In this edition of FOCUS In Sound, we meet a Burroughs Wellcome Fund grantee who participated in the development of a remarkable new pathogen detection technology that may be vastly important in the detection and surveillance of COVID-19, among several other pathogens. He and his colleagues have just had a landmark paper published in Nature, describing the technology and its importance in the battle against the pandemic pathogen. With this story moving so rapidly, I should include that we recorded this interview on April 17, 2020.
Transcription of “Interview with Paul Blainey”
00;00;03;27 – 00;00;33;02
Ernie Hood
Welcome to Focus In Sound, the podcast series from the Focus newsletter published by the Burroughs Wellcome Fund. I’m your host, science writer Ernie Hood. In this edition of Focus In Sound, we meet a Burroughs Wellcome Fund grantee who participated in the development of a remarkable new pathogen detection technology that may be vastly important in the detection and surveillance of COVID 19, among several other pathogens.
00;00;33;21 – 00;01;12;25
Ernie Hood
He and his colleagues have just had a landmark paper published in Nature describing the technology and its importance in the battle against the pandemic pathogen. With this story moving so rapidly, I should include that we record of this interview on April 17th, 2020. Dr. Paul Blainey is a career member of the Broad Institute of MIT and Harvard and a tenured associate professor in the Department of Biological Engineering at M.I.T. He is an expert in micro analysis systems for studies of individual molecules and cells.
00;01;13;09 – 00;01;45;24
Ernie Hood
He is applying this technology to advance the understanding of DNA protein interactions, evolutionary processes, functional differences between cells, disease processes and drug target discovery. Paul holds a B.S. in chemistry and a B.A. in mathematics from the University of Washington and earned his Ph.D. in physical chemistry from Harvard University. He completed his postdoctoral research at Stanford University in the laboratory of Steven Quake.
00;01;46;11 – 00;02;23;23
Ernie Hood
He was recognized by the Burroughs Wellcome Fund in 2011 with the career award at the scientific interface. When he was still at Stanford, the award description in 2011 was particularly prescient, as it talked about from single cells to populations using microfluidics, genomics and culture to better understand infectious disease. In the post genomic era. The just published Nature paper is titled Massive Multiplexed Nucleic Acid Detection with CAS 13.
00;02;24;09 – 00;02;36;06
Ernie Hood
The new platform it describes may be a huge game changer in the quest for large scale testing for COVID 19 infections. Paul Blainey, welcome to Focus In Sound.
00;02;36;12 – 00;02;38;14
Paul Blainey
Thank you very much. I’m so glad to be here.
00;02;38;25 – 00;02;46;12
Ernie Hood
Paul, introduce us to this new testing platform that you and your colleagues have developed called Karman CAS 13.
00;02;46;21 – 00;03;20;08
Paul Blainey
This has been a wonderful effort by a really amazing team. And so let me start by acknowledging the rest of the team. This was a really tightly integrated collaboration between my research group, Pardis Sabeti Research Group and Brode and Deb Hong’s research group at the Breast. And in particular, I want to acknowledge a lot of the junior team members, particularly postdocs Sherry Ackerman, Cameron Myhrvold and two students, Gautham Thakur and Kathryn Frechette, who made just a special contribution along with the broader team.
00;03;20;22 – 00;03;51;05
Paul Blainey
Now the system we put together is a really interesting and powerful fusion of new microfluidic technology and an amazing CRISPR based nucleic acid detection assay called Sherlock. And so what we did was find a way to implement the Sherlock assay chemistry in teeny, tiny nanometer scale microdroplets that are spread out in an array that enables us to read them out using microscopy.
00;03;52;00 – 00;04;07;22
Paul Blainey
And so what this has enabled is a capability to run many, many different nucleic acid detection tests. And here we do have a focus on detecting viral sequences. And to do this quickly and at a low cost per test.
00;04;07;22 – 00;04;12;18
Ernie Hood
How has CRISPR been incorporated into the system? And what role does it play.
00;04;13;08 – 00;04;29;20
Paul Blainey
In our system? CRISPR enzyme CAS 13, plays a role in the nucleic acid detection chemistry, so it binds nucleic acid molecule and helps generate a signal that we detect using optical microscopy.
00;04;29;29 – 00;04;40;24
Ernie Hood
Was the ability to detect the COVID 19 coronavirus something you were already working on, or was it a situation where you could expand your system to include it?
00;04;41;16 – 00;05;06;08
Paul Blainey
So I’ll back up and give a little bit more history around the microfluidic platform. We started work on this quite a number of years ago for a totally different application. We invented this platform for small molecule drug screening and it was still several years ago that we decided to repurpose the microfluidic platform from small molecule screening to infectious disease diagnostics.
00;05;07;01 – 00;05;39;02
Paul Blainey
And so COVID 19 and the SARS-CoV-2 virus were not on our radar at all. Our interest with the platform was to develop and deploy what we refer to as a pan viral assay panel that includes assays for essentially all the important viruses in the world that infect humans. And so from the beginning we did have a Corona virus panel, but at that time, COVID two was not known to the world.
00;05;39;22 – 00;05;54;22
Paul Blainey
And so while the paper was in review, we learned about the outbreak, of course, and moved to really quickly develop a new assay for the SARS-CoV-2 virus and incorporate that into our large pan viral assay panel.
00;05;55;03 – 00;05;59;09
Ernie Hood
Did you have to make adjustments on the fly to accommodate the pandemic virus?
00;05;59;17 – 00;06;22;03
Paul Blainey
One of the things that’s really wonderful about our assay system is that it’s actually quite easy to incorporate new content, and we don’t have a lot of issues with cross-talk among different assays. So it was actually relatively straightforward to incorporate a new test to cover the strains involved in the outbreak. And we were able to do that in a short period of time.
00;06;23;03 – 00;06;35;11
Ernie Hood
Paul, I do want to hear more about the Carmen CAS 13 platform, but before we expand our discussion, tell me, what do you see as the headline here, particularly given the current pandemic?
00;06;35;25 – 00;07;10;26
Paul Blainey
I think the headline here is really one about hope. We’re incorporating here not only a new assay chemistry, it’s actually not CRISPR technology, but PCR technology that’s on the front lines of nucleic acid diagnostics addressing the outbreak today. And so there are these powerful new CRISPR based assay chemistries. And then also on the instrumentation side, we’re introducing this microfluidic platform for Microscale testing, which has some advantages in terms of reducing the cost per test and enabling many tests to be done.
00;07;11;15 – 00;07;30;22
Paul Blainey
And so I think in the context of the pandemic, the headline is really that there’s a lot of room for creativity and innovation to develop new types of tests to address it. And given the current situation, I think it’s quite clear we’re going to need an all of the above strategy to beat back the pandemic.
00;07;31;16 – 00;07;39;02
Ernie Hood
How will use of this system contribute to improvements in COVID 19 testing? I know that’s been a major issue worldwide.
00;07;39;17 – 00;08;08;06
Paul Blainey
Our system is really focused on test throughput and it can vary efficiently. Test each patient sample for a large number of target sequences, which could be different parts of one virus, different strain, variations of one virus, or a whole diversity of viruses in each sample. And so it’s fairly unique in that regard. We have not constructed it in a way that’s suitable yet for rapid point of care testing.
00;08;08;21 – 00;08;20;21
Paul Blainey
And so we see the role for the reported version of the system as being in surveillance either for clinical screening tests or for a public health screening and surveillance testing.
00;08;21;21 – 00;08;24;03
Ernie Hood
Is the turnaround rapid in this case?
00;08;24;13 – 00;08;47;25
Paul Blainey
The test in the micro health system currently takes several hours to return a result. So it’s not it’s not really suitable for rapid point of care testing. Now, we’re already working on future versions that would be much faster and use really simple instrumentation that would be well-suited to a point of care implementation or testing at the point of care.
00;08;48;14 – 00;08;57;26
Ernie Hood
I understand from the paper that the platform is sensitive, specific, and statistically robust. Can you tell us a little bit more about that?
00;08;58;07 – 00;09;31;28
Paul Blainey
Absolutely. We were really glad to see that even in the micro-scale nanometer format that the Kaman testing platform maintains the animal or sensitivity that had previously been demonstrated for the Sherlock assay chemistry. And so it really has this exquisite sensitivity while maintaining really high specificity. At the same time, now one of the unique features of our droplet array platform is that each test actually consists of many of these nanometer droplet replicates.
00;09;32;08 – 00;10;04;00
Paul Blainey
And so that gives us a lot of statistical robustness in order to make sure that we make the right call for each test, because we can check the results across the many nanometer scale replicate assay reactions. Another feature is that that average number of reactions per test is continuously adjustable, and so we can dial in the statistical power of the test case by case so that it’s most suitable for the application that it’s being used for by all.
00;10;04;00 – 00;10;24;22
Ernie Hood
The experts keep claiming that the only way we’re really going to get ahead of this pandemic and perhaps prevent a recurrence is a mass of expansion of testing, both point of care testing and surveillance testing, as you’ve been describing. Is this the vehicle to accomplish at least part of that daunting task?
00;10;25;10 – 00;10;57;06
Paul Blainey
Well, I think our system plays an important role alongside some of these other testing systems and modalities and in its current form. Yes. Particularly for surveillance, as you describe. And I do agree that this kind of widespread testing is going to be really important in helping reopen the world’s economy as we recover from the outbreak. Now, on top of that, I think it’s also pretty important that we continue with surveillance and with broad surveillance for many different types of viruses.
00;10;57;13 – 00;11;03;29
Paul Blainey
Such as our platform can enable in order to make sure that we detect and get ahead of the next outbreak that heads our way.
00;11;04;27 – 00;11;09;08
Ernie Hood
So how will the platform be rolled out and scaled for widespread use?
00;11;09;20 – 00;11;35;01
Paul Blainey
Well, thanks for asking. We’re already moving in that direction at the Broad Institute to test whether the system is going to be suitable for screening clinical samples from the outbreak. Now, beyond that, we’re looking at partnering and are already in advanced discussions with the government and with different companies that have appropriate instrumentation and manufacturing systems in order to deploy our system.
00;11;35;26 – 00;11;38;12
Ernie Hood
So are you already thinking in those terms and.
00;11;38;27 – 00;11;47;29
Paul Blainey
Not even just thinking? Ernie, We’re really taking strong action and pushing hard to make the most positive impact on the outbreak that we can.
00;11;48;23 – 00;11;59;00
Ernie Hood
Paul Obviously, Carmen has 13 is going to be tremendously useful for much more than just COVID 19. Would you elaborate on that aspect for us?
00;11;59;22 – 00;12;33;17
Paul Blainey
Well, yeah, that is one of the unique advantages of our system is it’s so flexible in terms of adding new tests and is so efficient when conducting many different tests per sample. We think it does have a great role to play there. And so in addition to the PAN viral panel that we report, it’ll also likely be useful to create region specific or outbreak specific assay panels that really target the most relevant pathogens that are circulating in a given location at a given time.
00;12;34;00 – 00;12;48;21
Paul Blainey
So with respect to the current pandemic, we’ve created now a respiratory panel that includes the outbreak strain as well as other respiratory viruses against which clinicians will need to make differential diagnosis.
00;12;49;24 – 00;13;02;18
Ernie Hood
What are the advantages of the Carmen CAS 13 platform compared to others in terms of costs and sample volume requirements? I saw some reference to those aspects in the paper and found it very interesting.
00;13;02;27 – 00;13;35;24
Paul Blainey
Yeah. So the Carmen CAS 13 platform does have exceedingly low costs and low sample volume requirements per test. So this is enabled by the low volume of each test reaction that’s carried out. That’s two nanometers in the current system and it results from the microfluidic automation that the platform enables. And so that eliminates the requirement for complex liquid handling equipment or a lot of manual labor, even when many tests are being conducted.
00;13;36;05 – 00;14;04;24
Paul Blainey
One of the challenges when one is interested to carry out a lot of different tests per sample is the sample consumption. And so our PAN viral test panel includes more than 150 assays, which could be a problem in terms of sample consumption using a conventional approach. But because our reactions are so small, it’s no problem at all to carry out hundreds of tests, even from a small clinical sample.
00;14;05;14 – 00;14;08;26
Ernie Hood
So this is a real victory for microfluidics, isn’t it?
00;14;09;23 – 00;14;37;15
Paul Blainey
Yeah, I think it might be, although only time will will tell. I’m a big fan of microfluidic technology myself and it’s frustrating sometimes to see how much of a challenge it is for the world to adopt the most advanced microfluidic technologies. And I think there are different theories about why that’s the case. One has to do with the complexity of the instrumentation that’s required to run microfluidic devices.
00;14;37;26 – 00;15;04;17
Paul Blainey
And so one of the focuses we had in developing the micro Dropper ray platform was really keeping it as simple as possible. And so it’ll be really interesting to see how that potentially enables greater adoption than other microfluidic systems. The other interesting aspect of that platform we’re using for Carmen Cas 13 testing is that it’s actually a fusion of two different flavors of microfluidics.
00;15;05;01 – 00;15;20;11
Paul Blainey
We use both microdroplets, which are small water droplets surrounded by a carrier, oil and micro well arrays, which are planar surfaces studded with small micro wells into which we put the droplets.
00;15;20;29 – 00;15;27;24
Ernie Hood
Tell us also about the massive capacity chip you designed, which allows more than 4500 tests per chip.
00;15;28;09 – 00;15;53;23
Paul Blainey
Yeah, absolutely. So I want to give credit to Toshi Ackermann, the postdoc in my lab, who actually designed and developed the procedure for for using that chip along with support from our broader droplet array project team. This is a chip that we refer to as the chip. It’s about the size of a smartphone and has a capacity to handle hundreds of thousands of droplets just under one chip.
00;15;54;13 – 00;16;04;22
Paul Blainey
And so that’s really the capability that enables us to process so many samples and so many assays for different viral targets all in one go.
00;16;05;16 – 00;16;12;02
Ernie Hood
That is very impressive. Absolutely. So where is your and your team’s research going from here?
00;16;12;20 – 00;16;44;28
Paul Blainey
Well, in the immediate term, we are very focused on deploying Kaman CAS 13 technology to make a difference in the context of the current outbreak. And so we do have a big focus on these conversations with government and corporate partners about how to deploy this technology for large scale testing here in the U.S. and around the world. Now, stretching out to the intermediate time scale, we are very interested in developing the next generation of carbon testing technology.
00;16;45;11 – 00;16;56;04
Paul Blainey
And our focus there is to reduce costs even further, generate systems suitable for deployment at the point of care and improve the turnaround time of the tests.
00;16;57;02 – 00;17;13;29
Ernie Hood
We will certainly look forward to those developments. Paul, It’s been an enlightening conversation and believe me, we are all pulling for you and your group to keep the important innovations coming as we face this incredible global challenge. Thank you for speaking with us.
00;17;14;13 – 00;17;15;15
Paul Blainey
Well, it’s been a pleasure.
00;17;16;26 – 00;17;25;08
Ernie Hood
We hope you’ve enjoyed this edition of the Focus In Sound podcast. Until next time, this is Ernie Hood. Thanks for listening.
