Speaking of Science: Synthetic Biology (designer cells and antibodies) with Professor Shalin Naik

Professor Naik spoke to the emerging topic of synthetic biology, and how it is transforming the ways in which we’re approaching health and medical research, and science more broadly. Because when it comes to synthetic biology, it's most important to have imagination more than anything else.

Listen to Professor Naik ‘Speak of Science’, generously answer audience questions and the inspirational advice he would give to upcoming and emerging scientists looking to get into the field of synthetic biology – You don’t want to miss this one!

Recorded on Thursday 15 August 2024 from 11:00 – 12:00 AEST.

Video transcript

Professor Steve Wesselingh 0:00
A really exciting one. I'd like to start by acknowledging the Traditional Custodians of the Lands on which we're all meeting. We're all meeting on different lands, but I'm meeting on the Wurundjeri Lands of the Kulin Nation, and I'd like to acknowledge their elders past and present. I'd also like to acknowledge any Aboriginal or Torres Strait Islanders that are meeting with us today. Really important to make that acknowledgement.

Before we get started, a bit of a housekeeping. If you want to ask questions, please put them in the chat and then I'll try and get those questions up at the end. This will be recorded and will be available on the NHMRC website. Anyone who can't watch it all today can watch it at another time, or if there's anyone who's not watching today and you want to tell them about how wonderful the presentation was today, you can tell them that it's on the website.

This week is particularly important because it's National Science Week. It's an annual celebration that promotes and encourages interest in science, engineering, maths, technology and innovation and really aims to tell everyone about the importance and the relevance of science to everyday life. This was established in 1997 and ever since then it's been, a sort of, growing event and it's now been running throughout August. Celebration of science now has more than 1000 events and attracts over a million Australians across the country and these events cater for a really wide audience from children to adults, to science amateurs, to professionals with all the same goal to talk about how important science is and most importantly, inspire our younger generation to be fascinated by science in the world we live in and hopefully become scientists.

Obviously at NHMRC we continue to be really inspired and excited by the huge potential of the research that we fund and actually, I personally believe that it's only through our research that we're going to solve some of the really big health challenges that we're facing at the moment. We're not going to solve them by administrative issues. We're not going to solve them through funding. We're actually going to solve them by really high-quality research, solving those huge health challenges that are facing us at the moment.

Obviously in my position, I'm privileged to see firsthand some of the amazing stories of NHMRC-funded researchers, the research they're doing and the problems they're solving. That is a really good introduction to our speaker today because he's no exception to this, solving some amazing problems with really high-quality science. I'm really looking forward to his presentation and listening and learning from Professor Shalin Naik, who's a cell biologist and a laboratory head at WEHI and at the University of Melbourne.

Shalin’s research considers how the cells of the immune system are formed from blood stem cells, with the objective of advancing strategies for manipulating blood stem cells that may have future applications to stem cell or immune therapies and also cancer therapies. Shalin worked in the Netherlands Cancer Institute prior to returning to Australia to run his own stem cell research lab at WEHI. The Naik Laboratory focus is technology-driven with a philosophy that studying single cells at different levels and integrating this information with a view to revealing the mechanisms behind their fate, both in health and in disease.

Shalin currently serves as the Chair and Co Convener for the OZ Single Cell and is a member of the International Organising Committee of the Human Cell Atlas. In 2013, he was awarded the prestigious Young Tall Poppy Award of the Year, which celebrates researchers with notable scientific achievements who communicate well with the wider community. Obviously, that's a really important part of Science Week. He also received the Burnet Prize in 2021, which is awarded to the most pioneering research of the preceding year at WEHI. It's a pretty hard prize to win, so this is really impressive. In addition, Shalin was a highly valued and highly regarded member of the NHMRC Health Research Impact Committee for the 2021 to 2024 triennium I'm really excited to hear about synthetic biology, designer cells and antibodies. So Shalin, bit of pressure on you, but you know, over to you now.

Professor Shalin Naik 5:09
Thanks so much, Steve.

I'd first like to also acknowledge the Traditional Owners of the Lands on which we meet today, the Wurundjeri Lands of the Kulin Nation and pay my respects. I live here, I'm dialling in from home in Abbotsford and the beautiful Yarra River near me. I can only imagine what that must have looked like many hundreds of years ago and thousands of years ago. I'd also like to pay tribute to National Science Week, which is why we're here.

The communication of science is something I'm very passionate about. I'm not going to talk about this today, but you might have seen me on TV shows called Ask the Doctor on ABC, I did a podcast called The Jab Gab during COVID where comedians and scientists met. I think it's really important for us to get very complex science concepts across to the public in a much more simple way where possible without belittling the important work and the important complexity that still underlies that. I think we can do both.

Now, this is the first time I'm giving such a talk. I would not consider myself a synthetic biologist per se, but I guess I'm an aspiring synthetic biologist. Today is my take on what synthetic biology should be and my talk title was around cell and protein design or antibody design. But I've decided I'm going to focus on cells today because synthetic biology is massive and I'm just going to stick to a couple of key concepts today around cell design. I'm going to first share my screen and wait a minute. All right, I hope that is looking OK. Perhaps not. Let's try this. Alright, can someone just tell me if that's looking OK?

Professor Steve Wesselingh 7:24
Perfect. That looks good.

Professor Shalin Naik 7:25
Great. Thank you.

My name is Shalin, like violin, and Naik, like kayak. That's how you pronounce it. I'm at the Immunology Division at the Walter and Eliza Hall Institute, and let's talk about synthetic biology.

What is synthetic biology? Biology is the study of living organisms, and engineering is the design and building of machines and structures. What synthetic biology is the design and building of biological systems and functions and it's a relatively recent development, I would say in the last kind of 20 years. We'll go through a little bit of the timeline, but we're only just getting started. To be honest, in the area of medic, medicine and medical research, we're just scratching the surface.

This is a giant timeline. You're not expected to read all of this, but in this timeline from a review, it covers the history all the way back from here, when evolution and natural selection was proposed by Darwin, Mendelian Heredity. Then fast forward to 1953, the structure of DNA. Now it's hard to believe that just what was that 70 years ago? 70 years ago, we discovered the DNA, and now the things that we're doing with DNA are just amazing. Synthetic biology, at its heart, is really about engineering DNA to encode for certain cells, proteins in cells or proteins on their own to do wonderful things. But it took a long road before we could get here. Sequencing DNA was very important, part of the process that we had to get that right. Initially it was very slow, but we had to find ways to amplify DNA. You must know about polymerase chain reaction, that's how we amplify pieces of DNA.

Fast forward to the 2000 and that's when we started creating genetically engineered machines, these so called ‘GEMS’. We can do genome scale models in bacteria because they're a much easier cell type to work with. it wasn't until the mid-2000s that biology as an engineering discipline here on the top right branched away from biology as a science discipline. That's because it's one thing to learn nature's rules, and it's another thing to use those rules to try and create something new. Biology as a science discipline must continue. It does continue and will always continue as far as I'm concerned, but biology as an engineering discipline is really just entering our kind of consciousness at the moment. For many people, they're well into synthetic biology, but I would say for the majority of us, we haven't quite grasped what it is and what it can do. I hope the purpose of this talk is to try and open the mind about what is possible with synthetic biology.

This is a national synthetic biology road map that was released by CSIRO, and they talk about some numbers around the revenue that can stem from this and the jobs and of course, it's going to be very important for the economy in all sorts of sectors.

What is synthetic biology? It was a term that was coined in 1974 by the geneticist Waclaw Szybalski. Sorry if I butchered that last name. He talked about the standardisation and abstraction of biological components and proposed that they'll unlock the full potential of biological engineering. It's about engineering biological solutions to industrial health and environmental challenges. This is part of the synthetic biology road map from CSIRO. Now you might say, well, isn't synthetic biology, like isn't genetic engineering just synthetic biology? You've synthesised something that doesn't exist in nature. By all means that's true, but we're going beyond just one single trans gene, like a GFP or one single mutation that's creating something or fixing one particular gene to a level of complexity that goes beyond that. I guess it's a bit like considering a toy, a Lego toy car, which just has four wheels and a Lego piece on the top, versus a big elaborate machine that has many different components to it. Now we're basically on on our way to that big complex machine, but we're not there yet because there's a lot of things to consider before we get there.

Now, people in the synthetic biology field often think about it in the concept of the DBTL principles. The D stands for design, which is let's define a function and select some genetic components that we can engineer into bacteria or mammalian cells to impart some function. Then we're going to build it. In order to do that, we have to synthesise DNA from scratch, assemble it, and we have to put it inside the host organism. Then we're going to test, did our design actually work? Did it do what we expected it to do? It may or may not have, but we will certainly learn from that experience. We'll analyse the results, refine it for the next iteration and then redesign. This DBTL life cycle is something that we often consider when we're thinking about synthetic biology principles. As you can imagine, it's a bit like engineering. It's a bit like testing a new contraption you you you've either made at home or it's something as complex as, you know, an iPhone or something like that.

The thing is, SynBio more than ever, more than almost any other discipline really, requires genuine interdisciplinarity. It's the combination of biology, engineering and design, and it can encompass many different things. Now saying synthetic biology, sometimes people roll their eyes because like synthetic biology means everything. Well, yes, it kind of does, but so does molecular biology. Molecular biology can mean many different things. It can mean doing a PCR, it can mean understanding the molecular biology of the cell or everything in between. In that same way, synthetic biology broadly has a definition that it is taking nature's toolbox and creating something new. But it can have many different applications. You can just read for yourself the different disciplines that are required to kind of perform synthetic biology.

There are many applications of synthetic biology in agriculture, in conservation, in manufacturing biofuels, brewing synthetic meat. I just wanted to this has nothing to do with health and medical research, but kind of one of my favourite examples is synthetic meat. We would love to live in a world where you know, we could have guilt-free meat and some of the companies that are doing that for example, is a company Vow Food. As a bit of a PR stunt, what they did was clone the mammoth, the woolly mammoth now extinct woolly mammoth gene because we can get the sequence from sequencing the DNA of the woolly mammoth. They took the myoglobin gene, which is the most abundant protein in muscle cell, and they cloned it into a sheep cell, replaced the sheep myoglobin with woolly mammoth myoglobin and they grew up vats and vats of cell culture, got all those cells, the myoblasts they put them together in the giant meatball that you see in there and they cooked it. Now, they did not eat it because it is not safe to do so and it's it was really just a conversation starter recording according to the company. It even got on Steve Colbert's Late Show and I hear from people who were there that the that the smell was so delicious that they wish they could have eaten it, but obviously they could not. But this is just one aspect where we're creating a guilt-free, now extinct, animal burger. Alright, and I just use that as an example as that's in the food sector, but what could we create in the medical sector equivalent to that? That is going to be really interesting, really useful, but obviously important to keep lots of things in mind when we do that. I'll come back to that later. What I will talk about today is the use of synthetic biology and medical research and medicine. I'm going to use a couple of examples from the field, but also a couple of examples from our lab.

Now within the applications of SynBio and medicine and medical research, they could be used for diagnostics, they could use be used for therapeutics and as I mentioned, those synthetic machines or synthetic designs could be the proteins themselves, could be antibodies, cytokines, or even kind of novel proteins which take the best bits of different protein and put them together or it can be completely AI-generated proteins that have novel functions that we might be that might be useful the human health. But today I'm going to focus on cells. Now cells can be engineered for human health, and they could be engineered in bacteria. People are doing this to try and kind of help our gut microbiome, but also do crazy stuff like send electrical signals from the gut microbiome to your like device and tell you how your how your gut health is doing. You could do that in yeast to, to produce new medicines and you know, kind of synthetic insulin and modified insulin are are prime examples of that. But today I'm going to be talking about mammalian cells.

These are what I call the four R’s of cell design. A version of this has been described by others, but I think of cells as machines that have their own machinery, and we can certainly engineer new machinery into those cells. Let's think about receiving. Maybe a cell can receive a signal and that could be cancer, inflammation, tissue, or it could receive a signal from infection state or cell state, but it could be something else like a pathogen. Maybe it's receiving that signal not through a receptor that exists in nature, but one that we engineer, right? Imagine a receptor that detects a particular strain of COVID, for example, and when it detects that COVID, it sends a signal and then that cell releases a bunch of cytokines that prevent COVID infection or releases a bunch of antibodies that gum up the virus, for example. Or it could detect harmful environmental pathogens, right? Cells don't normally receive signals from environmental pathogens but if you could engineer a receptor to that, why not? The relay of the signal is very important. How do you get that signal from the surface or inside of the cell to a switch that then allows it to do something? There are many synthetic relays signals that people have been created. The most famous of these are synthetic notch signals, so you can attach a receptor to anyone you want and as soon as it binds the the signalling protein goes all the way into the cell and activates a particular circuit.

Once you've activated that switch, what do you want the cell to do? Do you want it to communicate with other cells? Do you want it to migrate to a particular location? Do you want it to be patented in a certain way? Do you want to kill something, express a gene, differentiate into a different cell type, secrete something, remodel the environment? I mean these are all possibilities that either exist in nature that you could borrow, you can cut and paste the module into your new cell type and perform functions that the cell normally did not exhibit. And the last one is record. This is kind of one of my favourite areas. I won't talk about it today, but cell recording is something that doesn't really exist in nature in a very useful way. Of course, we record things in nature like you can have changes to the epigenome. That's a kind of recording. But what I'm talking about is pure synthetic recording. A cell gives us a signal, and then you convert that signal into, let's say, an RNA molecule, which is reverse transcribed into DNA and then is plonked into the locus. If you can keep recording different barcodes of different signals, let's say it's inflammation or environmental sensing or the number of divisions, and you record it in one particular locus of the DNA, or multiple loci of the DNA, you could record the history of the cell. You could link a cell past with its present, so that's something we're particularly excited about, but I won't have time to talk to you about it today.

What kind of signals can you receive? You could have natural or design receptors as I mentioned, against naturally environmental pathogens, environmental antigens, toxins or endogenous molecules. The relay signal that brings the switch, well, it could be a transcriptomic switch induced expression of an RNA. It could be an epigenomic switch. Maybe you want to shut down a particular genomic locus, make it not express a gene, or maybe you want to open it up. Could be proteomic. Maybe the switch is changing the confirmation of a protein from one to the other, which now allows the protein that's otherwise silent to now be active. Or it could be an electrical signal. Maybe it sends an electrical signal either within the body or to a device that you're wearing recording. As I was mentioning, maybe you could record day and night genes or cell cycling genes and if they can get incorporated to the DNA, you have a ticket tape of the cell's history. In terms of responding short, long-range communication, you can induce tissue patterning and you could even interface with a device. This just giving you a flavour of the kinds of aspects of the physiology that we might need to consider.

What are the key activities here? I won't go through each one, but as you can imagine, synthetic biology might harness many different aspects of biology that you're tuning. Of course, inevitably we'll be using some of the DNA editing machinery such as the CRISPR/Cas-9 systems, but also the evolution of the different CRISPR-like enzymes. We might be using machine learning and artificial intelligence to help us predict what the things we need to affect in order to get the response that we want. We might engineer proteins in a particular way, we might create a genetic circuit and you can create logic gates. For example, if a cell sees signal A and signal B, only then can it respond or if it sees signal A and signal C, it should definitely not respond. Things like that. We can create these logic circuits in the DNA. Now the technology exists but still continues to evolve where you can program a cell to do something according to a set of rules.

I'll give you one example of sin biomedical research, and that is one from our lab, and that is to measure clonal heterogeneity. What do I mean by that? Imagine you have a population of stem cells, or a population of cancer cells, or a population of embryo cells. Now when you measure a population and you put 10 cells in a dish or 10 cells in a mouse and you measure what it makes, imagine you generate red, blue and green cells. But you don't actually know clonally what happened. It could be that those 10 cells each made red, green and blue cells. Or it could be that a subset made red, a subset made blue, a subset made green, or it could be various permutations and combinations of this. And unless and until you can track every cell in that population, you will never know. So how can we achieve this? We've been working on barcoding cells for a very long time, and that is to basically introduce a unique synthetic DNA barcode into each of these cells. We traditionally done this using a lentivirus, which is basically a virus. It delivers genetic material, that genetic material integrates into the DNA, but each virus has a different DNA barcode of 100 nucleotides. Then it's when it's inherited to it's daughter cells, the daughter cells also have that same barcode so just like you can track a FedEx package across the country, you can track a clone's fate.

Until now we have to take cells, put a virus on, infect them, culture them and then put them inside. But wouldn't it be great if we could create a barcode inside a cell inside a live host organism so that we're not touching the natural environment? So that's what we did with locks code in-vivo barcoding. Tom Webber pictured there, he's a theoretical physicist turned biologist who came up with this idea. Now I won't go through the mechanics of it thoroughly, but basically, it's 13 DNA barcodes and they're flanked by these sequences called LoxP Sites. And if the LoxP Sites are exposed to a free enzyme, you can basically flip and cut and flip and cut between those triangles you see there in random combinations. Would you believe that just these 13 barcodes give you a theoretical number of barcodes of 30 billion, that can turn into 30 billion different barcodes, which is quite incredible. Now practically it's a bit less than that, but now what you have is single little piece of DNA and when you give it the switch, it kind of shuffles the DNA and creates a barcode and then it's inherited by all of its daughter cells. Now you can measure what every cell did in a host organism without ever having, you know, manipulated that mouse in any significant way. As a result, we have this mouse and we're studying all kinds of novel biology and revealing all sorts of interesting things.

I'll just go through one today, which is the fate of the epiblast. Basically, we create a LoxCode barcoding mouse, don't worry about the details there. But basically, when we create these mice, we have a pregnant mouse in which the embryos are being developed. Now during this phase, there is a stage at about embryo day 5.5 when there's an epiblast. Now an epiblast is basically a ball of cells where we've known that there's some, maybe some bias in those epiblasts, but we haven't really known what they do. For many people, they just consider them pluripotent, meaning every cell in that ball of cells is capable of making every other cell in the tissue in the final organism.

That was a question we had, so we made the barcodes at day five while the embryo was still in the mother. Then at day 12.5, we dissected these embryos, and we dissected them into 40 pieces to basically understand which of those original ball of about 200 cells turned into all of these tissues.

This is the only data slide I'll show you today, but this was the answer. All I want you to take from this is that every column is a different barcode, a different LoxCode, and therefore that LoxCode represents an original embryonic cell. Then if you see a colour, it means it made some of the tissue that you can see in the rows here.

We've got, let me just get my pointer in case that wasn't working. Blood, heart, lung, liver, gut, kidney, gonad, arms, foots, legs, mesoderm, brain, different parts of the brain, forebrain, hind brain, neural tissue in the tail. The bigger the circle, the more of that tissue it generated. What you can see is if every epiblast cell made everything, the whole thing would be covered in colour and dots. But it's not. Actually, when you computationally extract those, we find that there's certain tissues that were already destined. The clones in the epiblast were already destined to make certain categories of tissue types. For example, there was a neurological biassed set of clonal fates already in the epiblast. There's an organ biassed set of clonal fates, a limb biassed set of clonal fates, mesenchymal kind set of fates. Blood. There's a whole bunch of blood-only epiblast cells at that point and also some for the gut as well. We can go beyond just measuring what they do, and Tom Webber was able to then take that data and actually create mathematical simulations. What you're seeing here are at the centre of this kind of radial diagram is a single cell and then it's next layer is when one cell made two cells, and then the two are split into four, and four into eight, sixteen into thirty-two etc. It fans out. Each one of these is a clonal pedigree, it's a model clonal pedigree and the colour are the different cell types it makes. We can model now based on this data, what is the cell-by-cell division trajectory that we can infer from our barcoding data of how an epiblast turn into the many different tissues. Here is a genuinely pluripotent epiblast cell. It made blood, it made brain, and it made these different organs. The colour is reflective of these colours here, but this one is very neurologically biased. It made neurons and neural tube. This is one example of the kinds of things you can do with synthetic biology in medical research and learn something new about nature or a medical question.

But I think probably what we're all aspiring to is how we're going to use synthetic biology in medicine. Let's talk about CAR-T cells. CAR-T cells are the poster child of synthetic biology in medicine. Now, if you're not aware, a T Cell is a type of immune cell, a type of white blood cell that you have that goes around and kills cells. It can kill an infected cell, a pathogen infected cell, but it can also kill a cancer cell. But the issue is that the immune response is designed to educate that T Cell about the thing it needs to kill. For example, the reason you get sick is first you get infected, let's say with a common cold virus, and then affects your cells and you feel terrible and then there are these dendritic cells, which is my favourite cell. They go around and chomp up little bits of infected lung epithelium, and then they go to the lymph nodes and that's why you get sore lymph nodes up here and here and under your armpits and they're educating the T Cells about the identity of the bug and these T Cells. Then if the T Cell recognises the bug, it then proliferates like crazy. Just divides, divides until it makes millions of cells, then it goes out and kills all the infected cells or it helps B Cells make antibodies to clear it. But wouldn't it be great if you could a priori, meaning ahead of time, decide what the T Cell should kill?

A research lab in Pennsylvania in the US came up with this idea of a CAR, a Merrick antigen receptor. Basically, they said, why don't we take a bit that's normally found in an antibody, so an antibody is a type of protein that basically blocks cells. That's what you make when you get your COVID vaccine to block the virus, and we'll take just one little bit of that called a single chain variable fragment. Just take a little bit of that and we'll stick it on the bit that signals into a T Cell, and we'll create this thing called a CAR-T Cell. OK, so now the T Cell, when it encounters the thing that you instructed it to interact with, when it encounters that, it will send a signal for that T Cell to then kill. Now that has revolutionised many the treatment of many different cancers and I'll get to that in a second. But basically, that CAR can be against anything you decided to be. Could be cancer cell, it could be another autoimmune cell, it could be anything you want it to. Now we have a cell that is a programmed killer.

This is Emily Whitehead. She was one of the first patients who received CAR-T Cells and she had acute lymphoblastic leukaemia, and she basically hadn't survived any other therapies, sorry, none of the therapies had worked for her. This CAR-T Cell was the last resort, and it completely cleared her ALL, her acute lymphoblastic leukaemia, and she's still living to this day. That was really the start of a revolution of one type of immunotherapy called CAR-T Cells and if you look them up, you'll see they've just gone massive.

The number of research activities, the number of companies that have formed to try and make better CAR-T Cells for different things is just huge. It's working in a lot of haematological cancers like leukaemia, what not. It's still yet to demonstrate really good efficacy in terms of an approved drug for solid cancers like lung cancer or breast cancer. But hopefully that nut is cracked in time. But the other interesting thing is, well, the lymphoblastic leukaemia is a lymphoid cell like a B Cell. Some researchers said, the other thing that has B Cells that we don't want, is autoimmune disease and so they've now created CAR-T Cells against autoimmune diseases and they're curing in some patients autoimmune diseases like Lupus. That's a really exciting development so watch this space. It's not just cancer, it could also be autoimmune disease.

This is an example from our institute. Tumours are heterogeneous and one of my favourite cells as I mentioned is the dendritic cell, in fact the dendritic cell type 1. That was discovered by Ken Shortman, my PhD supervisor back in 1992 at WEHI. This is a really great Australian story it turns out. Ken Shortman found DC1 in mouse. He was accused of stamp collecting for many years and fast forward 20 years later, they discovered the same cell type in humans, but it had different markers, so they were kind of barking up the wrong tree for a long time. They finally found it and it turns out that this cell is really important in activating T Cells to kill tumours, right through mechanisms I won't go through today. But no one's been able to make them in a dish in sufficient numbers. Our lab has been working on making enough of them in a dish for therapeutic reasons. But what the Steve Nuts lab came up with, Shengbo and Michael Chopin in their lab, came up with the idea of a dendritic cell specific CAR, so the CAR is a bit different to a T Cell. The CAR recognised the cancer, but it sends a different signal, sends a DC activation signal. Now the DC gets activated only when it sees a tumour and when it does that, it activates many different T Cells against all of the different tumour antigens that are inside and leads to enhanced tumour clearance. We're really excited about this particular application and hoping to actually get it to patients, right. This is something where we really think just a bit of creativity, bit of thinking about the problem, about the order of things that need to happen could lead to a really great new therapy.

I guess that leads me to this point I want to make here, which is it's fine to think about design, build, test and learn, but what we really need is imagination. It's one thing to say I can discover new biology and I will find imaginative ways to discover what already exists in nature. It's another thing to say, no, I'm going to create something from scratch. Here's a problem that no one's been able to crack maybe if we brought this together and screened for that and, you know, complemented it with this, we could create something that can go and target that particular problem. If there's only one message, I want to get out today, it is that for me, synthetic biology it's most important to have imagination more than anything else. I think that's a great avenue for people who are imaginative by nature or engineering by nature to come into this discipline.

Let's imagine a couple of things. Where is synthetic biology headed in medicine? Well, it's already in this space but just think about cells that could record the presence of cancer. Like could we have living diagnostics? Yes, we have the CAR-T Cells that go around and kill the cancer cells but one of the big issues we have is, well, when is the cancer coming back? Currently you have to go to the hospital, book yourself in, go onto one of these expensive machines and scan for the cancer and it might get missed. Hopefully it doesn't, but wouldn't it be great if, and I'm not talking about five years from now, maybe this is ten years, twenty years from now, I don't know. But what if we had living diagnostics? What if you've got cells in your body that are sentinels and they're going around looking for cancer, and when they see cancer, they record it inside their cells so that when you take them out in a blood draw, you can measure that they encountered cancer. Or maybe they send a signal to your device that says “hey, something's coming back” then you don't have to go every time to a big expensive machine and, you know, stress out every six months. Maybe you could, you know, just wait for the signal to come through on your watch, right? Just imagine, imagine cells that can monitor inflammation. You have it present in your lung. Let's say you have a particular chronic lung condition, and it can measure the different types of signals that you're getting and that could inform the kind of drug that you need, because inflammation is very complex. If you could decide which types of inflammation there are, maybe you could design better treatments. Maybe you can measure gut health if you've had, I don't know, a couple of weeks on junk food and eating sugary snacks, and your microbes in your gut are releasing some signals and say “oh, your balance is not quite right, redress it.” Maybe you could send something to your watch. Also, living therapeutics. What about cells that you inject that when they encounter nerve damage can be triggered to differentiate into new neurons? Or they could go to a site of scar tissue, dissolve the scarification and regenerate new cells. Or maybe you've got a living pharmacy inside your body that can deliver the multiple drugs that you need so instead of taking a pill every day, maybe have an implant which contains living cells that can produce drugs and basically, when it gets a signal that a certain drug is needed, let's take insulin for example, then it can produce that insulin. Maybe it's a living diagnostic that doesn't need continuous replenishment with a device or an injectable or anything like that. Now, a lot of these seem far fashioned, a bit scary and maybe not safe, but if this is the reality, what let's have that thought experiment, what does it look like to get there? What are the safety concerns? What do we have to do?

This is my little pet now, which is, you know, how are we going to do this? I think we need to think about a new way of doing science and I've kind of come up with this term called CIDER science, which is ‘Collaborative Ideation, Distributed Execution of Research.’ What if we could find ways to bring in the minds of many together? Maybe the idea generators don't have to be the idea executors, right? Because currently in research, we come up with the idea, we get the grant, we get the student, we make things happen in our labs or we collaborate. But what if we could actually think about a different way of doing science? Maybe everyone has a share of the intellectual property, and maybe we'll get clinicians involved from the starts to say, well, if you really want to make this a therapy. Because let's face it, the goal of synthetic biology is to solve problems, not to make discoveries, although we might make some discoveries along the way. And maybe we could find different ways to think about authorship, which is currently something we discuss.

Maybe those grand challenges we bring people together for will say hello if we envision a future of synthetic cells, how do we address them to a specific location in the body? Because we don't want to get them all stuck in the lung and liver, which typically that's where they all get stuck when you inject something. You know, how could we record an event in the cell? How could we trigger a three-step event? First it has to migrate here, it has to turn into cell type 1 and then later when an encounter signal has to turn into cell type 2, right? Do we need some epigenetic switches that are built into our designer cell? How do we kill cancer based on its genotype, meaning the gene sequence, not its phenotype? Could we create patient avatars in vitro that instead of testing on patients, we can test a version of them, a synthetic version of them in a dish, and see if we can predict what might work?

Now, I mentioned it briefly, but really, we have to think about the ethical, legal and societal implications of this. This is new and we want to bring the public along on our journey. We don't want to, you know, be creating these, you know, Frankenstein things without having a good hard look at what the consequences are both internally in our own minds and within our teams, but also to engage society and ask them, you know, what do you think about this? What do you think the dangers are? What are your perceptions on this?

What are the ethics of emerging technologies, the risks and benefits that end users? Do we have equity? Could it be misguided use? Could it harm the ecosystem, health and the environment? How do we feel about our interaction with nature? I mean, we already use genetically modified insulin and we've got Xeno transplants now, but still, this is this is the next iteration of something new and how does it affect public policy? That's a whole other thing that will need to be considered in the future.

The synthetic biology market is going to be huge, that's true. And you know, the US government is really thinking about this as well. This is from a white paper from the US government. They say we need to develop genetic engineering technologies and techniques to be able to write circuitry of cells and predictably programme biology in the same way in which we write software and programme computers. This is the sort of thing that we need to do. Now, we're not really in that space yet, but I think we can get there.

My vision, an Australian Centre for Designer Cells. Now of course you know what that's going to, you know the acronym for that's going to be, and my kind of motto for that is we've learnt the rules of biology, now let's try and break them. There's a couple of disclaimers there. We have certainly not all the rules of biology. There's still a long way to go and basic research should never stop, that is critical. We can break the rules, sure, but we've got to do ethically, equitably, safely, sustainably, responsibly, and legally. I'll just finish on this final quote before I take questions from Richard Feynman. What I cannot create, I do not understand. Maybe we can design what we want and create something and, and then understand how that can be used for medical research and medicine in the future.

Finally, I just want to acknowledge the people who've contributed to some of the data or some of the thinking. First and foremost, to Tom Webber, who's a Senior Post Doc in in the lab and he really is the synthetic biology guru who's been leading the charge on a lot of that in my lab with the help of Matthew and Jesse. But over the years, I've been talking a lot with other kind of key people in this field, Jose Polo, Ryan Lister, Ernst Wolvertang and Christine Wells and Megan Munsie. At WEHI I've been talking a lot with Ethan Goddard Borger, WaiHong Tham and Melissa Call on some of these concepts and ideas. With that, happy to take any questions.

Professor Steve Wesselingh 44:04
Thanks so much. That was incredibly inspiring and such a great talk for Science Week because you're looking at the horizon really. That is so exciting the horizon scanning, but you know, we obviously at NHMRC do quite a lot of horizon scanning as well. Synthetic biology obviously is up there in lights, but so is AI, artificial intelligence. I guess I wasn't aware of the intersection so much of the two. Just interested, maybe my first question, I've got some questions on the chat and I'm happy for other people to put questions up there. But just interested in your view of the intersection between AI and synthetic biology because they really are the two bright lights on the horizon, aren't they?

Professor Shalin Naik 44:54
Absolutely and they absolutely intersect. I think we're only scratching the surface of what it could look like, but I'll just give a couple of examples.
Protein design, you might have heard of AlphaFold, which is the way you can plug in the sequence of a protein and now it can predict its structure in ways that traditionally you would have needed to employ crystallography and go to the synchrotron and get the crystal structure. Nowadays you can plug it into AlphaFold and get a pretty good idea. Doesn't solve all structures, doesn't solve for all proteins, but it has a good idea. But now what other people are doing is hallucinating proteins. It's called protein hallucination. You can basically engineer the AI algorithm to say, “I want you to be able to,” I'm just going to make up an example: here's an RNA of a particular sequence and I want you to cut it at this specific location. The software, that's what people are striving towards, is to get software to find a protein that binds that RNA and when it binds it changes the confirmation and then cuts the RNA. That's just one example. 
There are other things called synthekines, which are hybrid cytokines that allow you to bind different receptors and signal in different ways to the nature's toolbox.

Or you might consider the use of AI to say look, here are the gene expression patterns we see in our big single cell data set for example. Can you highlight to me what you think are the key nodes that are controlling particular subsets? And it might give out a prediction, and then you can synthesise circuits to target just those. Now again, with this DBTL process, you would try it out, see if it works and what kind of works, let's go back to the drawing board, what have we learnt and try again, and again and kind of emerge something there. But I think absolutely, AI is going to be revolutionary in the protein design that will be incorporated into these cells, or to figure out which gene expression patterns we need to shut down or turn on, as well as many other aspects.

Professor Steve Wesselingh 47:03
Fantastic. Ruth, online, wants to know why the mammoth meatballs aren't safe? Just to inform you, Ian online said we might grow hair all over our bodies.

Professor Shalin Naik 47:14
This is entirely true. Who knows?

No, so from what I understand and again, I was not involved in this, from what I understand, it was very much not generated under good food proprietary conditions. Also, the safety of eating mammoth myoglobin and sticking it into another gene is just you know, I personally don't think it's going to be unsafe, but certainly there are questions around this. But I think from what I gather, the point was it was a conversation starter more than anything that we can go. However, Vow Foods, to my understanding, have released a product that they're selling in Singapore that you can buy now and eat. But it is not mammoth, it's species that exist here on Earth. But I think all of the stem cells were derived from living animals. Ethically there were no animals that were harmed in the production of that product is from what I understand.

Professor Steve Wesselingh 48:14
There's a couple of questions from Bob. One, I'll paraphrase a little bit, and I'm sure you'd agree with this, developing treatments, should we actually be concentrating on developing preventions? But I think you alluded to that, but interested in your comment on that and in fact, I think you indicated that prevention might be the way to go.

Professor Shalin Naik 48:34
Yeah, absolutely. Here's the thing, right? Human nature is hard to change. I like a burger, I like a chocolate, but I know it's not necessarily good for me in high quantities. But what could I have as an adjunct there? Maybe the prevention could be the prevention before and worryingly, the incidence of colorectal cancer is on the rise amongst young people, 25- to 40-year-olds. The stats I've seen are quite worrying. Perhaps that's somewhere where we can understand, well, could we either prevent these cancers from generating in the first process if we understand what are the causes of the mutagenic events? Could we prevent it in that way by maybe suppressing signalling or suppressing DNA damage or whatever the case may be? That's one particular example. Or maybe we can prevent infection through environmental sensors in our bodies. But there's all sorts of ways you could consider to prevent disease using synthetic biology rather than just treating it.

Professor Steve Wesselingh 49:44
The next question from Bob was about in vitro hematogenesis and the proposal to make human eggs and sperm from ordinary skin and blood cells, and do you have concerns about that?

Professor Shalin Naik 50:01
I don't know enough about that so I will take that question on notice. That's not something I'd be easily answer in this format.

Professor Steve Wesselingh 50:12
Right. Then there's some questions about, which all allude to the same thing, and I totally get it. Are our research ethics committees able to keep up?

Professor Shalin Naik 50:24
Well, we've seen this a lot, haven't we in history? We've seen this with genomic sequencing. We've seen this with genetic engineering itself. Right now, there's a moratorium on creating any permanent, sorry lineage, permanent genetic modifications in the sperm and eggs. But you can do it somatically, meaning in cells that will be there while you live and when you die, they'll die with you. Certainly, it's going to be challenging, I have no doubt but that's something that we absolutely need to be conscious of, aware of, and plan for because as you know, research progresses, and the policies will have to be created de novo in many cases. There's a famous case of Jose Polo at Monash University who created the iBlastoid. He's like “look we did these experiments, we terminated them when they're considered problematic in the current legal frameworks. But what do we do now?” That's currently being examined and considered, and the research is on pause until that time from what I gather. It's going to be challenging, but I think we're up to the task.

Professor Steve Wesselingh 51:41
Yeah and just for everyone else, obviously NHMRC is intimately involved in that and particularly in the iBlastoid one with our Embryo Licensing Committee. It has to be hand in hand really. We've got to develop and ask those questions and that's why it's so important for NHMRC and for our committees to be totally aware of what's happening around the country with talks like this, which is just brilliant. 
The other thing I really liked was the device interface concept. I think the people at NHMRC know that I'm a bit of an Apple junkie. But interfacing with your Apple Watch or interfacing with an Apple Vision Pro, particularly in someone say with ALS or something like that where they've lost movement to perhaps everything except their eyes or something, you know, do you see opportunities there?

Professor Shalin Naik 52:35
Yeah, I think there are massive opportunities that we've made really great strides in medical devices and miniaturisation and whatnot. The interface and typically those sensors are detecting metabolites or soluble molecules and sending a signal.

I think the big challenge is going to be what does device interface look like with living cells or measuring other modalities. Like can you measure fragments of DNA and sequence them in situ, right? Could you measure circulating tumour DNA and sequence it while it's already on your watch? I don't think that's out of the realms of possibility because you might know there's this company called Oxford and Nanopore where they've got this MinION, they call it, it's a little sequencer you just plug into USB, you add DNA, and it sequences DNA. Well, if you've got that, could we sequence our DNA in situ, circulating tumour cells, or could we sequence the DNA of a microbiome and understand the composition? That could be very interesting. Could we have cell sensors? Because cells are exquisite sensors, they can detect a single molecule of something and then amplify that signal. Why aren't we harnessing a cell as a way to amplify that signal? But maybe that cell is in its own cartridge. It's living independently of your body, so there's no safety risk, but it's interfacing with your bloodstream through a permeable membrane. Could that be a thing? I don't know.

Professor Steve Wesselingh 54:06
Fantastic. We're running out of time here. But I think it all goes to one of your slides, which is about imagination, doesn't it? It's just brilliant. I might just ask you one final question and I suspect it's going to be about imagination but what's the one piece of advice that you would give to an early or mid-career researcher, or to a year 12 student or a PhD student?

Professor Shalin Naik 54:36
There's a couple of things. Number one, learn computer science, I mean, that's compulsory now I think everywhere. Learn computer science, keep up with the latest algorithms, technology and get that under your belt. Even if it's not your forte, just force yourself to get into it because it's going to be everywhere. 
Number two, learn fundamental biological principles and be curious. Be curious about how nature works, how it interacts with each other. 
Third, think about engineering. If we're talking about synthetic biology, think about engineering principles, and perhaps do a degree which incorporates multiple disciplines and don't necessarily go do a synthetic biology degree. I'm sure there's going to be an emerging number of synthetic biology degrees and I hope they're all really good, but you don't have to do a synthetic biology degree. Go and read about engineering, how iPhones are made, how TV's are made, how bridges are made, but also do an art class right? You might get inspiration from art that you can incorporate in your science.

The last one is imagination. Like try and think outside the box. Nature's given us a set of rules, but we don't have to adhere to them.

Professor Steve Wesselingh 55:51
Fantastic. As I said before, I think this has been such a brilliant talk for Science Week and the horizon scanning that you've provided, showing us the things we need to think about, things we need to think about in our own committees, actually. But as well for everyone else who's been on and listening. 
Thank you so much for being part of our celebration for National Science Week and you're now one of the alumni of Speaking of Science and if you look at those alumni, it's a pretty impressive alumni. Congratulations. But you know, I enjoyed it and I think everyone else would have enjoyed it so much.

We really want to emphasise to everyone that this was recorded and will be on the web. I think science students, medical students and researchers around the country should all be having a look at this because a lot of the future of science is here in this talk.

Thank you very much and thank you to everyone who came online and particularly thank you for those who put up questions, which we were able to give to Shalin. Thank you very much. There's lots of thanks appearing in the chat and lots of claps. Really such a great session. Thank you very much. Thanks everyone. See you next time.

Professor Shalin Naik 57:11
Thanks everyone for joining us. See you later.
 

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