I moved to Boston 10 years ago from Chicago, with an interest in cancer and in chemistry. You might know that chemistry is the science of making molecules or, to my taste, new drugs for cancer. And you might also know that, for science and medicine, Boston is a bit of a candy store. You can't roll a stop sign in Cambridge without hitting a graduate student. The bar is called the Miracle of Science. The billboards say "Lab Space Available."
Preselio sam se u Boston iz Čikaga, pre 10 godina, zanimali su me rak i hemija. Možda znate da je hemija nauka o pravljenju molekula ili, što se meni sviđa, novih lekova za rak. Možda takođe znate da je, što se nauke i medicine tiče, Boston neka vrsta poslastičarnice. U Kembridžu, ne možete da stavite ni saobraćajni znak za stop, a da ne udarite nekog studenta na doktoratu. Čak se i kafić zove "Čudo nauke". Na bilbordima su oglasi "Imamo poslovni prostor za laboratoriju".
And it's fair to say that in these 10 years, we've witnessed absolutely the start of a scientific revolution -- that of genome medicine. We know more about the patients that enter our clinic now than ever before. And we're able, finally, to answer the question that's been so pressing for so many years: Why do I have cancer? This information is also pretty staggering. You might know that, so far, in just the dawn of this revolution, we know that there are perhaps 40,000 unique mutations affecting more than 10,000 genes, and that there are 500 of these genes that are bona-fide drivers, causes of cancer.
Može se reći da smo, u ovih 10 godina, svedoci samog početka naučne revolucije, koja se odnosi na genomsku medicinu. Sada znamo više nego ikada ranije o pacijentima koji nam dolaze u bolnice. Konačno smo u stanju da odgovorimo na pitanje koje se postavlja već toliko godina: zašto imam rak? Informacije o tome su prilično zapanjujuće. Možda znate da, iako smo još na početku ove revolucije, znamo da postoji oko 40.000 jedinstvenih mutacija koje pogađaju više od 10.000 gena, i da, među tim genima, ima 500 gena koji zaista i utiču, i izazivaju rak.
Yet comparatively, we have about a dozen targeted medications. And this inadequacy of cancer medicine really hit home when my father was diagnosed with pancreatic cancer. We didn't fly him to Boston. We didn't sequence his genome. It's been known for decades what causes this malignancy. It's three proteins: ras, myc, p53. This is old information we've known since about the 80s, yet there's no medicine I can prescribe to a patient with this or any of the numerous solid tumors caused by these three ... Horsemen of the Apocalypse that is cancer. There's no ras, no myc, no p53 drug.
Međutim, u poređenju sa tim, imamo oko desetak tzv. ciljanih lekova. Ova nesposobnost u lečenju raka me je lično pogodila, kad je moj otac dobio dijagnozu za rak pankreasa. Nismo ga doveli u Boston. Nismo sekvencionirali njegov genom. Već je decenijama poznato šta izaziva ovaj malignitet. To su tri proteina - Ras, MIC i P53. To su stare informacije koje znamo još od '80-ih, a ipak ne postoji lek koji mogu da prepišem pacijentu koji ima ovaj ili bilo koji drugi od brojnih čvrstih tumora koje izazivaju ova tri jahača apokalipse koju zovemo rak. Nema leka usmerenog na Ras, MIC ili P53.
And you might fairly ask: Why is that? And the very unsatisfying yet scientific answer is: it's too hard. That for whatever reason, these three proteins have entered a space, in the language of our field, that's called the undruggable genome -- which is like calling a computer unsurfable or the Moon unwalkable. It's a horrible term of trade. But what it means is that we've failed to identify a greasy pocket in these proteins, into which we, like molecular locksmiths, can fashion an active, small, organic molecule or drug substance.
Mogli biste, s pravom, da pitate: zbog čega? Vrlo nezadovoljavajući, ali ipak naučni odgovor je da je suviše teško. Iz različitih razloga su, ova tri proteina ušla u jednu sferu u našoj oblasti koja se naziva "genom bez lekova" to je kao da kažemo "kompjuter koji ne pretražuje podatke" ili kad bismo rekli da je nemoguće hodati po Mesecu. To je grozan tehnički termin. Ali, to znači da nismo uspeli da identifikujemo "masni džep" u ovim proteinima, u koji bismo mogli da, kao molekularni bravari, ubacimo aktivni, mali, organski molekul ili komponentu leka.
Now, as I was training in clinical medicine and hematology and oncology and stem-cell transplantation, what we had instead, cascading through the regulatory network at the FDA, were these substances: arsenic, thalidomide, and this chemical derivative of nitrogen mustard gas. And this is the 21st century. And so, I guess you'd say, dissatisfied with the performance and quality of these medicines, I went back to school, in chemistry, with the idea that perhaps by learning the trade of discovery chemistry and approaching it in the context of this brave new world of the open source, the crowd source, the collaborative network that we have access to within academia, that we might more quickly bring powerful and targeted therapies to our patients.
Za vreme moje specijalizacije za kliničku medicinu hematologiju i onkologiju i transplantaciju matičnih ćelija, ono što je postojalo umesto toga, što je skakutalo kroz mrežu propisa Federalne Agencije za Lekove, su bile ove supstance arsen, talidomid i ovaj hemijski derivat azotnog tzv. "senfnog gasa". A ovo je 21.vek. Budući da sam bio, u najmanju ruku, nezadovoljan učinkom i kvalitetom ovih lekova, počeo sam da učim hemiju sa idejom da možda, učeći tehniku otkrivanja hemijskih komponenti i pristupajući tome na način ovog vrlog novog sveta korišćenja tzv. koncepta slobodnog pristupa i tzv. grupnog pristupa tj. kolaborativne mreže koju koristimo u naučnim institucijama, da bismo mogli brže da ponudimo moćne i usmerene terapije našim pacijentima.
And so, please consider this a work in progress, but I'd like to tell you today a story about a very rare cancer called midline carcinoma, about the undruggable protein target that causes this cancer, called BRD4, and about a molecule developed at my lab at Dana-Farber Cancer Institute, called JQ1, which we affectionately named for Jun Qi, the chemist that made this molecule. Now, BRD4 is an interesting protein.
Molim vas da imate na umu da je ovo posao koji još traje, ali bih danas želeo da vam ispričam priču o vrlo retkom raku koji se zove karcinom srednje linije, i o ciljnom proteinu, proteinu za koji nema lekova koji se naziva BRD4, i o molekulu sintetisanom u mojoj laboratoriji u Dejna Farber Kancer Institutu koji smo nazvali JQ1, u čast Džun Či, hemičara koji je sintetisao ovaj molekul. BRD4 je zanimljiv protein.
You might ask: with all the things cancer's trying to do to kill our patient, how does it remember it's cancer? When it winds up its genome, divides into two cells and unwinds again, why does it not turn into an eye, into a liver, as it has all the genes necessary to do this? It remembers that it's cancer. And the reason is that cancer, like every cell in the body, places little molecular bookmarks, little Post-it notes, that remind the cell, "I'm cancer; I should keep growing." And those Post-it notes involve this and other proteins of its class -- so-called bromodomains. So we developed an idea, a rationale, that perhaps if we made a molecule that prevented the Post-it note from sticking by entering into the little pocket at the base of this spinning protein, then maybe we could convince cancer cells, certainly those addicted to this BRD4 protein, that they're not cancer.
Mogli biste da se zapitate, dok rak radi sve te stvari kojima pokušava da nam ubije pacijenta, kako se uopšte seti da je rak? Kada razmota svoj genom, podeli se na dve ćelije i ponovo se zamota, zašto ne postane oko, ili jetra, jer ima sve gene neophodne za to? Ali seća se da je rak. Razlog je taj da rak, kao svaka ćelija u telu, postavlja male molekularne oznake, samolepljive papiriće, koje podsećaju ćeliju, "ja sam rak, treba da nastavim da rastem." Te samolepljive poruke obuhvataju ovaj i druge proteine te klase, takozvane bromodomene. Mi smo razvili ideju, osnovu istraživanja, da, možda, ako bismo napravili molekul koji bi sprečio tu poruku da se zalepi tako što bi ušao u mali džep u osnovi ovog proteina koji se tu obrće, onda bismo mogli da ubedimo ćelije raka, naročito one koje su zavisne od BRD4 proteina, da one nisu ćelije raka, da nisu kancer.
And so we started to work on this problem. We developed libraries of compounds and eventually arrived at this and similar substances called JQ1. Now, not being a drug company, we could do certain things, we had certain flexibilities, that I respect that a pharmaceutical industry doesn't have. We just started mailing it to our friends. I have a small lab. We thought we'd just send it to people and see how the molecule behaves. We sent it to Oxford, England, where a group of talented crystallographers provided this picture, which helped us understand exactly how this molecule is so potent for this protein target. It's what we call a perfect fit of shape complementarity, or hand in glove.
Tako smo počeli da radimo na tom problemu. Napravili smo biblioteke hemijskih jedinjenja i, na kraju smo stigli do ove, i nekih sličnih supstanci nazvane JQ1. Budući da nismo farmaceutska kompanija, mogli smo da radimo neke stvari, imali smo izvesnu fleksibilnost, koju farmaceutska industrija nema. Jednostavno smo počeli da ovu supstancu šaljemo prijateljima. Moja laboratorija je mala. Pomislili smo da samo pošaljemo ovaj molekul drugima i vidimo kako se ponaša. Poslali smo ga u Oksford, u Englesku, gde je grupa talentovanih kristalografa napravila ovu sliku, što nam je pomoglo da shvatimo zašto je, u stvari, ovaj molekul tako efikasan za ovaj ciljani protein. To je ono što nazivamo savršenim uklapanjem komplementarnih delova, kao ruka u rukavici.
Now, this is a very rare cancer, this BRD4-addicted cancer. And so we worked with samples of material that were collected by young pathologists at Brigham and Women's Hospital. And as we treated these cells with this molecule, we observed something really striking. The cancer cells -- small, round and rapidly dividing, grew these arms and extensions. They were changing shape. In effect, the cancer cell was forgetting it was cancer and becoming a normal cell.
Ovo je vrlo redak rak, ovaj rak zavistan od BRD4. Radili smo sa uzorcima materijala koji su sakupili mladi patolozi u Brigam ženskoj bolnici. Kada smo ove ćelije tretirali tim molekulom, primetili smo nešto zaista zadivljujuće. Ćelije raka, male, okrugle ćelije koje se brzo dele, su formirale ove produžetke. Menjale su oblik. U stvari, ćelija raka je počela da zaboravlja da je kancerozna i postajala je normalna ćelija.
This got us very excited. The next step would be to put this molecule into mice. The only problem was there's no mouse model of this rare cancer. And so at the time we were doing this research, I was caring for a 29-year-old firefighter from Connecticut who was very much at the end of life with this incurable cancer. This BRD4-addicted cancer was growing throughout his left lung. And he had a chest tube in that was draining little bits of debris. And every nursing shift, we would throw this material out. And so we approached this patient and asked if he would collaborate with us. Could we take this precious and rare cancerous material from this chest tube and drive it across town and put it into mice and try to do a clinical trial at a stage that with a prototype drug, well, that would be, of course, impossible and, rightly, illegal to do in humans. And he obliged us. At the Lurie Family Center for Animal Imaging, our colleague, Andrew Kung, grew this cancer successfully in mice without ever touching plastic.
Bili smo veoma uzbuđeni zbog toga. Sledeći korak bi bio da se ovaj molekul upotrebi na miševima. Jedini problem je bio što, za ovaj redak rak, nema modela na miševima. U vreme kada smo radili ovo istraživanje, brinuo sam se o 29-godišnjem vatrogascu iz Konektikata koji je bio maltene na samrti zbog ovog neizlečivog raka. Ovaj BRD4-zavisni rak mu je rastao kroz levo plućno krilo, i imao je kateter u grudima za dreniranje otpadnih materija. U svakoj smeni ovaj materijal se bacao. Došli smo kod ovog pacijenta i pitali da li bi sarađivao sa nama. Da li bismo mogli da uzmemo te dragocene, retke kancerozne materije iz grudnog katetera, da ih prevezemo na drugi deo grada i ubacimo u miševe i pokušamo da izvedemo kliničku studiju i stignemo do stupnja prototipa za lek? To bi bilo i nemoguće i protivzakonito, s pravom, da se uradi na ljudima. On se složio. U Centru za vizuelizaciju procesa kod životinja "Porodica Luri" moj kolega, Endrju Kang, je uspešno formirao ovaj kancer kod miševa i to bez korišćenja plastike.
And you can see this PET scan of a mouse -- what we call a pet PET. The cancer is growing as this red, huge mass in the hind limb of this animal. And as we treat it with our compound, this addiction to sugar, this rapid growth, faded. And on the animal on the right, you see that the cancer was responding. We've completed, now, clinical trials in four mouse models of this disease. And every time, we see the same thing. The mice with this cancer that get the drug live, and the ones that don't rapidly perish.
Možete videti ovaj PET sken miša, mi ga zovemo "ljubimac PETko". Rak se povećava, što se vidi kao ova crvena, ogromna masa u zadnjoj nozi životinje. A kada primenimo tretman našom supstancom, ova zavisnost od šećera, ovaj brzi rast, iščezava. I kod životinje sa desne strane, vidite da rak reaguje na tretman. Sada završavamo kliničke studije na četiri mišja modela ove bolesti. Svaki put primećujemo istu stvar. Miševi sa rakom koji prime lek preživljavaju, dok oni koji ne prime lek, brzo uginu.
So we started to wonder, what would a drug company do at this point? Well, they probably would keep this a secret until they turn the prototype drug into an active pharmaceutical substance. So we did just the opposite. We published a paper that described this finding at the earliest prototype stage. We gave the world the chemical identity of this molecule, typically a secret in our discipline. We told people exactly how to make it. We gave them our email address, suggesting that if they write us, we'll send them a free molecule.
Tu smo se zapitali, šta bi farmaceutska kompanija uradila na tom stupnju? Pa, oni bi to verovatno držali u tajnosti dok ne prevedu ovaj prototip leka u aktivnu farmaceutsku supstancu. Mi smo uradili upravo suprotno. Objavili smo rad koji opisuje ovo otkriće na najranijem stupnju prototipa za lek. Dali smo celom svetu hemijski identitet ovog molekula, što je obično tajna u našoj oblasti. Tačno smo objasnili ljudima kako da ga naprave. Dali smo im našu imejl adresu, i tako nagovestili da, ako nam pišu, da ćemo im besplatno poslati molekul.
(Laughter)
U suštini, pokušali smo da stvorimo
We basically tried to create the most competitive environment for our lab as possible. And this was, unfortunately, successful.
najveću moguću konkurenciju našoj laboratoriji. I to nam je, na žalost, uspelo. (Smeh)
(Laughter)
Jer sada, pošto smo podelili ovaj molekul,
Because now, we've shared this molecule, just since December of last year, with 40 laboratories in the United States and 30 more in Europe -- many of them pharmaceutical companies, seeking now to enter this space, to target this rare cancer that, thankfully right now, is quite desirable to study in that industry. But the science that's coming back from all of these laboratories about the use of this molecule has provided us insights we might not have had on our own. Leukemia cells treated with this compound turn into normal white blood cells. Mice with multiple myeloma, an incurable malignancy of the bone marrow, respond dramatically to the treatment with this drug. You might know that fat has memory. I'll nicely demonstrate that for you.
samo od decembra prošle godine, 40 laboratorija iz SAD-a i još 30 iz Evrope - mnoge od njih su farmaceutske kompanije i sada pokušavaju da uđu u ovu oblast, usmerenu na ovaj retki rak koji je, upravo sada, na sreću, sasvim poželjna tema za ispitivanje u toj industriji. Ali naučni podaci, koji zauzvrat, stižu iz svih tih laboratorija o primeni ovog molekula pružaju nam uvid, koji možda nikada ne bismo imali da smo radili sami. Ćelije leukemije tretirane ovim jedinjenjem postaju normalna bela krvna zrnca. Miševi sa višestrukim mijelomima, neizlečivim malignitetom koštane srži, reaguju vrlo dramatično na tretman ovim lekom. Možda znate da masno tkivo može da pamti. Baš lepo što mogu to da vam demonstriram.
(Laughter)
I, zapravo, ovaj molekul
In fact, this molecule prevents this adipocyte, this fat stem cell, from remembering how to make fat, such that mice on a high-fat diet, like the folks in my hometown of Chicago --
sprečava taj adipocit, tu masnu matičnu ćeliju. da se seti kako da pravi mast tako da miševi sa ishranom bogatom mastima, kao što jedu ljudi u mom rodnom gradu Čikagu,
(Laughter)
fail to develop fatty liver, which is a major medical problem.
ipak ne razvijaju tzv. "masnu jetru", što, inače, predstavlja veliki medicinski problem.
What this research taught us -- not just my lab, but our institute, and Harvard Medical School more generally -- is that we have unique resources in academia for drug discovery; that our center, which has tested perhaps more cancer molecules in a scientific way than any other, never made one of its own. For all the reasons you see listed here, we think there's a great opportunity for academic centers to participate in this earliest, conceptually tricky and creative discipline of prototype drug discovery.
Ono što smo naučili iz ovog istraživanja ne samo moja laboratorija, nego naš institut, i generalno, ceo Harvard medicinski fakultet, je da imamo posebne akademske resurse za otkrivanje lekova i to da naš centar, koji je, ispitao više kancer-molekula, na naučni način, nego bilo koji drugi, nije nikada napravio nijedan sopstveni. Iz svih ovih razloga koje vidite ovde navedene, mislimo da postoji odlična prilika za akademske centre da učestvuju u ovoj mladoj, konceptualno nedefinisanoj i kreativnoj disciplini pronalaženja prototipova za lekove.
So what next? We have this molecule, but it's not a pill yet. It's not orally bioavailable. We need to fix it so we can deliver it to our patients. And everyone in the lab, especially following the interaction with these patients, feels quite compelled to deliver a drug substance based on this molecule. It's here where I'd say that we could use your help and your insights, your collaborative participation. Unlike a drug company, we don't have a pipeline that we can deposit these molecules into. We don't have a team of salespeople and marketeers to tell us how to position this drug against the other. What we do have is the flexibility of an academic center to work with competent, motivated, enthusiastic, hopefully well-funded people to carry these molecules forward into the clinic while preserving our ability to share the prototype drug worldwide.
I šta dalje? Imamo ovaj molekul, ali to još nije pilula. Ne može se uzimati oralnim putem. Moramo to da sredimo, da bismo mogli da ga dajemo našim pacijentima. Svi u laboratoriji se, naročito posle kontakta sa ovim pacijentima, osećaju posebno motivisani da naprave lek baziran na ovom molekulu. Ovo je trenutak kad moram da kažem da nam treba vaša pomoć i vaša pronicljivost, vaše kolaborativno učestvovanje. Za razliku od farmaceutske kompanije, mi nemamo proizvodnu liniju u koju možemo ubaciti ove molekule. Nemamo tim prodavaca i snabdevača koji nam mogu reći kako da postavimo ovaj lek u odnosu na druge. Ono što mi imamo je fleksibilnost akademskog centra u radu sa kompetentnim, motivisanim, ljudima sa puno entuzijazma i sa, nadajmo se, puno novca, da ove molekule prenesu do kliničke upotrebe, pri tome čuvajući sposobnost za razmenu prototipova lekova među naučnicima širom sveta.
This molecule will soon leave our benches and go into a small start-up company called Tensha Therapeutics. And, really, this is the fourth of these molecules to kind of "graduate" from our little pipeline of drug discovery, two of which -- a topical drug for lymphoma of the skin and an oral substance for the treatment of multiple myeloma -- will actually come to the bedside for the first clinical trial in July of this year -- for us, a major and exciting milestone. I want to leave you with just two ideas. The first is: if anything is unique about this research, it's less the science than the strategy. This, for us, was a social experiment -- an experiment in "What would happen if we were as open and honest at the earliest phase of discovery chemistry research as we could be?"
Ovaj molekul će uskoro izaći iz laboratorije i otići u malu novo-formiranu kompaniju pod nazivom "Tenša Terapije". Zapravo, to je četvrti od ovih molekula, koji, na neki način, maturira iz naše male produkcije novih lekova, od koji će dva - topični lek za kožne limfome, i oralna supstanca za tretman višestrukih mijeloma zaista i stići do bolnica za prvu kliničku studiju u julu ove godine. Za nas, to je veliko i uzbudljivo dostignuće. Za kraj, želim da vam prenesem ove dve ideje. Prva je to da, ako je išta specifično u vezi sa ovim istraživanjem, to je manje naučne, a više strateške prirode za nas je ovo bio društveni eksperiment, o tome šta se dešava kada pokušamo da budemo otvoreni i iskreni, u najranijoj fazi istraživanja hemijskog otkrivanja lekova, i to u najvećoj mogućoj meri.
This string of letters and numbers and symbols and parentheses that can be texted, I suppose, or Twittered worldwide, is the chemical identity of our pro compound. It's the information that we most need from pharmaceutical companies, the information on how these early prototype drugs might work. Yet this information is largely a secret. And so we seek, really, to download from the amazing successes of the computer-science industry, two principles -- that of open source and that of crowdsourcing -- to quickly, responsibly accelerate the delivery of targeted therapeutics to patients with cancer.
Ovaj niz slova i brojeva, simbola i zagrada, koji mislim da može da se pošalje SMS porukom, ili preko Tvitera, širom sveta, je hemijski identitet našeg prototip-jedinjenja. Informacija koja nam najviše treba od farmaceutskih kompanija, informacija o tome kako ovi rani prototipovi lekova mogu da rade. A ipak, ova informacija je najčešće tajna. Mi zapravo težimo tome, da primenimo neverovatne uspehe 2 principa informatičke industrije: tzv. "slobodnog pristupa" i tzv. "grupnog pristupa" da bismo efikasno i odgovorno ubrzali proces dopremanja ciljanih terapija do pacijenata sa rakom.
Now, the business model involves all of you. This research is funded by the public. It's funded by foundations. And one thing I've learned in Boston is that you people will do anything for cancer, and I love that. You bike across the state, you walk up and down the river.
I taj poslovni model uključuje sve vas. Ovo istraživanje je finansirano od strane celog društva. Finansiraju ga fondacije. Jednu stvar sam naučio u Bostonu, a to je, da će građani Bostona uraditi sve za kancer, i to mi se jako sviđa. Vozite bicikl preko cele države.
(Laughter)
Idete u organizovane šetnje celom dužinom reke.
I've never seen, really, anywhere, this unique support for cancer research. And so I want to thank you for your participation, your collaboration and most of all, for your confidence in our ideas.
(Smeh) Zaista, nigde do sada nisam video ovako jedinstvenu podršku istraživanjima raka. Zato bih želeo da vam zahvalim za učestvovanje, vašu saradnju i, pre svega, za poverenje u naše ideje.
(Applause)
(Aplauz)