Gene editing can now change an entire species — forever   Leave a comment



So this is a talk about gene drives, but I’m going to start by telling you a brief story. 20 years ago, a biologist named Anthony James got obsessed with the idea of making mosquitos that didn’t transmit malaria.
It was a great idea, and pretty much a complete failure. For one thing, it turned out to be really hard to make a malaria-resistant mosquito. James managed it, finally, just a few years ago, by adding some genes that make it impossible for the malaria parasite to survive inside the mosquito.
But that just created another problem. Now that you’ve got a malaria-resistant mosquito, how do you get it to replace all the malaria-carrying mosquitos? There are a couple options, but plan A was basically to breed up a bunch of the new genetically-engineered mosquitos release them into the wild and hope that they pass on their genes. The problem was that you’d have to release literally 10 times the number of native mosquitos to work. So in a village with 10,000 mosquitos, you release an extra 100,000. As you might guess, this was not a very popular strategy with the villagers.
Then, last January, Anthony James got an email from a biologist named Ethan Bier. Bier said that he and his grad student Valentino Gantz had stumbled on a tool that could not only guarantee that a particular genetic trait would be inherited, but that it would spread incredibly quickly. If they were right, it would basically solve the problem that he and James had been working on for 20 years.
As a test, they engineered two mosquitos to carry the anti-malaria gene and also this new tool, a gene drive, which I’ll explain in a minute. Finally, they set it up so that any mosquitos that had inherited the anti-malaria gene wouldn’t have the usual white eyes, but would instead have red eyes. That was pretty much just for convenience so they could tell just at a glance which was which.
So they took their two anti-malarial, red-eyed mosquitos and put them in a box with 30 ordinary white-eyed ones, and let them breed. In two generations, those had produced 3,800 grandchildren. That is not the surprising part. This is the surprising part: given that you started with just two red-eyed mosquitos and 30 white-eyed ones, you expect mostly white-eyed descendants. Instead, when James opened the box, all 3,800 mosquitos had red eyes.
When I asked Ethan Bier about this moment, he became so excited that he was literally shouting into the phone. That’s because getting only red-eyed mosquitos violates a rule that is the absolute cornerstone of biology, Mendelian genetics. I’ll keep this quick, but Mendelian genetics says when a male and a female mate, their baby inherits half of its DNA from each parent. So if our original mosquito was aa and our new mosquito is aB, where B is the anti-malarial gene, the babies should come out in four permutations: aa, aB, aa, Ba. Instead, with the new gene drive, they all came out aB. Biologically, that shouldn’t even be possible.
So what happened? The first thing that happened was the arrival of a gene-editing tool known as CRISPR in 2012. Many of you have probably heard about CRISPR, so I’ll just say briefly that CRISPR is a tool that allows researchers to edit genes very precisely, easily and quickly. It does this by harnessing a mechanism that already existed in bacteria. Basically, there’s a protein that acts like a scissors and cuts the DNA, and there’s an RNA molecule that directs the scissors to any point on the genome you want. The result is basically a word processor for genes. You can take an entire gene out, put one in, or even edit just a single letter within a gene. And you can do it in nearly any species.
OK, remember how I said that gene drives originally had two problems? The first was that it was hard to engineer a mosquito to be malaria-resistant. That’s basically gone now, thanks to CRISPR. But the other problem was logistical. How do you get your trait to spread? This is where it gets clever.
A couple years ago, a biologist at Harvard named Kevin Esvelt wondered what would happen if you made it so that CRISPR inserted not only your new gene but also the machinery that does the cutting and pasting. In other words, what if CRISPR also copied and pasted itself. You’d end up with a perpetual motion machine for gene editing. And that’s exactly what happened. This CRISPR gene drive that Esvelt created not only guarantees that a trait will get passed on, but if it’s used in the germline cells, it will automatically copy and paste your new gene into both chromosomes of every single individual. It’s like a global search and replace, or in science terms, it makes a heterozygous trait homozygous.
So, what does this mean? For one thing, it means we have a very powerful, but also somewhat alarming new tool. Up until now, the fact that gene drives didn’t work very well was actually kind of a relief. Normally when we mess around with an organism’s genes, we make that thing less evolutionarily fit. So biologists can make all the mutant fruit flies they want without worrying about it. If some escape, natural selection just takes care of them.
What’s remarkable and powerful and frightening about gene drives is that that will no longer be true. Assuming that your trait does not have a big evolutionary handicap, like a mosquito that can’t fly, the CRISPR-based gene drive will spread the change relentlessly until it is in every single individual in the population. Now, it isn’t easy to make a gene drive that works that well, but James and Esvelt think that we can.
The good news is that this opens the door to some remarkable things. If you put an anti-malarial gene drive in just 1 percent of Anopheles mosquitoes, the species that transmits malaria, researchers estimate that it would spread to the entire population in a year. So in a year, you could virtually eliminate malaria. In practice, we’re still a few years out from being able to do that, but still, a 1,000 children a day die of malaria. In a year, that number could be almost zero. The same goes for dengue fever, chikungunya, yellow fever.
And it gets better. Say you want to get rid of an invasive species, like get Asian carp out of the Great Lakes. All you have to do is release a gene drive that makes the fish produce only male offspring. In a few generations, there’ll be no females left, no more carp. In theory, this means we could restore hundreds of native species that have been pushed to the brink.
OK, that’s the good news, this is the bad news. Gene drives are so effective that even an accidental release could change an entire species, and often very quickly. Anthony James took good precautions. He bred his mosquitos in a bio-containment lab and he also used a species that’s not native to the US so that even if some did escape, they’d just die off, there’d be nothing for them to mate with. But it’s also true that if a dozen Asian carp with the all-male gene drive accidentally got carried from the Great Lakes back to Asia, they could potentially wipe out the native Asian carp population. And that’s not so unlikely, given how connected our world is. In fact, it’s why we have an invasive species problem. And that’s fish. Things like mosquitos and fruit flies, there’s literally no way to contain them. They cross borders and oceans all the time.
OK, the other piece of bad news is that a gene drive might not stay confined to what we call the target species. That’s because of gene flow, which is a fancy way of saying that neighboring species sometimes interbreed. If that happens, it’s possible a gene drive could cross over, like Asian carp could infect some other kind of carp. That’s not so bad if your drive just promotes a trait, like eye color. In fact, there’s a decent chance that we’ll see a wave of very weird fruit flies in the near future. But it could be a disaster if your drive is deigned to eliminate the species entirely.
The last worrisome thing is that the technology to do this, to genetically engineer an organism and include a gene drive, is something that basically any lab in the world can do. An undergraduate can do it. A talented high schooler with some equipment can do it.
Now, I’m guessing that this sounds terrifying.
Interestingly though, nearly every scientist I talk to seemed to think that gene drives were not actually that frightening or dangerous. Partly because they believe that scientists will be very cautious and responsible about using them.
So far, that’s been true. But gene drives also have some actual limitations. So for one thing, they work only in sexually reproducing species. So thank goodness, they can’t be used to engineer viruses or bacteria. Also, the trait spreads only with each successive generation. So changing or eliminating a population is practical only if that species has a fast reproductive cycle, like insects or maybe small vertebrates like mice or fish. In elephants or people, it would take centuries for a trait to spread widely enough to matter.
Also, even with CRISPR, it’s not that easy to engineer a truly devastating trait. Say you wanted to make a fruit fly that feeds on ordinary fruit instead of rotting fruit, with the aim of sabotaging American agriculture. First, you’d have to figure out which genes control what the fly wants to eat, which is already a very long and complicated project. Then you’d have to alter those genes to change the fly’s behavior to whatever you’d want it to be, which is an even longer and more complicated project. And it might not even work, because the genes that control behavior are complex. So if you’re a terrorist and have to choose between starting a grueling basic research program that will require years of meticulous lab work and still might not pan out, or just blowing stuff up? You’ll probably choose the later.
This is especially true because at least in theory, it should be pretty easy to build what’s called a reversal drive. That’s one that basically overwrites the change made by the first gene drive. So if you don’t like the effects of a change, you can just release a second drive that will cancel it out, at least in theory.
OK, so where does this leave us? We now have the ability to change entire species at will. Should we? Are we gods now? I’m not sure I’d say that. But I would say this: first, some very smart people are even now debating how to regulate gene drives. At the same time, some other very smart people are working hard to create safeguards, like gene drives that self-regulate or peter out after a few generations. That’s great. But this technology still requires a conversation. And given the nature of gene drives, that conversation has to be global. What if Kenya wants to use a drive but Tanzania doesn’t? Who decides whether to release a gene drive that can fly?
I don’t have the answer to that question. All we can do going forward, I think, is talk honestly about the risks and benefits and take responsibility for our choices. By that I mean, not just the choice to use a gene drive, but also the choice not to use one. Humans have a tendency to assume that the safest option is to preserve the status quo. But that’s not always the case. Gene drives have risks, and those need to be discussed, but malaria exists now and kills 1,000 people a day. To combat it, we spray pesticides that do grave damage to other species, including amphibians and birds.
So when you hear about gene drives in the coming months, and trust me, you will be hearing about them, remember that. It can be frightening to act, but sometimes, not acting is worse.

La conferenziera, Jennifer Doudna, insieme alla college Emmanuelle Charpentier, ha inventato un metodo per modificare i genomi del DNA. Il metodo (la tecnologia) si chiama CRISPR-Case9.

La scoperta è stata fatta nell’ambito di una ricerca volta a capire in che modo i batteri combattono le infezioni virali. Nelle celle di molti batteri c’è un sistema immunitario chiamato CRISPR che permette di identificare e distruggere DNA virali.

Di questo CRISPR fa parte una proteina che si chiama Cas9 ed è attraverso le funzioni di questa proteina che gli scienziati hanno oggi la possibilità di eliminare o di inserire specifici “bits” di DNA nelle cellule con un’incredibile precisione.

Questa tecnologia è già stata usata per modificare il DNA di topi, scimmie e anche altri organismi. Alcuni scienziati cinesi hanno dimostrato di poter utilizzare la tecnologia CRISPR per cambiare dei geni in embrioni umani, e alcuni scienziati di Filadelfia hanno usato CRISPR per rimuovere il DNA del virus da cellule umane infette da HIV.

La possibilità di modificare i genomi solleva questioni di carattere morale che vanno considerate, perché questa tecnologia può essere utilizzata non solo in cellule di adulti ma anche in quelle di embrioni. È per questo che io e i miei colleghi abbiamo aperto il dibattito, per poter considerare le implicazioni etiche e sociali di questa tecnologia.

Quello che voglio fare ora è spiegare che cos’è la tenologia CRISPR, a che punto siamo oggi, e perché io penso che dobbiamo esercitare prudenza nell’andare avanti con questa tecnologia.

Quando un virus infetta una cellula, vi inietta il suo DNA. In un batterio, il sistema CRISPR permette di prelevare il DNA del virus e di inserirlo a “pezzettini” nel cromosoma – il DNA – del batterio. Questi pezzettini vengno inseriti in un luogo chiamato CRISPR – l’abbreviazione sta per “Clustered Regularly Interspaced Short Palindromic Repeats”.

Questo è un meccanismo che permette alle cellule di ricordare nel tempo i virus ai quali sono state esposte. E quello che è importante è che questi “bits” di DNA sono trasmessi anche alla progenie della cellula, così che le cellule sono protette dai virus non solo per una ma per molte generazioni di cellule. Le cellule hanno così un ‘registro’ delle infezioni, e, come dice il mio collega Blake Wiedenheft, il CRISPR è di fatto come una vaccinazione genetica. Una volta che i bits di DNA sono stati inseriti nel cromosoma del batterio, la cellula genera una copia di una modecola chiamata RNA (color arancione nell’immagine), che è un’esatta replica del DNA del virus. RNA è un cugino chimico del DNA e permette l’interazione con molecole di DNA che hanno una sequenza parallela.

Dunque, quei bits di RNA che si trovano nel CRISPR si associano con la proteina Cas9 (nell’immagine qui è bianca), e formano un ‘complesso’ che agisce come una sentinella nella cellula. Essa perlustra tutto il DNA della cellula per trovare dei luoghi che hanno una sequenza parallela agli RNA; e, quando li trova (la molecola blu in quest’immagine è il DNA), questo complesso si associa con quel DNA e permette a Cas9 di tagliare il DNA del virus. Insomma, possiamo immaginare il complesso RNACas9 come un paio di forbici che riescono a tagliare il DNA. E ciò che è importante è che è possibile programmare questo complesso in modo che riconosca certe sequenze di DNA e le spezzi.

Insomma, è possibile utilizzare questa attività per modificare il genoma, permettere alle cellule di apportare un preciso cambiamento del DNA nel punto in cui avviene il taglio – un po’ come si riesce a correggere un errore di battuta con un programma di scrittura.

Abbiamo pensato di utilizzare il sistema CRISPR per modificare i genomi perché le cellule riescono a riconoscere i DNA spezzati e a ripararli. Quando una cellula, vegetale o animale, identifica una rottura nel suo DNA, riesce a ripararla o incollando insieme le due estremità con una minima modifica della sequenza in quella posizione, o integrando un nuovo pezzetto di DNA al posto della rottura. Allora, se riusciamo a introdurre delle rotture nel DNA in posti predefiniti, possiamo indurre le cellule a riparare quelle fratture, incorporando nuove informazioni genetiche. Dunque, se riusciamo a programmare CRISPR in modo che faccia un taglio del DNA nel punto preciso, o vicino a una mutazione che determina, per esempio, la fibrosi cistica, si induce la cellula a riparare quella mutazione.

Ora, “genome engineering” non è una cosa nuova ma i vecchi metodi erano molto complicati o inefficienti. La tecnologia CRISPR è invece relativamente semplice. Si potrebbero paragonare le vecchie tecnologie al metodo di spegnere un computer e farlo ripartire tutte le volte che c’è bisogno di usare una nuova funzione del software, mentre CRISPR è come un software per il genoma, possiamo programmarlo facilmente con questi pezzettini di RNA.

Dunque, una volta che si è fatto un taglio nel DNA, si provoca una riparazione, e questo ha dei risultati incredibili, come correggere le mutazioni che causano l’anemia o il morbo di Huntington. Io penso che la prima applicazione della tecnologia CRISPR avverrà nel sangue, visto che è più facile inserire questo ‘strumento’ nelle cellule liquide che nei tessuti solidi.

Ora come ora, si applica la tecnologia su modelli di malattie umane negli animali, come i topi. Si provocano determinati cambiamenti nel DNA delle cellule per vedere in che modo queti cambiamenti influenzano un tessuto o addirittura, come in questo caso [evidentemente quello presentato in diapositive dalla conferenziera] un intero organismo.

In questo esempio, la tecnologia CRISPR è stata usata per modificare un gene, quello che determina il colore nero del mantello di questi topi. Pensate che questi topolini bianchi sono diversi da quelli pigmentati soltanto in virtù di una minuscola differenza in un solo gene – dell’intero genoma – , e sono in tutto il resto assolutamente ‘normali’. E quando analizziamo la sequenza del genoma di questi animali, vediamo che la motidica del DNA è avvenuta esattamente nel punto in cui noi l’abbiamo indotta usando la tecnologia CRISPR.

Altri esperimenti si stanno facendo sulle scimmie. Qui cerchiamo di sperimentare l’applicazione di questa tecnologia su certi tessuti, studiando per esempio in che modo introdurre CRISPR nelle cellule. Vogliamo anche capire meglio in che modo il DNA viene riparato dopo essere stato tagliato, e come controllare gli effetti di un errore nel punto su cui si applica il taglio, e se l’uso di questa tecnologia porta conseguenze non previste.

Io penso che questa tecnologia si potrà applicare clinicamente entro i prossimi 10 anni, certamente su degli adulti. Ritengo probabile che saranno offerte terapie sperimentali, e forse anche già approvate, entro questo lasso di tempo; il che è evidentemente entusiamante. Ma proprio a causa di questo entusiasmo sono già state fondate compagnie, finanziate da capitali d’investimento, allo scopo di commercializzare la tecnologia CRISPR.

Bisogna considerare che la tecnologia CRISPR può essere utilizzata anche a fini di “enhancement” (aumento della performance). Pensate che si potrebbe cercare di “engineer” degli essere umani con proprietà ‘migliorate’, per esempio con ossa più solide, o meno esposti a malattie cardiocircolatorie, o magari con proprietà considerate desiderabili come l’avere gli occhi di un certo colore, o essere più alti, o cose di questo genere. Umani fatti su misura, se volete. Per il momento, non sappiamo ancora quali sono i geni che determinano i tratti che ho menzionato, ma è importante sapere che la tecnologia CRISPR ha la capacità di produrre quei tali cambiamenti, una volta che la conoscenza del genoma sarà più completa.

Questo fa nascere delle questioni etiche che dobbiamo considerare attentamente, ed è per questo che io e i miei colleghi abbiamo chiesto una sospensione globale delle applicazioni cliniche della tecnologia CRISPR in embrioni umani, perché noi abbiamo il tempo di riflettere sulle implicazioni di queto utilizzo. C’è un precedente importante per questa sospensione, quando nel 1970 gli scienziati si accordarono per chiedere una moratoria sugli esperimenti delle clonazioni molecolari, finché si potesse attentamente verificare la sicurezza di quella tecnologia.

Quindi, non ci sono ancora essere umani dal genoma pre-programmato, ma l’idea non appartiene più alla science-fiction. Piante e animali dal genoma pre-programmato esistono già; e questo ci pone davanti a una responsabilità enorme, quella di riflettere attentamente sulle conseguenze impreviste, oltre che sull’impatto desiderato, di scoperte scientifiche così significative.


Bruno Giussani: Questa tecnologia comporta possibilità straordinarie, come tu hai indicato; e la tua presa di posizione nel chiedere una sospensione è assolutamente responsabile. Certo, ci sono i risultati terapeutici della tecnologia, ma quelli pubblicizzati dai media sarebbero soprattutto quelli non terapeutici. Il giornale “The Economist” ha pubblicato un articolo dal titolo “Programmare l’umanità”, che ruota tutto intorno all’idea delle funzioni migliorate geneticamente, non intorno alla cura delle malattie. Quali sono state le reazioni dei tuoi colleghi scienziati, in Marzo, quando hai raccomandato la sospensione e la riflessione su questa tecnologia?

Risposta. I miei colleghi sono stati felici di avere l’opportunità di discutere apertamente su questo. Trovo delle reazioni molto diverse, sia fra i colleghi scienziati sia nel pubblico in generale. Proprio per questo l’idea va discussa e considerata attentamente.

BG: A dicembre ci sarà un incontro importante, convocato da te e i tuoi colleghi, insieme alla National Academy of Sciences e ad altre istituzioni. Che cosa speri che venga fuori da questo convegno, concretamente?

Risposta: Spero che vengano resi manifesti i punti di vista di individui vari così come dei diretti interessati, che desiderano utilizzare questa tecnologia in modo responsabile. Non sarà possibile arrivare ad una posizione condivisa consensualmente, ma penso che dovremmo alneno renderci sonto delle questioni sollevate da questa tecnologia mentre procediamo nello studio.

BG: Alcuni tuoi colleghi, come George Church, di Harvard, per esempio, dicono: “Sì, le questioni etiche sono essenzialmente una questione di sicurezza. Noi facciamo esperimenti, li ripetiamo, li ripetiamo e li ripetiamo ancora sugli animali e in laboratorio e poi, non appena appaiono abbastanza sicuri, li trasferiamo sugli esseri umani.” Questo sembra rappresentare l’altra ‘scuola di pensiero’, secondo la quale noi dovremmo davvero approfittare di questa opportunità e renderla operativa. Si può prevedere una divisione nel mondo scientifico a questo proposito? Cioè, si può pensare che certuni frenino perché hanno preoccupazioni di tipo morale ed altri vadano invece avanti perché certi stati hanno regolamenti più flessibili, o magari non ne hanno per niente?

Risposta. Immagino che su qualunque nuova tecnologia, e particolarmente su questa, ci siano opinioni differenti, ed è comprensibile. Penso che alla fine questa tecnologia verrà utilizzata per pre-programmare degli essere umani, ma penso anche che fare una cosa di queto genere senza riflettere preliminarmente sui possibili rischi e conseguenze sarebbe un modo di operare irresponsabile.

BG: Ci sono anche altre tecnologie e altri campi scientifici che si stanno sviluppando fortemente, come nel tuo caso. Penso per esempio all’intelligenza artificaile, ai robot autonomi e così via. Sembra che nessuno abbia aperto una discussione (a parte per i robot militari autonomi) in questi campi, o chiesto una sospensione. Pensi che la discussione che tu lanci possa servire di modello per altri campi?

Risposta. Penso che sia difficile per degli scienziati uscire fuori dal loro laboratorio. Parlo per me stessa, che non mi sento del tutto a mio agio nel farlo. Ma penso che il fatto di essere all’origine di questa tecnologia pone una responsabilità sulle spalle mie e dei miei colleghi. E direi anche che io spero davvero che altre tecnologie vengano considerate alla stessa stregua, così come io vorrei riflettere su tecnologie di altri campi che possano implicare notevoli conseguenze al di fuori della biologia.

0:12A few years ago, with my colleague, Emmanuelle Charpentier, I invented a new technology for editing genomes. It’s called CRISPR-Cas9. The CRISPR technology allows scientists to make changes to the DNA in cells that could allow us to cure genetic disease.

0:32You might be interested to know that the CRISPR technology came about through a basic research project that was aimed at discovering how bacteria fight viral infections. Bacteria have to deal with viruses in their environment, and we can think about a viral infection like a ticking time bomb — a bacterium has only a few minutes to defuse the bomb before it gets destroyed. So, many bacteria have in their cells an adaptive immune system called CRISPR, that allows them to detect viral DNA and destroy it.

1:04Part of the CRISPR system is a protein called Cas9, that’s able to seek out, cut and eventually degrade viral DNA in a specific way. And it was through our research to understand the activity of this protein, Cas9, that we realized that we could harness its function as a genetic engineering technology — a way for scientists to delete or insert specific bits of DNA into cells with incredible precision — that would offer opportunities to do things that really haven’t been possible in the past.

1:42The CRISPR technology has already been used to change the DNA in the cells of mice and monkeys,other organisms as well. Chinese scientists showed recently that they could even use the CRISPR technology to change genes in human embryos. And scientists in Philadelphia showed they could use CRISPR to remove the DNA of an integrated HIV virus from infected human cells.

2:09The opportunity to do this kind of genome editing also raises various ethical issues that we have to consider, because this technology can be employed not only in adult cells, but also in the embryos of organisms, including our own species. And so, together with my colleagues, I’ve called for a global conversation about the technology that I co-invented, so that we can consider all of the ethical and societal implications of a technology like this.

2:39What I want to do now is tell you what the CRISPR technology is, what it can do, where we are todayand why I think we need to take a prudent path forward in the way that we employ this technology.

2:54When viruses infect a cell, they inject their DNA. And in a bacterium, the CRISPR system allows that DNA to be plucked out of the virus, and inserted in little bits into the chromosome — the DNA of the bacterium. And these integrated bits of viral DNA get inserted at a site called CRISPR. CRISPR stands for clustered regularly interspaced short palindromic repeats. (Laughter)

3:24A big mouthful — you can see why we use the acronym CRISPR. It’s a mechanism that allows cells to record, over time, the viruses they have been exposed to. And importantly, those bits of DNA are passed on to the cells’ progeny, so cells are protected from viruses not only in one generation, but over many generations of cells. This allows the cells to keep a record of infection, and as my colleague, Blake Wiedenheft, likes to say, the CRISPR locus is effectively a genetic vaccination card in cells. Once those bits of DNA have been inserted into the bacterial chromosome, the cell then makes a little copy of a molecule called RNA, which is orange in this picture, that is an exact replicate of the viral DNA. RNA is a chemical cousin of DNA, and it allows interaction with DNA molecules that have a matching sequence.

4:24So those little bits of RNA from the CRISPR locus associate — they bind — to protein called Cas9, which is white in the picture, and form a complex that functions like a sentinel in the cell. It searches through all of the DNA in the cell, to find sites that match the sequences in the bound RNAs. And when those sites are found — as you can see here, the blue molecule is DNA — this complex associates with that DNA and allows the Cas9 cleaver to cut up the viral DNA. It makes a very precise break. So we can think of the Cas9 RNA sentinel complex like a pair of scissors that can cut DNA — it makes a double-stranded break in the DNA helix. And importantly, this complex is programmable, so it can be programmed to recognize particular DNA sequences, and make a break in the DNA at that site.

5:26As I’m going to tell you now, we recognized that that activity could be harnessed for genome engineering, to allow cells to make a very precise change to the DNA at the site where this break was introduced. That’s sort of analogous to the way that we use a word-processing program to fix a typo in a document.

5:48The reason we envisioned using the CRISPR system for genome engineering is because cells have the ability to detect broken DNA and repair it. So when a plant or an animal cell detects a double-stranded break in its DNA, it can fix that break, either by pasting together the ends of the broken DNA with a little, tiny change in the sequence of that position, or it can repair the break by integrating a new piece of DNA at the site of the cut. So if we have a way to introduce double-stranded breaks into DNA at precise places, we can trigger cells to repair those breaks, by either the disruption or incorporation of new genetic information. So if we were able to program the CRISPR technology to make a break in DNA at the position at or near a mutation causing cystic fibrosis, for example, we could trigger cells to repair that mutation.

6:51Genome engineering is actually not new, it’s been in development since the 1970s. We’ve had technologies for sequencing DNA, for copying DNA, and even for manipulating DNA. And these technologies were very promising, but the problem was that they were either inefficient, or they were difficult enough to use that most scientists had not adopted them for use in their own laboratories, or certainly for many clinical applications. So, the opportunity to take a technology like CRISPR and utilize it has appeal, because of its relative simplicity. We can think of older genome engineering technologiesas similar to having to rewire your computer each time you want to run a new piece of software,whereas the CRISPR technology is like software for the genome, we can program it easily, using these little bits of RNA.

7:53So once a double-stranded break is made in DNA, we can induce repair, and thereby potentially achieve astounding things, like being able to correct mutations that cause sickle cell anemia or cause Huntington’s Disease. I actually think that the first applications of the CRISPR technology are going to happen in the blood, where it’s relatively easier to deliver this tool into cells, compared to solid tissues.

8:22Right now, a lot of the work that’s going on applies to animal models of human disease, such as mice.The technology is being used to make very precise changes that allow us to study the way that these changes in the cell’s DNA affect either a tissue or, in this case, an entire organism.

8:42Now in this example, the CRISPR technology was used to disrupt a gene by making a tiny change in the DNA in a gene that is responsible for the black coat color of these mice. Imagine that these white mice differ from their pigmented litter-mates by just a tiny change at one gene in the entire genome, and they’re otherwise completely normal. And when we sequence the DNA from these animals, we find that the change in the DNA has occurred at exactly the place where we induced it, using the CRISPR technology.

9:18Additional experiments are going on in other animals that are useful for creating models for human disease, such as monkeys. And here we find that we can use these systems to test the application of this technology in particular tissues, for example, figuring out how to deliver the CRISPR tool into cells.We also want to understand better how to control the way that DNA is repaired after it’s cut, and also to figure out how to control and limit any kind of off-target, or unintended effects of using the technology.

9:55I think that we will see clinical application of this technology, certainly in adults, within the next 10 years.I think that it’s likely that we will see clinical trials and possibly even approved therapies within that time,which is a very exciting thing to think about. And because of the excitement around this technology,there’s a lot of interest in start-up companies that have been founded to commercialize the CRISPR technology, and lots of venture capitalists that have been investing in these companies.

10:30But we have to also consider that the CRISPR technology can be used for things like enhancement.Imagine that we could try to engineer humans that have enhanced properties, such as stronger bones,or less susceptibility to cardiovascular disease or even to have properties that we would consider maybe to be desirable, like a different eye color or to be taller, things like that. “Designer humans,” if you will. Right now, the genetic information to understand what types of genes would give rise to these traits is mostly not known. But it’s important to know that the CRISPR technology gives us a tool to make such changes, once that knowledge becomes available.

11:17This raises a number of ethical questions that we have to carefully consider, and this is why I and my colleagues have called for a global pause in any clinical application of the CRISPR technology in human embryos, to give us time to really consider all of the various implications of doing so. And actually, there is an important precedent for such a pause from the 1970s, when scientists got together to call for a moratorium on the use of molecular cloning, until the safety of that technology could be tested carefully and validated.

11:54So, genome-engineered humans are not with us yet, but this is no longer science fiction. Genome-engineered animals and plants are happening right now. And this puts in front of all of us a huge responsibility, to consider carefully both the unintended consequences as well as the intended impacts of a scientific breakthrough.

12:21Thank you.


12:30(Applause ends)

12:32Bruno Giussani: Jennifer, this is a technology with huge consequences, as you pointed out. Your attitude about asking for a pause or a moratorium or a quarantine is incredibly responsible. There are, of course, the therapeutic results of this, but then there are the un-therapeutic ones and they seem to be the ones gaining traction, particularly in the media. This is one of the latest issues of The Economist — “Editing humanity.” It’s all about genetic enhancement, it’s not about therapeutics. What kind of reactions did you get back in March from your colleagues in the science world, when you asked or suggested that we should actually pause this for a moment and think about it?

13:12Jennifer Doudna: My colleagues were actually, I think, delighted to have the opportunity to discuss this openly. It’s interesting that as I talk to people, my scientific colleagues as well as others, there’s a wide variety of viewpoints about this. So clearly it’s a topic that needs careful consideration and discussion.

13:28BG: There’s a big meeting happening in December that you and your colleagues are calling, together with the National Academy of Sciences and others, what do you hope will come out of the meeting, practically?

13:38JD: Well, I hope that we can air the views of many different individuals and stakeholders who want to think about how to use this technology responsibly. It may not be possible to come up with a consensus point of view, but I think we should at least understand what all the issues are as we go forward.

13:56BG: Now, colleagues of yours, like George Church, for example, at Harvard, they say, “Yeah, ethical issues basically are just a question of safety. We test and test and test again, in animals and in labs, and then once we feel it’s safe enough, we move on to humans.” So that’s kind of the other school of thought, that we should actually use this opportunity and really go for it. Is there a possible split happening in the science community about this? I mean, are we going to see some people holding back because they have ethical concerns, and some others just going forward because some countries under-regulate or don’t regulate at all?

14:28JD: Well, I think with any new technology, especially something like this, there are going to be a variety of viewpoints, and I think that’s perfectly understandable. I think that in the end, this technology will be used for human genome engineering, but I think to do that without careful consideration and discussionof the risks and potential complications would not be responsible.

14:53BG: There are a lot of technologies and other fields of science that are developing exponentially, pretty much like yours. I’m thinking about artificial intelligence, autonomous robots and so on. No one seems — aside from autonomous warfare robots — nobody seems to have launched a similar discussion in those fields, in calling for a moratorium. Do you think that your discussion may serve as a blueprint for other fields?

15:18JD: Well, I think it’s hard for scientists to get out of the laboratory. Speaking for myself, it’s a little bit uncomfortable to do that. But I do think that being involved in the genesis of this really puts me and my colleagues in a position of responsibility. And I would say that I certainly hope that other technologieswill be considered in the same way, just as we would want to consider something that could have implications in other fields besides biology.

15:44BG: Jennifer, thanks for coming to TED.

15:46JD: Thank you.




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