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Follow That Cell Prize Winners

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Transcript

Beckel-Mitchener: My name is Andrea Beckel-Mitchener and I'm a program coordinator with the NIH Single Cell Analysis Program. Before we hear about the prize winning solutions, I want to take a moment to describe the Challenge and how was conceived and pursued. Several years ago the NIH was granted the authority to award prizes for competitions through legislation known as the America COMPETES Act -- or COMPETES for short. COMPETES allows for the generation of innovative solutions to challenging problems in biomedical science. Distinct from grants and contracts, awarding prizes a different way to stimulate creativity and tap into different pools of talent. The Follow That Cell competition is part in the Single Cell Analysis Program,run by the Common Fund in the NIH Office of the Director. Follow That Cell challenges solvers to propose ways to analyze the dynamic state a single cell and exam its function over time. Breakthroughs may ultimately allow researchers and doctors to identify infected cells or cells that are resistant to certain drugs or cells that may become cancerous. This competition is being run in two phases. The first phase, which has just been completed, is called a theoretical challenge, which means solvers had to submit written solutions proposing innovative ways to analyze single cells.
We were looking for methods that had not been tried before and those that may even be a little risky. Those solutions were received last December and were evaluated by a panel of experts, who commented and scored the entries. These evaluations were reported to the judges, whose job it was to select prize winners and additional finalists, all of whom are eligible to move on to Phase Two, where they can make their ideas a reality by developing and testing their solution. Phase two entries will be submitted and judged in 2017. So we can now get started with the interview part the webcast. And so doctor Blainey
we can start with you. If you can introduce yourself and mention any team members that contributed to your Phase One solution. And in laymen terms briefly describe what your solution is all about.

Blainey: Sure. My name's Paul Blainey. I'm an assistant professor of biological engineering at MIT, as well as a core faculty member at the Broad Institute, also here in Cambridge, Massachusetts. And we had a group of four team members, including myself, and a graduate student in my lab, Jacob Borrajo, who is
a MIT biological engineering student; Atray Dixit another graduate student in the health science technology program. It's joint program between MIT and Harvard, who's advised by Aviv Regev. And finally, another faculty member Al Shalek, who just started his own lab at chemistry at MIT. And
our idea to solve the Follow That Cell challenge was rather than to physically sample cells, as we typically do in single-cell analysis, to engineer
cells in order to spit out the molecules that we want to analyze -- freeing us to obtain multiple time points per cell as well as potentially to bring this measurement to massive numbers of cells in vitro, or potentially even in living organisms.

Beckel-Mitchener: Thank you. That sounds great. So what do you think the applications or some other downstream benefits will be of your technology?

Blainey: I think the biggest advantage that we'll gain, assuming it works, is that its going to become a lot easier do single cell experiments. Today people utilize a lot of really fancy complex instrumentation, and microfluid technology in particular, in order enable single cell technology. And that means that only a few labs really are able to do this. And even those labs can only process a limited number of cells. I think if we have a molecular technology that enables single cell analysis, it'll bring this capability to a much larger number of research labs.

Beckel-Mitchener: And we're curious here at the NIH. How did you find out about the Follow That Cell challenge and what made you think about submitting as solution?

Blainey: Well, a lot of my friends know that my lab works on single cell analysis. And I think I must have gotten about half a dozen emails, letting me know about this challenge. It was really from my friends and colleagues.

Beckel-Mitchener: So peer-pressure, basically? That sounds good. OK, what are the potential benefits then, do you think in your mind, about contributing to a prize competition -- or involving yourself in a prize competition -- compared to applying for grants.

Blainey: Well I think the thing that's great about a prize competition is the level of excitement it generates. You know, our team was -- really we had a lot of fun putting together the application. It sort of energized us to push our thinking beyond the usual boundaries that we constrain ourselves to, when we think about completing a specific project on a limited term, on a limited budget. And so it had the effect of really opening up our thinking. I think, on the other side, its really important to recognize that its really great as a supplement to traditional funding mechanisms, because obviously implementing our solution is going to cost real money. And so it's also important that we have opportunities to apply for regular research grants, to pay for the work.

Beckel-Mitchener: OK. Great! Thank you very much. I think we'll next move on to Dr. James Ankrum. If you'd like to introduce yourself and we'll go through the same thing. If you can give us a little bit of information about your solution.

Ankrum: I'm James Ankrum. I'm assistant professor in biomedical engineering at the University of Iowa, and I'm also a member of the Diabetes Research Center here at the University of Iowa, as well. So my solution is on self-destructing cellular barcodes. And basically the way that I came to the challenge was to figure out how can we recognize single cells. Just like you and I can go to a busy shopping center and you'll recognize a friend, what kinds of attributes can we give cells so we get that same kind of instant recognition of what a cell is, regardless of the environment of cells. We're making small particles that have different composition of fluorescent fluorophores(?) embedded in the particle. And that essentially gives that particle a fluorescent signature -- the ability to see that particular cell that has this one micron bead on the inside. We'll look at its fluorescent signature and then know that this cell is Cell A or that this cell is Cell B. What this allow us to do is to actually do a single cell analysis, whether at a microwell level or with flow cytometry. You can characterize single cell secretion, single cell surface marker expression. Then we can also put that cell in a complex multicellular environment and see uniquely how does this cell actually interact with other cells. And then correlate that with all that single cell data. It's really powerful bridging technology to allow us to take information from the single cell analysis platform and correlate that with both multicellular in vitro, as well as potentially in vivo, outcomes and disease models.

Beckel-Mitchener: That sounds great. Sounds like you already answered by my question number two. So I'm going to ask you how you found out about the Follow That Cell Challenge and why you were interested in submitting a solution.

Ankrum: Yes. I've been interested in InnoCentive as a concept for a while. And so I periodically will just go to their website and peruse the different challenges. I like people's creativity, like Kickstarter, Indiegogo. And InnoCentive is on my list of things I check out as well. So when I saw that Single Cell Analysis platform, I thought "hey, some of the stuff I've done with particles and asked: "Could we adapt it to this challenge?"

Beckel-Mitchener: Great. That sounds really good. So and then moving along, what do you think are the advantages of prize competitions as an addition to other mechanisms that stimulate creativity.

Ankrum: Yes. They're definitely a supplement to traditional funding. But they're kind of fun. And I actually found it very enjoyable to write this proposal. One, being an engineer, having someone kind of put their need statement out there -- things they want in a solution. King of fun to ?????? strengths to my solution. The other aspect, it was much easier to put together this application than the traditional grant. I didn't have to do a budge justification or any of these personnel justifications. I could really focus on the science, and that's really the fun part that excites me. So I really enjoyed pouring all my time and energy into putting the proposal together.

Beckel-Mitchener: Wonderful. Thank you. OK we'll move on to Doctor Chen. If you'd like to introduce yourself. Now your solution is a little bit different, because you're actually looking at proteins. Everybody else who was a prize-winning finalist was actually looking at gene expression. So we're very interested to hear about your solution and how you came about thinking about this.

Chen: Yes. So my name is Brian Chen. I'm an assistant professor at McGill University, in the departments of medicine and neurology and neurosurgery. I'm also a member of the Center for Research In Neuroscience, which is we're located here at Montreal General Hospital. So our solution is a system that we're developing to observe and track when and where proteins are made within the cell. And how much of a protein molecule is produced within the cell. So when a gene is expressed into a protein -- which are the molecules or machines that enact all of the functions of a cell. So this solution will allow scientists the ability to be able to follow the status of the molecules -- when and where they're produced and how this changes over time in a living animal.

Beckel-Mitchener: That sounds good. And what do you think the applications are if your solution does work and the advances are made? How do you feel that science and medicine will benefit?

Chen: You know, we think that there's a broad range of applications for our system -- for example, in clinical medicine stem cell therapy, where you want to reduce the number of invasive surgeries. If you were to be able to track when a specific diagnostic protein is being produced by the stem cell, then you can track whether or not what the status of the cell is -- whether it's healthy or not. Whether it's producing the right proteins its supposed to produce, for example, a therapeutic protein. Other potential applications for our solution are, of course, to help basic scientists in understanding how protein molecules change over time in a living animal in single cells.

Beckel-Mitchener: Sounds good. Thank you. And how did you come to hear about the Follow That Cell challenge? And same question: What do you think are the benefits and maybe the drawbacks of a challenge, compared to a grant or contract.

Chen: Yeh. I found out about it through the Single Cell Analysis Program of the NIH. I've been a big fan of the program for a long time. And also through a program officer, a scientific officer, at the NIH, the NINDS, the National Institute of Neurological Disorders (actually NIMH). David Panchision was the one that informed me at the Society for Neuroscience in Washington D.C. He said I should apply for it. So I thought it was an exciting challenge.

Beckel-Mitchener: Great! And you feel its different from a grant for what reason? The same reasons others have said or do you have additional things to add?

Chen: I think its great, the InnoCentive challenges. It's a way to tap a lot of the resources across the world.It brings in the creativity and potential thinkers from industry, for example, the garage tinkerers and the inventors of the world. The only qualification is you have a good idea. I think the prize aspect of it generates a lot of excitement. But it also should incentivize businesses, for example, and all the creative potential thinkers within industry, as well as the academics. So I think, I thought it was very nice. I enjoyed it.

Beckel-Mitchener: Great! Thank you. Ok, we'll move on to doctor Eberwine and the team. If you'd like to introduce yourselves and tell us about your solution.

Eberwine: Thank you, Andrea. I'm Jim Eberwine. I'm professor of systems pharmacology and translational therapeutics at Penn. And I co-direct our program in single cell biology. And I represent a team of investigators in this particular challenge that includes Jai-Yoon Sul, who is sitting here with me. He's an assistant professor of pharmacology here at Penn and an expert on biophotonics, Ulo Langel, who is professor of neurochemistry at Stockholm University and also Professor of neurochemistry at Tartuff University in Estonia, who is a peptide synthesis guru, David Cappelleri, who is assistant professor of mechanical engineering at Purdue University, and an expert on image analysis and algorithm development, and finally, Junhyong Kim, who is a professor of biology here, who's an expert on bio-computation. And our solution for this particular challenge involves interrogation of the process of biological process of transcription -- as it's occurring in real time, by monitoring the activity of endogenous enzymes. And so the idea is to modify these endogenous enzymes so that a particular peptide we call a blinker peptide can interact with it. And upon that interaction, as the RNA polymerase is moving down the DNA template, making RNA, we're interrogating that RNA as it's being made. And we have points on our blinker peptide, allowing it to interrogate particular regions of the RNA that's being made. And the time between those hallmark points of the RNA, reflect the sequence of those particular points. So we're able to take our blinking timing and map it back to the annotated genome that is present in the data bases. This is built on the work of many people, including the very beautiful x-ray crystallographic work of Tom and many others, who create a structure to allow us to find where the RNA polymerases where we need to be able to capture our sequences.

Beckel-Mitchener: That sounds very interesting. So please tell us how you feel that your technology, if it ends up working, will impact biomedicine or other research across the world.

Eberwine: Yes. I think that to be able to interrogate gene expression in real time allows you many opportunities over what we can currently do. So a cell can actually serve as its own control in that case. As anyone who's tried to develop a drug or some sort of pharmaceutical screen of some sort, often-times your controls are cells other than the ones you are experimentally interrogating. Here you could actually look at a cell prior to drug manipulation, as a drug -- and see the difference in the gene expression. There are many other advantages, including that we all should be able to use this technology on live cells in the intact microenvironment. So we should be able to put our compounds into cells, where those cells are in connectivity with other cells, and look at gene expression within those cells, as it occurring in time. Working up to this, we're doing things in the test tube to show that the technology will work. And hopefully in the process of optimizing the technology in the test tube, we'll create a sequencing platform that allows the sequencing -- essentially of the single cell transcriptome outside of the live cell -- over the course of just a couple minutes. So we'd actually be able to define all the RNA sequences within a small sample very quickly. But the goal, of course, is to go into the live cell. And so we're working very hard to try and make that a reality and hope the technology will work.

Beckel-Mitchener: That sounds great. So I have the same question for you. As a long-time grantee of the NIH, including some of our innovative grantee awards, a Pioneer Award, a Eureka Award, how do you feel about the NIH launching itself into challenges and competitions?

Eberwine: You know, it's an interesting question, Andrea. I think it's a really interesting approach. The idea, I think, that NIH had in establishing this is to try to stimulate creative science. Creative science is difficult to assess and very difficult to fund. Because often times you don't have data that will show you that technology will work. And so by creating the challenge concept, people from all over the world can see what you're trying to do. And if they have an interest == or perhaps even have some insights on the problem, or perhaps you've been working on the problem -- may then be able to interact with you, see what you've been doing and may establish or help establish a collaboration -- and hopefully additional funding. So I think there are pluses to it from that perspective. A minus to this particular challenge is that you couldn't use NIH monies to create the preliminary data. So that makes it difficult to actually generate data showing that technologies can work. But I think with the challenge itself -- and the prize winners and other people who will be competing for the final prize, with the publication of their abstracts, with their, hopefully, willingness to interact with industry and people from around the world -- hopefully this will help creative science in a way that the standard NIH program can't.

Beckel-Mitchener: Great! Thank you very much. And last, but not least, we'd like to hear from Dr. Pourmand. Please introduce yourself, tell us where you're from, and describe your project.

Pourmand: I'm Nader Pourmand, associate professor in biomedical engineering at School of Engineering at University of California Santa Cruz. Our solution is founding two technologies that we have been trying to develop. And working on specifically nanopipettes, which is a tiny tip that can go into cells, multiple times and either inject aspirate or sense material inside the cells, without killing the cells. We can go back to the same cell multiple times without changing any function of the cells. And since we can do aspiration, we can aspirate a tiny amount of cell material, cell content, including RNAs and DNAs -- and possibly measuring PH and ????? inside the cell. We are taking out the RNA from a single cell multiple times. And usually less than one percent of the cell content. The challenge was, and is, how to analyze those small quantity of materials. So we are planning to build -- and also we are starting to develop nanogenomics, in order to analyze those tiny amounts of material that we are aspirating from the cells. By combining these two technologies, we can follow the very same cells over time, exposing to drug and see how cells are sensitive to certain drugs and how they acquire, for instance, resistance and mutations in order to build resistance for certain drugs specifically in chemotherapy. That's our solution.

Beckel-Mitchener: That sounds great. And you've already alluded to the fact that you are working on it in terms of cancer sensitivity -- the drug for cancer.

Pourmand: We are working both on cancer and, actually, neural cells, to understand how basically neurons affected by all these tissues that we have ?????.

Beckel-Mitchener: OK. Very good. And last question: How did you find out about the Follow That Cell challenge and what was your motivation to propose a solution?

Pourmand: First actually it was the same as Paul. A lot of my colleagues know that we are working on single cells and single cell analysis and single cell biopsy. And the very first day that it had been announced, I don't know, over ten colleagues sent me emails saying that we should apply for this. And after looking, I thought "oh yeah," this is exactly what we should be doing and what we can do. And the motivation is to understand the mechanism -- how cells are behaving over the course of treatment, stress or drug or anything else. It's not only for cancer, we can apply for any other applications that needs to understand cellular mechanisms. How a cell changes its course in order to react to certain ????.

Beckel-Mitchener: Thank you. Very good. Does anybody else have any other comments that they would like to make outside of our scripted questions? Again, these will all be edited. Is there something that you'd like to speak on or make a point of -- or something you may have missed? Everybody good? OK, terrific! Jim

Eberwine: Andrea, can I make one comment? I did want to mention that I think one of the advantages, again, to the challenge is the fact that it's open to everyone. It wasn't just open to NIH researchers or people who were funded. So people who have a creative or interesting idea could apply for this -- and that is not possible under the standard NIH or NSF grant guidelines. So I think this does help stimulate creativity in the field -- and people thinking about this. So I think this is definitely one of the advantage of the program as well.

Beckel-Mitchener: Great! Thank you for that addition. All right, I want to thank you all for joining us for this web broadcast. And for our viewers that are watching this, you can read more about the solutions that you heard about today, as well as the solutions submitted by the other finalists, on the NIH Single Cel Analysis Program website. And that can be found at commonfund.nih.gov/singlecell/challenge. Congratulations to all of you and good luck to all of our Phase Two solvers.

Eberwine: Thank you.

Beckel-Mitchener: We appreciate your time. Thank you so much.

Others: Thanks, bye, congratulations to all the winners.