 Without further ado, Professor Song for Zidia. So cute. I'm sorry. I just fall in love with them every time. Like, like I even thought I'd do it. That's Samantha and that's Eddie. They're four years old. Or as we say, the effing fours right now. Okay, so let me start. They really are sweet. My son sure circuited the house because we won't get into that. Okay. He wanted to show us. He was very proud, but somehow he knew how to grunt himself. But the tweezers were burnt and melted. Okay. Takes after grandpa. Okay. So thank you very much for the introduction. Kind of was, I thought I would talk to you about some of the research that I do in my lab. I hopefully you'll find it interesting. And basically what we're trying to do is just make every hypochondriac out there in the world happy by being able to do point of care diagnostics. So, and honestly, that's one of my motivations now. So what I'm really interested in and very motivated is like, how can anyone really efficiently diagnose cancer? And what I've sort of shown here is sort of an outline of what the doctor goes does. Now I understand what you mean by pulling it there. Okay. Like essentially what does a doctor do in terms of diagnosing cancer in a patient? And you can see it's a very complex process where essentially in the end a doctor would have to biopsy a tumor. There would have to be extra sample processing and cell purification to try to access these cancer cells that may be in the tumor. And then do something called aminofenotyping or aminostating. That is that there are receptors on the surface of the cell that identify that cell in a particular way. And we have antibodies that are attached with what we call fluorophores that can glow under certain wavelengths of light. And with that we can identify different types of markers or proteins that are on the surface. And this is done through something called fax or macs and also just general microscopy. So just to give you sort of an idea of fax and macs because then you'll see how simple our device is really. Fax is a multi-million dollar machine that's in the hospital. And essentially, again, what a doctor or technician will do will be to take these cells that he or she is obtaining from the doctor. It's really a pathologist. And then they will stain these cells and then run it through a machine that essentially, oops, sorry about that, that essentially will sort of run these cells across a flow of water, across laser light. The cells will glow different colors and then you can sort them based upon different colors. It's a very complex process. It takes a couple of days sometimes and you definitely need a technician to help you out. There's another sort of generation technology and that's called macs. It's based upon attaching magnetic nanoparticles on the surface of a cell and then essentially using magnets to hold the cells that have been sort of tagged with magnetic particles. And then essentially you can just sort of remove the cells that you don't want and then ultimate, and the cells that you do want are held by magnets and then you can remove the magnets and then in the end you can then collect the cells of interest. Now the thing is, is that all these instrumentations they're at the hospital, they're at all debates, they're at UCSF, et cetera, but they all require, again, the sample prep that's very extensive and you can lose your sample along the way. It's very difficult to isolate subpopulations and cell viability to do post-analysis. Everybody talks about these days you might have heard in the news about personalized medicine. This is where that would come into play, where you want to be able to take those cells from a patient and then try all different drugs to see what drugs might actually save that patient or at least improve prognosis. All of this costs time, technical expertise, and everything like that. So this just gives you an example. This is at USC, their Comprehensive Cancer Center, but this is actually a fax machine that really would take over this whole stage right here. Multi-million dollar system. What I want to tell you is a story of what we're doing in the lab in terms of cancer diagnosis. So I've just given you generally what happens in the very general terms with oncologists. One of my best friends that I met in college, Lucy Godley at University of Chicago, is a hematologist oncologist. And she told me a very compelling story that I was really amazed. And this is also something that she's very passionate about. So there's a leukemia that's known as apromylicic leukemia. And it's among all the leukemias. It is rare in the sense that only about 7% of newly diagnosed APL patients could die within the first 48 hours upon presentation. Essentially, these patients who have APL in the most extreme form just bleed out. And really, you have essentially 48 hours to diagnose it and then give them a pill that I'll talk about in the next slide. In the US, we have great health care to some extent. We won't get into the politics of that. But essentially, 7% can die. In the third world country is where the technicians, the instrumentations are not available. Up to 50% of patients could die of this particular disease. And it's really, really, really sad. And the thing is, is that if you could diagnose APL right then and there, you can give them this pill, it's known as atra. Just one pill, if you give that patient that one pill within 48 hours of the patient bleeding out, you save the patient. If you give the atra to a patient who does not have APL, nothing will happen. And so one would wonder, well, why don't you just give a patient that you suspect that has APL, give them that drug? And the reason being is that insurance companies, it's a very expensive drug. So the insurance companies want to have an absolute diagnosis of APL before the doctors allow to administer atra. And my friend Lucy has had many patients die in the ER because she cannot beat that 48-hour clock with the formal diagnosis. So let me just show you, and this is morose, but it's kind of interesting, sort of like, what is involved to actually do point of care and how our technology, we hope, will actually address the situation. So diagnosing APL, you do have this 48-hour window. And what really happens is it's very subtle that the patient will suddenly start to have a fever and will have bleeding gums and feel sort of just general malaise, okay? It gets to a point where the patient decides, oh, I have to go to the ER, something's wrong. They'll take, they'll do a blood draw, they'll do a CBC count, and you'll see that the doctor will see, oh, it's patients anemic, has elevated white blood cells, and so forth, possibly APL. He'll send, he or she will send the blood over to the pathologist so that they can actually immunophenotype the APL. So in other words, they would use the FACTS-MAX to actually do immunostanding of white blood cells to see if these specific markers exist. And then there would be confirmation and then ATRA could be administered. So again, one of the problems is that what if that pathologist has gone home? Or what if you just don't have a pathology lab as you might have in third-world countries, okay? What we're trying to do after I heard this very compelling story from my best friend, well, we decided, well, is there a way that my lab, what we develop, well, whether or not we can actually cut that 48-hour window, be able to give confirmation of APL and then be able to administer ATRA. And here, we're not even talking about, you know, we're only talking about most, like, 15 minutes. That's how fast our diagnostic chip works. Okay, so let me just show you what we're doing. And this is a picture of the chip itself. That chip, actually, we're developing in the lab, we're hoping to insert it into an iPhone. Okay, so that gives you the sense. This was this big fax machine that I was talking about. We want to be able to have, everyone could be able to have, they can insert the chips into an iPhone and do a diagnosis for themselves. That's why I'm also saying a hypochondriac. This is their dream. Okay? My mom is very happy. Okay, this chip work and so forth. I really have to tell you, we were inspired very much over 10, 15 years ago, really dating myself by nature. So there's something that should say alpha. I'm sorry about that. I never know how to use the computer unless a student teaches me. So anyway, that's supposed to say alpha hemolysin. It's a protein pour, and it comes from a staph bacteria. Okay? And this is what the crystallographic structure looks like. The main thing you should know is that it really looks, if you look down on that protein, it looks like a cylinder. And it's what the staph bacteria uses to dump toxins into your cells, into your gut. Okay? Then in 1994, there was a group that essentially they were able to use this pour and insert it into a lipid layer, so essentially a fat layer. And essentially they were able to do something called resistive pulse sensing. And the beauty of this technique is just, as I show you right here, that essentially what you can do is you can just measure the current across that pour, that protein pour, and then essentially you will measure a constant current, but when a cell, or for me it's a cell, but for the bacteria it's some kind of particle or toxin, when it passes through that pour, you see a drop-off in current. Okay? And then as the cell or particle passes all the way through from one reservoir into the next, you see a rise in current. And this is called resistive pulse sensing because you get pulses out every time something passes through the pour. Now, what people have done in the 90s and even to this day is that they've been able to do single molecules, essentially they're able to detect single molecules passing through this pour. There's hopes that you can actually do DNA single molecule DNA sequencing. And there's a company out there that's supposed to announce within the month that they've actually been able to achieve this and then you'd be able to sequence your DNA for dollars. And again, this is great for a hypochondriac. Okay? And then essentially you can do all this genetic modification to get specificity. Okay? You can see that sort of the length sales is all on the nanometer scale. All right. So essentially alpha-hemialycin is very, very delicate. And so one of the things that my group decided is, well, why do we have to use a protein pour, a biological protein pour? Can we do something? Can we make it out of something else? And in the end, we ended up using something, using a plastic, so. I just want to say one word to you. Just one word. Yes, sir. I'm listening. Yes, sir. Plastics. So, and I think it's appropriate that I'm now at Berkeley. So anyway, okay. So I'm going to show you our plastic devices. They cost pennies, quite literally. And what it's really made out of, instead of a pour, we have just a straight channel. It's made using lithography. And this channel is made out of, it's done using photolithography. And we do something called soft lithography. That is, we make a negative master of whatever we're trying to make. In this case, it's actually the channel. And we run particles through. But let me just show you. This is called. So this is soft lithography. Okay. And essentially what we use is a printing technology, photolithography, to create negative relief structures. And then what we do is we end up pouring our silicone rubber onto our chip. And the silicone rubber is what you would use in, which is what you would get at Home Depot. It's RTV silicone. It's what you would use to cock up your bathroom. So you can always go to Home Depot and do this at home. And I have done it. Okay. And then in the end, you can cure this silicone goop and then peel it off, literally cut it out of your substrate. And then essentially it would be a perfect mold of whatever you were trying to make. And then you can seal it onto another substrate. So this is hard to do. I've actually brought one that we've got made. It's a great demo. So this is a silicone rubber mold of an array of posts. They're on the micron scale. And you can see how well it replicates it. And that is how you get it to make a nice diffraction app. I've made the silicone rubber too thick because usually I can actually stretch it and then you can do it before you transform it. But anyway, I can cast it around. But it's... Okay, so... It's cool. Okay. I like... I one day want to make a silicone rubber mold of myself. Okay. I too. It's really kind of freaky. Okay. So let me tell you about these devices. I know it's very disturbing. My graduate students are like, what the hell are you doing? Okay. So this technology is very simple. We use a DC measurement. We literally run these chips off of a 15-volt battery. And all we're doing is measuring cells as they pass through our channel, which we call the poor. Okay. And that would be like the alpha hemolysin. Okay. And we just measure current. We are able to do CBCs. And this is just an example. So the current pulse magnitude that we measure corresponds to actually the cell size. Okay. Because it's a volume to volume ratio that we can measure. A volume of the particle versus the volume of the poor. And so we can actually take the magnitudes of our pulses and get cell size. What we can also do, this is a case where we've actually looked at the cell's blood and that we're able to count red blood cells and white blood cells and differentiate them. They're different sizes. Okay. We can also do something else, which is essentially equivalent to immunotyping. We can actually functionalize the glass surface that the mold sits on top of. And we can actually functionalize certain antibodies. Those antibodies can interact specifically. And then the cell takes longer to pass through the channel. And we see that in terms of a current pulse, transit time. Okay. Or the width of this pulse right here. Okay. So what you can just see is essentially what we did was we were looking for a particular marker. This is a leukemia marker, CD34. Okay. And what we're able to see is that by taking leukemia cells, we can run it through our device that corresponds either to CD, that has anti-CD34. So the cells pass through and stick and just travel much more slowly than if there's nothing in the channel or is functionalized with isotype control. So that's sort of specific. So let's skip over that. Okay. But we can also do so much more with this device. And that is what we're working on right now is looking at circulating tumor cells. Okay. And this is a new topic for my lab. So circulating tumor cells are cells that blub off of a primary tumor and they travel in the body and they're thought to be responsible for metastases. And it's often the metastases that kills the patient versus the primary tumor. The problem with CTCs is that they're very, very rare. We're talking about one to ten cells in seven and a half mils of blood. And the number of CTCs can really indicate whether or not a patient is going to survive or what is really the prognosis of that patient. Right now there's only one FDA-approved system. It's called the Varenex Cell Search. And what it bases itself on is maps, magnetic cell sorting, using these magnetic nanoparticles. And they're looking for CTCs that are EPCAM positive. And that's a particular marker for a particular type of tumor. The problem is that it's also looking for these one to ten cells per essentially ten mils of blood and the success in counting is only 60%. And that's FDA-approved. So what I want to show you is what our device can do if we functionalize it with anti-EPCAM and look for that EPCAM marker. And essentially what you see is what we've done is we've mixed different types of colon cancer cells with one that are either positive or negative for EPCAM. And essentially I always like to show people this one right here. That is, we can actually pick out that one of the cells that are positive for EPCAM out of a hundred or so cells that are negative. So we're much better than pheronex at this point. So I'm kind of sort of speeding along because I used up so much time trying to get my demo to work. But essentially what you can see is really that our device is that there's no sample preparation. Literally what we do is we actually just take blood from a patient, we just take blood from a mouse or whatever, and we just inject it into our device. And the device was prepared with certain antibodies and so forth. Only small volumes are needed. So instead of taking that 10 mils of blood out of a patient that you would do when you go to quest diagnostics to get a CBC done, we can actually just take a prick up your finger. So it's very much like also like detection of diabetes or essentially measuring your sugar content. It's rapid and very sensitive. We can do our measurements within minutes and we can tell someone if we're positive for whatever marker positive for whatever type of leukemia. It's done with traditional device fabrication. Literally the devices that we make are circa 1960s micro fabrication technology. So what's in your iPhone is a lot more complicated than this device here. It's very compact and expensive and disposable. Our chips are literally just an inch by an inch in an area. And it is user friendly. We have high school students now running experiments in our lab. So that's a good test. You know, you'd be surprised. In the end, we're hoping that anybody can use these devices in the home or in the clinic or really even in the remote locations. So where we're really heading off right now is that we really want to be able to detect the presence of disease like APL. We've actually expanded also this technology so that right now we can also literally count HIV viral particles in human plasma. This is something that cannot be done with current technology. We want to be able to determine minimal residual disease. We want to be able to have the patient to be able to actually monitor his or her disease as he or she is doing therapy and be able to report it back to the doctor through the iPhone. And essentially this is a whole list of other things that we can do. Okay. So in the end, I just want to say that we just have a very powerful technique that can be life-saving. Again, I just want to remind you this is what my friend Lucy has to do when if a patient presents sort of basically is presenting himself as bleeding out in the emergency room. She has a 48-hour window that she has to work against to try to prove that this patient has APL and that then she can give that patient Atra. We're hoping that we can be able with this simple chip be able to do detection of this disease within minutes upon presentation in the ER. And so with that, I just want to acknowledge my entire group. I have a large group, lots of undergrads, lots of grad students, and a variety of collaborators in my funding. So thank you. I think I could be all your mothers. Yeah, sure. Can I say I write 10 cells every 10 milliliters? Yes. If you have, if a patient has 10 cells per 10 milliliters, that's bad. That's really, really bad. It's not, it's really bad. So, um, I see the plastic being maybe inside the body to be able to pick something up. But we're not even going to pick a blood anymore. Like, how are you getting it? So that's a really great question, right? Right, so we'd only be able to do pricks. So the question is, you know, I'm talking about for circling tumor cells, we're talking about one to 10 cells per 10 mills of blood, essentially. But the things that our device can do are essentially sort of a prick of blood. Okay, so clearly we can't, you know, we can't compete against the statistics that way. So this is where I can't tell you what we're really doing to address that particular part because of Siemens' funding make. So, I need a month to clear out what I can say. Don't put that on the internet. So, um, please cut that out. I'm in trouble. But essentially, our diagnosis chip would be on the back end after we do all the sample pricks who go through 10 mills of blood, then we'll be able to tackle circling tumor cells. Absolutely. So, it turns out, the question is, do we see any clogging in our chips when we use blood? And that is the most amazing question that we have never seen clogging with blood. And we don't know why. There is something, you know, sometimes you just luck out. We don't know. We've actually, you know, we have films of whole blood passing through. It's really cool. You can see red blood cells traveling through. We've never seen clotting and stuff. So, there's something special about it. And the really cool thing is that if you remove all the red blood cells, you remove everything, and just look at just plain cells through, like, you know, white blood cells, that's when you get clogging. So, the red blood cells actually help us. So, yeah. What's the timeline that you're hoping for to get this impossible? So, what is the timeline that we hope to get this in the hospitals? So, for the APL, we're hoping that we can actually, we're funded by the NIH on that project, and we're hoping that we'll be able to go into pre-clinical application, like in the next year or two. So, I feel like I've really done something, and then my mom would actually understand what I do. She only understands the Henry Schoen thing, so. At least it made her happy, so. Yeah. So, you said you look at viruses. Did you have to change the pore size of viruses? Sorry? Did you have to change pore size? Ah, great question. If we wanted to look at viruses, did we have to change the pore size? We actually have a twist now with our device that we actually insert nodes in the channel, and these nodes actually give us a characteristic electronic signature that we can pull out very quickly and very nicely. So, we can actually have a huge channel, microns, and we can pick up the, you know, 120 nanometer cross, you know, HIV virus. So, it's really become a very sensitive device. One more question. So, what kind of electric signal are you getting? Are you worried about, you were talking about you want to get a third world country, but awesome. Yeah. Are you worried about temperature and conditions and things like that, playing a part in the electric signal? So, great question. So, if we were to actually put this into third world countries, or, you know, what would we have to worry about environmental concerns? So, we do have to, the one thing that we're still investigating is whether or not, how long do these antibodies last? And, you know, you know, clearly, they're good at a certain temperature. And so, essentially, we'd have to develop it so that someone who's going to use it would have to inject the antibody in into the device and then be able to use it. But otherwise, it's pretty hardy. Hardy device. Yeah. Can you use, like, label-free, like, label-free chips that you're being equipped to say, like, your example with the APL. Mm-hmm. They may be multiplexed together, like, specifically, like, lithographed. Absolutely. And specifically towards a different type of disease, like, say, detecting, like, say, the common cold, or even, like, even drug detection. Absolutely. So, the question is, you know, with our device, you know, can we actually multiplex it? Can we have various other detections, you know, look for other things as well? And the answer is, yes. We're, you know, we're doing R&D in my lab. We make these devices. But if you were actually to put it into a real, you know, manufacturing process, you could put hundreds of things on a single chip and then diagnose it. It's really great for a hypochondriac. You can really diagnose everything you ever wanted to know, so. Do you have any more questions? Okay. Any other questions? Okay. It's hard to seem to. Yeah. Are you going to have further populations to support your job? So, do you have any questions? Ah, great question. Do you want to work in my lab? Ah, absolutely. That's something that we have in the work. So, it turns out these F-CAM positive cells only are sort of a sub-population of epithelial-based cancers. And so, there's a whole host of other ones that people are trying to search for. And we have a project that we're going to use high-seq analysis to do biomarker discovery. So, people know that. I'm a physicist. I'm learning as I go the biology, you know. I did low-temperature stuff. So, my advisor will be with you. So, you'll probably qualify. Okay, well, thank you. And how would you interface the, how would you interface each one of the chip modules to talk to a computer? So, and talk to a computer and, like, eventually allow results to be transmitted to a computer or say, like, electronic record, patient records or use, like, the vital signs of pain. Right. So, the question is sort of, how would we collect the data and so forth and really transmit it? So, again, I offer you a job as well. I actually have this great research scientist who's working on that right now. Like, how would you interface it with the iPhone? How would you interface it with the computer and then be able to transmit all the data? So, what we have going for us is a DC measurement. So, things are very, very simple. Thank you so much. Thanks very much.