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.
Ceramah ini adalah tentang gene-drive (penggerak gen) tapi akan saya mulai dengan cerita singkat. 20 tahun lalu, ahli biologi bernama Anthony James terobsesi dengan ide membuat nyamuk yang tidak menularkan 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.
Sebuah ide hebat, dan cukup besar untuk gagal total. Ternyata sangat sulit untuk membuat nyamuk kebal malaria. James akhirnya berhasil, beberapa tahun belakangan ini, dengan menambahkan gen yang mencegah parasit malaria untuk hidup di dalam tubuh nyamuk.
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.
Tapi itu membuat masalah baru. Kini saat Anda mendapati nyamuk yang kebal terhadap malaria, bagaimana cara menggantikan semua nyamuk pembawa malaria? Ada beberapa pilihan. Rencana A pada intinya mengembangbiakkan sekelompok nyamuk hasil rekayasa genetika melepaskannya di alam liar dan berharap gen mereka diturunkan. Masalahnya adalah Anda harus melepas dengan jumlah 10 kali lebih banyak dari nyamuk alami agar berhasil. Jadi di sebuah desa dengan 10.000 nyamuk, Anda harus membuat 100.000. Seperti yang Anda tebak, hal ini bukanlah strategi populer di masyarakat.
(Laughter)
(Tawa)
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.
Januari lalu, Anthony James menerima surat elektronik dari ahli biologi bernama Ethan Bier. Bier bercerita bahwa dia dan muridnya, Valentino Gantz, menemukan alat yang tidak hanya menjamin bahwa satu sifat gen dapat diturunkan, tapi juga dapat menyebar amat cepat. Jika mereka benar, itu adalah solusi dari masalah yang dia dan James coba selesaikan selama 20 tahun.
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.
Sebagai pengujian, mereka merekayasa dua nyamuk membawa gen anti-malaria dan alat baru ini, sebuah gene-drive, yang akan saya jelaskan. Akhirnya, mereka mengondisikan nyamuk yang membawa gen anti-malaria agar memiliki mata berwarna merah, bukan putih seperti warna aslinya. Itu agar memudahkan untuk mengamati nyamuk hasil rekayasa dan yang bukan.
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.
Jadi mereka mengambil dua nyamuk anti-malaria bermata merah mencampurnya di kotak dengan 30 nyamuk bermata putih, untuk berkembang biak. Pada dua generasi, nyamuk-nyamuk itu menghasilkan 3.800 keturunan. Bukan itu yang mengejutkan. Inilah yang mengejutkan: hanya dengan mencampurkan dua nyamuk bermata merah dan 30 nyamuk bermata putih, Anda mengira mata-putih lah yang dominan. Namun, saat James membuka kotak itu, keseluruhan dari 3.800 nyamuk bermata merah.
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.
Saat saya bertanya pada Ethan Bier, dia sangat gembira sampai-sampai berteriak di telpon. Itu karena keseluruhan nyamuk bermata merah menyalahi aturan mutlak biologi, genetika Mendel. Saya persingkat, tapi genetika Mendel berdalil saat jantan dan betina kawin, bayi mendapat sifat turunan DNA dari kedua induk. Jadi, jika nyamuk alami adalah aa dan nyamuk rekayasa adalah aB, di mana B adalah gen anti-malaria, keturunan harusnya selaras permutasi berikut: aa, aB, aa, Ba. Sedangkan, dengan gene-drive baru ini, semuanya adalah aB. Secara biologis, hal itu tidaklah mungkin.
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.
Jadi apa yang terjadi? Hal pertama yang terjadi adalah ditemukannya alat penyunting gen bernama CRISPR di tahun 2012. Sebagian besar Anda mungkin tahu CRISPR, jadi saya persingkat bahwa CRISPR memungkinkan ilmuwan menyunting gen secara akurat, mudah, dan cepat. Alat ini bekerja dengan memanfaatkan mekanisme pada bakteri. Terutamanya, ada protein yang berfungsi seperti gunting dan memotong DNA, dan ada molekul RNA yang mengarahkan gunting itu ke titik manapun yang Anda mau. Hasilnya seperti perangkat pengolah kata untuk gen. Anda dapat mengambil seluruh gen, memasukkan satu, atau hanya mengubah satu huruf (nukleotida) pada gen Dan dapat dilakukan pada semua spesies.
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.
Baiklah, ingatkah Anda tentang dua masalah gene-drive di awal? Pertama, adalah sulit untuk merekayasa nyamuk agar kebal malaria. Masalah itu sudah hilang, berkat CRISPR. Tapi tersisa masalah logistik. Bagaimana menyebarluaskannya? Di sinilah kecerdikan dimulai.
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.
Beberapa tahun lalu, ahli biologi Harvard bernama Kevin Esvelt memikirkan apa yang terjadi jika Anda berhasil memasukkan CRISPR tak hanya ke dalam gen baru tapi juga mesin yang melakukan pemotongan dan penyisipan. Dengan kata lain, bagaimana jika CRISPR melipatgandakan dirinya sendiri. Semua berakhir dengan mesin penyunting gen yang bekerja abadi. Dan itulah yang benar terjadi. Gene-drive CRISPR yang dibuat Esvelt tak hanya menjamin sifat yang diturunkan, tapi jika digunakan pada sel germline, alat itu secara otomatis melipatgandakan gen baru Anda pada dua kromosom dari setiap individu. Hal ini seperti pencarian dan penggantian global, dalam istilah ilmiah, itu membuat heterozigot menjadi homozigot.
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.
Jadi, apa artinya? Di satu sisi, kita memiliki alat yang sangat ampuh, namun juga mengkhawatirkan. Hingga kini, fakta bahwa gene-drive tak berfungsi dengan baik sebenarnya melegakan. Biasanya, saat kita ikut campur dengan gen organisme, kita membuatnya evolusinya terancam. Ahli biologi dapat membuat lalat buah mutan semau mereka tanpa mengkhawatirkannya. Jika beberapa lepas, seleksi alam akan mengurusnya.
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.
Apa yang menakjubkan, ampuh, dan menakutkan dari gene-drive adalah itu akan segera sempurna. Dengan asumsi sifat alami Anda tidak cacat secara evolusi, seperti nyamuk yang tak dapat terbang, gene-drive berbasis CRISPR akan menyebarkan rekayasanya tanpa henti hingga setiap individu di satu populasi memilikinya. Kini, tidak mudah membuat gene-drive yang dapat berfungsi, tapi James dan Esvelt percaya kita mampu.
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.
Kabar baiknya adalah hal ini membuka pintu pada hal hebat lainnya. Saat memasukkan gene-drive anti-malaria pada 1 persen nyamuk Anopheles, spesies yang menularkan malaria, peneliti memperkirakan itu akan menyebar ke seluruh populasi dalam setahun. Jadi dalam satu tahun, Anda dapat melenyapkan malaria. Praktiknya, kita masih berjarak beberapa tahun untuk mampu melakukannya, tetap, 1000 anak-anak mati karena malaria setiap harinya. Dalam setahun, angka itu dapat mendekati nol. Hal sama untuk demam berdarah, chikunguya, demam kuning.
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.
Dan kebaikan lainnya. Taruhlah Anda ingin melenyapkan spesies invasif, seperti ikan Karper dari Great Lakes. Dapat dilakukan dengan melepas gene-drive yang membuat keturunannya jantan semua. Hanya dalam beberapa generasi, tak akan ada betina, tak ada lagi karper. Secara teori, ratusan spesies alami yang terancam punah dapat dipulihkan.
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.
Baiklah, itu kabar baiknya, dan ini kabar buruknya. Gene-drive sangat efektif hingga pelepasan yang tidak disengaja dapat mengubah seluruh spesies, dengan sangat cepat. Tindak pencegahan Anthony James cukup bagus. Dia membiakkan nyamuknya di lab bio terisolasi dan dia memakai spesies yang tidak berasal dari Amerika jadi meski beberapa lepas, mereka akan mati, karena tak ada pasangannya. Tapi juga benar adanya jika selusin Karper yang tak dapat menghasilkan betina secara tak sengaja lepas ke Asia, mereka dapat memusnahkan seluruh populasi spesies karper asli. Dan itu sangatlah mungkin, mengingat keterhubungan dunia kita. Sebenarnya, itulah penyebab adanya spesies invasif. Dan itu hanyalah ikan. Hewan seperti nyamuk dan lalat buah, tidak ada cara untuk mengisolasi mereka. Mereka melintasi samudra setiap saat.
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.
OK, kabar buruk lainnya adalah gene-drive tidak hanya terbatas pada spesies target. Itu karena aliran gen, dengan kata lain, spesies terdekat darinya dapat kawin silang. Jika itu terjadi, satu gen dapat melintasi satu spesies, seperti Karper Asia mengontaminasi Karper lainnya. Bukan hal yang buruk jika drive hanya membawa sifat seperti warna mata. Faktnya, ada kemungkinan kita akan melihat gelombang lalat buah aneh dalam waktu dekat. Tapi akan jadi petaka jika drive dirancang untuk memusnahkan suatu spesies.
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.
Hal mengkhawatirkan terakhir adalah teknologi ini, untuk merekayasa gen organisme dan termasuk gene-drive, mudah dilakukan di lab manapun. Mahasiswa bisa membuatnya. Murid SMA yang cerdas, dengan peralatan memadai dapat membuatnya.
Now, I'm guessing that this sounds terrifying.
Kini, saya tebak hal ini terdengar mengerikan.
(Laughter)
(Tawa)
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.
Namun yang menarik, hampir setiap ilmuwan yang saya temui tidak berpendapat bahwa gene-drive menakutkan ataupun membahayakan. Sebagian, mungkin karena mereka percaya ilmuwan akan awas dan bertanggungjawab menggunakannya.
(Laughter)
(Tawa)
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.
Sejauh ini, memang benar. Tapi gene-drive juga mempunyai beberapa batasan nyata. Ini hanya bekerja pada spesies yang bereproduksi secara seksual. Syukurlah, tak dapat digunakan pada virus atau bakteri. Dan lagi, sifat rekayasa hanya menyebar pada keturunan. Jadi mengubah atau mengeliminasi populasi hanya mungkin jika spesies itu memiliki siklus reproduksi yang cepat, seperti serangga, vertebrata kecil: tikus atau ikan. Pada gajah dan manusia, butuh berabad-abad agar satu sifat menyebar secara signifikan.
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.
Lagi pun, meski dengan CRISPR, tidak mudah membuat sifat yang benar-benar cacat. Misalkan Anda ingin lalat buah yang makan buah segar, bukan buah busuk, dengan tujuan menyabotase pertanian Amerika. Pertama Anda harus temukan gen mana mengendalikan pilihan makanan lalat itu, yang mana adalah proyek yang sangat sulit dan lama. Lalu Anda harus mengubah gen yang dapat mengubah sifat alami lalat sesuai dengan keinginan Anda, yang juga merupakan proyek yang lebih lama dan sulit. Dan mungkin juga gagal, karena gen pengendali perilaku adalah kompleks. Jadi jika Anda teroris dan harus memilih antara program penelitian awal yang melelahkan, membutuhkan tahunan kerja lab, dengan kemungkinan gagal, atau membuat bom? Opsi terakhir yang paling mungkin.
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.
Khusus hal ini adalah benar karena dalam teori, seharusnya mudah pula membuat drive-pembalik. Drive yang dapat menghapus dan mengganti rekayasa gene-drive pertama. Jadi saat satu perubahan tidak dikehendakki, Anda dapat melepas drive ke dua yang berfungsi berlawanan, setidaknya dalam teori.
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?
Ok, jadi sampai di mana kita? Kita bisa mengubah keseluruhan suatu spesies sesuai kehendak. Haruskah? Apakah kita Tuhan, sekarang? Saya tidak yakin. Tapi saya yakin hal ini: Pertama, beberapa genius bahkan berdebat tentang bagaimana meregulasi gene-drive. Di saat yang sama, genius lainnya bekerja membuat pengaman gene-drive, seperti regulasi otomatis; mampu lenyap dalam beberapa generasi. Itu bagus. Tapi teknologi ini masih membutuhkan diskusi. Dan mengingat hakikat gene-drive, diskusi itu haruslah global. Bagaimana jika drive Kenya tak disetujui Tanzania? Siapa memutuskan untuk melepaskan sebuah gene-drive yang dapat terbang?
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.
Saya tak bisa menjawabnya. Yang dapat kita lakukan untuk terus maju adalah berdiskusi tentang risiko dan manfaat dan bertanggung-jawab atas pilihan kita. Tak hanya pilihan untuk menggunakan gene-drive, tapi juga untuk tidak menggunakannya. Manusia berkecenderungan untuk percaya bahwa pilihan terbaik adalah mempertahankan status-quo. Tapi itu tidak selamanya benar. Gene-drive berisiko, dan itu butuh didiskusikan, tapi malaria masih ada saat ini dan membunuh 1000 orang per hari. Untuk melawannya, kita semprotkan pestisida yang membahayakan spesies lain, termasuk amfibi dan burung.
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.
Jadi saat Anda mendengar gene-drive bulan depan, dan percayalah, Anda akan mendengarnya, ingatlah hal itu. Beraksi memang menakutkan, tapi kadang berdiam diri adalah lebih buruk.
(Applause)
(Tepuk tangan)