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."
Prije 10 godina preselio sam se u Boston, iz Chicaga, sa zanimanjem za rak i kemiju. Možda znate da je kemija znanost stvaranja molekula -- ili po mom ukusu, novih droga za rak. I također možda znate da je za znanost i medicinu Boston nešto poput trgovine slatkiša. Ne možete svinuti znak stop na Cambridgeu, a da ne naletite na postdiplomca. Bar se zove Čudo Znanosti. Plakati kažu „Dostupan laboratorij.“
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.
I pošteno je reći da smo u ovih deset godina svjedočili apsolutnom početku znanstvene revolucije -- genomske medicine. Sada, više nego ikada prije znamo o pacijentima koji ulaze u našu klinku. I u mogućnosti smo, konačno, odgovoriti na pitanje koje nas je pritiskalo mnogo godina: zašto imam rak? Ova informacija je također prilično zapanjujuća. Možda znate da je do sada, u svitanju ove revolucije, poznato da postoji možda 40.000 jedinstvenih mutacija koje utječu na više od 10.000 gena i da postoji 500 od tih gena koji su dobrovoljni upravitelji, uzroci raka.
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.
Ipak usporedno, imamo dvanaestak ciljanih lijekova. A ta neadekvatnost medicine raka zaista je pogodila srž kad je mom ocu dijagnosticiran rak gušterače. Nismo ga prevezli u Boston. Nismo sekvencionirali njegov genom. Desetljećima je poznato što uzrokuje ovaj malignitet. To su tri proteina -- Ras, MIC i P53. To je stara informacija koju znamo još od osamdesetih, no ipak još uvijek ne postoji lijek koji mogu prepisati pacijentu s ovim ili bilo kojim od brojnih solidnih tumora uzrokovanih od ova tri konjanika apokalipse koji se zovu rak. Nema Ras, ni MIC ni P53 lijeka.
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.
I imate svako pravo pitati: zašto je to tako? I veoma nezadovoljavajuć, iako znanstven, odgovor je da je preteško. Da su iz nekog razloga, ova tri proteina ušla u prostor u jeziku našeg područja koji se zove genom kojeg je nemoguće liječiti -- to je kao da nazovete kompjuter nemogućim za surfanje ili Mjesec nemogućim za hodanje. To je užasan naziv struke. Ali to znači da nismo uspjeli identificirati masne džepove u ovim proteinima u kojima poput molekularnih bravara, možemo oblikovati aktivne, male, organske molekule u supstancu lijeka.
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.
Dok sam se obučavao u kliničkoj medicini i hematologiji i onkologiji i transplantaciji matičnih stanica, umjesto toga imali smo, kaskadirajući kroz regulatornu mrežu FDA, bile su to supstance -- arsen, talidomid i taj kemijski derivat iperit dušika. A ovo je 21. stoljeće. I moglo bi se reći, nezadovoljan učinkom i kvalitetom ovih lijekova, otišao sam natrag u školu na kemiju s idejom da bi se možda učeći zanat kemije koja otkriva i ako joj pristupim u kontekstu ovog hrabrog novog svijeta otvorenih izvora, izvora mase, suradničke mreže kojoj smo pristupili unutar akademije, da bismo možda brže mogli donijeti moćnije i ciljane 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.
I molim vas da ovo smatrate radom koji je u tijeku , ali danas bih vam želio ispričati priču o veoma rijetkom raku pod imenom midline karcinom, o ciljnom proteinu, ciljnom proteinu koji se ne može liječiti, a uzrokuje ovaj rak, zvanom BRD4 i o molekuli razvijenoj u mom laboratoriju u Dana Farber Institutu za rak nazvanom JQ1 koji smo strastveno nazvali po Jun Qiju, kemičaru koji je stvorio ovu molekulu. 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 se upitati, s obzirom na sve stvari koje rak pokušava učiniti ne bi li ubio našeg pacijenta, kako zapamti da je rak? Kada smota svoj genom, podijeli se na dvije stanice i ponovo se odmota, zašto se ne pretvori u oko, u jetru s obzirom da ima sve potrebne gene kako bi to napravio? Sjeća se da je rak. A razlog tome je da rak, poput svake stanice u tijelu, ostavlja male molekularne oznake, male naljepnice koje podsjete stanicu „Ja sam rak; trebao bih nastaviti rasti.“ I te naljepnice uključuju ovaj i ostale proteine te vrste -- takozvane bromodomene. Pa smo razvili ideju, racionalnu, da možda, ako napravimo molekulu koja sprječava naljepnicu da se zalijepi prilikom ulaska u mali džep na osnovi ovog proteina koji se vrti, onda bismo možda mogli uvjeriti stanice raka, naravno one ovisne o svom BRD4 proteinu da nisu rak.
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 raditi na ovom problemu. Razvili smo knjižnice spojeva i s vremenom došli do ove i sličnih supstanci nazvanih JQ1. S obzirom da nismo farmaceutska tvrtka, mogli smo raditi određene stvari, imali smo određene fleksibilnosti za koje poštujem što ih farmaceutska industrija nema. Počeli smo je slati našim prijateljima. Imam mali laboratorij. Mislili smo da bismo mogli poslati ljudima i vidjeti kako će se molekula ponašati. I poslali smo je u Oxford u Englesku gdje je ekipa talentiranih kristalografa osigurala ovu sliku koja nam je pomogla da točno razumijemo kako je ova molekula tako moćna za ovaj ciljani protein. To je ono što zovemo savršeno slaganje komplementarnosti oblika ili 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.
Dakle, ovo je veoma rijedak rak, ovaj rak ovisan o BRD4. Radili smo s uzorcima materijala koje je skupio mladi patolog u bolnici Brigham Women. I kako smo liječili te stanice s ovom molekulom, opazili smo nešto veoma upečatljivo. Stanicama raka, malim i okruglima koje su se brzo dijelile, narasle su ruke i nastavci. Mijenjale su oblik. Kao rezultat, stanice raka su zaboravljale da su rak i postajale su normalne stanice.
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.
Zbog toga smo bili jako uzbuđeni. Sljedeći korak bi bio staviti ovu molekulu u miša. Jedini problem je bio u tome što nema mišjeg modela za ovaj rijedak rak. U vrijeme kad smo radili na ovom istraživanju, brinuo sam se za 29-ogodišnjeg vatrogasca iz Connecticuta koji je bio na kraju svog života s tim neizliječivim rakom. Taj rak ovisan od BRD4 je rastao kroz njegovo lijevo plućno krilo i imao je cijev u prsima u koji su se odlijevali mali komadići krhotina. I za vrijeme svakog njegovanja bacili bismo taj materijal. Prišli smo tom pacijentu i upitali ga bi li surađivao s nama. Možemo li uzeti taj vrijedan i rijedak kancerogeni materijal iz cijevi koja vodi iz njegovih prsa, odvesti to preko cijelog grada i staviti u miša i pokušati napraviti klinički test i suprotstaviti mu prototip lijeka? To bi bilo nemoguće i naravno, ilegalno napraviti na ljudima. I on nam se obvezao. U Lurie Obiteljskom centru za snimanje životinja, moj kolega, Andrew Kung, uspješno je uzgojio ovaj rak u mišu bez da je dotakao plastiku.
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 vidjeti ovaj PET scan miša -- zovemo ga pet PET. Rak raste kao ova crvena, velika masa u stražnjim nogama ove životinje. I kako ga liječimo našim spojem, ova ovisnost o šećeru, taj ubrzani rast je blijedio. I na životinji koju vidite desno, vidite da rak reagira. Sada smo završili klinička istraživanja na četiri mišja modela ove bolesti. I svaki puta smo vidjeli istu stvar. Miš s ovim rakom koji je dobio lijek živi, a oni koji ne dobiju ubrzano umiru.
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.
Počeli smo se pitati što bi farmaceutska kompanija učinila u ovom trenu? Vjerojatno bi čuvali ovu tajnu dok ne bi prototip lijeka pretvorili u aktivnu farmaceutsku supstancu. Pa smo mi učinili totalno suprotno. Objavili smo članak koji opisuje ovo otkriće u najranijem stadiju prototipa. Dali smo svijetu kemijski identitet ove molekule što je obično tajna u našoj disciplini. Rekli smo ljudima kako smo je točno napravili. Dali smo im naše e-mail adrese, predlažući da, ako nam pišu, poslat ćemo im besplatnu molekulu.
(Laughter)
Zapravo smo pokušali stvoriti
We basically tried to create the most competitive environment for our lab as possible. And this was, unfortunately, successful.
najkonkurentniji okoliš za naš laboratorij, što je više moguće. I to je nažalost bilo uspješno. (Smijeh)
(Laughter)
Zato što, sada kada smo podijelili ovu molekulu,
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.
od prosinca prošle godine, u 40 laboratorija u SAD-u i još 30 u Europi -- mnoge od njihovih farmaceutskih kompanija traže sada kako ući u taj prostor kako bi nanišanili ovaj rijedak rak koji je trenutno srećom, prilično poželjan za proučavanje u toj industriji. Ali znanost koja dolazi natrag iz svih tih laboratorija o upotrebi ove molekule nam je osigurala uvide koje možda sami ne bismo vidjeli. Stanice leukemije tretirane ovim spojem pretvaraju se u normalne stanice bijele loze. Miševi s multiplim mijelomima, neizliječivim malignitetom koštane srži, dramatično reagiraju na liječenje ovim lijekom. Možda znate da mast ima pamćenje. Drago mi je što vam to mogu demonstrirati.
(Laughter)
I zapravo, ova molekula
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 --
spriječava ovaj adipocit, ovu masnu matičnu stanicu da se sjeti kako napraviti mast tako da miševi na dijeti bez visokih masnoća, poput ljudi iz mog rodnog grada Chicaga,
(Laughter)
ne uspiju razviti masnu jetru,
fail to develop fatty liver, which is a major medical problem.
koja je 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 nas je ovo istraživanje naučilo -- ne samo moj laboratorij, već naš institut i hardvardsku Medicinsku školu još više -- jest da imamo jedinstvene resurse u akademiji za otkrivanje lijeka -- da naš centar koji je testirao možda više molekula raka na znanstveni način nego na bilo koji drugi, nikad nije sam za sebe. Za sve razloge koje vidite ovdje nabrojene, mislimo da postoji velika prilika za akademske centre da sudjeluju u ovoj najranijoj, konceptualno lukavoj disciplini za otkriće prototipa lijeka.
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.
Dakle, što dalje? Imamo ovu molekulu, ali to još nije pilula. Još nije oralno dostupna. Moramo je popraviti da je možemo dostaviti našim pacijentima. I svi se u ovom laboratoriju, posebno prateći interakciju s tim pacijentima osjećaju prilično prisiljenima da naprave supstancu baziranu na ovoj molekuli. Ovdje moram reći da bi nam dobro došla vaša pomoć i vaši uvidi, vaša suradnja. Za razliku od farmaceutske kompanije, nemamo cjevovod u koji možemo pohraniti ove molekule. Nemamo tim prodavača i trgovaca koji nam mogu reći kako smjestiti ovaj lijek nasuprot drugog. Ono što imamo je fleksibilnost akademskog centra da radi sa sposobnim, motiviranim, entuzijastičnim, nadajmo se dobrostojećim ljudima koji nose ove molekule naprijed u kliniku dok održavaju našu sposobnost da dijelimo prototip lijeka širom svijeta.
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?"
Ova molekula će uskoro napustiti naše klupe i otići u malo poduzeće koja se tek pokreće pod imenom Tensha Therapeutics. I stvarno ovo je četvrta od ovih molekula koja nekako završava od našeg malog cjevovoda otkrića lijeka, od kojih će dva -- tematski lijek za limfom kože, oralna supstanca za liječenje multiplog mijeloma -- zapravo doći do nas kao prvi klinički pokus u srpnju ove godine. Za nas, velika i uzbudljiva prekretnica. Želim vas ostaviti sa samo dvije ideje. Prva je da ako je išta jedinstveno u vezi ovog istraživanja, da je to mnogo manje znanost nego strategija -- da je ovo za nas bio socijalni eksperiment, eksperiment u kojem bi se dogodilo da smo toliko otvoreni i iskreni u najranijoj fazi otkrića kemijskog istraživanja koliko možemo biti.
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, brojki, simbola i zagrada koja se može poslati, pretpostavljam, ili podijeliti na Twitteru širom svijeta, je kemijski identitet našeg prethodnog spoja. To je informacija koju najviše trebamo od farmaceutskih kompanija, informacija o tome kako bi ovi rani prototipovi lijekova mogli raditi. Ipak, ta informacija je u velikoj mjeri tajna. I tako zaista tražimo kako bismo kopirali dva principa izuzetnog uspjeha industrije računalne znanosti: princip otvorenog izvora i princip izvora mnoštva do brzog i odgovornog ubrzanja pošiljke ciljanih terapeutika do pacijenata s 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.
Sada poslovni model uključuje sve vas. Ovo istraživanje je financirano od strane javnosti. Financirano je iz temelja. I jedna stvar koju sam naučio u Bostonu je da ćete vi ljudi sve učiniti za rak -- i volim to. Vozite biciklom kroz državu. Hodate gore i dolje uz rijeku.
(Laughter)
(Smijeh)
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.
Nikada nisam zaista nigdje vidio tu jedinstvenu podršku za istraživanje raka. I zato vam želim zahvaliti na vašem sudjelovanju, vašoj suradnji i najviše od svega vašoj vjeri u naše ideje. (Pljesak)
(Applause)