoć raznih kirurških tehnika. Sigurno ste čuli za jednu od poznatijih poput duboke moždane stimulacije, kod koje se elektroda usađuje u dubinu mozga kako bi upravljali sklopom neurona i poboljšali neurološku funkciju. Uistinu je nevjerojatna tehnologija po tome što je poboljšala sudbinu pacijenata s Parkinsonovom bolešću, s teškim tremorom, sa snažnim bolovima. Međutim, neuromodulacija ne znači popravak. I san funkcionalnih neurokirurga je popraviti mozak. Mislim da se približavamo ovom snu.
And I would like to show you that we are very close to this. And that with a little bit of help, the brain is able to help itself.
Željela bih vam pokazati da smo vrlo blizu tome. Uz vrlo malu pomoć, mozak si može sam pomoći.
So the story started 15 years ago. At that time, I was a chief resident working days and nights in the emergency room. I often had to take care of patients with head trauma. You have to imagine that when a patient comes in with a severe head trauma, his brain is swelling and he's increasing his intracranial pressure. And in order to save his life, you have to decrease this intracranial pressure. And to do that, you sometimes have to remove a piece of swollen brain. So instead of throwing away these pieces of swollen brain, we decided with Jean-François Brunet, who is a colleague of mine, a biologist, to study them.
Priča je počela prije 15 godina. U to sam vrijeme bila glavni specijalizant, radila danju i noću u hitnoj službi. Često sam skrbila o pacijentima s traumama glave. Morate pretpostaviti da kada vam pacijent dođe s teškom traumom glave, njegov mozak otiče i intakranijski tlak raste. Kako bi spasili njegov život, morate smanjiti taj intrakranijalni tlak. Da bi to učinili, nekada morate ukloniti dio oteknutog mozga. Ali umjesto bacanja tih komada oteknutog mozga, odlučili smo, sa Jean-François Brunetom, koji je moj kolega, biolog, proučavati ih.
What do I mean by that? We wanted to grow cells from these pieces of tissue. It's not an easy task. Growing cells from a piece of tissue is a bit the same as growing very small children out from their family. So you need to find the right nutrients, the warmth, the humidity and all the nice environments to make them thrive. So that's exactly what we had to do with these cells. And after many attempts, Jean-François did it. And that's what he saw under his microscope.
Što time mislim? Htjeli smo uzgojiti stanice iz tih komada tkiva. To nije jednostavan zadatak. Uzgajanje stanica iz komada tkiva gotovo je isto kao razvijanje vrlo male djece iz njihove obitelji. Morate naći prave hranjive tvari, toplinu, vlagu, i pravu okolinu kako bi napredovali. Upravo smo to morali učiniti s ovim stanicama. Nakon brojnih pokušaja, Jean-François je uspio. I to je vidio pod svojim mikroskopom.
And that was, for us, a major surprise. Why? Because this looks exactly the same as a stem cell culture, with large green cells surrounding small, immature cells. And you may remember from biology class that stem cells are immature cells, able to turn into any type of cell of the body. The adult brain has stem cells, but they're very rare and they're located in deep and small niches in the depths of the brain. So it was surprising to get this kind of stem cell culture from the superficial part of swollen brain we had in the operating theater.
To je za nas bilo veliko iznenađenje. Zašto? Zato što ovo izgleda potpuno isto kao kultura matičnih stanica, s velikim zelenim stanicama koje okružuju male, nezrele stanice. Možda se sjećate sa sati biologije da su matične stanice nezrele stanice, koje se mogu pretvoriti u bilo koji tip stanica u tijelu. Mozak odraslog čovjeka ima matične stanice, ali jako su rijetke i nalaze se duboko u malim udubinama u dubinama mozga. Iznenadilo nas je što smo dobili ovakvu kulturu matičnih stanica iz površinskog sloja otečenog mozga kojeg smo imali u operacijskoj sali.
And there was another intriguing observation: Regular stem cells are very active cells -- cells that divide, divide, divide very quickly. And they never die, they're immortal cells. But these cells behave differently. They divide slowly, and after a few weeks of culture, they even died. So we were in front of a strange new cell population that looked like stem cells but behaved differently.
Primjetili smo još nešto zanimljivo: Normalne su matične stanice vrlo aktivne stanice - stanice koje se dijele, dijele, dijele vrlo brzo. I nikad ne umiru, besmrtne su stanice. Ali ove se stanice ponašaju drugačije. Dijele se polako, i nakon nekoliko tjedana kultiviranja, čak su i umrle. Bili smo pred čudnom novom populacijom stanica koje su izgledale kao matične stanice ali su se ponašale drugačije.
And it took us a long time to understand where they came from. They come from these cells. These blue and red cells are called doublecortin-positive cells. All of you have them in your brain. They represent four percent of your cortical brain cells. They have a very important role during the development stage. When you were fetuses, they helped your brain to fold itself. But why do they stay in your head? This, we don't know. We think that they may participate in brain repair because we find them in higher concentration close to brain lesions. But it's not so sure. But there is one clear thing -- that from these cells, we got our stem cell culture. And we were in front of a potential new source of cells to repair the brain. And we had to prove this.
Trebalo nam je dugo vremena da bi shvatili odakle su došle. Došle su od ovih stanica. Ove plave i crvene stanice su doublecortin-pozitivne stanice. Svi ih imate u svom mozgu. Predstavljaju četiri posto kortikalnih stanica. One imaju vrlo važnu ulogu tijekom razvoja. Kad ste bili fetusi, pomogle su u razvoju vašeg mozga. Ali zašto ostaju u glavi? Ovo ne znamo. Mislimo da možda imaju ulogu u oporavku mozga jer ih nalazimo u većoj koncentraciji u blizini moždanih lezija. Ali nije sigurno. No jedna je stvar jasna - da smo iz ovih stanica, dobili našu kulturu matičnih stanica. Bili smo pred potencijalnim novim izvorom stanica za popravak mozga. I morali smo ovo dokazati.
So to prove it, we decided to design an experimental paradigm. The idea was to biopsy a piece of brain in a non-eloquent area of the brain, and then to culture the cells exactly the way Jean-François did it in his lab. And then label them, to put color in them in order to be able to track them in the brain. And the last step was to re-implant them in the same individual. We call these autologous grafts -- autografts.
A da bi to dokazali, odlučili smo dizajnirati eksperimentalni primjer. Ideja je bila biopirati dio mozga u dijelu mozga koji nije ključan i zatim kultivirati stanice točno onako kako je to Jean-François učinio u svom laboratoriju. I zatim ih označiti, obojati ih kako bismo ih mogli pratiti u mozgu. Zadnji je korak bio ponovo ih ugraditi u istu jedinku. To zovemo autolognim graftovima - autografovima.
So the first question we had, "What will happen if we re-implant these cells in a normal brain, and what will happen if we re-implant the same cells in a lesioned brain?" Thanks to the help of professor Eric Rouiller, we worked with monkeys.
Prvo pitanje koje smo imali, "Što će se dogoditi ako reimplantiramo ove stanice u normalan mozak, i što će se dogoditi ako reimplantiramo iste stanice u ozlijeđeni mozak?" Zahvaljujući pomoći profesora Erica Rouillera, radili smo s majmunima.
So in the first-case scenario, we re-implanted the cells in the normal brain and what we saw is that they completely disappeared after a few weeks, as if they were taken from the brain, they go back home, the space is already busy, they are not needed there, so they disappear.
U prvom scenariju, reimplantirali smo stanice u normalan mozak i primjetili da one potpuno nestaju nakon prvih nekoliko tjedana, kao da su odnešene iz mozga, odu natrag kući, taj je prostor već zauzet, nisu tamo potrebne, i nestanu.
In the second-case scenario, we performed the lesion, we re-implanted exactly the same cells, and in this case, the cells remained -- and they became mature neurons. And that's the image of what we could observe under the microscope. Those are the cells that were re-implanted. And the proof they carry, these little spots, those are the cells that we've labeled in vitro, when they were in culture.
U drugom slučaju, izvršili smo leziju, reimplantirali iste te stanice, ali sada, stanice su ostale tu - i postale zreli neuroni. I to je slika onoga što smo mogli vidjeti pod mikroskopom. To su stanice koje smo reimplantirali. I dokaz nose na sebi, ove male točkice, to su stanice koje smo obojili in vitro, dok su još bile u kulturi.
But we could not stop here, of course. Do these cells also help a monkey to recover after a lesion? So for that, we trained monkeys to perform a manual dexterity task. They had to retrieve food pellets from a tray. They were very good at it. And when they had reached a plateau of performance, we did a lesion in the motor cortex corresponding to the hand motion. So the monkeys were plegic, they could not move their hand anymore. And exactly the same as humans would do, they spontaneously recovered to a certain extent, exactly the same as after a stroke. Patients are completely plegic, and then they try to recover due to a brain plasticity mechanism, they recover to a certain extent, exactly the same for the monkey.
Ali, naravno, nismo tu mogli stati. Pomažu li ove stanice majmunu u oporavku nakon lezije? Za to smo trenirali majmune da izvrše test manualne spretnosti. Morali su dohvatiti komadiće hrane iz posudica. Bili su vrlo dobri u tome. I kad su dostigli vrhunac spretnosti, načinili smo leziju u motoričkom korteksu odgovornom za pokrete ruku. Majmuni su bili plegični, nisu više mogli micati rukama. I isto kao i kod ljudi, spontano su se oporavili do određene mjere, potpuno isto kao i nakon moždanog udara. Pacijenti su potpuno plegični, i pokušaju se oporaviti zahvaljujući mehanizmu plastičnosti mozga, oporave se do određene mjere, isto kao i kod majmuna.
So when we were sure that the monkey had reached his plateau of spontaneous recovery, we implanted his own cells. So on the left side, you see the monkey that has spontaneously recovered. He's at about 40 to 50 percent of his previous performance before the lesion. He's not so accurate, not so quick. And look now when we re-implant the cells: Two months after re-implantation, the same individual.
Kad smo bili sigurni da je majmun dosegao vrhunac spontanog oporavka, implantirali smo njegove stanice. Na lijevoj strani vidite majmuna koji se spontano oporavio. Sada je na 40 do 50 posto prijašnjih performansi prije lezije. Nije tako precizan, niti brz. I pogledajte sada, kada reimplantiramo stanice: Dva mjeseca nakon reimplantacije, ista jedinka.
(Applause)
(Pljesak)
It was also very exciting results for us, I tell you. Since that time, we've understood much more about these cells. We know that we can cryopreserve them, we can use them later on. We know that we can apply them in other neuropathological models, like Parkinson's disease, for example. But our dream is still to implant them in humans. And I really hope that I'll be able to show you soon that the human brain is giving us the tools to repair itself.
To su bili vrlo dobri rezultati za nas, kažem vam. Otada, shvatili smo mnogo više o ovim stanicama. Znamo da ih možemo krioprezervirati, možemo ih koristiti kasnije. Znamo da ih možemo koristiti u drugim neuropatološkim oblicima, poput Parkinsonove bolesti, na primjer. Ali naš je san i dalje implantirati ih u ljude. I uistinu se nadam da ću vam uskoro moći pokazati da nam ljudski mozak daje alate za samostalan popravak.
Thank you.
Hvala vam.
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(Pljesak)
Bruno Giussani: Jocelyne, this is amazing, and I'm sure that right now, there are several dozen people in the audience, possibly even a majority, who are thinking, "I know somebody who can use this." I do, in any case. And of course the question is, what are the biggest obstacles before you can go into human clinical trials?
Bruno Giussani: Jocelyne, ovo je nevjerojatno, sugran sam da sada deseci ljudi u publici, vjerojatno čak i većina, razmišljaju, "Znam nekoga kome bi ovo pomoglo." Ja razmišljam o tome, u svakom slučaju. Naravno, pitanje je, koje su najveće prepreke u kliničkim studijama na ljudima?
Jocelyne Bloch: The biggest obstacles are regulations. (Laughs) So, from these exciting results, you need to fill out about two kilograms of papers and forms to be able to go through these kind of trials.
Jocelyne Bloch: Najveća su prepreka propisi. (Smijeh) Od ovih uzbudljivih rezultata, morete popuniti oko dva kilograma papirologije da bi ova testiranja mogla nastaviti
BG: Which is understandable, the brain is delicate, etc.
BG: Što je razumljivo, mozak je delikatan, itd.
JB: Yes, it is, but it takes a long time and a lot of patience and almost a professional team to do it, you know?
JB: Da, jest, ali potrebno je puno vremena i mnogo strpljenja i gotovo profesionalan tim za to, znate?
BG: If you project yourself -- having done the research and having tried to get permission to start the trials, if you project yourself out in time, how many years before somebody gets into a hospital and this therapy is available?
BG: Ako možete projicirati - napravili ste istraživanje i tražili ste odobrenje za početak studija, ako možete predvidjeti, koliko je potrebno godina da kada netko dođe u bolnicu ima ovu terapiju dostupnu?
JB: So, it's very difficult to say. It depends, first, on the approval of the trial. Will the regulation allow us to do it soon? And then, you have to perform this kind of study in a small group of patients. So it takes, already, a long time to select the patients, do the treatment and evaluate if it's useful to do this kind of treatment. And then you have to deploy this to a multicentric trial. You have to really prove first that it's useful before offering this treatment up for everybody.
JB: Vrlo je teško reći. Ovisi, prvo, o odobrenju studija Hoće li nam propisi dozvoliti da krenemo uskoro? I zatim, morate napraviti ovakvu studiju na maloj skupini pacijenata. Potrebno je dosta vremena za odabir pacijenata, za provođenje terapije i procjenu je li ovakvo liječenje potrebno. I zatim morate razviti multicentričnu studiju. Morate prvo dokazati da je korisno prije nego ovu terapiju ponudite svima.
BG: And safe, of course. JB: Of course.
BG: I sigurno, naravno. JB: Naravno.
BG: Jocelyne, thank you for coming to TED and sharing this. BG: Thank you.
BG: Jocelyne, hvala vam što ste došli na TED podijeliti ovo. BG: Hvala vam.
(Applause)
(Pljesak)