Hi, my name is Jeff mortgage. I'm an assistant professor in the Department of Chemistry and Biochemistry. And that my lab here ED studies the structure and function, different enzymes that chemically modify RNA. And so I'm really excited to be here tonight to talk a little bit about the 20-20 Nobel Prize in Chemistry, which was awarded to Jennifer Dao Na and Emmanuel sharpened TA for their really groundbreaking work to understand this is amazing molecular complex called the CRISPR-Cas9. And this is an enzyme that has allowed scientists to edit DNA within the cell. It has the potential to rewrite the code of life to cure or different human diseases to improve agriculture. And as we'll talk about, is already really started to revolutionize biotechnology. So let's start by reminding ourselves about what we call the central dogma of molecular biology. And this is the idea that genetic information flows from DNA to RNA to protein. And so, if you'll remember, our genome is composed of DNA that contains the genetic code or blueprints for constructing everything in our cells and everything in our bodies. Short stretches of DNA that code for a particular protein, for example, are called students. And these genes can be transcribed into a similar molecule called RNA. And it's the RNA whose code bits directly read are translated by the cell to make proteins. And proteins are composed of this string of individual amino acids that once produced, they fold up into a complex three-dimensional shapes and carry out all the biochemical reactions required for life. And so what this crisper cast technology allows us to do is to precisely cut and edit or change the DNA code programmable positions. And any change made the DNA in this way then gets propagated to RNA and results in a change to the protein and potentially a change to its cellular function. So Jennifer Dao Na and a manual sharp NCA were awarded the 2020 Nobel Prize for really the fundamental biochemistry to showed how this crisper cast system works and how it might be repurposed and implemented as this incredibly powerful gene, gene, a genome editing tool. So just a really brief biography about laureates, Jennifer down. It was actually born in Washington DC. She enlarged heart grew up and he'll Hawaii. And she did her PhD at Harvard, a postdoc at CU Boulder in both cases, working for really very famous RNA biochemists who went on to win Nobel Prizes. Now she spent the majority of her independent career at UC Berkeley. This is where she did all of the work on CRISPR Cas and does Russia still is today. Many asha MCA was born in a small town outside of Paris, France. She did her PhD at the Pasteur Institute in microbiology. And then she moved to the States to do post-doctoral research at Rockefeller and NYU in New York City, St. Jude. She's currently the director and actually founder this Max Planck unit for the science of pathogens in Europe. But really all the other work on crisper cast that she did that resulted in winning the Nobel Prize was done prior to that at Umea University SP. Okay, so before we talk about the details of CRISPR, You know, I have to acknowledge how, how significant and important is it to women won the Nobel Prize in chemistry this year. And this is actually the first time that two women have together been awarded the Nobel Prize in chemistry, where I think any of the other science categories of integrals. And so Jennifer down in a manual sharpened TA, or just the sixth, seventh women over the last 120 years to win a chemistry Nobel Prize. And so they join and unfortunately very small but very prestigious group of women including Marie Curie, your inquiry, Dorothy Hodgkin out a Yona Francis Arnold, and now an annual Sharpe Menil sharpens yea and Jennifer Dao Na. And so you know, there's obviously still is massive, massive under-representation of women. But I think, and I hope that this is going to continue to improve and that we're going to see more and more and more and more women winning Nobel Prizes in the very near future and getting the acknowledgement for the amazing contributions to science. Alright, so let's talk about why they won the Nobel Prize this year. It's honestly, it's even a slight bit intimidating to give a general talk about CRISPR because it's been so well covered in the popular press. So there are hundreds, maybe thousands of articles and newspapers and magazines that had been written about CRISPR. There are YouTube videos, there are podcasts. Crispers even made its way into Hollywood. And this is the poster from the 2018 movie rampage starring Dwayne the Rock Johnson. The plumb line is essentially evil. Corporate scientists try to weaponize CRISPR. Things, of course go wrong. And you end up with a gigantic flying Wolf who can shoot porcupine spines or a crocodile, enormous crocodile with indestructible scales. And you know, they lay waste to cities, et cetera, et cetera. And so, you know, you might look at this and think, oh, well, no wonder CRISPR won the Nobel Prize when he what a powerful technology and must be. But while I think we can all recognize that this is a ridiculous exaggeration, I do you think that Hollywood is rightly captivated by the potential power of this CRISPR technology. And so let's take a closer look at what, where the technology comes from and what it can actually do. Alright, so Jennifer down, no, no manual SRP NCA. They had no intention of building a genome editing tool when they started working on CRISPR. As with so many other scientific discoveries, you know, this really arose out of just basic science to understand biology. And in this case to understand how bacteria stay healthy. So just like us and ourselves, bacteria get sick too. There are these little viruses called bacteriophages that can infect and kill bacterial cells. And he's fade. Now, bacteriophages or phages for short, can inject their DNA into bacterial cells, which results in the cell producing viral proteins. And these viral proteins really go on to hijack the molecular machinery of the bacterial cell and force it to make more and more and more. These infectious phage particles. This eventually kills the bacterial solid, bursts open and releases all these infectious particles to go on and in fact other nearby bacterial cells. And in this way, this phage bacteriophage as sort of propagate themselves through this lifecycle. But just like our bodies, which have an immune system, bacterial cells have ways to fight these infections too. And so one of these mechanisms is CRISPR. And so it turns out that bacterial cells that are lucky enough to survive a bacteriophage infection, I can store little bits of phage DNA into their own genomes and crisper DNA. It's really just a, a region of the bacterial genome or bacterial DNA stores these little pits. Phage DNA from previous infection, all these individual color blocks. So CRISPR stands for clustered, regularly interspaced, short palindromic repeats, which is a bit of a mouthful, but really it's basically just this region of bacterial DNA where you have these bits of viral DNA that had been stored from previous infections in-between short repeated sequences of bacterial DNA. And what scientists had found was that in combination with nearby CRISPR associated or Cas genes, which code for cas proteins. This CRISPR DNA could use the sorted this memory is encoded in the DNA sequences from previous page infections to provide immunity against future phage and tap fused future phage attacks. Alright, so this is where manual Chapin NTA enters the story. I'm in her lab, may crucial discoveries about how the bacterial cell takes information that was stored in this CRISPR DNA and converts this into molecules of RNA called crisper RNA and trace RNA. And that these two RNA molecules really work in combination with proteins encoded by these cast students to block phage infection. In parallel, Jennifer down as Lavater recently started working on trying to understand some of the actual Cas protein proteins themselves. And they were interested in the structure and function and purify these and work with them in test tubes. And so after Jennifer down in a manual sharp NTA mats at a scientific conference and pressure eco in 2011. They started a collaboration that really actually very quickly led to a molecular understanding of how CRISPR worked as a bacterial immune mechanism. And so what the Dao Na and sharpened TA lab showed was that a particular protein called Cas nine, shown here. In blue. I'll combine both the tracer and crisper RNA. And that this CRISPR RNA contains, which contains the memory of previous viral DNA sequences encoded bit on acts as a guide to, to really identify and bring this whole Cas nine complex to invading viral DNA shown here. And so having identified this viral DNA through the information encoded in this CRISPR RNA. Rna molecule. Cas nine can then open up and really cut both strands of the viral DNA. And so in this way, the crisper cast really identifies and shops up these invading viral DNAs in the bacterial cell, which prevents phages from producing their own viral proteins and blocks infection. So this work really along with work from any other labs, solved a decades old mystery of how these CRISPR DNA sequences work with caps cast students as a bacterial immune system. But what, you know importantly what Jennifer dominant in a manual sharp and you quickly realize and showed was that just simply by changing the sequence of the RNA molecule that guides Cas nine to its DNA target. You can actually reprogram this entire enzyme to cut DNA, essentially any location along DNA. This means you could use Cas nine is a pair of molecular scissors to open up and cut DNA anywhere in the genome, just by dialing in the appropriate sequence into your guide RNA. And once you've made these precise cuts that break open the DNA, what you can do, it turns out, is supply DNA template with any DNA sequence you like for the repair process, which allows you to insert either small or large segments of DNA at the cut site or directly edit the DNA sequence. And the dao de lab, along with others, including the Shang Lab at MIT, showed that you could target DNA and the genomes of eukaryotic cells like our own, really opening up the possibility of using this technology to edit human DNA. So since these really fundamental discoveries from the down and sharp and TA labs, use of crisper cast systems has really exploded. And so these are now incredibly, incredibly powerful research tools to manipulate the genomes, different cells in different organisms. These can be used as biosensors to detect incredibly small amounts of RNA and DNA. Scientists have shown that the crisper could really be used in what are called gene drives to potentially edit the genomes of, of not just a single organism, but actually a whole population of organisms. And so people have talked about using this technology to edit the genomes of a whole population of mosquitoes. For example, to either eradicate the mosquitoes or to reduce their ability to carry these, really carry and transmit these really deadly human diseases like Zika, dengue virus. Crispr tools have also found wide use already in Agriculture and Food Sciences. I'm so scientists have shown that you can edit the genomes of rice plants to make them more resistant to blight and droughts. It edited the genomes of tomatoes to produce higher numbers of tomato fruits per plant to allow them to grow in a wider variety of conditions, environments. And there's been some work to edit the genome of mushrooms to make them not brown when a, when they sit out. Which doesn't seem like the most pressing foods problem that I can imagine. But it gives you an idea of the range of possibilities of different traits that can be engineered using this very precise genome, genome editing technology. Okay? And then finally editing the genome, the DNA in human cells. So one recent example of this is using CRISPR to treat sickle cell anemia. Sickle cell anemia is a disease where mutations in the gene for hemoglobin is the protein that transports oxygen in your red blood cells. People who have this mutation or hemoglobin molecules stick together and aggregate into, into large groups. In this ca, causes the miss shaping or the sickling of red blood cells. And so this leads to a very, very debilitating, painful disease. It's actually very, very difficult to treat. And so just last year, scientists have started trying out treatment for sickle cell anemia that uses CRISPR to correct some of these changes. And so far the patients who have received this R, it's only been a year, but they're doing really, really well and have almost symptom-free after getting this CRISPR based treatment for sickle cell anemia. And so, you know, really any, any genetic, any disease that has a genetic component in humans could potentially be targeted by some of these CRISPR therapists. And I think we're gonna see more and more of these attempts to use gene editing to treat many different types of kidney disease. Okay? And so, you know, maybe there are already some sort of thorny ethical questions crossing your mind from the last slide. But a big question that really arises with this powerful CRISPR-Cas9 technology is, you know, should we be editing our genes at all? A particular are heritable jeans, though those are the ones that get passed on to future generations. This example I talked about doing genome editing to help correct defects and hemoglobin caused sickle-cell anemia, or these are in somatic cells. And so the genetic changes there don't get passed on to future generations. But you could easily imagine making changes to regions of our genome that will get passed on to many, many generations indefinitely. And so this is my four-month old sign, Jonas. He seems to be pretty good as he is generally pretty good sleeper at night, which is great. But you know what if it was possible to edit his genome while he was still an embryo? To potentially increase intelligence or athleticism or lower has risks of many really serious diseases throughout his life. Not all of this is possible at the moment because we don't know enough about the genome yet necessarily. But some of it is, is actually possible as something that's starting to be possible. But the problem that scientists are wrestling with is that if you make changes to the genome that can be inherited, these get passed on to future generations and you start to change the evolution of the human species, the course of evolution of the game. And so this is something that's, as I said, sciences are struggling with organizations like the WHO and the National Academy of Sciences. Are they not committees and guidelines that are really now banned the editing of heritable union genes for the moment. Many scientists agree though, that eventually there, there may be room to apply this technology to Trent to tackle some really serious heritable genetic diseases. Okay, so all these applications are incredibly important, exciting. But I'll leave you with the thought that the 20-20 Nobel Prize in chemistry was really awarded for the fundamental biochemistry that Jennifer down. No, no manual sharp NTA did to first understand how these these crisper cast systems worked. A bacterial immune mechanism. And then they took that and show that you could repurpose this as a genome editing tool. And this highlights really why funding for basic science is so important. Because it's through these inquiry based experiments that we sometimes find some of the most transformative technologies like CRISPR-Cas9. Ok, so I'll end there and just say thanks to the organizers for giving me a chance to talk about this really amazing technology, an amazing price. Thanks to you for listening and I'm sure that my future self will be happy to answer any questions. Thank you.
Chemistry Talk - Jeff Mugridge, Assistant Professor Department of Chemistry & Biochemistry
From Jeff Mugridge November 09, 2020
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