Disease detection at your fingertips with Professor Dayong Jin

Dayong Jin: Good evening everyone. I’m Dayong Jin from Faculty of Science. Today I’m here to show you a couple of example how we are going to use light to treat disease. I’m an ARC Future Fellow, and also the director for the new Institute for Biomedical Materials and Devices, and I’m also the director of ARC research hub for integrated devices for end-user analysis [at low levels] – IDEAL. As you can see, this hub is a highly focused on industry research and user-driven research. Two weeks ago, we had a wonderful hub official launch at UTS, everybody very happy. The key focus for this hub research is to develop portable, easy to use devices for disease diagnostics. I’m holding this device, you could be very familiar. You can spend ten bucks, buy three of them, for pregnancy test. The results could be very easy to read, and the device itself, it can be quite reliable. So, the question is, can we develop some similar technology which is portable but we can detect more complicated disease, like cancer? So, the answer is yes, we can do this by collaborative research. So, this is an example of our hub to working collaboratively with the University of South Australia and also four Australian industry partners. We try to put together the latest development of technology, like biotechnology, nanotechnology, photonics technology, which is the light technology I’m going to focus on today, and micro-fluidics, you know, communication technology – integrate all of this technology together into small devices. If you can remember back to ten years ago, everybody want to integrate music player, mobile phone, internet and GPS together into a small handheld device. That was a dream ten years or twenty years ago. And nowadays you can see the telecommunications technology already enable a mobile phone version device for you to do a lot of things by one device. So, for the biotechnology detection devices, and this is our design, you can have a lot of nanomaterials, which is porous, also have photonics material which is give you a very bright light, you can directly see the disease, and also you have an analytical chemistry technique developed for the last couple of decades, and then you can bring them smaller. So, to build a truly portable device for a single test, you know, for a very simple test, the detection in this space goes much beyond than you detecting cancer. You can also use this detection technology to detecting the circulating tumour cells and to understand the stage of the cancer patients. Also, you have, you know, this is a similar problem, really, to detect the pathogens and infections in our water, in our food. But the requirement can be very high, you know, if we have more ten cryptosporidium pathogen in ten litres, large volume of water, and when you drink it you can get sick. So, we define this detection and sensing technology and a single problem, so we call this is a needle in a haystack single problem. Once you can detect single, you know everything. So as a physicist by training, many years ago we start to summarise the key challenge. What’s the typical challenge in this field? So, we start to think from physics point of view, they are the sensitivities, which means your detection has to be sensitive enough and your speed needs to be fast enough. High throughput means you can simultaneously detect and multiple analyse at the same time, and resolution, we spend a lot of time in the recent years to challenge, you know, what’s the highest resolution we can see a single cell, we can see a sub-cellular structure, we can see even a single molecule. At this level, you can have a much better understanding about the fundamental of life. When I show this picture to many people, you have an impression, what are they? Australia? Actually, they are not Australia; they are tiny, tiny little single ell. They are single platelet cell under a fluorescent microscope. Using this traditional fluorescent microscope, the best you can do is you can see some things similar like this, right? But using a new technology we develop in the last couple of years, we call super resolution technology, super resolution microscopy technology, you can see lots of more details into the sub-cellular level and into the organ [inaudible] level inside the cell. So, by providing this new map, I call map, you could have a much better understanding of the fundamentals of biology. For example, many years ago you probably remember, when we drive we rely on a printed map, which give you quite limited information, okay? Very fixed and very limited information. But a couple of years ago, Google did something really clever, so they combined the satellite image and sending cars with cameras, with sensors, around every street, and you collecting all the images from different street, you correlate these images into the satellite image, then you can build the street view. In the biology, this is our dream. We want to apply different technology, different imaging technology, different nano-centred technology and build the inside, the street view version of inside a single cell. Once we know that, you could have much better understanding of the fundamental of diseases, and you could monitor and even predict the disease, or monitor the [inaudible] status of a healthy human being as well. So, before we talking about how we use light to realise all of these dreams, I have to show you,  you know, what’s the fundamental of light, and what’s light? We all know God create light before the God creating us, so what is light? Light can be conceived as two different physical models. So, one model is a quantum picture, you know, the quantum picture of a light, talking about the light is actually have many, many particles, we call photons. When we talk about electricity, we know the fundamental element of electricity is electrons. The same goes for light, and the fundamental of light is electrons – is photons. Okay? So, this little movie shows you the latest outcome, you know, from a scientist that use a super-fast camera. They take images every 20 pico-seconds, and you can record whole batch of photons, they’ve been bounced back by a mirror. The photon’s like a tennis ball, so when you hit a tennis ball on the wall, the ball will be reflected back, so this is a photon meets the mirror in a [inaudible] pulse, still with like billions of photons – quite a lot. And then once the photons hitting on the mirror, you’ve got reflected, so this is called reflection, okay? The other model we called the wave model, so you know, we know the sound each different sound, they are the vibration of the, you know, they have different vibration. The different frequency gives you different tune, but this one is light where you have a white light in front of a passing through a prism. The prism will separate the light into different colours, and the different colours representing different frequency – you know, the light wave frequency. They have different, you can recognise different colours. In biological world, biotechnology, we use colour quite a lot, use colour to differentiate different biological substance. Also, when light have an interaction with some matters, like when you get light heating on a material, and in particular this material we all know – jellyfish, right? So, when you’re shining a UV or blue light into a jellyfish, the jellyfish will emit beautiful green. This is a very colourful, beautiful green. What are they? So, they contain some material called protein, so this special protein, they will receive the light and slow down the frequency of the light. So, by slowing down the frequency of the light, you can change the colour from UV blue to green. But this way, you can separate your [inaudible] light and the emission light, and you can use this special material as a probe to label your targets, like a cancer cell or even sub-cellular structure, then you shining a light by blue, then you check whether this material got green, and where you got the green, and that – but this way, you build a fluorescent microscope. So, this is really the fundamental structure of a fluorescent microscope, they use a mirror. So, this mirror, they have quite special property, so when you have blue light hitting on the mirror, the mirror will reflect the light. But when you have a red light hitting on the mirror, the mirror will transmit a red light. So, this special mirror is the most fundamental element in the fluorescent microscope these days. I want to give you a – do a simple experiment. I take a mirror out of my microscope in the lab; this is a very simple mirror, but when you have a red laser, you can see this is a red laser, and you probably can see from the other end, so this is a red laser, right? So that means they are transmission. But whilst you have a green laser, the light – the mirror will reflect the green. Right? So, you wouldn’t see the green passing through, but from the other side, you see this mirror will perfectly reflect all the green. So, this is the principle for all the fluorescent microscope – by using this mirror and to separate your excitation light and emission light. When we’re talking about a fluorescent microscope, there are two very important recent Nobel Prize project, you know, relate to fluorescent imaging. One is 2008 Nobel Prize in Chemistry to three scientists who initially discovered there exist a fluorescent protein in jellyfish, and they can separate this protein out of jellyfish, and you can use this protein to label the single cell. And you can see once you separate the different colour of a protein and you can label, specifically label, two different compartments of a single cell. The red one is a cell, you know, membrane proteins, and the green one is the microtubule structure inside the cell, and the blue one is the cell nucleus, which is the headquarters of a single cell. And also, we can use different colours to label bacteria, to understand, to diagnose, the infections. The other recent, very recent Nobel Prize in 2014 awarded to three scientists who independently developed different technology to improve the resolution of a microscope. So, this is s a traditional resolution, which is a traditional high-end fluorescent microscope can do to see a single cell, but this one a super resolution, you can see. The super resolution provides much better and more detail for biologists and medical doctors to understand the fundamentals, the basics, of disease and the single cell. In this field, our researchers at the University of Technology Sydney has significantly contributed to the development of super resolution. This paper we published last year, talking about developing a new super resolution technology to deliver the best, the highest resolution in the world at the moment is 19 nanometre resolution. The [inaudible], so this is a single cell, if we think about single cell like this big, and we’re thinking about the nucleus like this big, this one is on the surface of a nucleus. Each single cell nucleus, they are like the headquarters, they’re sending signals to the cell and asking them what to do. Okay? So, by chemistry, by biology molecules. So, what we’re trying to image in this experiment is to see, you know, how the nucleus they send the molecules and chemistry outside, from inside to outside, through a structure called nuclear pore complex. So, this enlarge the picture from here, and this is further enlarge the picture, and you can see this is a ring structure, like an O-ring structure, of a nuclear pore complex. And now, the optical resolution allowed you to see this tiny little small hole on the nucleus for you to understand the live cell communication and structure information. 

Voiceover: A tiny mirror could make a big difference for scientists trying to understand what’s happening inside living cells. Cells are three-dimensional, and that’s a problem for scientists trying to see pores and other tiny structures. Existing microscopes provide high resolution in the x and y axis, but not the z axis, which is what scientists see when they look directly into the cell, perpendicular to the glass slide on which cells are usually examined. But by growing cells on tiny mirrors and imaging them use super resolution microscopy, a team of scientists from Peking University, the University of Technology Sydney and Georgia Tech are addressing this challenge. Their new technique creates interference patterns as light waves pass through a cell on the way to the mirror and then back again after being reflected. The interference patterns provide, at a single plane within the cell, significantly improved resolution in the z axis.

Dayong Jin: Alright! So, you can see, this is a simple example to show you the complicated, more powerful technology doesn’t mean you have to use complicated technology. The technology itself is very simple – you can use a simple, you know, a mirror, rather than grow yourself on the glass-top substrate, and this new technology provides a lot more scope and a lot more information for the biologists to understand the basics of life science. And also, is a typical example for international collaboration, so in this case, you know, we work with scientists from China, from US, United States, you know, to get this project delivered a couple of years ago. Alright. I’ll show you another example how we use the other different dimension to separate the target cell from the background samples. So, we call it time-result microscopy technique. This picture is the microscope I built right after my PhD study may years ago. At that time, we had quite limited resources to build more expensive microscope, so what I can do is find the old generation microscope, and you can see this is an old generation microscope, I chopped the head off and [inaudible] mirror I show you just now, and then you can build a UV LED as excitation, and then you’re collecting the red emission from the target signal. The most special, powerful uniqueness from this microscope is this one allowed you to see the target without background. How we do that? It’s pretty much like the scenario when everybody’s sitting at home watching TV, and suddenly the house getting powered off. So, then you see everything else went to darkness immediately, but the screen of your TV will last a little bit longer, okay? So, this is a special material which has a slightly longer fluorescent lifetime. So, in biology, we use a material quite similar to this material. We can use this material to label, in this case, a single giardia cell with a long fluorescent lifetime; then, by using a [inaudible] flashlight to excite every sample, and during the flash time you have an optical chopper – you have the chopper blade, a fast rotating, but during the flash time, the chopper blade will block the access for detection. But after the excitation light, the chopper blade will move away and then the short fluorescent material, they disappear immediately, and then the long lifetime material will stay in the picture. So, this simple technology, again, allowed you to directly see the single cell without any background. Okay? So, you can further apply this technique to [inaudible] multiple colour – the lifetime and the colour – and you can simultaneously detect giardia and you can also count how many cryptosporidium from green label. So, by this way, you have simultaneously high throughput detection multiple analyse in one image. And we further extend the technology to detecting cancer. So, this image shows you a prostate cancer cell, okay? So, we label this red fluorescent material on the red cancer cell, and we image this cancer cell out of urine, because urine we know you have a lot of background information, and it’s very hard to directly find them, you know, find the needle in the haystack, it’s very hard to find them. But this way, because you remove all the background information and you see you can clearly find where are the cancer, and how many are they? So, by doing this task, you probably can, you know, we are working really, you know, collaboratively with this Sydney-based company called Mnemonic International and they developed the protein technology for you to directly, specifically find the cancer cell, and we’re trying to put together this research effort to develop a direct technology for you to find how many cancer cells from the first urine in the morning, and then to diagnose, you know, the risk of prostate cancer. And you know, the current method for prostate cancer detection is PSA test. Three out of five positive PSA-positive patients can be false positive. Okay? So, then you scare a lot of people, and most seriously [inaudible] can miss a lot of patients who already got cancer but the PSA result shows negative, so this is a quite big problem. But by developing this sort of technology, you can directly see – you can directly count how many prostate cancer in the first urine in the morning, and then significantly improve the detection accuracy and also, by the way, this is a non-invasive detection method. It’s a lot of, you know, more acceptable than the biopsy testing. So, this, we believe, going to be the future of prostate cancer detection. The other challenge is when the disease starts to come, they only express a very little amount of biomarker, disease biomarker. So, this is a typical image we take in an electron microscope, which has a might much higher resolution but of course is a million-dollar machine. And then you can see on the surface of, in this it’s leukaemia [inaudible] cancer cell, and you can see on the surface of the single cell, you have quite a limited number of biomarkers. This is particularly true when the disease just start to come. And the challenge is, can you quantify the number of biomarkers per single cell, which you could require much higher resolution and you require much higher sensitivity. So, in the recent year, we developed this technology called SuperDot technology, which is very exciting – my team currently, majority of my team are focusing on this technology now. You can see, we start to use nanotechnology, we can develop a lot of well-controlled single nanoparticles at different size, but the uniqueness for this particle is, they can combine multiple photons. So, electricity is very hard to combine two electrons into one electron, but in photonics, you can combine multiple photons – one, two, three, four, even five photons together to emit single photons. The one feature for this would be you can use a [inaudible] light, but they can penetrate much deeper through the tissue, and then you can combine the multiple infrared light and can work them into visible ones, and you can see them moving just now – [inaudible] how you make this nanoparticles and you shining by infrared light and you can see beautiful bright green and blue fluorescence. So, this will bypass a lot of problem in biology, particularly for the deep tissue imaging, because we know the light doesn’t penetrate deep through the tissue. I got another experiment I want to show you, very simple, so this is a green light, right? So, if I’m shining the green light towards my finger, and from the other side I don’t think anybody can pick up any green light. But if I have a red light, which is a less powerful laser, but you probably can pick up the red signal from the other side, can you? So that means the red light, they penetrate much deeper. What about infrared light? The light near these infrared window, we call optical transparency window. You can see – the laser one I use around this [inaudible] range, but once you further remove the [inaudible] longer into near infrared window, the tissue, you know, the tissue will be – the light will transmit much deeper into the tissue. So, this will allow you to use a light-based technology to directly see the tumour cell, so this is a new result we received, we collected, a couple of months ago with, again, a collaboration with Fudan University in China. You can see this is a poor mouse, we inject this material into tumour, so by shining a near infrared light, you can directly see actually, where’s the tumour? So, optical is much simpler and easier, so this will allow the doctors to clearly see the boundary between tumour cell and healthy cell, and you know exactly where to cut, okay? So, this is an example and also the latest research result. So far, we only talk about how to use light for diagnose your disease and detecting single-cell and disease biomarkers. And you can also use light to trigger the drug release for the therapy, for the treatment. So, this is some latest the review paper by our collaborator in China – they put together nice review and quite long article, but I really like this image because you can see, by developing this material, which is a multi-shell and porous material with different components, the goal – and by the way, they are tiny; this is a scale by 15 nanometres, and you know, more than a million smaller than the diameter of our human hair, so very, very small one. So, you can build multiple functions into one material, and this new material will allow you to carry the drugs, also allow you to do MRI imaging and optical imaging. When you put the drug, when you throw in the drug, each particle can have a tiny, tiny amount of drug, so much, much below the safety threshold, and this nanoparticle can recognise the cancer tumour cell and you can use this infrared light to trigger this nanoparticle and let them to release a drug when you see they are already in the tumour region. So, this guarantees a much safe operation of chemotherapy and radiotherapy, so this is very promising technology for our future. In the same time, we try to study the fundamental science, like chemistry and materials science, to see how possible we can control each single nanoparticle, and we can possibly we can start to build multiple functionality into one. So, this is the case to show you, you know, how we play in the lab by growing different shape, different functionality, into the nanoparticle, and different structure of this nanoparticle. By doing that, you could develop a nanoscale sensor, exactly like how the Google is sending different cars to drive on each street to take the pictures from there and build a street view. And if you have a nanoscale, different set of nanoscale sensor, you could start to have multiple sensor built into a single particle, and then you can drive this different particle to different sub-cellular compartment, and you start to collecting the localised temperature [inaudible] value, the traffic condition, intracellularly. So, but this way, I think this is a very ambitious goal, but I think it’s highly possible for us to achieve this goal. Alright. By the end of my talk, I still emphasise the importance of collaboration. So, the future technology really belongs to people who can build international, interdisciplinary and industry collaboration and start to tailor the technology and the science and to integrate diferent technology together. Alright. Finally, I would like to thank the funding agent, which is the Australian Research Council, through different funding schemes, and also my team of students and postdocs, who has working really hard and drive this technology behind. Thank you so much.

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