Carmen
In this episode, we speak with JJ, who is a biomedical engineer working in tissue engineering and regenerative medicine. In the discussion, she explains what stem cells are, and how they can be used in biomedical engineering.

Hi JJ. Welcome to the show. Let’s start by answering the question, what is a stem cell?

I guess for a non biotech or biomed audience, would you say that a simple analogy would be a stem cell is like a child going through school, they’re open to any option, and they can specialize in anything? So as they mature, they specialize in a particular path?

JJ
Yes, that’s exactly spot on. And actually, I always show a cartoon to my students when I talk about stem cells. And it’s basically like picturing a dish with some cells inside it. And the cartoon was called Parental Advice for Stem Cells – You Can Be Anything You Want When You Grow Up. And the two defining characteristics of stem cells is one, that they have differentiation capacity. So what that means is that stem cells are not specialized. They’re just stem cells. They have the ability to become more specialized cells, like a parent cell, or cartilage cell or fat cell. So what we mean by differentiation capacity is that the stem cell is able to differentiate into a more specialized cell type. And that is one of the defining characteristics.

The second defining characteristic is that they have self renewal capacity. So what that means is that they’re able to make more copies of themselves, as well. So you can imagine when you’re trying to repair an organ, or tissue using your stem cells, which your body does naturally, anyway. When you have stem cells coming out of your bone marrow or going to an injured area of bone, you don’t want all the stem cells to come out from your bone marrow, and then there’s nothing left in the bone marrow, right? Because, you know, once the stem cells come out and do the repairing, they’re not going to go back to the bone marrow. So this self renewal capacity really means that those stem cells can split themselves, and they have a copy retained, where they originally are from, and then others must go out and do their thing. So they’re able to make more copies of themselves, basically.

Carmen
Can you tell us more about why stem cells are great to use in your work?

JJ
Stem cells respond to their surroundings, and that’s one of the main reasons why we use them for therapeutic purposes, because we can condition their environment, and they will do different things, depending on the information that they get from the environment. And they build different things around themselves. So it’s almost like, you get signals from your environment, and then you build a house around yourself, and then you build parts of the house, depending on your lives, but it’s also conditioned to the environment you live in, for instance, is that like a cold place or is that like in the middle of a grass field or something, or in the mountain.

Carmen
That was gonna be my question.

JJ
In a house it is going to be different. Yeah. So that’s essentially what a stem cell does. So in research, we also use things like, although I don’t personally, but things like embryonic stem cells. So these are isolated from discarded IVF embryos. And they can be used for scientific research. And there are ethical issues with using them in a clinical sense. But nevertheless, there is a very good reason for using them. And that’s because adult stem cells have a limited ability to become all cell types of the body. So they’re very good at becoming bone, cartilage, and fat and maybe muscle. But when you’re talking about the heart, the kidney, the brain, these MSCs are not extremely useful, because they’re not biologically programmed to do so.

Whereas you can do that with embryonic stem cells, because they have a higher level of potency, because they’re able to become a wider range of tissues. But again, there’s problems with that, because there’s ethical issues, and also the fact that, because the embryonic stem cells are taken from somebody else, like that could be another person, then you still get this problem where you would have done a rejection. Because if you take someone else’s cells and put them into yourself, then you’re going to reject those cells. So that was the main problem behind the years. And then now there’s been new developments, which I probably won’t go into now, because of the interest of time unless you’re really interested. But we are now able to artificially engineer stem cells that have the same ability as embryonic stem cells to become all cell types of the body, but then that can be derived from the patient themselves. And that’s really exciting. And these cells are called Induced Pluripotent Stem Cells. And if you’re interested, definitely go and have a look. There’s heaps of information about it, but it’s a fascinating discovery. And the scientists who originally came up with this idea and published their research were awarded Nobel Prizes recently.

Carmen
How do you use stem cells and bioactive components to develop new therapies?

JJ
So I work a lot with stem cells now. I didn’t used to. I’m a biomedical engineer. So in my PhD, I actually did a lot on developing new bioactive materials to regrow bone and cartilage. And that was really interesting in itself because it had a lot of principles of engineering design and problem solving. My work now still involves problem solving. That is more so like, I design experiments now to test specific things. And now I work, I moved into a more biological focus in my current research. And that was because in my postdoc, I joined a lab that focused on a disease called osteoarthritis, which is a degenerative condition of the joints that I think a lot of us will be familiar with. Our parents have it, my parents have it, even some of my younger peers have it. And it definitely doesn’t just affect old people where your joints become really painful, especially your knees and hips are the most common ones, and you have trouble walking. And in the end, it’s just pain management. And at the very end, you just replace your joint altogether and go through a surgery, which is definitely not optimal. So my supervisor at the time was focusing on this disease, but also investigating the pathophysiology of it. And I went into the lab and I wanted to establish a new research direction. So I took my engineering kind of approach and said, “what can we do to develop a better therapeutic that is not currently being explored for this disease?”. And I looked into stem cells, because stem cells have been tried in a range of studies, both in preclinical and also some clinical studies. And I would say that so far the results are inconsistent. So I wanted to understand why that was. And that sort of prompted my research into stem cells.

The stem cells that I use are sourced from the adult human body, so we harbor it in our body. And they can be found in places like the bone marrow, in your fat tissue, like your fat around your body. So you can get it from a liposuction, or from umbilical cords, or people who give birth and discard the umbilical cord that can be used to isolate these stem cells. They’re called Mesenchymal Stem Cells, or we call them MSCs for short, like just the abbreviation of the term. And these cells, I guess, are the most common ones that we use from a therapeutic perspective, and there’s a variety of different ways to use them. The most common ones, just very briefly, obviously, in tissue repair and regeneration, we can use them to, in my space using MSCs, to regrow cartilage and bone and joint tissues and fat reconstruction, for breast reconstruction, for instance, growing spatial muscle fibers. Yeah, so tissue regeneration is a main one.

They also have amazing properties whereby they secrete bioactive factors and signaling molecules. So they can produce biological signals that reduce inflammation and increase their repair. And that is I would say, one of the main reasons why they’re used in a therapeutic sense, even in like people with heart attacks to help the heart regrow, to help the heart itself regrow, rather than doing the regrowing themselves, if that makes sense, from the biological factors they secrete. And you can also engineer stem cells to deliver specific bioactive factors to target areas. And of course, you can generate human models in the lab using the stem cells. So for instance, I can grow a mini piece of bone using MSCs in the lab and use that to test drugs for bone diseases, for example. And of course, there’s some fascinating and outside the square thinking use of stem cells, like MSCs can be used to grow bone cartilage, fat, and muscle and whatever not. So we could use them to grow an artificial hand robot and reduce the reliance on animal products. And that’s definitely a booming field. And I expect to see more coming out of that in the future years.

Carmen
What are extracellular vesicles? And how are they used?

JJ
So these vesicles are tiny. So by tiny, I mean they’re nanometer sized. So we have centimeters, which is usually the things that we work with. Not work with, but like the things that we see everyday like cups or whatever, they are centimeter size, and then you go down to millimeter size, which is quite very, very small now. So we’re talking about, like, the thickness of a fingernail or something like that. And then going down even further is micrometers. So that’s 1000 times less than the millimeters, and then down 1000 times more from that is nanometers, and that is approximately if you have any idea of viruses. They’re really small viral particles that is on the size of nanometers. So we’re talking about vesicles that are produced, that are almost like envelopes of information produced by all cell types, including stem cells. And their biological information is captured in these vesicles, which are on the nanometer size. So they’re anywhere from maybe 30 nanometers to a few 100 nanometers. And they carry a lot of different signals. And they’re not the only means of communication by the cell to their surroundings, but they’re a primary method of communication between cells. And they capture lots of different things like nucleic acids. So by that we mean messenger RNAs, DNAs and microRNAs and whatever not. So that’s a major part of signaling. There’s also proteins, there’s enzymes, there’s lipids. So that’s what I mean by bioactive factors, or signaling molecules, which is really a combination of the signals that the cells are outputting, in terms of things from the RNA and DNA level all the way to proteins, and lipids and enzymes. And all of this information is packaged together, and delivered to the cell surroundings as a form of communication, like molecular letters, that the cell writes to the cells around it to communicate about how it’s going. And the significance of this is really, for instance, if you have an organ that is injured, because of whatever reason, the cells within that organ can produce these vesicles and with a signal sort of package saying, “oh, I need help, I am dying here. Can you send help?”. And then for instance, stem cells in the surrounding or from other areas of the body can be recruited there because they respond to these signals and then come to these places, or they produce similar vesicles. And that contains other signals that will help the cells there repair. And that is the great thing about stem cells that I didn’t really touch on before, especially Mesenchymal Stem Cells like MSCs and the main reason why people use this a lot. And the reason why I looked into it in the first place was because they naturally produce signals that can reduce inflammation in your organs and tissues, and also encourage them to self repair, and also encourage new blood vessels to form to deliver new nutritious factors. So that’s a great thing about them. And that’s why it’s really worthwhile looking into the sorts of signals delivered by stem cells and how we can manipulate that, to better help tissues and organs repair.

Carmen
It sounds like they’re really adaptable, almost like plasticine. You can adapt them to whatever need you have at the time. And that gives you a lot of flexibility in your work.

JJ
Definitely. So like again, going back to how well stem cells respond to the environment, MSCs are very responsive to the environment. So that includes the biochemical environment. So that’s like adjusting the concentration of chemical factors within the environment, like various molecules, like DNAs, RNAs and proteins that can help them output different functions. And also if you grow the MSCs on surfaces that have different stiffness or imagine if you put them on soft bed as opposed to hard bed, they respond differently as well. And using a combination of these ways to manipulate the behavior of stem cells, they can output different combinations of bioactive signaling molecules that can serve different purposes.

Carmen
So really, you’re creating an environment that says, “I need you to be really firm in your new environment. And I’m setting the pace now so that you’ll be at home when you go to the new place that I put you in?”

JJ
Kind of yes and no. What I try to do now is not to use the stem cells themselves as a therapeutic, because that is the more established approach, but the results are quite inconsistent again, as I said, for various reasons. So in the specific area of osteoarthritis that I work in, the environment is a chronically diseased environment. So it’s a disease that has been happening for a very long time. And I guess the main hallmark of osteoarthritis is that the cartilage gets damaged. And that makes the bone rub on bone. And that’s why it becomes really painful. And the earlier approaches to repairing this was to put a beautiful new piece of cartilage inside and sort of go, “Oh, we’ve repaired the cartilage”, which won’t work because the body will attack that new piece of cartilage and make it degrade again. So addressing the environment is really important. And my findings have actually shown that in the laboratory where you’re using cells interacting with each other and looking at those interactions, to say that if you put stem cells into, because they respond to the environment. If you put them into a diseased environment, over the long term they also respond to this diseased environment and take on diseased characteristics too. And that could be one of the reasons at least, why our long term results using stem cells have not given rise to consistent benefits. And so my approach now, I guess, which is developing a new frontier among similar approaches in this particular field, is to use, for example, manipulate the stem cells so that they produce vesicles like these nanoscale vesicles I was talking about where the biological signals are captured within these vesicles. And we use these vesicles as a therapeutic rather than the cells themselves.

Carmen
Very interesting. And thank you for explaining how that’s changed over time, because I think stem cells made their debut a while back, and we had a basic understanding of how it could be used in therapeutics. So it’s really good to understand how that technology has changed over time.

If I can ask you to explain vesicles in a little bit more detail, I’ll tell you what I think I understand from what you explain, and you can correct me where it needs correction. So vesicles are these envelopes that have different pieces of information. I wanted to understand if they have a combination of lots of different things, so DNA, proteins, enzymes all in one vesicle, or if they have to have discrete individual pieces of information per vesicle?

JJ
So the combination, I would say, and all the vesicles that are produced at a certain time period by the same cell will contain a range of all of these factors. And they may have a bit of variation in the molecular contents. But nevertheless, I think the general trend is the same. And I think the field will struggle to answer your question because I have to say this field of extracellular vesicles, we call them EVs, or extracellular means out of the cell. So, vesicles that came out of the cell. That’s why they’re called extracellular vesicles. So the field of EVs has only really just evolved in the last 3 to 5 years. People have been studying them for maybe like the last two decades when the concept first came across, but at that time, they were not called EVs, they were called something else. And then it was mainly studied in the past as a diseased biomarker or cells. Diseased cells and cancerous cells will produce these EVs and people started looking into these really tiny vesicles, and saw that these vesicles contained some molecular information that sort of points to the parent cell being a disease, so maybe we can use that to diagnose cancer. So that’s where it sort of really originated. And later on, people were like, “oh, stem cells produce these too” or “other cell types do this too, maybe we can use them as therapeutics”. And so I will say the field of looking into using stem cell derived vesicles as a therapeutic, which has really only just evolved in the last 3 to 5 years and methods of standardization in terms of standardizing how to isolate these vesicles, how to characterize them, how to apply them to downstream therapeutic purposes, I would say the standardization is still in progress. And there’s an International Society of Extracellular Vesicles that is leading the frontier for the standardization processes. Also the potential of applying them clinically later on. So what I’m trying to say is this is a really new field and a lot of the things that we know today are changing by the minute, and what I’m telling you now, it’s just based on our knowledge in the last couple of years about this. But what we do understand is yes, as you said, so it will be each vesicle has a collection of different molecular species. So by that we mean like DNA, RNA, proteins, whatever. But what’s really interesting as well, and that was not possible a couple of years ago is that we now have not, I’m not using them personally, but people are developing advanced analysis methods to be able to analyze not only single cells, but also single vesicles on the nanoscale level. So we take a single nanoscale vesicle and we can analyze the contents of that vesicle now using specialized and very highly technical and vast facilities, which very few research labs have access to around the world but definitely an area of very intense interest.

Carmen
Really amazing and thank you for explaining how research works in that. You know information that’s far and that might change as more information comes to light. I think that’s an important thing for people to understand. Because I know there’s a question sometimes in the public, “Why do scientists say this is what we know right now and it will change?”. So thank you for that.

JJ
It is a really important point because I think growing up, I always felt whatever is written down in a textbook is the way that it is, right? That’s just the way it is. And that’s what we know. And it won’t change. That is not true. A stem cell textbook now that you look at is going to be very different to what it was when I went to school and learned during my undergrad. And I think that’s an amazing thing about science that we’re learning such new things every day, because it’s the researchers that are doing the research at the forefront of these different fields that is writing our textbooks on this knowledge that then gets passed down to the next generation. And I didn’t realize what important role that we play in this process. I thought it was just all there someone had written and that’s just the way it is. That’s not really the case. We are actually at the forefront, verifying these principles. And we’re building on new knowledge and some of that new knowledge. And I hope, even with my personal research about the mechanisms of how these vesicles interact with themselves, and vice versa, in the future, maybe I’ll contribute to maybe even just a paragraph in the stem cell textbook. And that will be like my life achievement.

Carmen
So thank you for that explanation about how vesicles work. So my understanding now is that it’s more than just a letter that’s going from cell to cell. It’s maybe a portfolio of information or a project brief, Excel 1 and Excel 2. I need you to execute top points, 1 to 5 in this manner. Would that be fair to say?

JJ
Yeah, that’s actually a really nice real life kind of analogy to what they’re doing. I would say that’s very well captured.

Carmen
Okay, good. What is tissue engineering? We know that civil, mechanical, electronic engineering. So how does tissue engineering define?

JJ
So tissue engineering is amazing. And I would say this, because I would say it’s the most multidisciplinary field in engineering and I wouldn’t even classify it as engineering completely. I would say it bridges among engineering, science and medicine. And that is unique to tissue engineering and probably biomedical engineering in general. So tissue engineering belongs under biomedical engineering, under the branches of engineering. And biomedical engineering sort of evolved as a medium between engineering and the life sciences, or the medical sciences. And tissue engineering evolved from that now, as a separate sort of, I guess, specialization area in biomedical engineering. So the idea is to use engineering principles, but it’s really a marriage between biology and engineering, and a lot more. And the fundamental idea is to use various methods, including some of the ones you mentioned, like materials, and bioactive factors and manufacturing technologies, and whatever not, but to use a variety of techniques that are across engineering, science and medicine, really, to build new tissues. So we are trying to regrow organs and tissues and body parts, instead of fixing a problem through things like drugs and artificial implants. So to give an idea, I suppose. So say, if you have a fracture, or missing piece of bone, and is causing you a lot of problems. So the traditional way of treating is to give you drugs that might relieve your pain, and to give you like, metal screws and plates and implants to put into your body, which lasts there for a while, and partly replaces the functions of the tissue but not completely and definitely is nowhere near the native anatomy of the tissue that is missing. And for tissue engineering, our idea is to use some sort of method to regrow the bone that you’re missing, so that you get your own bones back and you don’t have that long term problem or what if this implant fails and or this implant is not really part of my body. So that is the fundamental idea of tissue engineering. And it assays multidisciplinary, because even just off the top of my head, it includes things like cell biology, material science, molecular biology, nanotechnology, computer science, biomechanics, biomanufacturing, and a lot more. It’s sort of like anything you can think of in STEM probably has a role to play in tissue engineering.

Carmen
What is the difference between regenerative medicine and tissue engineering? You had a point when we talked previously about the difference between regenerative medicine and tissue engineering. Could you touch on that a little bit?

JJ
So I would say in the field, a lot of people use these terms interchangeably, so tissue engineering and regenerative medicine. So it seems like they capture the same thing. And usually one does not go without the other. But I think there are still in my understanding some differences between the two. I would say, having worked in both fields, I worked in tissue engineering, which is to rebuild organs and body parts using various techniques. For instance, I developed new bioactive materials to help regrow cartilage and bone, and that is definitely tissue engineering. I will say what I’m doing now is more regenerative medicine. So that would include understanding the biological interactions driving biological processes, as well as using that knowledge to better repair and regrow tissues. So you know, all this stuff that I was doing about investigating the interactions between diseased cells and stem cells that will count as regenerative medicine, but not really tissue engineering as such, because we’re not rebuilding new things. And also, people, for instance, are working in what’s called developmental biology. So understanding how limbs grow, understanding how a cell goes from a stem cell to a bone cell. So for instance, it would be classified as, in my understanding would be, regenerative medicine, but maybe not tissue engineering as such, because we haven’t really rebuilt any organs and tissues. But we’re understanding the fundamental biological processes associated with that. And I guess that’s why it’s called medicine. And it’s sort of looking at it in the regenerative light, but maybe not necessarily undertaking the specific processes to regrow that organ or tissue just as yet.

Carmen
I think that makes a lot of sense. So, tissue engineering is to build, to engineer something, and regenerative is to regrow from the existing materials, or the existing sites, not just place something new, where there’s damage or some problem arising. Is that fair to say?

JJ
Yeah, I think so. That captures most of it. But also, I guess, regenerative medicine could be about fundamental biological processes as well. So understanding how an embryo grows from an embryo to an actual person, how your limbs grow in terms of how do you grow your hands, like it’s a lot of different tissues. You’ve got skin, you’ve got bone, you’ve got muscles, you’ve got nerves, and you’ve got blood vessels, and all this stuff, like how does all that come together? And that fundamental understanding is critical to us being tissue engineers to be able to use that knowledge and then apply it to growing tissues. But that is not tissue engineering, really, in itself to my understanding, but regenerative medicine encompasses all of that, like building up all this biological knowledge, as well.

Carmen
It’s understanding how an embryo grows, for example. Are there elements of developmental biology in that as well, or are they so intertwined, it’s hard to differentiate them at that fundamental level?

JJ
I think developmental biology definitely has a role to play. So like we said, this goes back to what actually makes an engineer. I would say the engineers are the ones that solve people’s problems. And that is not what a scientist does. And that is not what a medical specialist does. And I pride myself in being an engineer because I solve people’s problems. And as a biomedical engineer, I solve problems relating to human health and disease. So I think the fundamental thing about engineering is that we are not necessarily inventing, like we’re not necessarily gaining new knowledge, although we are when we develop new techniques, but we’re really sort of applying the knowledge that science and medicine has built up to apply that to solving problems, and in this case, is building new tissues and organs. Whereas regenerative medicine could be much broader. So it also encompasses the knowledge gain that needs to happen for us to be able to regenerate and regrow tissues and organs. So it includes the whole pipeline of the process.

Carmen
That makes a lot of sense. Thank you for explaining that. And I guess, for people who work in different countries and in different areas of science, maybe even different fields, or just explain that in different areas, you might call someone a scientist, and in another field, they might be a technician or a researcher. And sometimes the titles are used interchangeably, but scientists, research assistants, technicians, they might also be working to problem solving. But in biomedical engineering, specifically, an engineer is set up to solve a problem.

JJ
And it’s such a multidisciplinary field. I’m not saying that biomedical engineering requires the input of engineers or scientists or medical specialists or technicians or mathematicians, and people who work with animals, for instance, because we need to do some animal testing, and so many different aspects. Even people from law or business and industry, because we need people to help us translate our discoveries, translate as in bring them actually to patients to benefit patient’s wellbeing and health care. So it is really a very multidisciplinary field. And we need input from all these multidisciplinary areas to be able to bring a product forward to the clinic.

Carmen
So in other words, anyone can be a problem solver if they have the right question, and they have the right team and multidisciplinary is the way to go?

JJ
Yes, definitely.

Carmen
Okay, great. Can the public support researchers, scientists, and engineers?

JJ
Sure. First, I really like to say a big thank you for this opportunity to get some of this information out to the public, for people who might be interested. And this is something that I’m really passionate about, and that is close to my heart. And you say what can we do. And I say we, I mean as both a researcher and a member of the scientific and public community. And I think it’s a great first step, at least for our general audience to be engaged in science, in STEM in general, because I think that’s an important first step to have belief in science and to have the curiosity to know more, and to understand how the field operates, and what the scientists, technologists, engineers, researchers, medical specialists, and mathematicians are actually doing to create these life transforming technologies for our society. And that’s really important. And that goes into some of the problems that we’ve had, for instance, with vaccine hesitancy, and they could be very well educated and informed people. They could be very sensitive people. I’ve seen a post on Twitter about it because of the misinformation that is around about this kind of just…people not knowing and understanding enough and not believing in what STEM can do. And I think that is a fundamental problem that may need to be addressed before we can push forward some of these technological advances to actually make the changes in society. So I really hope that. So I’m really grateful for opportunities like this, to be able to be a part of the driving force for getting good science communication out there for people to engage with science, debate science, learn science, and potentially also contribute to it, even if not at the forefront of being a researcher actually making these discoveries. But for instance, promoting a diverse representation of STEM professionals in the media, believing in, for instance, people who may not naturally come across as being a STEM authority, like those who might be women, those who might have weird colored hair, those who may have disabilities, those who may not have English as their first language. Those traits do not define the quality of the science that you’re doing. And I think there needs to be more diverse representation of STEM professionals going out to the public and going to the media and to have public trust in these people and in the science that they do, and hopefully also increase funding support as well, different sorts of funds, for instance, cancer funds, or for specific diseases. A lot of it is funded through philanthropy and that could make a real difference in whether a new therapy gets developed or not. And also just, I guess, increase the port for outreach activities to schools and the general public. And also to have the public actively participate in these activities is great for educating the next generation and getting kids interested in STEM, and that’s something that I’m really passionate about. And I try and take as many of these school visits, opportunities and public science presentation opportunities, as much as possible to try and encourage that.

So I guess on a closing note, I would say that, I really wish that in our next generation because of the efforts by researchers like us and with other STEM professionals, to have a really diverse representation of what an engineer, scientist and medical researcher could look like, and to have belief in our work, and what we can do to transform society and so that our children’s generation can grow up taking for granted that STEM professionals can come in all different shapes and sizes, and they can picture themselves, whoever they may be, as the next ones to make these breakthrough advances in science, engineering, medicine, technology and beyond, to transform our society and to become the next generation of the STEM workforce.

Carmen
Thank you so much, JJ.

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