Biologist Explains One Concept in 5 Levels of Difficulty - CRISPR | WIRED

Biologist Explains One Concept in 5 Levels of Difficulty – CRISPR | WIRED



my name is Neville San Gianna I'm a biologist at New York University and the New York genome Center and I've been challenged today to teach one concept in five levels of increasing complexity my topic is CRISPR CRISPR is a new area of biomedical science that enables gene editing and it's helping us understand the genetic basis of many diseases like autism or cancer I think today everyone can leave with understanding something about CRISPR at some level a Tegan do you know what we're here to talk about today we are here to talk about science we're here to talk about something called CRISPR have you heard of that no CRISPR is a tool that scientists are using to edit or change genomes do you know what a genome is no it's kind of like an instruction manual the instruction manual that makes you who you are sometimes there's mistakes in the instruction manual like people get sick like allergies do you have do you have friends at school that have allergies that's good that you actually know exactly what you're allergic to for people that have really severe allergies we could erase we're in that in that big instruction manual where they have those allergies and maybe make it so that they don't have those allergies anymore do you know what CRISPR is absolutely not CRISPR is a way to edit the genome do you know what a genome is yeah it's the DNA DNA is kind of the language that the genome is written in and the genome itself is is an instruction manual it describes how to make you how tall you should be what color hair you have or what color eyes you have so what CRISPR is and an easy way to think about it it's like a molecular pair of scissors that can go through that long long genome and find specific places make small cuts and edit it what do you think about being able to edit genomes then you could change we changed things about a person if you edit the DNA sure so how do we determine what's what's the right uses thing I don't think you should be used for almost cosmetology research like for people just be like oh I want to be five foot six instead of five foot four or like reasons that aren't necessarily the most informed I just think if it could genuinely help someone like if someone had cancer and there was a way to fix it or like slow down the growth so a lot of the work that we do in my lab is about being engineers of DNA we try and look to see what mutations caused diseases and see if when we change those mutations if we can take a sick cell or organism and make it healthy again you graduate technically cuz the p53 when it's defect it doesn't that's what causes cancers p53 is the most common mutation in cancer that's that's right yeah that's a great idea actually to use CRISPR to target tumor cells and restore p53 to fix that that mutation so to make that cut with these scissors and fix it have you heard about CRISPR yes this revolutionary team editing tool I know there have been previous gene editing tools but CRISPR is more revolutionary in that it's more precise and a little bit more affordable do you know how CRISPR works so it works where you have this CRISPR this caste 9 complex protein calcium protein caste 9 protein complex along with something called a guide RNA that's right that's right and that RNA will basically tell this protein where to go and what you need to sort of cut out right and this is what makes the CRISPR system very programmable is that the low piece of guide RNA is easy to make we can program CRISPR to go to many different places in the genome quite easily but I've heard they're like close to almost curing muscular dystrophy with it but there's a lot of I guess ethical issues that come up with it too one of the really nice things actually about CRISPR is that we can use it in human cells no if you ask most people should you use it to cure cancer most people would say yeah those those are good good uses but there are other areas that are a little bit more problematic like editing the germline means something that could be passed off ethics wise a lot of people have that natural reaction of fear against something new because it has a lot of potential and we just don't know where it can take us yet it was sort of similar to like when people started doing in vitro fertilization test-tube babies to B that was the kind of scare totally exactly but now we see it's perfectly fine as long you know it's regulated and so there's been a lot of talk about using CRISPR for gene editing in humans and that that can be a controversial thing I think very naturally there's many aspects of ethics that need to be looked at firstly if we're talking about using CRISPR are we using it in somatic cells such as t-cells or are we using it in embryos or germ stem cells and the issue with that is now you're modifying the genome at a germline levels any unintended consequences could go forward many generations you're saying with germline is sure there's unintended consequences but there's also lack of consent if you are not around you can't consent exactly so these future generations or products of CRISPR they can't consent another I think ethical component is if CRISPR does make it to market who will have access to it is that going to be cost prohibitive we'll only a certain select few be able to use it as many new cancer drugs are today right right will that be how it is yeah would people start using it for non therapeutic reasons and I think this then can get into a whole slippery slope so I think a lot of people are concerned maybe that CRISPR will be used in kind of frivolous ways maybe just to choose somebody's eye color or or how tall they are what color hair they have and I think what a lot of people don't realize maybe is that the state of genetics is not quite there it's nice to think that I can go in and choose exactly what I color I want but fundamentally science doesn't exactly know all of that yet we don't know every single gene related to eye color nor the regulatory mechanisms nor the epigenetics this is a right so so we can use CRISPR now to try and understand better how do our genes relate to these these different features these different phenotypes that that we have there is a lot of work left to do before we even know well I think what are the knobs and dials what are the controls that you know affect eye color or how tall you are so I think this question right now even though it's important to discuss I kind of feel like it's more theoretical right now yeah or is it really even a point necessary for conversation because people are going out every single day and getting plastic surgery to change how they look how is this any different and in the same slant people are using in vitro fertilization right so this is manipulating genomes you're choosing which embryos to implant so we're almost doing little aspects of what CRISPR has the potential to do so Matt what are you doing right now in the lab and how are you using gene editing in your own work right now one of the questions I've been very much interested in is trying to understand the effect of human genetic variation on using CRISPR casts nine reagents because you and I just sitting here different millions of different in locations within our genome we use these guide RNAs which are 20 base pairs and we match it to different places in the genome but what if there's a mutation at that site and how does that affect a mutation that's different between you and me it's the same site but there's a slight difference in the DNA between you and it is exactly let's say in you it's a perfect match in me there's one that's actually a mismatch and how does that affect things in the lab because maybe it won't be as efficient it won't be able to bring caste 9 to the correct site and cut there so when when people are using CRISPR now in the lab are they really sequencing the exact cell type they use sequencing reading out the genome of that cell before they use CRISPR not many do that it would ultimately the best way to do it for sure because the reference genome that was published in 2001 was kind of just one person's genome and as we know very well from sequencing many different individuals there are a lot of differences and so there are some concerns that when you use these in the lab that you're intending for a cut to be made in this one place in the genome but if there happens to be a mismatch there because there's some variant in the cells that you're studying maybe it won't cut there at all and even maybe worse is that maybe it'll cut somewhere else because maybe now it can match elsewhere so you're saying right now that it's it's kind of early days with CRISPR and that there's a lot of technical issues that really need to be ironed out that it's not anything can be targeted at any time we're trying to develop the scientific steps that will take us to that kind of total genome control it is still the early days and as much progress that's been done which is actually quite remarkable given how new this technology is I mean we're just a few years away from when it was really started being used for these applications however having said that I holds a lot of potential and I think can get there but there's a lot of issues and concerns that need to be worked out I was going to say that a lot of what inspired me to get into bioengineering are movies movies like Jurassic Park which both shows the good the bad sides of manipulating the nature around us and so maybe it's a bit of a silly question but what do you think in our lifetime will we see something like Jurassic Park where humans have actually engineered different different animals anything is possible I'm not sure that we will see that in our lifetimes but I would be very excited to attend Jurassic Park if that were the case having said that I do think that CRISPR Cassadine does have a lot of potential to two things that are kind of out of the box in the past few years we've been able to tackle ideas that people didn't think we're possible before that more than anything CRISPR has created a whole open field of opportunities and so whether or not that leads us Jurassic Park I can't tell you that answer for sure but I certainly hope that it does and I think you're right that the opportunities might be much broader than just biomedical science it might be things like using DNA as a hard drive being able to use CRISPR as a diagnostic instead of just a tool for editing and we yeah use cells to record data over time with with CRISPR can we use CRISPR to track cells in a developing embryo I think this is one of the most exciting recent uses of CRISPR I've seen that I would have never predicted a year ago the dominant paradigm right now is CRISPR is just for cutting DNA but when you think of it more as a general platform a pointer to a location in a genome then that becomes a very very powerful thing do you think CRISPR will be helpful for understanding human variation beyond what we already have just by sequencing people's genomes yes absolutely I think that the real power of CRISPR lets us to follow up on this genetic information that we've been studying and following for a very long time now there been a lot of studies where you take a group of people with disease X and people without that disease and you see if any mutations seem to be preferentially in the group with the disease and kind of absent in the group without the disease people have observed these differences but what you're saying is the CRISPR we can now test is this causal this factor if we make this mutation does it cause the disease does it either create sickle-cell anemia or ameliorate sickle cell anemia and prevent prevent it do you think we'll ever be at a place where based on looking at someone's genome and these kinds of CRISPR functional screens we can predict what kinds of diseases these people might get 10 20 years in the future I think that's certainly a great goal as of now we tend to focus on variants or mutations that we know the function what about mutations we've never seen before something that comes from let's say UV radiation in melanoma or something I think that we will ultimately have the power to do that and so thinking about when you start from mutation do you look at the expression of RNA is that change is it changing things at the protein level so this is interesting so you mentioned that we can analyze genomes the DNA level and then you said the RNA level looking at the expression of genes and then the proteins the products that they actually make with proteomics or mass spectrometry but do you think it's kind of like another level of understanding the function of the genome or do you view it as part of one one of those those levels I do think it provides a different level of data the ability to rapidly and genome-wide assess and make changes at the DNA level and then look at the resulting changes of the RNA and protein level I think is something that we haven't been able to do and is now I think on a rapidly advanced understanding at a genetic level at the DNA level of a lot of different diseases so so you and I have done functional screens we've done these large-scale CRISPR screens where we modify many genes thousands of genes or thousands of locations in the genome all in kind of a test system but do you ever see this one day the idea of these multiplex pooled CRISPR screens going into the clinic that we actually take a clinical cell line a cell line from a patient absolutely I think that is kind of one of the ultimate goals ultimately it would be very nice to be able to correct the mutations for these diseases we've known about for sometimes hundreds of years and we just haven't been able to do anything about there's a lot of kind of ethical issues surrounding very reasonably using CRISPR in the clinic I think there's a lot of concern about trying to use CRISPR technology other genome technologies to make humans designed in a specific way whether you want to change eye color height or things like that like kind of irony of that situation is that the genetics of a lot of the traits that are you know you can see by just looking at a person are quite complex and are not worked out in the same way so you're saying that the ethical problem is not really right now a clear and present issue because for many of the perhaps a little bit more superficial traits that we have we don't really even know what what genes can control these these traits so it's probably a good idea to start thinking a little bit about engineering somatic cells versus germline cells which are passed on to future generations and I think one nice thing is that most scientists agree that for at least for human gene editing that we need to focus on somatic cells which really impacts a lot of people with these diseases and that there's many many issues around editing the germline where there you're doing something that might be inherited for for many many generations so it's kind of an interesting misconception that people think that CRISPR is just one thing just one enzyme casts nine I think that's a really great point and that speaks to just how fast the technology is developing because it started with us just knowing about cast nine but in just one cast nine right s pyogenes cast nine was kind of the first one used for gene editing in human cells exactly and just in the past few years this this toolbox has now been expanded well past that for example you can look into other different species of bacteria to find cast 9 ok so cast 9 is over many different species it's over a tremendous amount of bacteria and so you had reference strep pyogenes cast 9 well if they you look into Staphylococcus aureus you can also find cast 9 and that cast line is just slightly different it can target different regions of the genome and so that opens up a whole new set of possibilities in terms of genome editing so it increases the targetable space within the human genome you can target more regions that you couldn't with that first first cast line and what I find actually is a really interesting thing is that there's this huge meta genomic diversity of different CRISPR systems and most of them are really just not even well characterized yet and I think the best example that we were talking about it earlier is this new RNA targeting CRISPR so instead of cutting DNA it targets RNA and I think this is just one example of a complete paradigm shift I don't think anyone have necessarily predicted at the beginning that this would be one of the things that just was created and existed in nature and it just took some time for people to uncover it I think it's a great good example why it's important and actually the fund base basic science because you sometimes when you start out down a certain path you never know where you're gonna end up in the end the more research I can be done in this area can really unleash new possibilities finding new things different versions of cast 9 or other things that function like cast 9 or things completely different than at this moment I can't even think of the possibilities are endless to be a little cliche about it now literally I think they are endless for sure I think it's great for people of all ages to understand CRISPR and at least a little bit about genome engineering because so much of the world today revolves around biology also there's something about self understanding we really want to understand ourselves and what makes up ourselves and CRISPR and gene editing is another way to get at what is the substance underlying us

34 thoughts on “Biologist Explains One Concept in 5 Levels of Difficulty – CRISPR | WIRED”

  1. correct me if i’m wrong but i don’t think most people would mind if a hereditary disease was edited out of their ancestor’s genes

  2. I’m between level 4 and 5 but it was quiet interesting listening to the different opinions.

    I wrote my lectures essay in biotechnology about CRISPR and it’s different systems and I also had the chance to interview an expert. It is a fascinating tool and I’m exited to see which way scientists will go with CRISPR/Cas9.

  3. This boosted my ego just a little because as a freshman in high school I wrote a paper on the future consideration and legality of CRISPR/Cas9 and I followed the conversation through level 5 with the only exception being epigenetics. I just didn’t have the space in a six page paper to address it.

  4. The 14 year old talking about p53 really high lighted how poor my biology education was :/
    I went to a private religious school. it was more brainwashing than college prep studies.

Leave a Reply

Your email address will not be published. Required fields are marked *