I want to talk to you about one of the biggest myths in medicine, and that is the idea that all we need are more medical breakthroughs and then all of our problems will be solved. Our society loves to romanticize the idea of the single, solo inventor who, working late in the lab one night, makes an earthshaking discovery, and voila, overnight everything's changed. That's a very appealing picture, however, it's just not true. In fact, medicine today is a team sport. And in many ways, it always has been. I'd like to share with you a story about how I've experienced this very dramatically in my own work.
Želim da sa vama podelim priču o jednom od najvećih mitova u medicini, koji je uobličen idejom da je neophodno doći do još više otkrića u medicini i tada će svi naši problemi biti rešeni. Našem društvu se sviđa romantičarska ideja o jednom usamljenom istraživaču koji radeći do kasno u noć u laboratoriji dolazi do otkrića koje menja svet, i juhu, sve se promeni preko noći. Ta slika je veoma privlačna, međutim nije istinita. Činjenica je da je medicina danas timski sport. Na mnogo načina je to oduvek i bila. Želela bih da vam ispričam priču o dramatičnom načinu na koji sam ja to doživela u svom radu.
I'm a surgeon, and we surgeons have always had this special relationship with light. When I make an incision inside a patient's body, it's dark. We need to shine light to see what we're doing. And this is why, traditionally, surgeries have always started so early in the morning -- to take advantage of daylight hours. And if you look at historical pictures of the early operating rooms, they have been on top of buildings. For example, this is the oldest operating room in the Western world, in London, where the operating room is actually on top of a church with a skylight coming in. And then this is a picture of one of the most famous hospitals in America. This is Mass General in Boston. And do you know where the operating room is? Here it is on the top of the building with plenty of windows to let light in.
Ja sam hirurg, a mi hirurzi smo uvek imali poseban odnos prema svetlosti. Kada napravim rez unutar tela pacijenta, veoma je mračno. Neophodno je da osvetlimo to polje kako bismo videli šta radimo. Zbog toga su tradicionalno operacije uvek počinjale rano ujutru, kako bi se iskoristila dnevna svetlost. Ukoliko pogledate stare fotografije prvih operacionih sala, one su bile na krovovima zgrada. Na primer, ovo je najstarija operaciona sala na zapadu, u Londonu, a operaciona sala se u principu nalazi u krovu crkve gde dnevna svetlost lako prodire. Ovo je slika jedne od najpoznatijih bolnica u Americi. To je "Mass General" bolnica u Bostonu. Da li znate gde je ovde operaciona sala? Ovde je na vrhu zgrade osvetljena dnevnom svetlošću.
So nowadays in the operating room, we no longer need to use sunlight. And because we no longer need to use sunlight, we have very specialized lights that are made for the operating room. We have an opportunity to bring in other kinds of lights -- lights that can allow us to see what we currently don't see. And this is what I think is the magic of fluorescence.
Danas nam nije neophodna dnevna svetlost u operacionim salama. Obzirom da više ne moramo da koristimo dnevnu svetlost, posedujemo veoma posebna svetla koja su napravljena za operacione sale. Imamo mogućnosti da instaliramo različite vrste svetlosti, svetlost koja nam omogućava da vidimo ono što trenutno ne možemo da vidimo. U tome se krije, ja mislim, magija fluorescencije.
So let me back up a little bit. When we are in medical school, we learn our anatomy from illustrations such as this where everything's color-coded. Nerves are yellow, arteries are red, veins are blue. That's so easy anybody could become a surgeon, right? However, when we have a real patient on the table, this is the same neck dissection -- not so easy to tell the difference between different structures. We heard over the last couple days what an urgent problem cancer still is in our society, what a pressing need it is for us to not have one person die every minute. Well if cancer can be caught early, enough such that someone can have their cancer taken out, excised with surgery, I don't care if it has this gene or that gene, or if it has this protein or that protein, it's in the jar. It's done, it's out, you're cured of cancer.
Objasniću vam to malo. U toku studija medicine mi učimo anatomiju iz ilustracija kao što su ove, gde je sve obeleženo bojama. Nervi su žute boje, arterije su crvene, vene su plave. To je toliko lako da bi svako mogao da bude hirurg, zar ne? Međutim, kada pravi pacijent leži na stolu, ovo je ista ta disekcija vrata, nije tako lako uočiti razliku među različitim strukturama. Čuli smo nekoliko puta u toku proteklih dana da je rak veoma hitan problem u našem društvu, da je zaista neophodno da smanjimo stopu smrtnosti od jedne osobe u minuti. Ukoliko se rak dijagnozira rano, toliko rano da se rak može izvaditi iz tela, operaciijom, ne zanima me da li ima ovaj ili onaj gen, ili ima ovaj ili onaj protein, nalazi se u tegli. Završeno je, izvađen je, izlečen si od raka.
This is how we excise cancers. We do our best, based upon our training and the way the cancer looks and the way it feels and its relationship to other structures and all of our experience, we say, you know what, the cancer's gone. We've made a good job. We've taken it out. That's what the surgeon is saying in the operating room when the patient's on the table. But then we actually don't know that it's all out. We actually have to take samples from the surgical bed, what's left behind in the patient, and then send those bits to the pathology lab. In the meanwhile, the patient's on the operating room table. The nurses, anesthesiologist, the surgeon, all the assistants are waiting around. And we wait. The pathologist takes that sample, freezes it, cuts it, looks in the microscope one by one and then calls back into the room. And that may be 20 minutes later per piece. So if you've sent three specimens, it's an hour later. And very often they say, "You know what, points A and B are okay, but point C, you still have some residual cancer there. Please go cut that piece out." So we go back and we do that again, and again.
Ovako vadimo tkivo raka. Mi damo sve od sebe, na osnovu onoga što znamo i toga kako rak izgleda, kako se pacijent oseća, na osnovu odnosa raka i ostalih organa i našeg iskustva, kažemo, znate šta, rak je uklonjen. Uradili smo dobar posao. Izvadili smo ga. To je ono što hirurg kaže pacijentu koji leži na operacionom stolu u sali. Mi u tom trenutku u stvari ne znamo da li smo sve izvadili. Moramo uzeti uzorak tkiva sa operacije, uzorak koji je u pacijentu, i moramo to poslati patolozima na analizu. Pacijent je u međuvremenu na operacionom stolu. Medicinske sestre, anesteziolog, hirurg, pomoćno osoblje - svi čekaju. I mi čekamo. Patolog dobije uzorak, zamrzne ga, iseče, pogleda pod mikroskopom jedan po jedan slajd i pozove operacionu salu. Potrebno je oko 20 minuta po uzorku. Ukoliko ste poslali tri uzorka, čekate sat vremena. Veoma često kažu, "Znate šta, tačke A i B su u redu, ali na tački C i dalje imate ostatke tkiva raka. Molim vas uklonito to." Tako da mi to uradimo ponovo, i onda još jednom.
And this whole process: "Okay you're done. We think the entire tumor is out." But very often several days later, the patient's gone home, we get a phone call: "I'm sorry, once we looked at the final pathology, once we looked at the final specimen, we actually found that there's a couple other spots where the margins are positive. There's still cancer in your patient." So now you're faced with telling your patient, first of all, that they may need another surgery, or that they need additional therapy such as radiation or chemotherapy. So wouldn't it be better if we could really tell, if the surgeon could really tell, whether or not there's still cancer on the surgical field? I mean, in many ways, the way that we're doing it, we're still operating in the dark.
Ceo taj proces: "U redu, završili smo. Mislimo da smo izvadili ceo tumor." Veoma često nekoliko dana nakon što pacijent ode kući, dobijemo telefonski poziv: "Izvinite, kada smo pogledali krajnje patološke analize, kada smo pogledali poslednji uzorak, pronašli smo da je ostalo još nekoliko tačaka gde su obrisi pozitivni. I dalje ima ćelija raka u pacijentu." Tako da se sada suočavate sa tim da pre svega treba da kažete pacijentu da mu je možda potrebna još jedna operacija, ili da im je neophodna dodatna terapija u vidu radio - ili hemo-terapije. Zar ne bi bilo bolje ako bismo zaista mogli da procenimo, ako bi hirurg zaista mogao da tvrdi da li je ili nije prisutno tkivo raka u operacionom polju? Iz mnogo uglova, način na koji mi to radimo je takav da mi i dalje operišemo u tami.
So in 2004, during my surgical residency, I had the great fortune to meet Dr. Roger Tsien, who went on to win the Nobel Prize for chemistry in 2008. Roger and his team were working on a way to detect cancer, and they had a very clever molecule that they had come up with. The molecule they had developed had three parts. The main part of it is the blue part, polycation, and it's basically very sticky to every tissue in your body.
Dok sam bila na hirurškom usavršavanju 2004. imala sam veliku sreću da upoznam dr Rodžera Čena, koji je kasnije dobio Nobelovu nagradu za hemiju 2008. Rodžer i njegov tim su istraživali načine detekcije raka, i pronašli su veoma pametan molekul. Molekul do kojeg su došli je imao tri dela. Njegov glavni deo je u plavoj boji, to je polikatjon, i lako se lepi za bilo koje tkivo u telu.
So imagine that you make a solution full of this sticky material and inject it into the veins of someone who has cancer, everything's going to get lit up. Nothing will be specific. There's no specificity there. So they added two additional components. The first one is a polyanionic segment, which basically acts as a non-stick backing like the back of a sticker. So when those two are together, the molecule is neutral and nothing gets stuck down. And the two pieces are then linked by something that can only be cut if you have the right molecular scissors -- for example, the kind of protease enzymes that tumors make. So here in this situation, if you make a solution full of this three-part molecule along with the dye, which is shown in green, and you inject it into the vein of someone who has cancer, normal tissue can't cut it. The molecule passes through and gets excreted. However, in the presence of the tumor, now there are molecular scissors that can break this molecule apart right there at the cleavable site. And now, boom, the tumor labels itself and it gets fluorescent.
Zamislite da napravite rastvor koji je zasićen ovim lepljivim materijalom i da to ubrizgate u vene osobe koja boluje od raka, sve će biti osvetljeno. Ništa nije specifično. Tu ne postoji specifičnost. Ubacili su još dva dodatna dela. Prvi deo je polianjonski dodatak, koji prosto deluje kao zaštitni papir na poleđini nalepnice. Kada su ovi delovi zajedno, molekul je neutralan i ništa se za to ne vezuje. Ova dva dela su povezana nečim što može biti odsečeno ukoliko imate ispravne molekularne makaze - na primer, tip proteaze-enzima koji proizvode tumori. U ovom rastvoru, ukoliko napravite rastvor zasićen ovim trodelnim molekulima zajedno sa bojom, koja je prikazana u zelenom, i to ubrizgate u venu nekoga ko boluje od raka zdravo tkivo to ne može da procesuje. Molekul prođe kroz sistem i telo ga izbaci. Međutim, ako se tu nalazi tumor tada su tu i molekularne makaze koje mogu da rastave ovaj molekul baš tu gde se molekul može preseći. Sada, tras, tumor sam sebe obeleži i postaje fluorescentan.
So here's an example of a nerve that has tumor surrounding it. Can you tell where the tumor is? I couldn't when I was working on this. But here it is. It's fluorescent. Now it's green. See, so every single one in the audience now can tell where the cancer is. We can tell in the operating room, in the field, at a molecular level, where is the cancer and what the surgeon needs to do and how much more work they need to do to cut that out. And the cool thing about fluorescence is that it's not only bright, it actually can shine through tissue. The light that the fluorescence emits can go through tissue. So even if the tumor is not right on the surface, you'll still be able to see it.
Ovo je primer nerva oko kojeg se nalazi tkivo tumora. Da li možete da vidite gde je tumor? Ja nisam mogla kada sam radila na ovome. Ali ovde je. Fluorescentan je. Sada je zelen. Vidite, sada svako u publici može da kaže gde se rak nalazi. Možemo na licu mesta, u operacionoj sali, na molekularnom nivou, uočiti gde je locirano tkivo raka i hirurg zna šta treba da uradi i koliko ima posla oko odstranjivanja tumora. Dobra osobina fluorescencije je da, ne samo da je svetla, već svetli i kroz tkivo. Svetlost koju fluorescencija emituje prolazi kroz tkivo. Tako da čak ako tumor nije na samoj površini i dalje ćete moći da ga uočite.
In this movie, you can see that the tumor is green. There's actually normal muscle on top of it. See that? And I'm peeling that muscle away. But even before I peel that muscle away, you saw that there was a tumor underneath. So that's the beauty of having a tumor that's labeled with fluorescent molecules. That you can, not only see the margins right there on a molecular level, but you can see it even if it's not right on the top -- even if it's beyond your field of view. And this works for metastatic lymph nodes also.
U ovom filmu možete videti da je tumor zelene boje. Preko njega se nalazi normalan mišić. Vidite li to? Ja odstranjujem mišić. Ali čak i pre nego što uklonim taj mišić, videli ste tkivo tumora ispod njega. U tome se nalazi lepota toga što je tumor obeležen fluorescentnim molekulima. U tom slučaju možete ne samo da vidite ivice na molekularnom nivou, već ga možete uočiti iako nije na samom vrhu - iako je izvan vašeg vidnog polja. Ovo se može primeniti i u slučaju metastaza limfnih čvorova.
Sentinel lymph node dissection has really changed the way that we manage breast cancer, melanoma. Women used to get really debilitating surgeries to excise all of the axillary lymph nodes. But when sentinel lymph node came into our treatment protocol, the surgeon basically looks for the single node that is the first draining lymph node of the cancer. And then if that node has cancer, the woman would go on to get the axillary lymph node dissection. So what that means is if the lymph node did not have cancer, the woman would be saved from having unnecessary surgery.
Operacija senzornih limfnih čvorova je ne tako davno promenila način lečenja raka dojke, melanoma. Žene su bile podvrgavane operacijama koje su ih onesposobljavale i putem kojih su im izvađeni svi pazušni limfni čvorovi. Kada su senzorni limfni čvorovi uvedeni u procedure lečenja, hirurg u principu traži tačno određeni čvor koji je prvi drenažni limfni čvor tkiva raka. Ukoliko ima ćelija raka u čvoru, žena bi bila podrvgnuta operaciji pazušnih limfnih čvorova. To prosto znači da žene ne bi prolazile kroz nepotrebne operacije ukoliko se rak nije proširio na limfne čvorove.
But sentinel lymph node, the way that we do it today, is kind of like having a road map just to know where to go. So if you're driving on the freeway and you want to know where's the next gas station, you have a map to tell you that that gas station is down the road. It doesn't tell you whether or not the gas station has gas. You have to cut it out, bring it back home, cut it up, look inside and say, "Oh yes, it does have gas." So that takes more time. Patients are still on the operating room table. Anesthesiologists, surgeons are waiting around. That takes time.
Senzorni limfni čvorovi i način na koji to radimo danas su bukvalno nešto kao mapa puta kako biste znali gde da idete. Ukoliko se vozite auto-putem i želite da znate lokaciju sledeće benzinske pumpe, vi imate mapu koja vam kaže gde se ta pumpa nalazi. Ne govori vam ništa o tome da li ima ili nema benzina. Morate da je isečete, donesete kući, secirate, analizirate, i zaključite: "Da, ima goriva." To traži više vremena. Pacijenti su i dalje na operacionom stolu. Anesteziolozi i hirurzi prosto čekaju. Za to je potrebno vreme.
So with our technology, we can tell right away. You see a lot of little, roundish bumps there. Some of these are swollen lymph nodes that look a little larger than others. Who amongst us hasn't had swollen lymph nodes with a cold? That doesn't mean that there's cancer inside. Well with our technology, the surgeon is able to tell immediately which nodes have cancer. I won't go into this very much, but our technology, besides being able to tag tumor and metastatic lymph nodes with fluorescence, we can also use the same smart three-part molecule to tag gadolinium onto the system so you can do this noninvasively. The patient has cancer, you want to know if the lymph nodes have cancer even before you go in. Well you can see this on an MRI.
Uz pomoć naše tehnologije, mi to odmah možemo da saznamo. Vidite ovde mnogo malih, okruglastih izbočina. Neke od njih su natečeni limfni čvorovi koji deluju veće od drugih. Ko od nas nema natečene limfne čvorove kada se prehladi? To ne znači da su unutar njih ćelije raka. Uz pomoć naše tehnologije, hirurzi odmah mogu proceniti u kojim čvorovima ima ćelija raka. Ne bih previše dataljisala o ovome, ali pored toga što je naša tehnologija u stanju da obeleži tumor i limfni čvor sa metastazama fluorescencijom, ona nam omogućava i da koristimo isti onaj pametan trodelni molekul kako bismo dodali gadolinijum u sistem i radili sve to neinvazivnim postupkom. Pacijent boluje od raka, vi želite da znate da li su limfni čvorovi zaraženi pre nego što otvorite pacijenta. To možete uraditi uz pomoć MRI tehnologije.
So in surgery, it's important to know what to cut out. But equally important is to preserve things that are important for function. So it's very important to avoid inadvertent injury. And what I'm talking about are nerves. Nerves, if they are injured, can cause paralysis, can cause pain. In the setting of prostate cancer, up to 60 percent of men after prostate cancer surgery may have urinary incontinence and erectile disfunction. That's a lot of people to have a lot of problems -- and this is even in so-called nerve-sparing surgery, which means that the surgeon is aware of the problem, and they are trying to avoid the nerves.
Važno je znati u toku operacije šta treba odstraniti. Isto toliko je važno sačuvati strukture koje su značajne za funkcionisanje. Tako da je veoma važno izbegavati povrede nastale iz nepažnje. Sada govorim o nervima. Ukoliko povredimo nerve može doći do paralize, uzrokuju bol. U slučaju raka prostate, čak i do 60 odsto muškaraca nakon operacije prostate gubi kontrolu nad bešikom i doživljava probleme sa erekcijom. To je mnogo ljudi koji imaju puno problema, a ovo je čak nešto što zovemo zahvat koji štiti nerve, što znači da su hirurzi svesni problema i pokušavaju da zaobiđu nerve.
But you know what, these little nerves are so small, in the context of prostate cancer, that they are actually never seen. They are traced just by their known anatomical path along vasculature. And they're known because somebody has decided to study them, which means that we're still learning about where they are. Crazy to think that we're having surgery, we're trying to excise cancer, we don't know where the cancer is. We're trying to preserve nerves; we can't see where they are.
Znate li da su ovi mali nervi u okviru prostate toliko mali da nikada nisu uočeni. Pratimo ih samo uz pomoć poznate anatomske putanje uz krvne sudove. Za njh znamo jer je neko odlučio da ih izučava, što znači da mi i dalje učimo gde se oni nalaze. Ludo je pomisliti da radimo operaciju, pokušavamo da otklonimo rak, a ne znamo gde se nalazi. Pokušavamo da sačuvamo nerve, a ne možemo da uočimo gde su.
So I said, wouldn't it be great if we could find a way to see nerves with fluorescence? And at first this didn't get a lot of support. People said, "We've been doing it this way for all these years. What's the problem? We haven't had that many complications." But I went ahead anyway. And Roger helped me. And he brought his whole team with him. So there's that teamwork thing again. And we eventually discovered molecules that were specifically labeling nerves. And when we made a solution of this, tagged with the fluorescence and injected in the body of a mouse, their nerves literally glowed. You can see where they are.
Zapitala sam, se zar ne bi bilo sjajno kada bih pronašla način da vidim nerve uz pomoć fluorescencije? U početku nismo naišli na mnogo podrške. Ljudi bi rekli: "Radili smo to na ovaj način godinama. U čemu je problem? Nismo imali toliko komplikacija." Ali sam ja bez obzira na to nastavila. Rodžer mi je pomogao. Poveo je svoj ceo tim. Tako da je opet u pitanju timski rad. Na kraju smo otkrili molekule koji specifično obeležavaju nerve. Kada smo napravili rastvor tog molekula i obeležili ga fluorescencijom, a potom to ubrizgali u telo miša, njihovi nervi su prosto blistali. Možete videti gde su.
Here you're looking at a sciatic nerve of a mouse, and you can see that that big, fat portion you can see very easily. But in fact, at the tip of that where I'm dissecting now, there's actually very fine arborizations that can't really be seen. You see what looks like little Medusa heads coming out. We have been able to see nerves for facial expression, for facial movement, for breathing -- every single nerve -- nerves for urinary function around the prostate. We've been able to see every single nerve. When we put these two probes together ... So here's a tumor. Do you guys know where the margins of this tumor is? Now you do. What about the nerve that's going into this tumor? That white portion there is easy to see. But what about the part that goes into the tumor? Do you know where it's going? Now you do.
Ovde možete uočiti išijadični nerv miša, i vidite da ovaj veliki, masni deo možete lako uočiti. Ali, u suštini, na vrhu mesta gde vršim disekciju sada se nalazi mesto gde dolazi do finog grananja nerva koje baš i nije lako uočiti. Možete uočiti nešto nalik na glavu male Meduze koja se probija. Uspeli smo da vidimo nerve koji kontrolišu facijalnu ekspresiju, pokrete lica, disanje - svaki pojedinačni nerv - nerve koji kontrolišu urinarnu funkciju oko prostate. Mogli smo da uočimo svaki pojedinačni nerv. Pomešali smo ove dve probe i ... Ovo je tumor. Da li znate gde su granice tumora? Sada znate. Šta je sa nervom koji ulazi u tumor? Beličasti deo je lako uočiti. Šta se dešava sa delom koji ulazi u tumor? Da li znate gde se pruža? Sada znate.
Basically, we've come up with a way to stain tissue and color-code the surgical field. This was a bit of a breakthrough. I think that it'll change the way that we do surgery. We published our results in the proceedings of the National Academy of Sciences and in Nature Biotechnology. We received commentary in Discover magazine, in The Economist. And we showed it to a lot of my surgical colleagues. They said, "Wow! I have patients who would benefit from this. I think that this will result in my surgeries with a better outcome and fewer complications."
U suštini pronašli smo način da obojimo tkivo i bojama obeležimo operativno polje. To je podsećalo na otkirće. Mislim da će to promeniti hirurgiju. Objavili smo naše rezultate u "Proceedings of the National Academy of Sciences" (PNAS) i u "Nature Biotechnology" žurnal. To je propraćeno u časopisu "Otkriće", i u "Ekonomistu". Pokazali smo to mojim kolegama hirurzima. Rekoše: "Sjajno!" Moji pacijenti bi mogli da imaju koristi od ovoga. Mislim da će ovo rezultirati u boljim ishodima operacija i manje komplikacija."
What needs to happen now is further development of our technology along with development of the instrumentation that allows us to see this sort of fluorescence in the operating room. The eventual goal is that we'll get this into patients. However, we've discovered that there's actually no straightforward mechanism to develop a molecule for one-time use. Understandably, the majority of the medical industry is focused on multiple-use drugs, such as long-term daily medications. We are focused on making this technology better. We're focused on adding drugs, adding growth factors, killing nerves that are causing problems and not the surrounding tissue. We know that this can be done and we're committed to doing it.
Sada je neophodno da dođe do daljeg razvijanja naše tehnologije koju bi pratio razvoj neophodnih instrumenata koji bi nam omogućio da vidimo ovaj tip fluorescencije u operacionoj sali. Krajni cilj jeste da na ovaj način pomognemo pacijentima. Međutim, otkrili smo da u principu ne postoji jednostavan mehanizam kojim bismo sintetisali molekul za jednokratnu upotrebu. Razumljivo je da je veliki deo medicinske industrije fokusiran na lekove za višestruku upotrebu, kao što su dnevni lekovi koji se dugo koriste. Posvećeni smo tome da tu tehnologiju unapredimo. Posvećeni smo dodavanju lekova, dodavanju hormona rasta, ubijanju nerava koji uzrokuju probleme ali ne i okolnog tkiva. Znamo da se ovo može uraditi i posvećeni smo tom radu.
I'd like to leave you with this final thought. Successful innovation is not a single breakthrough. It is not a sprint. It is not an event for the solo runner. Successful innovation is a team sport, it's a relay race. It requires one team for the breakthrough and another team to get the breakthrough accepted and adopted. And this takes the long-term steady courage of the day-in day-out struggle to educate, to persuade and to win acceptance. And that is the light that I want to shine on health and medicine today.
Želim da završim ovom mišlju. Uspešan izum nije jedno veliko otkriće. To nije sprint trka. To nije događaj za solo trkača. Uspešni pronalsci su rezultat timskog sporta, štafete. Neophodan je jedan tim za otkriće i drugi tim koji će otkriće učiniti prihvaćenim. Sve to zahteva dugotrajnu, nepokolebljivu hrabrost za vođenje svakodnevne borbe da obrazujete, ubedite i konačno dođete do prihvatanja. To je svetlost kojom želim da obasjam zdravstvo i medicinu današnjice.
Thank you very much.
Hvala vam mnogo.
(Applause)
(Aplauz)