Jay Bradner: Open-source cancer research

Prevodilac: Ivana Gadjanski Lektor: Ana Zivanovic-Nenadovic

I moved to Boston 10 years ago from Chicago,

Preselio sam se u Boston iz Čikaga, pre 10 godina,

with an interest in cancer and in chemistry.

zanimali su me rak i hemija.

You might know that chemistry is the science of making molecules

Možda znate da je hemija nauka o pravljenju molekula

or, to my taste,

ili, što se meni sviđa, novih lekova za rak.

new drugs for cancer.

And you might also know that, for science and medicine,

Možda takođe znate da je, što se nauke i medicine tiče,

Boston is a bit of a candy store.

Boston neka vrsta poslastičarnice.

You can't roll a stop sign in Cambridge without hitting a graduate student.

U Kembridžu, ne možete da stavite ni saobraćajni znak za stop,

a da ne udarite nekog studenta na doktoratu.

The bar is called the Miracle of Science.

Čak se i kafić zove "Čudo nauke".

The billboards say "Lab Space Available."

Na bilbordima su oglasi "Imamo poslovni prostor za laboratoriju".

And it's fair to say that in these 10 years,

Može se reći da smo, u ovih 10 godina,

we've witnessed absolutely the start of a scientific revolution --

svedoci samog početka

naučne revolucije, koja se odnosi na genomsku medicinu.

that of genome medicine.

We know more about the patients that enter our clinic now

Sada znamo više nego ikada ranije

o pacijentima koji nam dolaze u bolnice.

than ever before.

And we're able, finally, to answer the question

Konačno smo u stanju da odgovorimo na pitanje

that's been so pressing for so many years:

koje se postavlja već toliko godina:

Why do I have cancer?

zašto imam rak?

This information is also pretty staggering.

Informacije o tome su prilično zapanjujuće.

Možda znate da,

You might know that, so far, in just the dawn of this revolution,

iako smo još na početku ove revolucije,

we know that there are perhaps 40,000 unique mutations

znamo da postoji oko 40.000 jedinstvenih mutacija

koje pogađaju više od 10.000 gena,

affecting more than 10,000 genes,

and that there are 500 of these genes that are bona-fide drivers,

i da, među tim genima, ima 500 gena

koji zaista i utiču,

causes of cancer.

i izazivaju rak.

Yet comparatively,

Međutim, u poređenju sa tim,

we have about a dozen targeted medications.

imamo oko desetak tzv. ciljanih lekova.

And this inadequacy of cancer medicine

Ova nesposobnost u lečenju raka

really hit home when my father was diagnosed with pancreatic cancer.

me je lično pogodila, kad je moj otac dobio dijagnozu

za rak pankreasa.

We didn't fly him to Boston.

Nismo ga doveli u Boston.

We didn't sequence his genome.

Nismo sekvencionirali njegov genom.

It's been known for decades what causes this malignancy.

Već je decenijama poznato

šta izaziva ovaj malignitet.

To su tri proteina -

It's three proteins: ras, myc, p53.

Ras, MIC i P53.

This is old information we've known since about the 80s,

To su stare informacije koje znamo još od '80-ih,

yet there's no medicine I can prescribe

a ipak ne postoji lek koji mogu da prepišem

to a patient with this or any of the numerous solid tumors

pacijentu koji ima ovaj

ili bilo koji drugi od brojnih čvrstih tumora

caused by these three ...

koje izazivaju ova tri

Horsemen of the Apocalypse that is cancer.

jahača apokalipse koju zovemo rak.

There's no ras, no myc, no p53 drug.

Nema leka usmerenog na Ras, MIC ili P53.

And you might fairly ask: Why is that?

Mogli biste, s pravom, da pitate: zbog čega?

Vrlo nezadovoljavajući, ali ipak naučni odgovor

And the very unsatisfying yet scientific answer is:

je da je suviše teško.

it's too hard.

That for whatever reason,

Iz različitih razloga su,

these three proteins have entered a space, in the language of our field,

ova tri proteina ušla u jednu sferu u našoj oblasti

that's called the undruggable genome --

koja se naziva "genom bez lekova"

which is like calling a computer unsurfable

to je kao da kažemo "kompjuter koji ne pretražuje podatke"

or the Moon unwalkable.

ili kad bismo rekli da je nemoguće hodati po Mesecu.

It's a horrible term of trade.

To je grozan tehnički termin.

But what it means

is that we've failed to identify a greasy pocket in these proteins,

Ali, to znači

da nismo uspeli da identifikujemo "masni džep" u ovim proteinima,

into which we, like molecular locksmiths,

u koji bismo mogli da, kao molekularni bravari,

can fashion an active, small, organic molecule or drug substance.

ubacimo aktivni, mali, organski molekul

ili komponentu leka.

Za vreme moje specijalizacije za kliničku medicinu

Now, as I was training in clinical medicine

and hematology and oncology and stem-cell transplantation,

hematologiju i onkologiju

i transplantaciju matičnih ćelija,

what we had instead,

ono što je postojalo umesto toga,

cascading through the regulatory network at the FDA,

što je skakutalo kroz mrežu propisa Federalne Agencije za Lekove,

su bile ove supstance

were these substances:

arsenic,

arsen, talidomid

thalidomide,

and this chemical derivative of nitrogen mustard gas.

i ovaj hemijski derivat azotnog tzv. "senfnog gasa".

And this is the 21st century.

A ovo je 21.vek.

And so, I guess you'd say,

Budući da sam bio, u najmanju ruku, nezadovoljan

dissatisfied with the performance and quality of these medicines,

učinkom i kvalitetom ovih lekova,

I went back to school, in chemistry,

počeo sam da učim hemiju

with the idea that perhaps by learning the trade of discovery chemistry

sa idejom da možda,

učeći tehniku otkrivanja hemijskih komponenti

and approaching it in the context of this brave new world

i pristupajući tome na način ovog vrlog novog sveta

of the open source,

korišćenja tzv. koncepta slobodnog pristupa

i tzv. grupnog pristupa

the crowd source,

the collaborative network that we have access to within academia,

tj. kolaborativne mreže koju koristimo u naučnim institucijama,

that we might more quickly bring powerful and targeted therapies

da bismo mogli brže

da ponudimo moćne i usmerene terapije

našim pacijentima.

to our patients.

And so, please consider this a work in progress,

Molim vas da imate na umu da je ovo posao koji još traje,

but I'd like to tell you today a story

ali bih danas želeo da vam ispričam priču

about a very rare cancer called midline carcinoma,

o vrlo retkom raku

koji se zove karcinom srednje linije,

i o ciljnom proteinu,

about the undruggable protein target that causes this cancer,

proteinu za koji nema lekova

koji se naziva BRD4,

called BRD4,

and about a molecule developed at my lab at Dana-Farber Cancer Institute,

i o molekulu

sintetisanom u mojoj laboratoriji u Dejna Farber Kancer Institutu

called JQ1,

which we affectionately named for Jun Qi,

koji smo nazvali JQ1, u čast Džun Či,

the chemist that made this molecule.

hemičara koji je sintetisao ovaj molekul.

Now, BRD4 is an interesting protein.

BRD4 je zanimljiv protein.

You might ask: with all the things cancer's trying to do to kill our patient,

Mogli biste da se zapitate, dok rak radi sve te stvari

kojima pokušava da nam ubije pacijenta,

how does it remember it's cancer?

kako se uopšte seti da je rak?

When it winds up its genome,

Kada razmota svoj genom,

divides into two cells and unwinds again,

podeli se na dve ćelije i ponovo se zamota,

why does it not turn into an eye, into a liver,

zašto ne postane oko, ili jetra,

jer ima sve gene neophodne za to?

as it has all the genes necessary to do this?

It remembers that it's cancer.

Ali seća se da je rak.

And the reason is that cancer, like every cell in the body,

Razlog je taj da rak, kao svaka ćelija u telu,

postavlja male molekularne oznake,

places little molecular bookmarks,

samolepljive papiriće,

little Post-it notes,

that remind the cell, "I'm cancer; I should keep growing."

koje podsećaju ćeliju, "ja sam rak, treba da nastavim da rastem."

Te samolepljive poruke

And those Post-it notes involve this and other proteins of its class --

obuhvataju ovaj i druge proteine te klase,

so-called bromodomains.

takozvane bromodomene.

So we developed an idea, a rationale,

Mi smo razvili ideju, osnovu istraživanja,

that perhaps if we made a molecule

da, možda, ako bismo napravili molekul

that prevented the Post-it note from sticking

koji bi sprečio tu poruku da se zalepi

tako što bi ušao u mali džep

by entering into the little pocket

at the base of this spinning protein,

u osnovi ovog proteina koji se tu obrće,

then maybe we could convince cancer cells,

onda bismo mogli da ubedimo ćelije raka,

certainly those addicted to this BRD4 protein,

naročito one koje su zavisne od BRD4 proteina,

that they're not cancer.

da one nisu ćelije raka, da nisu kancer.

And so we started to work on this problem.

Tako smo počeli da radimo na tom problemu.

We developed libraries of compounds

Napravili smo biblioteke hemijskih jedinjenja

i, na kraju smo stigli do ove, i nekih sličnih supstanci

and eventually arrived at this and similar substances

nazvane JQ1.

called JQ1.

Now, not being a drug company,

Budući da nismo farmaceutska kompanija,

we could do certain things, we had certain flexibilities,

mogli smo da radimo neke stvari, imali smo izvesnu fleksibilnost,

that I respect that a pharmaceutical industry doesn't have.

koju farmaceutska industrija nema.

We just started mailing it to our friends.

Jednostavno smo počeli da ovu supstancu šaljemo prijateljima.

I have a small lab.

Moja laboratorija je mala.

We thought we'd just send it to people and see how the molecule behaves.

Pomislili smo da samo pošaljemo ovaj molekul drugima

We sent it to Oxford, England,

i vidimo kako se ponaša.

Poslali smo ga u Oksford, u Englesku,

where a group of talented crystallographers provided this picture,

gde je grupa talentovanih kristalografa napravila ovu sliku,

which helped us understand exactly how this molecule is so potent

što nam je pomoglo da shvatimo

for this protein target.

zašto je, u stvari, ovaj molekul tako efikasan za ovaj ciljani protein.

It's what we call a perfect fit of shape complementarity,

To je ono što nazivamo savršenim uklapanjem

or hand in glove.

komplementarnih delova, kao ruka u rukavici.

Now, this is a very rare cancer,

Ovo je vrlo redak rak,

this BRD4-addicted cancer.

ovaj rak zavistan od BRD4.

And so we worked with samples of material

Radili smo sa uzorcima materijala

that were collected by young pathologists at Brigham and Women's Hospital.

koji su sakupili mladi patolozi u Brigam ženskoj bolnici.

Kada smo ove ćelije tretirali tim molekulom,

And as we treated these cells with this molecule,

we observed something really striking.

primetili smo nešto zaista zadivljujuće.

Ćelije raka,

The cancer cells --

small, round and rapidly dividing,

male, okrugle ćelije koje se brzo dele,

grew these arms and extensions.

su formirale ove produžetke.

They were changing shape.

Menjale su oblik.

In effect,

U stvari, ćelija raka

the cancer cell was forgetting it was cancer

je počela da zaboravlja da je kancerozna

i postajala je normalna ćelija.

and becoming a normal cell.

This got us very excited.

Bili smo veoma uzbuđeni zbog toga.

The next step would be to put this molecule into mice.

Sledeći korak bi bio da se ovaj molekul upotrebi na miševima.

The only problem was there's no mouse model of this rare cancer.

Jedini problem je bio što, za ovaj redak rak,

nema modela na miševima.

And so at the time we were doing this research,

U vreme kada smo radili ovo istraživanje,

I was caring for a 29-year-old firefighter from Connecticut

brinuo sam se o 29-godišnjem vatrogascu iz Konektikata

koji je bio maltene na samrti

who was very much at the end of life

with this incurable cancer.

zbog ovog neizlečivog raka.

This BRD4-addicted cancer was growing throughout his left lung.

Ovaj BRD4-zavisni rak

mu je rastao kroz levo plućno krilo,

And he had a chest tube in that was draining little bits of debris.

i imao je kateter u grudima za dreniranje otpadnih materija.

And every nursing shift, we would throw this material out.

U svakoj smeni

ovaj materijal se bacao.

And so we approached this patient

Došli smo kod ovog pacijenta

and asked if he would collaborate with us.

i pitali da li bi sarađivao sa nama.

Could we take this precious and rare cancerous material

Da li bismo mogli da uzmemo te dragocene, retke kancerozne materije

from this chest tube

iz grudnog katetera,

and drive it across town and put it into mice

da ih prevezemo na drugi deo grada i ubacimo u miševe

and try to do a clinical trial at a stage that with a prototype drug,

i pokušamo da izvedemo kliničku studiju

i stignemo do stupnja prototipa za lek?

well, that would be, of course, impossible

To bi bilo i nemoguće i protivzakonito, s pravom, da se uradi na ljudima.

and, rightly, illegal to do in humans.

And he obliged us.

On se složio.

At the Lurie Family Center for Animal Imaging,

U Centru za vizuelizaciju procesa kod životinja "Porodica Luri"

our colleague, Andrew Kung, grew this cancer successfully in mice

moj kolega, Endrju Kang, je uspešno formirao ovaj kancer kod miševa

without ever touching plastic.

i to bez korišćenja plastike.

And you can see this PET scan of a mouse -- what we call a pet PET.

Možete videti ovaj PET sken miša, mi ga zovemo "ljubimac PETko".

The cancer is growing

Rak se povećava, što se vidi

as this red, huge mass in the hind limb of this animal.

kao ova crvena, ogromna masa u zadnjoj nozi životinje.

A kada primenimo tretman našom supstancom,

And as we treat it with our compound,

this addiction to sugar,

ova zavisnost od šećera,

ovaj brzi rast, iščezava.

this rapid growth, faded.

And on the animal on the right,

I kod životinje sa desne strane,

you see that the cancer was responding.

vidite da rak reaguje na tretman.

We've completed, now, clinical trials

Sada završavamo kliničke studije

na četiri mišja modela ove bolesti.

in four mouse models of this disease.

Svaki put primećujemo istu stvar.

And every time, we see the same thing.

The mice with this cancer that get the drug live,

Miševi sa rakom koji prime lek preživljavaju,

and the ones that don't rapidly perish.

dok oni koji ne prime lek, brzo uginu.

Tu smo se zapitali, šta bi farmaceutska kompanija

So we started to wonder,

what would a drug company do at this point?

uradila na tom stupnju?

Well, they probably would keep this a secret

Pa, oni bi to verovatno držali u tajnosti

until they turn the prototype drug

dok ne prevedu ovaj prototip leka

into an active pharmaceutical substance.

u aktivnu farmaceutsku supstancu.

Mi smo uradili upravo suprotno.

So we did just the opposite.

Objavili smo rad

We published a paper that described this finding

koji opisuje ovo otkriće

at the earliest prototype stage.

na najranijem stupnju prototipa za lek.

We gave the world the chemical identity of this molecule,

Dali smo celom svetu hemijski identitet

ovog molekula, što je obično tajna u našoj oblasti.

typically a secret in our discipline.

We told people exactly how to make it.

Tačno smo objasnili ljudima kako da ga naprave.

We gave them our email address,

Dali smo im našu imejl adresu,

suggesting that if they write us,

i tako nagovestili da, ako nam pišu,

we'll send them a free molecule.

da ćemo im besplatno poslati molekul.

(Laughter)

U suštini, pokušali smo da stvorimo

We basically tried to create the most competitive environment

najveću moguću konkurenciju našoj laboratoriji.

for our lab as possible.

And this was, unfortunately, successful.

I to nam je, na žalost, uspelo.

(Smeh)

(Laughter)

Because now, we've shared this molecule,

Jer sada, pošto smo podelili ovaj molekul,

just since December of last year,

samo od decembra prošle godine,

with 40 laboratories in the United States

40 laboratorija iz SAD-a

and 30 more in Europe --

i još 30 iz Evrope -

mnoge od njih su farmaceutske kompanije

many of them pharmaceutical companies,

seeking now to enter this space,

i sada pokušavaju da uđu u ovu oblast,

to target this rare cancer that, thankfully right now,

usmerenu na ovaj retki rak

koji je, upravo sada, na sreću, sasvim poželjna tema

is quite desirable to study in that industry.

za ispitivanje u toj industriji.

But the science that's coming back from all of these laboratories

Ali naučni podaci, koji zauzvrat,

stižu iz svih tih laboratorija o primeni ovog molekula

about the use of this molecule

pružaju nam uvid, koji možda nikada

has provided us insights we might not have had on our own.

ne bismo imali da smo radili sami.

Leukemia cells treated with this compound

Ćelije leukemije tretirane ovim jedinjenjem

turn into normal white blood cells.

postaju normalna bela krvna zrnca.

Mice with multiple myeloma,

Miševi sa višestrukim mijelomima,

an incurable malignancy of the bone marrow,

neizlečivim malignitetom koštane srži,

respond dramatically

reaguju vrlo dramatično

to the treatment with this drug.

na tretman ovim lekom.

You might know that fat has memory.

Možda znate da masno tkivo može da pamti.

Baš lepo što mogu to da vam demonstriram.

I'll nicely demonstrate that for you.

(Laughter)

In fact, this molecule

I, zapravo, ovaj molekul

prevents this adipocyte, this fat stem cell,

sprečava taj adipocit, tu masnu matičnu ćeliju.

from remembering how to make fat,

da se seti kako da pravi mast

such that mice on a high-fat diet,

tako da miševi sa ishranom bogatom mastima,

like the folks in my hometown of Chicago --

kao što jedu ljudi u mom rodnom gradu Čikagu,

(Laughter)

fail to develop fatty liver,

ipak ne razvijaju tzv. "masnu jetru",

which is a major medical problem.

što, inače, predstavlja veliki medicinski problem.

Ono što smo naučili iz ovog istraživanja

What this research taught us --

not just my lab, but our institute,

ne samo moja laboratorija, nego naš institut,

and Harvard Medical School more generally --

i generalno, ceo Harvard medicinski fakultet,

is that we have unique resources in academia

je da imamo posebne

akademske resurse za otkrivanje lekova

for drug discovery;

that our center, which has tested perhaps more cancer molecules

i to da naš centar, koji je,

ispitao više kancer-molekula,

in a scientific way

na naučni način, nego bilo koji drugi,

than any other,

never made one of its own.

nije nikada napravio nijedan sopstveni.

For all the reasons you see listed here,

Iz svih ovih razloga koje vidite ovde navedene,

we think there's a great opportunity for academic centers

mislimo da postoji odlična prilika za akademske centre

to participate in this earliest, conceptually tricky

da učestvuju u ovoj mladoj, konceptualno nedefinisanoj

and creative discipline

i kreativnoj disciplini

of prototype drug discovery.

pronalaženja prototipova za lekove.

So what next?

I šta dalje?

We have this molecule, but it's not a pill yet.

Imamo ovaj molekul, ali to još nije pilula.

It's not orally bioavailable.

Ne može se uzimati oralnim putem.

We need to fix it so we can deliver it to our patients.

Moramo to da sredimo, da bismo mogli da ga dajemo našim pacijentima.

And everyone in the lab,

Svi u laboratoriji se,

especially following the interaction with these patients,

naročito posle kontakta sa ovim pacijentima,

osećaju posebno motivisani

feels quite compelled to deliver a drug substance

da naprave lek baziran na ovom molekulu.

based on this molecule.

It's here where I'd say

Ovo je trenutak kad moram da kažem

that we could use your help and your insights,

da nam treba vaša pomoć i vaša pronicljivost,

your collaborative participation.

vaše kolaborativno učestvovanje.

Unlike a drug company, we don't have a pipeline

Za razliku od farmaceutske kompanije,

mi nemamo proizvodnu liniju u koju možemo ubaciti ove molekule.

that we can deposit these molecules into.

We don't have a team of salespeople and marketeers

Nemamo tim prodavaca i snabdevača

to tell us how to position this drug against the other.

koji nam mogu reći kako da postavimo ovaj lek u odnosu na druge.

What we do have is the flexibility of an academic center

Ono što mi imamo je fleksibilnost akademskog centra

u radu sa kompetentnim, motivisanim,

to work with competent, motivated,

enthusiastic, hopefully well-funded people

ljudima sa puno entuzijazma i sa, nadajmo se, puno novca,

to carry these molecules forward into the clinic

da ove molekule prenesu do kliničke upotrebe,

while preserving our ability to share the prototype drug worldwide.

pri tome čuvajući sposobnost za razmenu

prototipova lekova među naučnicima širom sveta.

This molecule will soon leave our benches

Ovaj molekul će uskoro izaći iz laboratorije

and go into a small start-up company called Tensha Therapeutics.

i otići u malu novo-formiranu kompaniju

pod nazivom "Tenša Terapije".

And, really, this is the fourth of these molecules

Zapravo, to je četvrti od ovih molekula, koji,

to kind of "graduate" from our little pipeline

na neki način, maturira iz naše male produkcije novih lekova,

of drug discovery,

two of which -- a topical drug for lymphoma of the skin

od koji će dva - topični lek

za kožne limfome,

and an oral substance for the treatment of multiple myeloma --

i oralna supstanca za tretman višestrukih mijeloma

will actually come to the bedside for the first clinical trial

zaista i stići do bolnica

za prvu kliničku studiju u julu ove godine.

in July of this year -- for us, a major and exciting milestone.

Za nas, to je veliko i uzbudljivo dostignuće.

I want to leave you with just two ideas.

Za kraj, želim da vam prenesem ove dve ideje.

The first is: if anything is unique about this research,

Prva je to da, ako je išta

specifično u vezi sa ovim istraživanjem,

it's less the science than the strategy.

to je manje naučne, a više strateške prirode

This, for us, was a social experiment --

za nas je ovo bio društveni eksperiment,

an experiment in "What would happen if we were as open and honest

o tome šta se dešava

kada pokušamo da budemo otvoreni i iskreni,

at the earliest phase of discovery chemistry research

u najranijoj fazi istraživanja hemijskog otkrivanja lekova,

as we could be?"

i to u najvećoj mogućoj meri.

This string of letters and numbers

Ovaj niz slova i brojeva,

and symbols and parentheses

simbola i zagrada, koji mislim da može

that can be texted, I suppose,

da se pošalje SMS porukom,

or Twittered worldwide,

ili preko Tvitera, širom sveta,

je hemijski identitet našeg prototip-jedinjenja.

is the chemical identity of our pro compound.

It's the information that we most need from pharmaceutical companies,

Informacija koja nam najviše treba

od farmaceutskih kompanija,

the information on how these early prototype drugs might work.

informacija o tome kako

ovi rani prototipovi lekova mogu da rade.

Yet this information is largely a secret.

A ipak, ova informacija je najčešće tajna.

And so we seek, really, to download

Mi zapravo težimo tome,

da primenimo neverovatne uspehe

from the amazing successes of the computer-science industry,

2 principa informatičke industrije:

two principles -- that of open source and that of crowdsourcing --

tzv. "slobodnog pristupa" i tzv. "grupnog pristupa"

da bismo efikasno i odgovorno

to quickly, responsibly accelerate the delivery of targeted therapeutics

ubrzali proces dopremanja ciljanih terapija

to patients with cancer.

do pacijenata sa rakom.

Now, the business model involves all of you.

I taj poslovni model uključuje sve vas.

This research is funded by the public.

Ovo istraživanje je finansirano od strane celog društva.

It's funded by foundations.

Finansiraju ga fondacije.

And one thing I've learned in Boston

Jednu stvar sam naučio u Bostonu, a to je,

is that you people will do anything for cancer, and I love that.

da će građani Bostona uraditi sve za kancer, i to mi se jako sviđa.

You bike across the state, you walk up and down the river.

Vozite bicikl preko cele države.

Idete u organizovane šetnje celom dužinom reke.

(Laughter)

(Smeh)

I've never seen, really, anywhere,

Zaista, nigde do sada nisam video

this unique support for cancer research.

ovako jedinstvenu podršku

istraživanjima raka.

And so I want to thank you

Zato bih želeo da vam zahvalim

for your participation, your collaboration

za učestvovanje, vašu saradnju

and most of all,

i, pre svega, za poverenje u naše ideje.

for your confidence in our ideas.

(Applause)

(Aplauz)