Jay Bradner: Open-source cancer research

Prevoditelj: Senzos Osijek Recezent: Tilen Pigac - EFZG

Prije 10 godina preselio sam se u Boston, iz Chicaga,

I moved to Boston 10 years ago from Chicago,

with an interest in cancer and in chemistry.

sa zanimanjem za rak i kemiju.

You might know that chemistry is the science of making molecules

Možda znate da je kemija znanost stvaranja molekula --

or, to my taste,

ili po mom ukusu, novih droga za rak.

new drugs for cancer.

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

I također možda znate da je za znanost i medicinu

Boston is a bit of a candy store.

Boston nešto poput trgovine slatkiša.

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

Ne možete svinuti znak stop na Cambridgeu,

a da ne naletite na postdiplomca.

The bar is called the Miracle of Science.

Bar se zove Čudo Znanosti.

The billboards say "Lab Space Available."

Plakati kažu „Dostupan laboratorij.“

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

I pošteno je reći da smo u ovih deset godina

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

svjedočili apsolutnom početku

znanstvene revolucije -- genomske medicine.

that of genome medicine.

Sada, više nego ikada prije znamo o pacijentima

We know more about the patients that enter our clinic now

koji ulaze u našu klinku.

than ever before.

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

I u mogućnosti smo, konačno, odgovoriti na pitanje

koje nas je pritiskalo mnogo godina:

that's been so pressing for so many years:

Why do I have cancer?

zašto imam rak?

This information is also pretty staggering.

Ova informacija je također prilično zapanjujuća.

Možda znate da je do sada,

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

u svitanju ove revolucije,

we know that there are perhaps 40,000 unique mutations

poznato da postoji možda 40.000 jedinstvenih mutacija

koje utječu na 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 postoji 500 od tih gena

koji su dobrovoljni upravitelji,

causes of cancer.

uzroci raka.

Ipak usporedno,

Yet comparatively,

we have about a dozen targeted medications.

imamo dvanaestak ciljanih lijekova.

And this inadequacy of cancer medicine

A ta neadekvatnost medicine raka

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

zaista je pogodila srž kad je mom ocu dijagnosticiran

rak gušterače.

Nismo ga prevezli u Boston.

We didn't fly him to Boston.

We didn't sequence his genome.

Nismo sekvencionirali njegov genom.

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

Desetljećima je poznato

što uzrokuje 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 je stara informacija koju znamo još od osamdesetih,

yet there's no medicine I can prescribe

no ipak još uvijek ne postoji lijek koji mogu prepisati

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

pacijentu s ovim

ili bilo kojim od brojnih solidnih tumora

caused by these three ...

uzrokovanih od ova tri konjanika

Horsemen of the Apocalypse that is cancer.

apokalipse koji se zovu rak.

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

Nema Ras, ni MIC ni P53 lijeka.

And you might fairly ask: Why is that?

I imate svako pravo pitati: zašto je to tako?

I veoma nezadovoljavajuć, iako znanstven, odgovor je

And the very unsatisfying yet scientific answer is:

da je preteško.

it's too hard.

That for whatever reason,

Da su iz nekog razloga,

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

ova tri proteina ušla u prostor u jeziku našeg područja

that's called the undruggable genome --

koji se zove genom kojeg je nemoguće liječiti --

which is like calling a computer unsurfable

to je kao da nazovete kompjuter nemogućim za surfanje

ili Mjesec nemogućim za hodanje.

or the Moon unwalkable.

It's a horrible term of trade.

To je užasan naziv struke.

But what it means

Ali to znači

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

da nismo uspjeli identificirati masne džepove u ovim proteinima

u kojima poput molekularnih bravara,

into which we, like molecular locksmiths,

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

možemo oblikovati aktivne, male, organske molekule

u supstancu lijeka.

Dok sam se obučavao u kliničkoj medicini

Now, as I was training in clinical medicine

i hematologiji i onkologiji

and hematology and oncology and stem-cell transplantation,

i transplantaciji matičnih stanica,

what we had instead,

umjesto toga imali smo,

cascading through the regulatory network at the FDA,

kaskadirajući kroz regulatornu mrežu FDA,

bile su to supstance --

were these substances:

arsenic,

arsen, talidomid

thalidomide,

i taj kemijski derivat

and this chemical derivative of nitrogen mustard gas.

iperit dušika.

And this is the 21st century.

A ovo je 21. stoljeće.

And so, I guess you'd say,

I moglo bi se reći, nezadovoljan

dissatisfied with the performance and quality of these medicines,

učinkom i kvalitetom ovih lijekova,

I went back to school, in chemistry,

otišao sam natrag u školu na kemiju

s idejom

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

da bi se možda učeći zanat kemije koja otkriva

and approaching it in the context of this brave new world

i ako joj pristupim u kontekstu ovog hrabrog novog svijeta

of the open source,

otvorenih izvora,

izvora mase,

the crowd source,

the collaborative network that we have access to within academia,

suradničke mreže kojoj smo pristupili unutar akademije,

that we might more quickly bring powerful and targeted therapies

da bismo možda brže

mogli donijeti moćnije i ciljane terapije

našim pacijentima.

to our patients.

And so, please consider this a work in progress,

I molim vas da ovo smatrate radom koji je u tijeku ,

ali danas bih vam želio ispričati priču

but I'd like to tell you today a story

o veoma rijetkom raku

about a very rare cancer called midline carcinoma,

pod imenom midline karcinom,

o ciljnom proteinu,

about the undruggable protein target that causes this cancer,

ciljnom proteinu koji se ne može liječiti, a uzrokuje ovaj rak,

zvanom BRD4

called BRD4,

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

i o molekuli

razvijenoj u mom laboratoriju u Dana Farber Institutu za rak

called JQ1,

nazvanom JQ1 koji smo strastveno nazvali po Jun Qiju,

which we affectionately named for Jun Qi,

kemičaru koji je stvorio ovu molekulu.

the chemist that made this molecule.

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 se upitati, s obzirom na sve stvari koje rak pokušava učiniti ne bi li ubio našeg pacijenta,

kako zapamti da je rak?

how does it remember it's cancer?

Kada smota svoj genom,

When it winds up its genome,

divides into two cells and unwinds again,

podijeli se na dvije stanice i ponovo se odmota,

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

zašto se ne pretvori u oko, u jetru

s obzirom da ima sve potrebne gene kako bi to napravio?

as it has all the genes necessary to do this?

It remembers that it's cancer.

Sjeća se da je rak.

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

A razlog tome je da rak, poput svake stanice u tijelu,

ostavlja male molekularne oznake,

places little molecular bookmarks,

male naljepnice

little Post-it notes,

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

koje podsjete stanicu „Ja sam rak; trebao bih nastaviti rasti.“

I te naljepnice

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

uključuju ovaj i ostale proteine te vrste --

takozvane bromodomene.

so-called bromodomains.

So we developed an idea, a rationale,

Pa smo razvili ideju, racionalnu,

that perhaps if we made a molecule

da možda, ako napravimo molekulu

that prevented the Post-it note from sticking

koja sprječava naljepnicu da se zalijepi

prilikom ulaska u mali džep

by entering into the little pocket

at the base of this spinning protein,

na osnovi ovog proteina koji se vrti,

then maybe we could convince cancer cells,

onda bismo možda mogli uvjeriti stanice raka,

certainly those addicted to this BRD4 protein,

naravno one ovisne o svom BRD4 proteinu

that they're not cancer.

da nisu rak.

And so we started to work on this problem.

Tako smo počeli raditi na ovom problemu.

We developed libraries of compounds

Razvili smo knjižnice spojeva

i s vremenom došli do ove i sličnih supstanci

and eventually arrived at this and similar substances

nazvanih JQ1.

called JQ1.

Now, not being a drug company,

S obzirom da nismo farmaceutska tvrtka,

we could do certain things, we had certain flexibilities,

mogli smo raditi određene stvari, imali smo određene fleksibilnosti

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

za koje poštujem što ih farmaceutska industrija nema.

We just started mailing it to our friends.

Počeli smo je slati našim prijateljima.

Imam mali laboratorij.

I have a small lab.

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

Mislili smo da bismo mogli poslati ljudima i vidjeti kako će se molekula ponašati.

I poslali smo je u Oxford u Englesku

We sent it to Oxford, England,

gdje je ekipa talentiranih kristalografa osigurala ovu sliku

where a group of talented crystallographers provided this picture,

koja nam je pomogla da točno razumijemo

which helped us understand exactly how this molecule is so potent

kako je ova molekula tako moćna za ovaj ciljani protein.

for this protein target.

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

To je ono što zovemo savršeno slaganje

komplementarnosti oblika ili ruka u rukavici.

or hand in glove.

Dakle, ovo je veoma rijedak rak,

Now, this is a very rare cancer,

ovaj rak ovisan o BRD4.

this BRD4-addicted cancer.

Radili smo s uzorcima materijala

And so we worked with samples of material

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

koje je skupio mladi patolog u bolnici Brigham Women.

I kako smo liječili te stanice s ovom molekulom,

And as we treated these cells with this molecule,

we observed something really striking.

opazili smo nešto veoma upečatljivo.

Stanicama raka,

The cancer cells --

small, round and rapidly dividing,

malim i okruglima koje su se brzo dijelile,

grew these arms and extensions.

narasle su ruke i nastavci.

They were changing shape.

Mijenjale su oblik.

In effect,

Kao rezultat, stanice raka

the cancer cell was forgetting it was cancer

su zaboravljale da su rak

i postajale su normalne stanice.

and becoming a normal cell.

Zbog toga smo bili jako uzbuđeni.

This got us very excited.

Sljedeći korak bi bio staviti ovu molekulu u miša.

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

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

Jedini problem je bio u tome što nema mišjeg modela za ovaj rijedak rak.

U vrijeme kad smo radili na ovom istraživanju,

And so at the time we were doing this research,

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

brinuo sam se za 29-ogodišnjeg vatrogasca iz Connecticuta

koji je bio na kraju svog života

who was very much at the end of life

with this incurable cancer.

s tim neizliječivim rakom.

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

Taj rak ovisan od BRD4

je rastao kroz njegovo lijevo plućno krilo

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

i imao je cijev u prsima u koji su se odlijevali mali komadići krhotina.

I za vrijeme svakog njegovanja

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

bacili bismo taj materijal.

And so we approached this patient

Prišli smo tom pacijentu

and asked if he would collaborate with us.

i upitali ga bi li surađivao s nama.

Could we take this precious and rare cancerous material

Možemo li uzeti taj vrijedan i rijedak kancerogeni materijal

from this chest tube

iz cijevi koja vodi iz njegovih prsa,

and drive it across town and put it into mice

odvesti to preko cijelog grada i staviti u miša

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

i pokušati napraviti klinički test

i suprotstaviti mu prototip lijeka?

well, that would be, of course, impossible

To bi bilo nemoguće i naravno, ilegalno napraviti na ljudima.

and, rightly, illegal to do in humans.

I on nam se obvezao.

And he obliged us.

At the Lurie Family Center for Animal Imaging,

U Lurie Obiteljskom centru za snimanje životinja,

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

moj kolega, Andrew Kung, uspješno je uzgojio ovaj rak u mišu

bez da je dotakao plastiku.

without ever touching plastic.

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

Možete vidjeti ovaj PET scan miša -- zovemo ga pet PET.

Rak raste

The cancer is growing

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

kao ova crvena, velika masa u stražnjim nogama ove životinje.

I kako ga liječimo našim spojem,

And as we treat it with our compound,

ova ovisnost o šećeru,

this addiction to sugar,

taj ubrzani rast je blijedio.

this rapid growth, faded.

And on the animal on the right,

I na životinji koju vidite desno,

you see that the cancer was responding.

vidite da rak reagira.

We've completed, now, clinical trials

Sada smo završili klinička istraživanja

na četiri mišja modela ove bolesti.

in four mouse models of this disease.

I svaki puta smo vidjeli istu stvar.

And every time, we see the same thing.

The mice with this cancer that get the drug live,

Miš s ovim rakom koji je dobio lijek živi,

a oni koji ne dobiju ubrzano umiru.

and the ones that don't rapidly perish.

Počeli smo se pitati

So we started to wonder,

what would a drug company do at this point?

što bi farmaceutska kompanija učinila u ovom trenu?

Well, they probably would keep this a secret

Vjerojatno bi čuvali ovu tajnu

until they turn the prototype drug

dok ne bi prototip lijeka

into an active pharmaceutical substance.

pretvorili u aktivnu farmaceutsku supstancu.

Pa smo mi učinili totalno suprotno.

So we did just the opposite.

Objavili smo članak

We published a paper that described this finding

koji opisuje ovo otkriće

at the earliest prototype stage.

u najranijem stadiju prototipa.

We gave the world the chemical identity of this molecule,

Dali smo svijetu kemijski identitet ove molekule

typically a secret in our discipline.

što je obično tajna u našoj disciplini.

We told people exactly how to make it.

Rekli smo ljudima kako smo je točno napravili.

Dali smo im naše e-mail adrese,

We gave them our email address,

suggesting that if they write us,

predlažući da, ako nam pišu,

we'll send them a free molecule.

poslat ćemo im besplatnu molekulu.

(Laughter)

Zapravo smo pokušali stvoriti

We basically tried to create the most competitive environment

najkonkurentniji okoliš za naš laboratorij, što je više moguće.

for our lab as possible.

I to je nažalost bilo uspješno.

And this was, unfortunately, successful.

(Smijeh)

(Laughter)

Because now, we've shared this molecule,

Zato što, sada kada smo podijelili ovu molekulu,

just since December of last year,

od prosinca prošle godine,

with 40 laboratories in the United States

u 40 laboratorija u SAD-u

i još 30 u Europi --

and 30 more in Europe --

mnoge od njihovih farmaceutskih kompanija

many of them pharmaceutical companies,

seeking now to enter this space,

traže sada kako ući u taj prostor

to target this rare cancer that, thankfully right now,

kako bi nanišanili ovaj rijedak rak

koji je trenutno srećom,

is quite desirable to study in that industry.

prilično poželjan za proučavanje u toj industriji.

Ali znanost koja dolazi natrag iz svih tih laboratorija

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

o upotrebi ove molekule

about the use of this molecule

nam je osigurala uvide

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

koje možda sami ne bismo vidjeli.

Leukemia cells treated with this compound

Stanice leukemije tretirane ovim spojem

turn into normal white blood cells.

pretvaraju se u normalne stanice bijele loze.

Mice with multiple myeloma,

Miševi s multiplim mijelomima,

an incurable malignancy of the bone marrow,

neizliječivim malignitetom koštane srži,

respond dramatically

dramatično reagiraju

to the treatment with this drug.

na liječenje ovim lijekom.

You might know that fat has memory.

Možda znate da mast ima pamćenje.

Drago mi je što vam to mogu demonstrirati.

I'll nicely demonstrate that for you.

(Laughter)

In fact, this molecule

I zapravo, ova molekula

prevents this adipocyte, this fat stem cell,

spriječava ovaj adipocit, ovu masnu matičnu stanicu

from remembering how to make fat,

da se sjeti kako napraviti mast

such that mice on a high-fat diet,

tako da miševi na dijeti bez visokih masnoća,

like the folks in my hometown of Chicago --

poput ljudi iz mog rodnog grada Chicaga,

(Laughter)

ne uspiju razviti masnu jetru,

fail to develop fatty liver,

koja je veliki medicinski problem.

which is a major medical problem.

Ono što nas je ovo istraživanje naučilo --

What this research taught us --

not just my lab, but our institute,

ne samo moj laboratorij, već naš institut

i hardvardsku Medicinsku školu još više --

and Harvard Medical School more generally --

jest da imamo jedinstvene resurse u akademiji

is that we have unique resources in academia

za otkrivanje lijeka --

for drug discovery;

that our center, which has tested perhaps more cancer molecules

da naš centar

koji je testirao možda više molekula raka na znanstveni način

in a scientific way

nego na bilo koji drugi,

than any other,

never made one of its own.

nikad nije sam za sebe.

For all the reasons you see listed here,

Za sve razloge koje vidite ovdje nabrojene,

we think there's a great opportunity for academic centers

mislimo da postoji velika prilika za akademske centre

to participate in this earliest, conceptually tricky

da sudjeluju u ovoj najranijoj, konceptualno

lukavoj disciplini

and creative discipline

of prototype drug discovery.

za otkriće prototipa lijeka.

Dakle, što dalje?

So what next?

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

Imamo ovu molekulu, ali to još nije pilula.

Još nije oralno dostupna.

It's not orally bioavailable.

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

Moramo je popraviti da je možemo dostaviti našim pacijentima.

And everyone in the lab,

I svi se u ovom laboratoriju,

especially following the interaction with these patients,

posebno prateći interakciju s tim pacijentima

osjećaju prilično prisiljenima

feels quite compelled to deliver a drug substance

da naprave supstancu baziranu na ovoj molekuli.

based on this molecule.

It's here where I'd say

Ovdje moram reći

that we could use your help and your insights,

da bi nam dobro došla vaša pomoć i vaši uvidi,

your collaborative participation.

vaša suradnja.

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

Za razliku od farmaceutske kompanije,

nemamo cjevovod u koji možemo pohraniti ove molekule.

that we can deposit these molecules into.

Nemamo tim prodavača i trgovaca

We don't have a team of salespeople and marketeers

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

koji nam mogu reći kako smjestiti ovaj lijek nasuprot drugog.

What we do have is the flexibility of an academic center

Ono što imamo je fleksibilnost akademskog centra

da radi sa sposobnim, motiviranim,

to work with competent, motivated,

enthusiastic, hopefully well-funded people

entuzijastičnim, nadajmo se dobrostojećim ljudima

to carry these molecules forward into the clinic

koji nose ove molekule naprijed u kliniku

while preserving our ability to share the prototype drug worldwide.

dok održavaju našu sposobnost

da dijelimo prototip lijeka širom svijeta.

This molecule will soon leave our benches

Ova molekula će uskoro napustiti naše klupe

i otići u malo poduzeće koja se tek pokreće

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

pod imenom Tensha Therapeutics.

And, really, this is the fourth of these molecules

I stvarno ovo je četvrta od ovih molekula

to kind of "graduate" from our little pipeline

koja nekako završava od našeg malog cjevovoda otkrića lijeka,

of drug discovery,

od kojih će dva -- tematski lijek

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

za limfom kože,

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

oralna supstanca za liječenje multiplog mijeloma --

will actually come to the bedside for the first clinical trial

zapravo doći do nas

kao prvi klinički pokus u srpnju ove godine.

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

Za nas, velika i uzbudljiva prekretnica.

I want to leave you with just two ideas.

Želim vas ostaviti sa samo dvije ideje.

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

Prva je da

ako je išta jedinstveno u vezi ovog istraživanja,

it's less the science than the strategy.

da je to mnogo manje znanost nego strategija --

This, for us, was a social experiment --

da je ovo za nas bio socijalni eksperiment,

eksperiment u kojem bi se dogodilo

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

da smo toliko otvoreni i iskreni

at the earliest phase of discovery chemistry research

u najranijoj fazi otkrića kemijskog istraživanja

as we could be?"

koliko možemo biti.

This string of letters and numbers

Ovaj niz slova, brojki,

and symbols and parentheses

simbola i zagrada

that can be texted, I suppose,

koja se može poslati, pretpostavljam,

or Twittered worldwide,

ili podijeliti na Twitteru širom svijeta,

je kemijski identitet našeg prethodnog spoja.

is the chemical identity of our pro compound.

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

To je informacija koju najviše trebamo

od farmaceutskih kompanija,

the information on how these early prototype drugs might work.

informacija

o tome kako bi ovi rani prototipovi lijekova mogli raditi.

Yet this information is largely a secret.

Ipak, ta informacija je u velikoj mjeri tajna.

And so we seek, really, to download

I tako zaista tražimo

kako bismo kopirali dva principa izuzetnog uspjeha

from the amazing successes of the computer-science industry,

industrije računalne znanosti:

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

princip otvorenog izvora i princip izvora mnoštva

do brzog i odgovornog

to quickly, responsibly accelerate the delivery of targeted therapeutics

ubrzanja pošiljke ciljanih terapeutika

to patients with cancer.

do pacijenata s rakom.

Now, the business model involves all of you.

Sada poslovni model uključuje sve vas.

This research is funded by the public.

Ovo istraživanje je financirano od strane javnosti.

It's funded by foundations.

Financirano je iz temelja.

And one thing I've learned in Boston

I jedna stvar koju sam naučio u Bostonu

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

je da ćete vi ljudi sve učiniti za rak -- i volim to.

Vozite biciklom kroz državu. Hodate gore i dolje uz rijeku.

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

(Smijeh)

(Laughter)

Nikada nisam zaista nigdje vidio

I've never seen, really, anywhere,

tu jedinstvenu podršku

this unique support for cancer research.

za istraživanje raka.

And so I want to thank you

I zato vam želim zahvaliti

for your participation, your collaboration

na vašem sudjelovanju, vašoj suradnji

and most of all,

i najviše od svega vašoj vjeri u naše ideje.

for your confidence in our ideas.

(Pljesak)

(Applause)