Episode #29: COVID-19 Researcher Spotlight: Interview with Chan Zuckerberg Biohub Scientists

welcome to the covid19 researcher spotlight series i'm your host lydia morrison and today we're sharing an interview with three scientists from the san francisco bay area who worked to establish coven 19 testing for californians as a collaborative effort between ucsf and the chan zuckerberg biohub eric chao amy kistler and emily crawford have helped provide reliable coven 19 testing as well as genomic sequencing of sars cov2 to better understand and diagnose the spread of the coronavirus in california hi eric amy and emily thanks so much for joining me today thanks for having us yeah thanks for having us uh so i was wondering if we could sort of um circle up with each of you and have each of you tell us a little bit about your covert related research yeah i can i can go ahead and start this is emily my background is as a protein biochemist but in the past five years or so i've been focused on development of novel diagnostic methods for infectious diseases so um it was a relatively easy transition for me to start focusing entirely on covid19 when the pandemic began and i am now running a clinical diagnostic testing facility hosted by ucsf and the chan zuckerberg biohub where we we take samples from public health departments around the state of california and we return clinical clinically reportable pcr results showing presence or absence of of sars kobe 2 and eric has been helping out setting up the lab as well over the last few months this is eric my background is in genomics around next generation sequencing as well as automation and a lot of the focus of my previous research before covid is on improving ways of using technology to do genomic research such as new ways of doing ngs library prep different ways of using automation to enable higher throughput uh sample processing and so some of these skills definitely applied well to the current situation where we need to do a lot of nucleic acid-based tests to detect stars cov2 and um over the past couple of months i've been really involved in the ucsf chan zuckerberg biohub efforts to get a testing lab booted up and to scale up operations my name is amy kessler and i've been focusing on the sequencing efforts the genome sequencing efforts of the stars cov2 that are circulating in california my background is in viral genomics and virology and i was it was very natural transition uh for me to shift gears with the established metagenomic uh sequencing efforts that we've developed here at the biohub a number of them that emily has been significantly involved in um developing to pivot to begin looking at those strategies for mapping the distribution of stars kobe 2 to understand its transmission and circulation in california and amy just to stay on that topic how is your work in sequencing the genome of sars kovi 2 going to inform our understanding of the virus and inform our understanding of how it's moving through the state of california yeah so sars kobe 2 accumulates mutations at a rate of about one per every two weeks so we're seeing mutations mutations can arise over the course of transmission events and what this allows us to do is understand when we see cases arising how closely related they are in space and time as well as in genetic sequence and that helps us with collaborative information from epidemiologists at departments of public health where a number of the samples are coming from to really get a much higher resolution picture of how the virus is actually moving around each mutation or the sequences of the virus you could think of them as kind of like a bar code for the virus and so we can be following the viruses based on their barcodes as they move around the state that's really interesting emily just to follow up on specifically the research that you're doing could you talk us through the workflow for detecting sars cove 2 in in patient samples that you're receiving yeah sure so um i'll start by giving a little bit of background on how our testing facility um got started if that's okay so you know i've been a researcher a research scientist for my whole career and so so have uh eric and amy and most of the the people that we're working with now but back in march the governor of california made a few small tweaks to regulations around who can do clinical diagnostic you know clinically reportable diagnostic testing in the state and as a response to that ucsf realized that uh they were sort of sitting on a a great resource to help out the community which was you know a large number of graduate students and postdocs a lot of equipment a lot of expertise in doing um the thing that that's most needed by the state and by the world right now which is um testing people for sars kobe 2. so we in early to mid march we transitioned our research lab space into a clinical diagnostic space where we now take samples in and result out presence or absence of of sars kobe 2. and the process it is it's interesting it's been an interesting learning experience to understand um what the different challenges are with doing clinical diagnostic as opposed as opposed to doing a research test the most notable is that the the difficulties and the hard work all happens upstream of the of the analytical steps so we receive from our public health department partners uh hundreds and thousands per day actually of of tubes with samples in them so these are collection tubes containing the nasopharyngeal swabs that everyone is familiar with and we need to enter the patient information from that tube into our database and we need to transfer the material in the tube into 96 well plate format so that we can process it in high throughput and then actually proceed with the pcr so you know one one of the biggest challenges there is just how do you how do you take samples in tubes and transition them into plates um and actually eric has been sort of spearheaded the efforts to figure out how to do that early on we have a couple of different robotic solutions for making that that transition happen but it's something that as a researcher you you don't necessarily think about that step as being the biggest challenge but when you're actually trying to do this work at scale that that becomes potentially a big bottleneck so after the samples are in plates we do rna extraction just the way you would do in in any kind of typical research setting and we do that on again in 96 well format on a liquid handling robot um and then we um we transfer the sample the rna into a 384 well to do a pcr reaction and early on we played around with a few different sets of pcr probes and made the decision to use uh one n-gene probe and one e-gene probe which we thought performed best in our hands um and so that's that's how we developed our our eua assay based on on those two and then the the final step that's really important to to think about is the data processing and um another you know key aspect of setting up the lab was creating a limb system a laboratory information management system where we were able to uh keep track of of all of the uh information that sort of came with the tube to to begin with and then connect that to the results um in the end and the actual resulting resulting where the positive or negative result goes out to the clinician or the public health department that is taken care of by our our clinical lab partners over at ucsf i just wanted to highlight the just how the emily's workflows as somewhat our the sequencing workflow is kind of an outgrowth of emily's workflow yeah early on during the outbreak you know the the huge priority for us here was to develop surge capacity for testing um as we were seeing the pandemic unfold and you know what emily described got spun up in in an amazingly rapid time in in on the order of about a week till from ground zero to the first testing and am i correct emily before the clia hub eight days and so what what she described as it you know happened and tremendously rapidly and um in terms of the sequencing workflow that was something that was sort of a has been a secondary follow-on work in terms of the public health need and urgency and the work that emily and eric did to pull all this together actually uh we were on the sequencing side we had established metagenomic sequencing flows etc for basic research and so there was less development there that needed to be done from the ground up but a follow-on workflow needed to be developed in order to be able to a process the samples that people were sending directly to us as well as samples that were coming that we had clearance to carry out sequencing analysis that were coming through the clio hub testing lab so all the work that they did and the groundwork they laid was a great model for us as we built additional tools to enable both metagenomic and amplicon sequencing as far as kobe 2. and even at the level of you know a lot of the labs were sending us tubes and we move we needed to move things from tubes to plates to automate it much in the same way that they did downstairs and all the groundwork that eric laid for processing clinical samples also worked with processing rna samples that were sent to us from different labs around the state that's really phenomenal that you were able to implement those new systems and i'm sure there's lots of new regulatory requirements that you needed to meet um eight days seems like a phenomenally short amount of time to be able to accomplish that and eric do you want to speak a little bit to um what it took to be able to implement those robotics to uh allow for this magnitude of samples to be tested yeah definitely um i would say that everything that we're describing here is the work done by dozens and dozens of people at ucsf and biohub to get this together as you mentioned getting a lab booted up in in eight days to do clio testing is no small feat and a lot of this is really due to the really close cooperation and really tight teamwork uh between the groups here um i'd say especially with the uses of clinical labs that provided a lot of guidance um as emily and amy both mentioned you know we're all research scientists we don't do clia testing uh as are our professional lives and so we really depended on the expertise from from those groups uh to guide us on how to file the fda euas for our laboratory developed tests and without their their help it just wouldn't have happened but in terms of the robotics a lot of this is working with different vendors first to see which vendors could deliver equipment and in a rapid manner as you imagine you know you've heard about supply shortages for reagents for doing cobit testing the same thing is happening with equipment as well so the first thing was finding automation vendors that we could find they could provide the supplies and equipment in a timely manner we were able to do that and to also work closely with those automation vendors just to get the programs developed you know we had ideas of how we wanted the workflows to operate and work really closely with some of the application specialists at these automation companies to enable those workflows to happen well it's a good thing you had such strong relationships built with them already yeah definitely i think we've all used quite a bit of automation at biohub and over at ucsf and so we're definitely able to leverage those existing relationships so i'm curious now that you're up and running um and i know that california is experiencing um a surge in cases again right now you know we're recording this on july 17th um and california is sort of in the middle of a of a of a new wave or maybe the second half of the first wave um so how many samples are you able to process in a day and and what does that look like in terms of sample turnaround time yeah i can speak to that so um i think our average uh sam number of samples per day that we process hovers around a thousand per day um our our record which we set uh just this past sunday actually was 1932 samples processed in one day and so there's there has been a trend upward in in how many samples we're receiving and we're doing our best to accommodate that again working with just a phenomenal group of of people in the lab we're mostly staffed by volunteers ucsf phd students and graduate students and actually md students as well who come in and give us their time you know after they're done with their normal research days or um or classes or whatever it be you know they they really have been phenomenal in stepping up and um and coming in to help out and and donate their time we really appreciate that so much but we are uh we are also working on ways to improve our capacity because we know that it's it's very badly needed and we we're trying to do that while also keeping an eye on our turnaround time because we know that the value that we provide to the public health department partners is really in how how rapid we are when they send samples right now to quest or lab core unfortunately most of the time they have a several day turnaround time and that can be really detrimental to trying to control an outbreak so you know we know that we have to keep our sample numbers relatively low in order to um in order to not uh build up a backlog so that's that's kind of something that we that we think about regularly and we work closely again with our ucsf partners and we also work closely with the public health departments to you know communicate with them about what their needs are and how we can best meet them well that's really important and it sounds like the collaborations and the communication that you've been able to establish are really key to a lot of the success um of the turnaround time and the system that you have set up there to support the community and the state's testing efforts i'm curious amy why is this work important to you um one piece about the work that's important to me is just being able to apply you know modern 21st century approaches to this question that's really where technology can make a big contribution so you know a lot of the the tools that epidemiologists in the public health sector have available to them are not really that different you know boots on the ground epidemiology is um not that different from what's what was done during the pandemic of influenza in 1918 i mean certainly we have more some more sophisticated tools on that front but it does boil down to um you know kind of tracking down leads and you know digging through paperwork et cetera and if there's a way that we can contribute to helping them solidify their the data that they have that's important to make potentially really challenging public health interventions such as understanding if it's an outbreak in a congregate setting like a skilled nursing facility or some kind of a workplace where there's um and you know a question about whether that workplace needs to shut down really being able to have sequence data that is hard data that can help you clarify the inferences you have about whether something's an outbreak from a single introduction versus potentially multiple sources feeding into cases that are occurring around the same time can be incredibly helpful for our public health and just to be able to help them do that in you know a rapid way with these new technologies that may not be readily available in all the public health labs i think has been really important to me yeah and certainly an advantage for californians we have silicon valley is one of our neighbors and i think people generally think about california as you know the center of high technology and the idea of being able to whether it's testing or sequencing you know deploy all the technology and expertise that we have available in the state to help address the pandemic and maybe control or mitigate the outcomes associated with the pandemic that's really important to me to be a part of that and to be driving that forward so i know that um all of you are involved in a lot of collaborations um regarding covid19 research could you tell us about some of them sure um i can just talk briefly about some of the clinical research studies that we've been able to be involved in so another uh value to having this testing capacity has been not only to be able to to help with fulfilling public health needs but also to support research studies that have gone on in the community the most notable one that we participated in back in um gosh i guess it was back in april now or maybe may was a study in the mission district of san francisco where a ucsf group was able to partner with some local community groups in the mission district to set up a very comprehensive testing campaign over the course of a couple days where they tested about 4 500 people from one small census tract uh in the mission district um and we were able to process the samples there um and and deliver results and you know there were a number of people who um who tested positives uh many of whom were asymptomatic so that was uh valuable um information on an individual level as well as valuable um uh to understand the extent of asymptomatic infection in in our community um and and what was really valuable about that study um is that uh it was it was done by diane havelier's group at ucsf and they put a lot of thought into designing it in a way that we would get useful information out of it and kind of the the really key take home from from the results was that there was a very um strong increased risk of testing positive among people who were unable to work from home so people whose jobs required them to be out of the out of the home and be out in in the community you know this is what we refer to as essential workers um those are really where the people that that were being hardest hit and so it really uh highlighted for for us as a as a city and and as a community i guess how big the disparities are with this disease already where we're seeing um we're seeing certain groups of people hit really harder than than others and i think that that has helped us all to kind of refocus our our efforts both in testing as well as in in public policy to try to support the people who um who need it most um i can speak to the sequencing aspects that are both linked to the work that emily has been doing as well as independent uh basic research that we're doing here on sarsko v2 as that outbreak unfolds so the mission study that emily described was a really really great uh collaboration and example of the synergy that we can have between the testing that's going on the clia hub and the sequencing that we're carrying out at the biohub for research purposes so among uh the samples from the mission district uh study that emily described we identified and cherry picked through the automation practices that have been developed downstairs and upstairs we were able to through the limb system that was developed rapidly identify all the positive samples from the mission district study cherry pick them for sequencing upstairs perform sequencing and then begin to analyze how any patterns that we were seeing of the types of clusters that were identified epidemiologically in the really careful you know high high-touch epidemiologic work that diane havelier's group was doing and what in terms of the data that was going on in households or contacts among the people that in the community that participated in the study and the actual sequences of the viruses that we were seeing arising within the positives and so that was a really beautiful i feel like a really beautiful illustration of how the testing through the sequencing can help us to really understand how the virus is moving within a community and what was really gratifying i think i can speak for myself and probably for emily to to say that you know diane havelier's group was also going back and returning to the community to follow up with the families and the patients and the positives for treatment and further um clinical follow-up and so that was a great experience to be involved in that so there i i guess aside from that study there are sort of three categories of sequencing research that we're doing around the sars kobe 2 during the pandemic one is also somewhat tied with emily's work in that we are through the connections that emily forge with the departments of public health we extended those to invite departments of public health to provide us samples for sequencing for epidemiologic analysis we did that um in small scale and now that sort of turned into a sort of a bigger project where we've opened the doors for free sequencing to all uh county public health labs as well as the state public health lab and that's a project we're calling internally uh here at the biohub covic tracker but there have been some continued discussions with the department of public health of california and they're expanding and kind of connecting an effort a more statewide effort to call they're calling covid net that includes not just the biohub but other academic and potentially commercial labs that can facilitate sequencing of isolates across california to get a better understanding of the phylogenetic tree of stars cov2s circulating in california as well as to help public health labs with epidemiologic tracing so that's one big project and that's really been spearheaded by actually a data scientist at biohub joshua batson david dienerman and also our biosecurity fellow patrick askew well i'll certainly be interested to hear how those studies play out i think it's really important information um you know not just for the community of california but really for the united states as well as for the rest of the world right now you know i just wanted to thank you all for your collaborative spirit and your ingenuity in bringing this fast reliable testing and genomic sequencing to further the understanding of the spread to the state of california so emily amy and eric thank you so much for taking time out of your research schedules um to talk to me today thank you thanks for having us this interview was recorded prior to the clia hub covid19 testing facility being closed in october as testing capacity improved in california testing for the public health departments is now being conducted at ucsf among other locations overall the group completed more than 160 000 tests amy is continuing her work at the chan zuckerberg biohub with the recent surge in coven 19 cases in california her group has received a deluge of covet 19 positive samples for sars cov2 genome sequencing this covid tracker genomic epidemiology project with california county departments of public health and the state dph will continue into 2021 with an added emphasis on capacity building emily has returned to her research at ucsf and she continues to support the project as an independent consultant eric is currently back to running the technology team at the laboratory for genomics research a functional genomics collaboration between uc san francisco uc berkeley and glaxosmithkline the goal of this collaboration is to develop and deploy new crispr cast-based screening tools to better understand the genetic causes of diseases thanks for listening to this episode of the covet 19 researcher spotlight series join us next time when i interview senior scientist bajoyta roy who leads a lab in the rna research department here at new england bio labs bajoyta will walk us through the process of covid19 vaccine development with a focus on mrna vaccines and the promising candidates awaiting fda approval she'll also discuss with us how nab research scientists are working to improve and streamline mrna synthesis workflows

2021-01-26 21:58

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