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"sarah krispies" Discussed on Science Magazine Podcast
"2 million cells. Just to pause there, does that mean the mouse can basically only smell vanillin? It doesn't wipe away the others, but it will more readily respond to the receptor that's more common. Okay. And I wrecked my brain and I thought back to an old 1986 paper by scar, Pamela Scarr, where she had shown that you could isolate olfactory cilia from animals and you could elicit the signaling event. And then I married my idea for over representing one receptor with the cilia prep thinking that now if 2 million out of 10 million cilia represent one receptor, it should give a robust signal for the ligands that it responds to. So you're able to isolate the cilia and then look at what it's responding to. What we do is actually we generate the same second messenger cyclic AMP and then we use kits that are commercially available to break open the cilia and then quantify how much cyclic AMP was made. So you can see what molecule is stimulating the receptor that you express. You're able to measure that by an increase in cyclic AMP. Correct. And now, did you do that with multiple kinds of receptors or multiple kinds of molecules? Yes, actually, we only published two receptors in the sign signaling paper. I think we have almost up to a dozen receptors that we've been analyzing with odors and receptors. The difficult part is not making the animals the difficult part is creating a large repertoire of odors to interrogate the receptors. Making the odors is the hard part. I mean, you do need to have like 400 transgenic mice though, right? Sure. It's the delivery of the odors. So if you do liquid delivery, which is what most in vitro scientists do for, let's say, dopamine, serotonin. They're all liquid delivery. That's fine up until a certain concentration what we found was that the cilia begin to get damaged if you go too high in concentration. So you have to go low concentration. So that's part one. Part two is they're not very soluble the odor. So you're actually better off doing vapor phase delivery. And doing vapor phase delivery on, let's say, a thousand or 10,000 odors is a daunting setup to make. Optimally what my dream would be is we'll break it down instead of 10,000 odors. We'll say 2000 odors that are commonly used in foods and flavor and fragrances. So if you took 2000 and you match them to all 400 receptors, what we'd optimally like to know is, what is the high affinity odor for each receptor? And then once we know that, then you go interrogate the others to see if they can bind or be activated at such a high affinity. Now, would you have all 400 expressed and laid out and then you put different odors on that set of 400 or would you go one at a time? The work that needs to be done either way, but I think it's probably easier to take one receptor, one animal can generate 4000 wells worth of data. So in theory, we don't need a lot of animals to do this work. You need a lot of smells, not a lot of animals. Yeah. You need a deodorant, right? 2000 odors, you'll do them in triplicate that 6000 assays, okay, maybe that's two animals. So it's not the number of animals now that is preventing us. It is the way to interrogate the samples with 2000 odors. We can do them liquid delivery as a first step and that's what we would do. And then essentially we'd start cataloging, okay? Receptor X responds highly to odor one through 5. And so you wouldn't do something where you have all 400 and then you just bring in some bacon. And you cook the bacon, and then you see the entire experience of bacon across all of your receptors. We could do that for flavor and fragrance fingerprinting. If you wanted to fingerprint bacon, you would certainly do that. So is that one of the outgrowths of this? So once you've nailed down what you see as the high affinity binding for all these different receptors, then you can look across how they act in all these different situations. Absolutely. Our main grant that we're working on these days is there turns out to be probably an odor associated with the onset of Parkinson's disease. And this is what we're focused on the lab these days, which is we would like to identify a series of receptors that could distinguish the odor of people who are predisposed to Parkinson's disease versus those who are not. People have done studies where they use a dog to smell samples to see discriminate people who have illnesses. But is this also a step towards a mechanical nose where if you've identified the odorant molecules that signal Parkinson's, then you can build something that's more durable than cells in a dish. Cilia in a dish. That's exactly right. These cilia as we suspect that could be frozen for a long period of time, we are up to maybe 18 months over one year. So without losing significant efficacy. So here we just go to the freezer pull out a sample and we start working. Thank you so much for being here. Thank you, Sarah. So much for having this on. It's been a real pleasure. Paul Feinstein is a Professor of biology in the department of biological science at hunter college, special thanks to messiah omura for her help with this interview. You can find a link to the science signaling paper we discussed at science dot org slash podcast. And that concludes this edition of the science podcast. If you have any comments or suggestions right to us at science podcast at AAAS dot ORG. You can listen to the show on the science site at science dot org slash podcast, or you can search for science magazine on any podcasting app. This show was edited and produced by Sarah Krispy, with production help from patigi, Kevin McLean, and Meghan Cantwell. Transcripts are by scribbly, Jeffrey cook composed the music on behalf of science and his publisher, triple AS. Thanks for joining us.