Brug et øjeblik og tænk på en virus. Hvad er din første tanke? En sygdom? En frygt? Sandsynligvis noget meget ubehageligt. Men virus er forskellige. Nogle er basis for dødbringende sygdomme. Men andre kan rent faktisk kurere sygdomme. Disse virus kaldes "bakteriofager".
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."
Den første gang jeg hørte om bakteriofager var tilbage i 2013. Min svigerfar, som er kirurg, fortalte mig om en kvinde, som han behandlede. Kvinden havde en knæskade, som krævede gentagne operationer, og i den periode udvikledes en kronisk bakteriel infektion i hendes ben. Uheldigvis for hende, var bakterien, som var årsag til infektionen immun overfor alle de antibiotika, der var tilgængelige. På dette tidspunkt er det normalt eneste mulighed at amputere benet, for at stoppe infektionens yderligere spredning. Min svigerfar var desperat efter at finde en anden løsning, og som sidste udvej ansøgte han om forsøgs-behandling med bakteriofager. Og gæt engang. Det virkede. Efter 3 ugers behandling med bakterio- fager, var den kroniske infektion væk. hvor ingen antibiotika virkede. Jeg blev fascineret af dette lidt skøre koncept: virus kurerer en infektion. Jeg er stadig fascineret over bakteriofagernes medicinske potentiale. Jeg opsagde faktisk mit job sidste år, for at lave et firma i denne branche
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.
Men, hvad er en bakteriofag? Billedet, som du kan se her blev taget med et elektron-mikroskop. Og det betyder, at det du kan se på skærmen i virkeligheden er meget lille. Den kornede ting i midten, med hovedet og den lange krop og et antal fødder, det er billedet af en prototype af en bakteriofag. Den er lidt sød.
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.
(Latter)
(Laughter)
Kig nu på din hånd. I vores team, har vi estimeret at du har mere end 10 billioner bakteriofager på hver af dine hænder. Hvad skal de dog der?
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?
(Latter)
(Laughter)
Ja, virus er gode til at inficere celler. Bakteriofager er gode til at inficere bakterier. Og din hånd, såvel som resten af din krop, er et arnested for bakteriel aktivitet, som gør det til et ideelt jagtområde for bakteriofager. For bakteriofager jagter bakterier. Det er også vigtigt at bakteriofager er meget selektive jægere. Typisk, så kan en bakteriofag kun inficere en enkelt bakterieart. Den bakteriofag, som du ser her jager efter en bakterie, som kaldes Staphylococcus aureus. hvilket er kendt som MRSA i sin antibiotika resistente form. Den forårsager hud- eller sårinfektioner.
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.
Den måde bakteriofagen jager er med sine fødder. Fødderne er nogle meget følsomme receptorer, som leder efter den rigtige overflade på en bakterie celle. Når den finder det, vil bakteriofagen hæge sig fast på bakteriens cellevæg og indsprøjte sit DNA. DNA'et er i hovedet af bakteriofagen. og bevæger sig ind i bakterien gennem den lange krop. Nu vil bakteriofagen omprogrammere bakterien til at producere mange nye bakteriofager. Bakterien bliver i virkeligheden en bakteriofag fabrik. Når 50-100 bakteriofager er produceret inde i bakteriecellen, frigør bakteriofagerne et protein, som gennemtrænger bakteriens celle væg. Mens bakterien brister, flytter bakteriofagerne ud og går på jagt efter nye bakterier, de kan inficere.
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.
Undskyld, dette lød nok lidt som en skræmme virus igen. Men det er præcis den egenskab ved bakteriofager -- at opformere sig indeni bakterien og så dræbe den, -- som gør dem så interessante fra et medicinsk synspunkt. Den andet, som jeg finder yderst interessant er den skala, hvormed dette foregår. For blot fem år siden, vidste jeg virkelig intet om bakteriofager. Og i dag kan jeg fortælle dig, at de er et naturligt fundament. Bakteriofager og bakterier er begge organismer fra den tidligste evolution. De har altid eksisteret side om side og holdt hinanden i skak. Så dette er virkelig historien om Yin og Yang, om jægeren og byttet på et mikroskopisk niveau. Nogle forskere har endda beregnet at bakteriofager er den mest talrige organisme på vores planet. Så inden vi taler videre om deres medicinske potentiale, synes jeg, alle bør kende til bakteriofager og deres rolle på jorden: de jager, inficerer og dræber bakterier.
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.
Hvordan kan det så være, at vi har noget, der virker så godt i naturen, hver dag, overalt omkring os, og dog har vi, i det meste af verden, ikke et eneste lægemiddel på markedet som benytter dette princip til at bekæmpe bakterielle infektioner? Det simple svar er: ingen har endnu udviklet sådan et lægemiddel. ihvertfald ikke et, der lever op til de vestlige regulatoriske standarder, som sætter reglerne for en stor del af verden. For at forstå hvorfor, skal vi tilbage i tiden.
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.
Dette er et billede af Félix d'Herelle. Han er en af de to forskere, anerkendt for opdagelsen af bakteriofager. Men, da han opdagede dem tilbage i 1917 havde han ingen idé om hvad han havde opdaget. Han var interesseret i en sygdom, som kaldes bacille dysenteri, som er en bakteriel infektion, der forårsager alvorlig diarré, og som dengang, dræbte mange mennesker, fordi man ikke havde en behandling for bakterielle infektioner. Han tog prøver fra patienter, som havde overlevet denne sygdom. Og han opdagede at der skete noget skørt. Et eller andet i prøverne dræbte de bakterier, som man mente forårsagede sygdommen.
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.
For at undersøge hvad der skete, udførte han et genialt forsøg. Han tog en prøve og filtrerede den, indtil han var sikker på, at kun noget meget småt kunne restere, så udtog han en lille dråbe, som han tilsatte til nogle opformerede bakterier. Og han observerede at indenfor nogen timer, var bakterierne blevet dræbt. Han gentog så forsøget, filtrerede og udtog en lille dråbe, og tilsatte den til næste batch af friske bakterier. Han gentog dette 50 gange efter hinanden, hver gang med den samme effekt. Og på dette tidspunkt, lavede han to konklusioner. Den første og selvfølgelige: Ja, noget dræbte bakterierne og det var ikke væsken. Den næste: Det måtte være af biologisk oprindelse, fordi så lille en dråbe var tilstrækkelig til at have en så stor effekt. Han kaldte det, han havde fundet for: "en usynlig mikroorganisme", og gav den navnet: "Bakteriofag", som direkte oversat betyder: "bakterie spiser". Og forresten, dette er en af de mest fundamentale opdagelser af moderne mikrobiologi. Mange moderne teknikker bygger på forståelsen af bakteriofagers arbejde -- i gen-modificering men også på andre områder. Og netop i dag blev Nobel prisen i kemi bekendtgjort for to forskere, som arbejder med bakteriofager og udvikler medicin deraf.
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.
Men tilbage i 1920'erne og 1930'erne, så man også potentialet for lægemidler med bakteriofager. Omend stadig usynlig, du har fundet noget, som virkelig dræber bakterier. Firmaer som eksisterer i dag, såsom Abbott, Squibb eller Lilly, solgte medicin med bakteriofager Men realiteten er, at når du starter med en usynlig mikroorganisme så er det svært at nå frem til et pålideligt lægemiddel. Forestil dig blot at gå til FDA i dag for at fortælle dem alt om den usynlige virus, som du vil give til patienter. Så, da kemiske antibiotika dukkede op i 1940'erne, ændrede de fuldstændigt billedet. Og denne fyr spillede en stor rolle.
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.
Det er Alexander Fleming. Han vandt Nobel prisen i medicin for sit arbejde som bidrog til udviklingen af det første antibiotika, penicillin. Og antibiotika virker virkelig på en helt anden måde end bakteriofager. Størstedelen, hæmmer væksten af bakterier, og de er lidt ligeglade med hvilke bakterier, der er tilstede. Dem vi kalder bredspektrede antibiotika vil endda kæmpe mod en hel bunke af bakterier derude. Sammenlignet med bakteriofager som er meget specifikke, mod en bakterieart, viser dig en klar fordel.
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.
Men, dengang, må det have været som en drøm der blev til virkelighed. Du havde en patient med en formodet bakteriel infektion, du gav ham antibiotika, og uden rigtig at behøve at vide noget om bakterien, som var årsagen, ville mange af patienterne komme sig. Og efterhånden som vi udviklede flere antibiotika, blev de, første-valgs-behandling for bakterielle infektioner. De har øget vores forventede levetid betragteligt. Når vi i dag kan udføre kompleks medicinsk behandling og kirurgi, så er det fordi vi har antibiotika, og fordi vi ikke risikerer at patienten dør næste dag af en bakteriel infektion, som han kan være smittet med under operationen.
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.
Derfor glemte vi alt om bakteriofager specielt i vestlige landes medicin. Og selv da jeg voksede op var det til en vis grad forestillingen at: vi har løst problemet med bakterielle infektioner for vi har antibiotika. I dag ved vi selvfølgelig, at det er forkert. De fleste af jer har hørt om superbakterier. Det er bakterier som er blevet immune overfor mange, hvis ikke overfor alle, af de antibiotika vi har udviklet til at behandle infektioner
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.
Hvordan skete det? Ja, vi var ikke helt så smarte, som vi troede. Da vi startede med at bruge antibiotika overalt -- for at forebygge og behandle på hospitalerne; for forkølelser hjemme; for at holde dyrene raske på gårdene -- udviklede bakterierne sig. I det angreb af antibiotika der var rundt om dem, var det de bakterier, der bedst tilpassede sig, der overlevede. I dag, kalder vi dem "multi-resistente bakterier". Og lad mig give jer et skræmmende tal. I et nyligt studie bestilt af UK regeringen, blev det estimeret at i 2050, kan 10 millioner mennesker dø hvert år af multi-resistente infektioner. Sammenlign det med at der i dag dør 8 millioner af cancer hvert år og du vil se, at det er et skræmmende tal.
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.
Men den gode nyhed er, bakteriofager er her stadig. Og de er ikke imponeret af multi-resistens.
But the good news is, phages have stuck around. And let me tell you, they are not impressed by multidrug resistance.
(Latter)
(Laughter)
De jager og dræber gladeligt enhver bakterie Og de er forblevet selektive, hvilket i dag er en god egenskab. Vi kan i dag pålideligt identificere en bakteriel patogen, som forårsager en infektion i forskellige omgivelser. Og selektiviteten kan hjælpe til at vi mindsker de bivirkninger som normalt er forbundet med bred-spektret antibiotika. Men, den allerbedste nyhed er, at de ikke længere er usynlige mikroorganismer. Vi kan se på dem. Og det gjorde vi lige før. Vi kan sekvensere deres DNA Forstår hvordan de replikerer, og deres begrænsninger. Vi er nu i stand til at udvikle stærke og sikre bakteriofag-baserede lægemidler.
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.
Og det er i gang overalt i verden Mere end 10 biotek firmaer inklusiv vores eget, udvikler bakteriofager til behandling af infektioner Et antal kliniske forsøg er på vej i Europa og i USA. Jeg er sikker på der kommer et paradigmeskifte og renæssance for fag behandlinger. Jeg beskriver bakteriofagen på denne måde.
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.
(Latter)
(Laughter)
Bakteriofager er de superhelte vi har ventet på i kampen mod multi-resistente infektioner.
To me, phages are the superheroes that we have been waiting for in our fight against multidrug-resistant infections.
Så næste gang du tænker på en virus, så husk dette billede. Det kan blive en bakteriofag, der redder dit liv en dag.
So the next time you think about a virus, keep this image in mind. After all, a phage might one day save your life.
Tak.
Thank you.
(Klapsalve)
(Applause)