CRISPR technology is now targeting RNA-based diseases | Patrick Hsu | TEDxSanDiegoSalon

[Music] Nature has a lot to teach us throughout the history of biology and medicine some of the most impactful and surprising therapies have come from diverse branches of the Tree of Life in 1928 the Scottish microbiologist Alexander Fleming returned from vacation to find on his lab bench a petri dish containing a fungal mold that could kill an infectious bacterial culture he had discovered penicillin setting into motion the antibiotic revolution but Nature has also hidden many secret tools into bacteria themselves I'm a molecular biologist and a bioengineer and we're developing one of these tools in my lab to study genetic disease and hopefully to create new kinds of medicines over the last few years we have heard a lot about CRISPR as technology for changing DNA directly inside of living cells through a process called genome editing now what you may not know is that CRISPR wasn't originally developed by humans and actually it's not that new CRISPR was created by bacteria now bacteria have been using various CRISPR systems for a very long time to defend themselves against foreign attackers such an invasion could come in the form of a bacteriophage a bacterial form of a virus that's trying to inject its own genetic code into this much larger bacterial host now these bacteria then will summon their CRISPR systems to recognize this foreign genetic information to take a snapshot or a memory of it and turn it back against the threat as a template for Search and Destroy so you can think of CRISPR systems really has very elegance and effective immune defense system over the last decade or so the CRISPR field has been unraveling many of the details of how these work this knowledge has allowed us to start to manipulate them intentionally by taking CRISPR systems out of their native bacterial environment we can put them into human cells and simultaneously recode this original antiviral memory with a human sequence so now we can target nearly any sequence in our own genetic code at will because genetic mutations can lead to disease this has led to a lot of excitement that fixing mutations with CRISPR could lead to new kinds of genetically targeted medicines but CRISPR systems that target DNA with cast 9 which I helped to develop as a PhD student has gotten almost all of the attention this particular flavor of CRISPR which is being used by hundreds of labs around the world comes originally from bacteria that can live in your skin or in your throat now there's also a whole world of bacteria out there some of them are found primarily in soil or in water or even inside of our own gut and it turns out these bacteria have specialised due to their different environments and they've adapted their CRISPR systems as well some of these Krister systems don't target DNA but rather a different kind of molecule these CRISPR systems target RNA now what is RNA RNA is the dynamic counterpart to your relatively static DNA sequence your DNA genome more or less is the same in all the cells of your body and doesn't change throughout your lifetime so you can think of your DNA genome like a dictionary or a phrase book that contains all the words that can be used by your body cells in order to compose RNA messages so that those cells can have an actual conversation for example this is how cells can respond to infections by turning on inflammatory signals RNA can also help carry the instructions to turn a stem cell into a specific kind of cell like a skin cell or a brain cell and in this way a whole organism or person like you and me can form but on the other hand RNA can also cause cells to weaken or die RNA targeting CRISPR systems are generating a lot of excitement because there's a whole set of diseases where it's the RNA messages that go wrong inside of our cells these disorders then might respond better to RNA based solutions this discovering development of RNA targeting CRISPR has come about really in just the last two years why well it turns out there's been an explosion in genome sequence databases of a whole variety of organisms over just the last few years largely due to their rapidly falling cost of DNA sequencing this is helping some scientists for example to map out the diverse communities of bacteria that live in our gut called the microbiome to understand how these niches are shaped by infections or diseases like Crohn's or irritable bowel syndrome now because RNA messages can go up and down over time and they're highly dynamic the ideas are there some are any messages that can cause imbalances that can lead to disease being able to target these genetic defects directly is driving the clinical development of the class of drugs called gene therapies we thought to look in these new genome sequences potentially for new crispers and we recently set out to do exactly that in my lab where you took a computation or survey of these genome sequences and genome fragments and recently identified a new RNA targeting CRISPR system it's highly compact and it contains a single molecular machine that can be programmed by a guide RNA to find a matching target RNA it turns out that one variant of this system which comes from bacteria that live in the gut of New Zealand sheep turns out to work really well when transferred into human cells so we adapted the signature defense enzyme other system into technology we call Cass rx which of course stands for castor 18 d NL s from you know caucus flava patient's ex-beauty 3000 and T using Kassar X we can now directly target specific RNA messages inside of our own cells at will so now we can directly target them regulate their levels and also to change imbalances found in disease so the hope is can this be a new form of RNA based gene therapy by targeting RNA we won't have to make permanent changes to our DNA which could be safer furthermore RNA is dynamic meaning it goes up and down over time and it's different in the different cells of our body so eventually we might be able to control when and where a CRISPR therapeutic is acting so it's turned on only in the cells that carry that toxic RNA one place in the body where RNA messages can instruct cells to weaken or dies in the brain for example in a kind of dementia - called frontal temporal dementia or FTD now the specific genetic defects that cause FTD vary from patient to patient but often are thought to affect the balance of - are any messages in that cell that encode for an important protein in the brain called tau now this imbalance in tau over the course of a patient's lifetime progressively diminishes the health of the neurons in your brain eventually leading to nerve degeneration and memory loss we thought we might be able to use castor X to correct this imbalance and hopefully treat this disease so how would we do this well once again we can reach into nature's toolbox to find solutions to these challenges and viruses again are part of our story now most of you may think of viruses for their more negative disease-causing properties but for gene therapies we're instead using viruses for good we can cut out the viral genome and actually replace it with castor X and then take advantage of an important property of many viruses that they infect human cells so now we can use these engineered viruses to deliver a CRISPR therapeutic into cells of a patient we recently touched this in a lab but we can't just go to a person and ask for a sample of their brain so instead we took advantage of a technology called induced pluripotent stem cells where you can take skin cells for impatient and reprogram it into a stem cell now because the DNA of these cells hasn't changed these stem cells now they carry the same genetic defect that's found in these patients and using a combination of chemical and genetic instructions we can instruct this stem cell to turn into a brain cell and this way we can study FTD directly in the lab we packaged castor X into a therapeutic virus called a V and delivered it to these cells and show that we could correct this imbalance tap so that they look more like cells from healthy people now what are some of the next steps for this type of therapeutic proof-of-concept right first we want to move into animal models of the disease this will allow us to look at things you can't tell just by looking at the cells for example if you take cell ant animals that have the same genetic defect found in FTD we can dose them with a castor experice and put them through a battery of memory tests or look at the progression or maybe reversal of pathology in the brain this would also help us understand the amount of virus that would be safe and effective and hopefully inform the dosage that might be used in initial human clinical trials CRISPR technologies are opening up a whole world of possibilities for manipulating our own genetic information and also providing new avenues for combating debilitating RNA based diseases such as by removing toxic RNAs from our brain or defending against RNA based viruses like influenza zika ebola and the like furthermore because changes to earning our temporary quite different from the permanent changes caused by targeting DNA will eventually be able to create more advanced gene therapies where we can control the timing of the drug but there's still so much to do diseases that are caused by defects with one gene will be first in the line for gene therapy because we know what genetic defect we need a target and usually where which organ needs to be targeted but many diseases are caused by many genes it's a complex interaction both with each other but also with the environment for example in many dimensions like Alzheimer's disease this is something that I'm personally extremely passionate about two of my grandparents have Alzheimer's so we're working hard in my lab to try to figure out which gene combinations matter so someday this too could be next in line for gene therapy development we're just at the beginning of finding surprising new tools and unexpected places by searching in nature's already existing toolbox only we want to do so now not via serendipity but in a systematic data-driven way guided by genome technologies my lab continues to plumb the depths of the CRISPR world and other unexplored organisms and the weird may be unknown enzymes that they're using by continuing to interpret and improve upon the complex biological language that nature uses to operate will continue to find ways to improve human health from next generation antibiotics drug delivery systems to certainly genetic engineering tools so the next time you look in your fridge and maybe you see some molds or you find yourself eating some yogurt look closer nature is full of many secrets thank you [Applause] [Music] you

Channel: TEDx Talks

Views: 25,834

Rating: 4.852941 out of 5

Keywords: TEDxTalks, English, Science (hard), Biology, Body, Disease, Genetics, Health, Medicine, Research, Science

Id: h7YWqgXheYQ

Length: 12min 25sec (745 seconds)

Published: Wed Oct 17 2018