Take a moment and think about a virus. What comes to your mind? An illness? A fear? Probably something really unpleasant. And yet, viruses are not all the same. It's true, some of them cause devastating disease. But others can do the exact opposite -- they can cure disease. These viruses are called "phages."
Zastanite malo i razmislite o virusima. Šta vam prvo pada na pamet? Bolest? Strah? Verovatno nešto jako neprijatno. A ipak, nisu svi virusi isti. Istina, neki od njih izazivaju razorne bolesti. Ali drugi mogu učiniti potpuno suprotno - mogu izlečiti bolest. Ovi virusi se zovu „fagi“.
Now, the first time I heard about phages was back in 2013. My father-in-law, who's a surgeon, was telling me about a woman he was treating. The woman had a knee injury, required multiple surgeries, and over the course of these, developed a chronic bacterial infection in her leg. Unfortunately for her, the bacteria causing the infection also did not respond to any antibiotic that was available. So at this point, typically, the only option left is to amputate the leg to stop the infection from spreading further. Now, my father-in-law was desperate for a different kind of solution, and he applied for an experimental, last-resort treatment using phages. And guess what? It worked. Within three weeks of applying the phages, the chronic infection had healed up, where before, no antibiotic was working. I was fascinated by this weird conception: viruses curing an infection. To this day, I am fascinated by the medical potential of phages. And I actually quit my job last year to build a company in this space.
Prvi put sam čuo za fage 2013. godine. Moj tast, hirurg, mi je pričao o ženi koju je lečio. Žena je imala povredu kolena koja je zahtevala nekoliko operacija, zbog kojih joj se razvila hronična bakterijska infekcija u nozi. Na njenu žalost, bakterija koja je izazivala infekciju nije reagovala ni na jedan antibiotik koji je bio dostupan. Tako da je u tom momentu, obično, jedina opcija amputacija noge kako bi se sprečilo širenje infekcije. Moj tast je očajnički pokušavao da pronađe drugo rešenje, i primenio je eksperimentalni, najnoviji tretman koristeći fage. I znate šta se desilo? Uspelo je. U roku od tri nedelje od primene faga, hronična infekcija je bila izlečena, tamo gde nijedan antibiotik nije uspeo. Ovaj čudni koncept je bio fascinantan za mene: virusi leče infekciju. Do današnjeg dana, fasciniran sam medicinskim potencijalom faga. U stvari, dao sam otkaz prošle godine da bih osnovao kompaniju u ovoj sferi.
Now, what is a phage? The image that you see here was taken by an electron microscope. And that means what we see on the screen is in reality extremely tiny. The grainy thing in the middle with the head, the long body and a number of feet -- this is the image of a prototypical phage. It's kind of cute.
Šta je fag? Slika koju ovde vidite je napravljena elektronskim mikroskopom. Što znači da je ono što vidimo na ekranu u stvarnosti izuzetno sićušno. Ova zrnasta stvar u sredini sa glavom, dugačkim telom i više stopala - to je slika prototipa faga. Sladak je, na neki način.
(Laughter)
(Smeh)
Now, take a look at your hand. In our team, we've estimated that you have more than 10 billion phages on each of your hands. What are they doing there?
Sad, pogledajmo vaše ruke. Naš tim je procenio da imate više od 10 milijardi faga na svakoj ruci. Šta rade tu?
(Laughter)
(Smeh)
Well, viruses are good at infecting cells. And phages are great at infecting bacteria. And your hand, just like so much of our body, is a hotbed of bacterial activity, making it an ideal hunting ground for phages. Because after all, phages hunt bacteria. It's also important to know that phages are extremely selective hunters. Typically, a phage will only infect a single bacterial species. So in this rendering here, the phage that you see hunts for a bacterium called Staphylococcus aureus, which is known as MRSA in its drug-resistant form. It causes skin or wound infections.
Pa, virusi su dobri u inficiranju ćelija. A fagi su dobri u inficiranju bakterija. A vaša ruka je, kao i ostatak vašeg tela, leglo bakterijske aktivnosti, što je čini idealnim lovištem za fage. Zato što, na kraju krajeva, fagi love bakterije. Takođe je veoma važno znati da su fagi veoma selektivni lovci. Obično, fag će inficirati samo jednu vrstu bakterija. Dakle, na ovom prikazu ovde, fag koga vidite lovi bakteriju koja se zove zlatni stafilokok, poznatu kao MRSA, u svom obliku otpornom na antibiotike. Izaziva infekcije kože ili rana.
The way the phage hunts is with its feet. The feet are actually extremely sensitive receptors, on the lookout for the right surface on a bacterial cell. Once it finds it, the phage will latch on to the bacterial cell wall and then inject its DNA. DNA sits in the head of the phage and travels into the bacteria through the long body. At this point, the phage reprograms the bacteria into producing lots of new phages. The bacteria, in effect, becomes a phage factory. Once around 50-100 phages have accumulated within the bacteria cell, the phages are then able to release a protein that disrupts the bacteria cell wall. As the bacteria bursts, the phages move out and go on the hunt again for a new bacteria to infect.
Fagi love svojim stopalima. Stopala su u stvari izuzetno osetljivi receptori, u potrazi za pravom površinom bakterijske ćelije. Jednom kada je nađe, fag će se prikovati za zid bakterijske ćelije i ubaciti svoj DNK. DNK se nalazi u glavi faga i putuje u bakteriju kroz dugačko telo. U ovom trenutku, fag reprogramira bakteriju da proizvodi mnogo novih faga. Tako bakterija postaje fabrika faga. Kada se 50-100 faga nakupe unutar ćelije, fagi su tad u mogućnosti da oslobode protein koji slabi ćelijski zid bakterije. Kako bakterija pukne, fagi se iseljavaju i idu ponovo u potragu za novom bakterijom koju će inficirati.
Now, I'm sorry, this probably sounded like a scary virus again. But it's exactly this ability of phages -- to multiply within the bacteria and then kill them -- that make them so interesting from a medical point of view. The other part that I find extremely interesting is the scale at which this is going on. Now, just five years ago, I really had no clue about phages. And yet, today I would tell you they are part of a natural principle. Phages and bacteria go back to the earliest days of evolution. They have always existed in tandem, keeping each other in check. So this is really the story of yin and yang, of the hunter and the prey, at a microscopic level. Some scientists have even estimated that phages are the most abundant organism on our planet. So even before we continue talking about their medical potential, I think everybody should know about phages and their role on earth: they hunt, infect and kill bacteria.
Izvinjavam se, ovo je verovatno ponovo zvučalo kao strašni virus. Ali upravo ova sposobnost faga - da se razmnože u bakteriji i onda ih ubiju - ih čini izuzetno interesantnim sa medicinske tačke gledišta. Drugi deo koji je meni izuzetno interesantan je obim u kojem se to odvija. Pre samo pet godina, nisam imao pojma o fagima. A ipak, danas bih mogao da vam kažem da su oni deo prirodnog principa. Fagi i bakterije postoje od najranijih dana evolucije. I uvek su živeli u tandemu, držeći pod kontrolom jedni druge. Dakle, ovo je u suštini priča o jinu i jangu, o lovcu i plenu, na mikroskopskom nivou. Neki naučnici su čak procenili da su fagi najrasprostranjeniji organizmi na našoj planeti. Tako da, pre nego što nastavimo priču o njihovom medicinskom potencijalu, mislim da bi svi trebalo da znaju šta su fagi i koja je njihova uloga na zemlji: oni love, inficiraju i ubijaju bakterije.
Now, how come we have something that works so well in nature, every day, everywhere around us, and yet, in most parts of the world, we do not have a single drug on the market that uses this principle to combat bacterial infections? The simple answer is: no one has developed this kind of a drug yet, at least not one that conforms to the Western regulatory standards that set the norm for so much of the world. To understand why, we need to move back in time.
Pa, kako to da imamo nešto što tako dobro funkcioniše u prirodi, svakodnevno, svuda oko nas, a ipak, u većem delu sveta, nemamo nijedan lek na tržištu koji koristi ovaj princip u borbi protiv bakterijskih infekcija? Jednostavan odgovor je: niko još nije razvio ovakvu vrstu leka, bar ne takvog koji odgovara standardima zapadne kontrole koja je postavila pravila u većem delu sveta. Da bismo otkrili zašto, moramo se malo vratiti kroz vreme.
This is a picture of Félix d'Herelle. He is one of the two scientists credited with discovering phages. Except, when he discovered them back in 1917, he had no clue what he had discovered. He was interested in a disease called bacillary dysentery, which is a bacterial infection that causes severe diarrhea, and back then, was actually killing a lot of people, because after all, no cure for bacterial infections had been invented. He was looking at samples from patients who had survived this illness. And he found that something weird was going on. Something in the sample was killing the bacteria that were supposed to cause the disease.
Ovo je slika Feliksa De Herela. On je jedan od dva naučnika zaslužnih za otkriće faga. Samo, kad ih je otkrio, 1917. godine, nije imao predstavu šta je otkrio. Zanimala ga je bolest zvana bacilarna dizenterija, bakterijska infekcija koja izaziva tešku dijareju, i u to vreme je ubijala dosta ljudi, zato što, na kraju krajeva, nije postojao lek za bakterijsku infekciju. On je posmatrao uzorke pacijenata koji su preživeli bolest. I otkrio je da se nešto čudno dešavalo. Nešto u uzorku je ubijalo bakterije koje je trebalo da izazovu bolest.
To find out what was going on, he did an ingenious experiment. He took the sample, filtered it until he was sure that only something very small could have remained, and then took a tiny drop and added it to freshly cultivated bacteria. And he observed that within a number of hours, the bacteria had been killed. He then repeated this, again filtering, taking a tiny drop, adding it to the next batch of fresh bacteria. He did this in sequence 50 times, always observing the same effect. And at this point, he made two conclusions. First of all, the obvious one: yes, something was killing the bacteria, and it was in that liquid. The other one: it had to be biologic in nature, because a tiny drop was sufficient to have a huge impact. He called the agent he had found an "invisible microbe" and gave it the name "bacteriophage," which, literally translated, means "bacteria eater." And by the way, this is one of the most fundamental discoveries of modern microbiology. So many modern techniques go back to our understanding of how phages work -- in genomic editing, but also in other fields. And just today, the Nobel Prize in chemistry was announced for two scientists who work with phages and develop drugs based on that.
Da bi saznao šta se dešava, napravio je genijalan eksperiment. Uzeo je uzorak, filtrirao ga dok nije bio siguran da je ostalo jako malo, a potom je uzeo malu kap i dodao je sveže uzgojenim bakterijama. Onda je video da su u roku od nekoliko sati bakterije bile ubijene. Onda je on ponovio ovo, ponovo filtrirao, uzeo malu kap, dodao je u sledeću seriju svežih bakterija. Ovo je ponovio 50 puta, uvek gledajući isti efekat. U tom momentu, zaključio je dve stvari. Pre svega, što je očigledno, da, nešto je ubijalo bakterije, i to nešto je bilo u tečnosti. Drugo: to je moralo biti nešto biološke prirode, zato što je bila dovoljna samo mala kap da napravi tako veliki učinak. On je ovaj agens koji je pronašao nazvao „nevidljivi mikrob“ i dao mu naziv „bakterofag“, što u bukvalnom prevodu znači „žderač bakterija“. A inače, ovo je jedno od osnovnih otkrića moderne mikrobiologije. Mnoge moderne tehnike se vraćaju proučavanju toga kako fagi funkcionišu - u menjanju genoma, ali takođe i na drugim poljima. Upravo danas je najavljena dodela Nobelove nagrade iz hemije za dva naučnika koja su radila sa fagima i razvila lek na bazi njih.
Now, back in the 1920s and 1930s, people also immediately saw the medical potential of phages. After all, albeit invisible, you had something that reliably was killing bacteria. Companies that still exist today, such as Abbott, Squibb or Lilly, sold phage preparations. But the reality is, if you're starting with an invisible microbe, it's very difficult to get to a reliable drug. Just imagine going to the FDA today and telling them all about that invisible virus you want to give to patients. So when chemical antibiotics emerged in the 1940s, they completely changed the game. And this guy played a major role.
U 1920-im i 1930-im, ljudi su takođe odmah uočili medicinski potencijal faga. Na kraju krajeva, iako nevidiljivo, imali ste nešto što pouzdano ubija bakterije. Kompanije koje postoje i danas, kao što su Abot, Skvib i Lili, su prodavale pripremu faga. Ali u stvarnosti, ako počinjete sa nevidljivim mikrobima, veoma je teško dobiti pouzdan lek. Zamislite da idete danas u Upravu za hranu i lekove i govorite im o nevidljivom virusu koji želite da date pacijentu. Kada su se hemijski antibiotici pojavili 1940-ih, potpuno su promenili igru. A ovaj lik je odigrao važnu ulogu.
This is Alexander Fleming. He won the Nobel Prize in medicine for his work contributing to the development of the first antibiotic, penicillin. And antibiotics really work very differently than phages. For the most part, they inhibit the growth of the bacteria, and they don't care so much which kind of bacteria are present. The ones that we call broad-spectrum will even work against a whole bunch of bacteria out there. Compare that to phages, which work extremely narrowly against one bacterial species, and you can see the obvious advantage.
To je Aleksandar Fleming. Dobio je Nobelovu nagradu za medicinu zbog svog rada koji je doprineo razvoju prvog antibiotika, penicilina. A antibiotici su stvarno delovali veoma drugačije od faga. Većinom, oni sprečavaju rast bakterija, i nije ih mnogo briga koja je vrsta bakterija prisutna. Takozvani antibiotik širokog spektra će raditi protiv čitavog niza bakterija. U poređenju sa fagima, čije je delovanje prilično suženo protiv određene bakterijske vrste, možete videti očiglednu prednost.
Now, back then, this must have felt like a dream come true. You had a patient with a suspected bacterial infection, you gave him the antibiotic, and without really needing to know anything else about the bacteria causing the disease, many of the patients recovered. And so as we developed more and more antibiotics, they, rightly so, became the first-line therapy for bacterial infections. And by the way, they have contributed tremendously to our life expectancy. We are only able to do complex medical interventions and medical surgeries today because we have antibiotics, and we don't risk the patient dying the very next day from the bacterial infection that he might contract during the operation.
Tada je to verovatno izgledalo kao san koji se ostvaruje. Imali ste pacijenta kod koga se sumnja na bakterijsku infekciju, dali ste mu antibiotik, i bez ikakve potrebe da znate bilo šta o bakteriji koja je izazvala bolest, mnogi pacijenti su se oporavili. Tako smo razvili još antibiotika, koji su, s pravom, postali prvi izbor za terapiju protiv bakterijskih infekcija. Uzgred, oni su veoma doprineli produžetku životnog veka. Danas možemo da izvršimo kompleksne medicinske intervencije i operacije samo zahvaljujući antibioticima, bez rizika da će pacijent umreti sledećeg dana od bakterijske infekcije sa kojom je možda došao u kontakt tokom operacije.
So we started to forget about phages, especially in Western medicine. And to a certain extent, even when I was growing up, the notion was: we have solved bacterial infections; we have antibiotics. Of course, today, we know that this is wrong. Today, most of you will have heard about superbugs. Those are bacteria that have become resistant to many, if not all, of the antibiotics that we have developed to treat this infection.
Tako smo počeli da zaboravljamo na fage, pogotovo zapadna medicina. I u određenoj meri, čak i dok sam ja odrastao, važio je koncept da smo rešili problem bakterijskih infekcija jer imamo antibiotike. Naravno, danas znamo da je to pogrešno. Danas je većina vas verovatno čula za superbakterije. To su one bakterije koje su postale otporne na mnoge, ako ne na sve, antibiotike koje smo razvili da bismo lečili infekciju.
How did we get here? Well, we weren't as smart as we thought we were. As we started using antibiotics everywhere -- in hospitals, to treat and prevent; at home, for simple colds; on farms, to keep animals healthy -- the bacteria evolved. In the onslaught of antibiotics that were all around them, those bacteria survived that were best able to adapt. Today, we call these "multidrug-resistant bacteria." And let me put a scary number out there. In a recent study commissioned by the UK government, it was estimated that by 2050, ten million people could die every year from multidrug-resistant infections. Compare that to eight million deaths from cancer per year today, and you can see that this is a scary number.
Kako smo dospeli dovde? Pa, nismo bili toliko pametni koliko smo mislili da jesmo. Počeli smo koristiti antibiotike svuda - u bolnicama, za lečenje i prevenciju; kod kuće, za najobičnije prehlade; na farmama, da bi životinje ostale zdrave - bakterije su evoluirale. U najezdi antibiotika koji su bili oko njih, bakterije koje su preživele su one koje su najbolje mogle da se prilagode. Danas, njih zovemo „bakterije otporne na lekove“. Dozvolite mi da iznesem jedan zastrašujući broj. U nedavnom istraživanju koje je sprovela britanska vlada, procenjeno je da bi do 2050. godine deset miliona ljudi godišnje moglo umreti od infekcija otpornih na lekove. Uporedite to sa osam miliona godišnje smrtnih ishoda od raka danas, i videćete da je to zastrašujući broj.
But the good news is, phages have stuck around. And let me tell you, they are not impressed by multidrug resistance.
Ali, dobra vest je da su fagi još uvek tu. I da vam kažem, uopšte nisu impresionirani otpornošću na lekove.
(Laughter)
(Smeh)
They are just as happily killing and hunting bacteria all around us. And they've also stayed selective, which today is really a good thing. Today, we are able to reliably identify a bacterial pathogen that's causing an infection in many settings. And their selectivity will help us avoid some of the side effects that are commonly associated with broad-spectrum antibiotics. But maybe the best news of all is: they are no longer an invisible microbe. We can look at them. And we did so together before. We can sequence their DNA. We understand how they replicate. And we understand the limitations. We are in a great place to now develop strong and reliable phage-based pharmaceuticals.
I dalje srećno ubijaju i love bakterije oko nas. A i dalje su ostali selektivni, što je danas jako dobra stvar. Danas smo u mogućnosti da identifikujemo bakterijski patogen koji izaziva infekciju u mnogim prilikama. A njihova selektivnost će nam pomoći da izbegnemo neke nuspojave koje često prate antibiotike širokog spektra. Ali možda je najbolja vest od svih to da više nisu nevidljivi mikrobi. Možemo ih videti. I to smo i uradili zajedno. Možemo analizirati njihov DNK. Shvatili smo kako se razmnožavaju. I znamo njihova ograničenja. Nalazimo se na idealnoj poziciji da sada razvijemo jaku i pouzdanu farmakologiju baziranu na fagima.
And that's what's happening around the globe. More than 10 biotech companies, including our own company, are developing human-phage applications to treat bacterial infections. A number of clinical trials are getting underway in Europe and the US. So I'm convinced that we're standing on the verge of a renaissance of phage therapy. And to me, the correct way to depict the phage is something like this.
I to se dešava širom sveta. Preko 10 biotehničkih kompanija, uključujući i našu, razvijaju primenu ljudskih faga u borbi protiv bakterijskih infekcija. Broj kliničkih ispitivanja se odvija u Evropi i SAD. Tako da sam uveren da stojimo na pragu renesanse terapije fagima. A za mene, najbolji način da se opiše fag je nešto ovako.
(Laughter)
(Smeh)
To me, phages are the superheroes that we have been waiting for in our fight against multidrug-resistant infections.
Za mene, fagi su superheroji koje smo čekali u našoj borbi protiv infekcija otpornih na lekove.
So the next time you think about a virus, keep this image in mind. After all, a phage might one day save your life.
Dakle, sledeći put kada pomislite na viruse, imajte ovu sliku na umu. Na kraju krajeva, fag vam jednog dana može spasiti život.
Thank you.
Hvala vam.
(Applause)
(Aplauz)