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."
Mudeime de Chicago a Boston hai 10 anos, interesado no cancro e na química. Pode que xa saibades que a química é a ciencia que fabrica moléculas, ou no meu caso, novos fármacos para o cancro. E pode que tamén saibades, que para a ciencia e a medicina, Boston é coma unha tenda de lambetadas. Non podes pasar un stop en Cambridge sen dar cun estudante universitario. Ó bar chámanlle "o milagre da ciencia". A maioría dos anuncios falan de "Laboratorios dispoñibles".
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.
E poderiamos dicir que dende hai uns 10 anos estamos a presenciar a comezo dunha revolución científica: a medicina xenómica. Sabemos máis dos pacientes que entran nas nosas clínicas do que nunca soubemos. E podemos, por fin, responder á pregunta que nos ten urxido durante tantos anos: por que temos cancro? Esta información é bastante sorprendente. Pode que xa saibades que, por agora, nos comezos desta revolución, sabemos que hai coma unhas 40.000 mutacións que afectan a máis de 10.000 xenes; e que 500 deses xenes, dan lugar a cancros, de forma contrastada.
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.
Pero en cambio, temos coma unha ducia de medicamentos dirixidos. E esta falta de eficiencia no tratamento do cancro afectoume moito cando lle diagnosticaron cancro de páncreas ó meu pai. Non o trouxemos a Boston. Nin secuenciamos o seu xenoma. Hai décadas que se sabe que é o que causa estes tumores. Son tres proteínas: Ras, MIC e p53. Sabemos esta información xa dende os anos 70, pero aínda non se pode recetar unha menciña a un paciente con este ou calquera dos outros tumores que causan estes tres xinetes do apocalipsis que chamamos cancro. Non hai tratamento para a Ras, MIC ou 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.
E con toda razón vos preguntaredes: por que? A resposta, científica, pero non por iso menos decepcionante é que é moi difícil. Por algunha razón estas tres proteínas están nunha área do campo científico que chamamos "o xenoma intratable". Que é como chamar a un ordenador inexplorable, ou á lúa impaseable. Vaia, un estarrecedor termo do gremio. O que significa é que non damos atopado ningún buraco nestas proteínas no que poder, coma se fósemos cerralleiros, introducir algunha pequena molécula ou substancia orgánica activa.
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.
Namentres estudaba medicina clínica, hematoloxía e oncoloxía, e transplantes con células nai, o que atopábamos en troques no Regulamento da Axencia de Drogas e Alimentos eran estas substancias: arsénico, talidomida e este derivado químico do gas mostaza nitroxenado. E isto é o século XXI. E así, como vostedes dirían, insatisfeito co rendemento e calidade destes medicamentos, volvín a estudar químicas. Pensaba que quizais aprendendo o oficio dos descubrimentos químicos e dende o contexto deste novo e descoñecido mundo que é o do código aberto, o código-compartido, a rede colaborativa á que temos acceso no ámbito académico, quizais atopariamos terapias máis potentes e dirixidas ós pacientes con máis rapidez.
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.
Entendede que aínda é un proxecto en curso, pero gustaríame contarvos unha historia sobre un cancro pouco común, o das estruturas da liña media, sobre o transporte de proteínas, o transporte de proteínas intratable que causan este cancro, chamadas BRD4, e sobre unha molécla elaborada no meu laboratorio no Instituto para o Cancro Dana Farber chamada JQ1, chamada así por Jun Qi, o químico que a fabricou. A BRD4 é unha proteína interesante.
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.
Quizais vos preguntedes, con todo o que fai o cancro para tratar de matar ós pacientes, como se acorda de que é un cancro? Cando enrola o seu xenoma, se divide en dúas células e se desenrola de novo, por que non se convirte nun ollo, ou nun fígado? Ten os xenes necesarios para facelo. Pero sempre lembra que é un cancro. A razón é que o cancro, igual ca outras células do corpo, coloca unhas pequenas marcas moleculares, coma un Post-it, que lle recorda: "Son un cancro, teño que seguir crecendo." E estas notas inclúen esa e outras proteínas do mesmo tipo; os chamados bromodominios. Nós elaboramos unha idea, unha base lóxica: quizais se fabricásemos unha molécula que previse que se pegase esa nota entrando no buratiño da base desta proteína xiratoria, quizais poderiamos convencer as células canceríxenas, a esas adictas ás proteínas BRD4, de que non son un cancro.
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.
Así comezamos a traballar neste problema. Elaboramos unha cantidade importante de compostos e finalmente chegamos á JQ1 e outras substancias similares. Como non somos unha famacéutica, tiñamos varias opcións, tiñamos flexibilidade, que entendo que a industria farmacéutica non ten. Así que enviamos a JQ1 ós nosos amigos. Eu teño un pequeno laboratorio. Así que pensamos enviala e ver cómo se comportaba a molécula. Mandámola a Oxford, en Inglaterra, onde un grupo de destacados cristalógrafos xeraron esta imaxe, que nos axudou a comprender como a molécula era tan útil para transporte de proteínas. É o que chamamos un axuste perfecto, unha forma complementaria, un feito a medida.
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.
Este cancro é moi pouco común, este cancro adicto á BRD4 Traballamos entón con mostras de material recollido por patólogos novos do Hospital Brigham para mulleres. E namentres tratabamos estas células coa molécula, observamos algo moi asombroso. As células canceríxenas, pequenas, redondas, que se dividen rápido, facían uns brazos e prolongacións. Estaban a cambiar de forma. De feito, a célula canceríxena estaba esquecendo que era un cancro e convertíase nunha célula normal.
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.
Estabamos entusiasmados. O seguinte paso era inocular a molécula en ratos. Pero non hai modelos deste tipo de cancro para ratos. Mentras levabamos a cabo esta investigación, eu estaba tratando a un bombeiro de 29 anos que estaba case no final da súa vida a causa deste tipo de cancro. Este cancro adicto á BRD4 estaba crecendo no seu pulmón esquerdo. Tiña un tubo torácico que drenaba pequenos restos do cancro que se tiraban en cada quenda das enfermeiras. Así que nos achegamos a este paciente e lle pedimos que colaborase con nós. Queriamos coller ese material canceríxeno raro e valioso do tubo torácico, levalo ó laboratorio e inxectárlleo ós ratos para tratar de facer un ensaio clínico e probar o prototipo de tratamento. Sería imposible e, a dicir verdade, ilegal facelo en persoas. Axudounos. E no Centro de Imaxe da Familia Lurie, o meu compañeiro Andrew Kung fixo crecer con éxito este cancro nos ratos.
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.
Podedes ver nesta tomografía de positróns dun rato como crece o cancro, esa masa grande e vermella nas patas traseiras do animal. Cando o tratamos co noso composto, a adicción, o crecemento, parou. No animal da dereita vese como respondeu o cancro. Xa completamos ensaios clínicos en ratos con catro modelos da enfermidade e sempre obtemos o mesmo resultado: os ratos ós que inxectamos o fármaco sobreviven; os outros morren con rapidez.
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.
Comezamos entón a preguntarnos que faría unha farmacéutica no noso caso. Seguramente o manterían en segredo ata obter un principio activo a partir do prototipo. Pero nós fixemos o contrario. Publicamos un artigo que describía os achados na fase do prototipo. Demos ó mundo a fórmula química da molécula, o que sería xeralmente un segredo na nosa especialidade. Explicamos con exactitude cómo fabricala, e proporcionamos a nosa dirección ofrecéndonos a enviar unha molécula de forma gratuita se nola pedían.
(Laughter)
Basicamente tratamos de crear
We basically tried to create the most competitive environment for our lab as possible. And this was, unfortunately, successful.
un entorno cooperativo para o noso laboratorio o máis competivo posible. E tivo éxito, por desgracia. (Risos)
(Laughter)
Porque agora que xa compartimos a molécula,
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.
en decembro do ano pasado, con 40 laboratorios nos EEUU e outros 30 en Europa, moitos deles de empresas farmacéuticas procuran agora entrar neste espazo, en investigar sobre este cancro; agora, por fortuna, resulta interesante tratar o tema na industria. Pero a ciencia que retorna de todos eses laboratorios sobre o uso da molécula proporcionounos ideas que por nós mesmos nos obteriamos. As células con leucemia que se tratan con ela vólvense glóbulos brancos normais. Os ratos con mielomas múltiples, unha enfermidade incurable da médula ósea, responden de forma espectacular ó tratamento con este fármaco. Pode que saibades que a graxa ten memoria. É interesante poder demostralo.
(Laughter)
E de feito, esta molécula
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 --
evita que eses adipocitos, esas células nai graxas, recorden como facer graxa. Así, ratos cunha dieta con moita graxa, coma a da xente do meu pobo natal,
(Laughter)
non acaban cun fígado graxo,
fail to develop fatty liver, which is a major medical problem.
un problema médico bastante grave.
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.
O que este estudo nos ensinou; non só ó meu laboratorio, senón tamén ó noso instituto e á Facultade de Medicina de Harvard; é que no ámbito académico temos recursos excepcionais para descubrir fármacos, que o noso centro que ten feito máis probas ca ningún outro con moléculas relacionadas con cancro, nunca fixo ningunha en solitario. Por todo o que temos dito ata agora, pensamos que é unha boa oportunidade para que os centros académicos participen nesta disciplina, nova, creativa e conceptualmente complicada, que é a descuberta de prototipos farmacéuticos.
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.
E agora que? Temos unha molécula, pero non pílulas. Non hai unha forma de toma oral. Temos que conseguir que chegue ós pacientes. Todos no laboratorio, especialmente os que máis interaccionan cos pacientes, séntense bastente obrigados a produciren un fármaco a partir desta molécula. Agora é cando pido a vosa colaboración, axuda e ideas. A diferenza dunha empresa farmacéutica, non temos unha liña de distribución onde colocar as moléculas. Non temos un equipo de vendedores e comerciantes que nos digan como colocar o fármaco fronte ó resto. O que si temos é a flexibilidade de ser un centro académico, onde traballa xente competente, motivada e entusiasta, e esperamos que con fondos, para levarmos estas moléculas cara o paso clínico á vez que preservan a nosa capacidade para compartir o prototipo co resto do mundo.
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?"
A molécula pronto deixará o noso laboratorio para trasladarse a unha nova pequena compañía chamada Tensha Therapeutics. En realidade é a cuarta destas moléculas que se "gradúa" no noso laboratorio de descubrimentos. Dúas delas, un fármaco tópico para o linfoma de pel, unha substancia oral para tratar o mieloma múltiple, están a piques de comezar o seu primeiro ensaio clínico, en xullo deste ano. Para nós é un gran e estimulante fito. Quero deixarvos dúas ideas. En primeiro lugar, o excepcional da nosa investigación: non foi tanto a ciencia, senón a estratexia; isto foi para nós un experimento social. Queriamos comprobar que pasaría se fósemos tan abertos e honestos nas primeiras fases da investigación química como puidésemos.
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.
Esta cadea de letras, números, símbolos e parénteses que se pode mandar nun SMS, ou twittear mundialmente, é a fórmula química do noso composto. É a información que precisamos das compañías farmacéuticas, a información de cómo estes prototipos poderían funcionar. Pero esta información é xeralmente secreta. Así que nós esperamos sacar partido dos abraiantes éxitos da industria científica informática, dous principios: o código aberto e o "crowdsourcing", para acelerar de maneira responsable e rápida o acceso dos pacientes ás terapias dirixidas.
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.
Agora o modelo empresarial inclúevos a todos vós. Esta investigación finánciaa o público. Finánciana fundacións. E unha cousa que aprendín en Boston é que a xente de aquí faría calquera cousa polo cancro, e é algo que adoro. Recorrer o estado en bicicleta, subir e baixar o río...
(Laughter)
(Risos)
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.
En ningunha outra parte teño visto un apoio semellante para o estudo do cancro. Así que quero dárvos as grazas pola vosa participación, colaboración e sobre todo pola vosa confianza nas nosas ideas. (Aplausos)
(Applause)