• Anastasiya

Cellular Science and Healthy Aging with Stephen Minger

Updated: Dec 18, 2018

Today we are talking to Dr Stephen Minger, former Chief Scientist for Cellular Sciences for GE Healthcare. He has been at the forefront of human stem cell research for the past 20 years, and today he is talking to us about some of the applications of cellular science towards providing healthy aging and increasing longevity.


Please find below a link to our podcast. Alternatively, a transcript is provided further down.


https://soundcloud.com/user-419965201/cellular-science-and-healthy-aging-with-stephen-minger-v1/s-2u8Zh




0:00 Anastasiya

Hey everyone we're pleased to welcome you our listeners to the first podcast of Aikora health. We are a company that brings together scientists, entrepreneurs and investors who are involved in the longevity space and are interested in the overlapping themes of longevity, anti aging and life extension. We are starting by hosting an intimate dinner, with an expert in the longevity space and a curated audience which will take place in London soon. So if you'd like to stay tuned for more information please sign up to our newsletter. I am Anastasia and I'm here with my co-founder Sion. I have personally been involved in the technology space for several years working with tech startups and I’m currently working in the blockchain space. I've been very fascinated by the healthcare industry and it's intersection with tech and my personal interest is in innovations in the longevity space.

1:00 Sion

Hi, I am Sion. I am a data scientist working for the NHS which is the UK's national health service. I am passionate about the latest developments in longevity research, and help us all to live healthier for longer. So welcome to our first podcast. Today we're really excited to welcome Dr Stephen Minger, who is a scientific advisor for Aikora health. Stephen received his PhD in pathology in 1992, and after post-doctoral work in central nervous system gene therapy, neural transplantation and neural stem biology, he moved to the UK in 1996 and was appointed a lecturer in biomolecular Sciences at Kings College London. Over the past 20 years he has been at the forefront of human stem cell research, and has been awarded various licences by the UK Human fertilisation and embryology authority. More recently he was the chief Scientist for cellular Sciences at GE Healthcare, and was responsible for long-term global research strategy in regenerative medicine. He is now a consultant for various organisations in Europe and the USA. So Stephen we are glad that you can make it today.

2:38 Stephen

yep thank you very much for the invitation

2:42 Anastasiya

Can you tell us about your background and what compelled you to become a stem cell biologist?

2:53 Stephen

Yeah sure I'm not really sure I ever intentionally set out to become one. I had a long-standing interest in central nervous system disease particularly diseases like Alzheimer's but also spinal cord damage and other traumatic injuries and age-related disorders. When doing my PhD in the late 80s in Alzheimer's disease I became very frustrated with the tools that we had that time and what seemed to me to be a really just poisoned atmosphere about how we were ever going to really understand that disease with the tools that we had at the time which was mostly just post mortems of brain tissue. I became fascinated at the same time by pioneering research in Sweden where they were using human fetal tissue and were transplanting that into the brains of patients with with fairly moderate to severe disease and showing that they could rescue patients with the disease taking them off antiparkinsonian medication, and they could basically regain function in the absence of dopamine replacement, which was the standard therapy at that time.

The problem was that you needed tissue from very early aborted foetuses roughly 6 to 8 weeks after conception. Getting access to tissue this ages going to be extremely difficult, especially since we would need maybe 12 donors per patient. So I did a postdoc in California and my job there was to figure out if there was a way to somehow get around this reliance on freshly obtained fetal tissue, and in particular the numbers that were required. We were looking at ways of taking the cells from one donation and maybe getting 10 or even 100 equivalence of cells so we stumbled on the fact that if you went even earlier in gestation you could get cells that was still dividing in the embryo and under the right conditions would continue to expand. In the early 90s it was quite heretical that you could take cells from the brain and turn them into neurons. Initially this was met with scepticism.

I think this really kick-started the stem cell revolution because if you could do this in the brain people began to realise that you could do this in the liver or other tissues. when I moved to the UK in 96 I took that technology with me and we established the stem cell lab at Kings. we were working on neural stem cells but we realised it was going to be a dead end simply given the logistical dimensions of what we were trying to do. so we had already moved to another source of cells in this case from mouse embryonic stem cells which are derived from even earlier embryos of the mouse about 3 days after conception. With human fertility treatment we can generate the cells outside of the body and when successful gives rise to a baby. So this technology had been developed in London, well actually in Cambridge back in the 1970s. This year we are celebrating the 40th anniversary of the birth of Louise Brown who was the first IVF what they called back then test tube baby. In 1998 a group in Wisconsin so that they can make the equivalent of the mouse stem cells using what was by then a very established technology tickly for making transgenic mice it which you can put human disease causing genes. We've had Mouse models of disease for many years including for Alzheimer's. But with mouse cells you can only cure so many mice. We really wanted to do this for humans.

Me and others successfully petitioned the British government to allow for scientists in the UK to gain access to IVF rated embryos which could be donated for research. we started that in 2002 and we're lucky that we were very successful early on. We are one of the first groups in Europe to develop cell lines and we helped establish the UK stem cell bank. Our main interest again were cell replacement strategies for neurodegenerative and CNS conditions. we began by developing cell-based therapies for a whole variety of conditions but we ended up focusing on 15 including type 1 diabetes, liver replacement, making skin, bone cartilage, lung cells, CNS cells, retinal regeneration. We argued that cell replacement might benefits patients with very different conditions.

9:06 Sion

Did you have to know about a lot of different areas of medicine? Because it sounds like the scope of your research covered many different conditions?

9:16 Stephen

Yeah it did and I was one of the things that was really nice about what we were doing. my lab was in a position where people would come to us, and they would say we work on liver failure or heart failure would you be interested in helping us. so first of all you get to work with a lot of really cool people you are in fields outside of your core area. a lot of these guys are Pioneers in their own Fields. it was a great time because it felt like each month we were embarking on a new project and we would have to learn about the physiology, the cell biology, the pathophysiology for all these different disorders. it was really fun and really exciting and we were constantly learning new things.

10:15 Anastasiya

What are the current approaches that are quite transformative using cells in cancer treatment?

10:29 Stephen

This is different from stem cells. This has really exploded over the last 7 to 9 years.after I left King’s in 2009 to become initially the global head for R&D for almost a spin out company within ge Healthcare which was focus on cell based therapies we were developing technology which would allow commercial companies or academic teams to industrialize the production of cells. this is still very labour intensive and a lot of technicians are required. It is fraught with all sorts of problems. we stumbled on the fact that there were a group of cancer specialist in the US who happen to be using a bioreactor that ge had acquired for the production of vaccines and therapeutic proteins. It worked really well for growing a set of cells known as t cells. t cells are a type of white blood cell in our blood that is responsible for protecting us from disease.

What people like Steve Rosenberg from the national cancer Institute and Karl June from the University of Pennsylvania and Michelle Sanderlling from Sloane-Kettering in New York had discovered is that you could remove white blood cells from cancer patients and For Reasons which are not completely understood the immune system doesn't see leukaemia or solid tumors as foreign although they should because they are expressing antigens which are only seen during foetal development before there is an immune system. tumours should be recognised but they are not. What these three guys in particular and a whole bunch of other people subsequently had discovered, is that you could take white blood cells out from a cancer patient that are inert meaning they are not seen the tumour at all, and by genetically engineering them to express what scored a chimeric antigen receptor and then growing them up to very large numbers and infusion them back in the patient, you can in fact completely obliterate leukaemia--at least the strongest data is in B cell lymphoma. the patient's have a massive immune response when these cells are put back into the body and when this works it seems to work extremely well for about 50% of people with B cell lymphoma and you get a complete response even now 7 or 8 years after the first report came out there are patients with no detectable cancer whatsoever. In cancer, the only time this ever really happens is with bone marrow transplantation which is quite a difficult procedure which requires having access to a well matched donor to provide the bone marrow for the cancer patients and clinically it's a very difficult procedure and many patients don't engraft or they have a whole host of secondary problems which make their grafts very unstable. With the b cell lymphoma treatment it seems that once the cells have done their business they become very quiet and patients have almost no secondary responses.

This quality of response is extremely rare in conventional cancer therapy where normally you go in remove the tumor, and give patients radiotherapy with the expectation that ultimately their disease will come back. but in these B cell lymphoma patients if we been testing them every 6 months since they had their treatments and we don't see any evidence they have any b-cells left both malignant and normal. this is a little bit of a problem. We have to treat the patient with a drug to counteract the fact that they don't have B cells. This has really proved to be a transformative treatment and it has generated an immense amount of interest within the pharmaceutical Industries, with almost every major Pharma company now having a program in what called T cell therapy or cancer immunotherapy, and so huge amounts of money have piled into this. Not surprising given the transformative nature of this therapy.

15:55 Sion

How developed is this research? Is it close to being rolled out in hospitals?

16:04 Stephen

We have approved products now in the US and Europe. novartis and Gilead have both had approvals for their t cell programs. there are a whole bunch of caveats with this process, one of which is that it is hugely expensive. because of patient is somewhere between 350000 and half a million per patient. also production is still a significant problem, so other companies like ge and others are trying to establish automated production facilities a lot of this is still very manual. The other big unknown is whether these therapies will translate into other types of cancer which are solid tumours rather than liquid tumours. Solid tumours have mechanisms for stopping t cells dead almost like in the Matrix where the guy stops the bullets. these tumors are often wrapped in this thick membranous material called Stroma. we have some tantalizing data but at the moment most of it relates to liquid tumours. so it is early days but people have very very excited about this. when a patient is treated we think that this response may be for life. this is amazing.

If you look at www.clinicaltrials.gov there are about 6000 trials using stem cells. With stem cells we are starting to see some interesting results particularly with macular degeneration a form of age-related blindness--roughly if you live to be about 80 or 90 you have a 50% chance of already being blind-- and there's very little in terms of therapeutic options. There several trials, including one in London with my friend Pete Cothy, who have put in back these support cells in the eye called retinal epithelium, he has got patients who were pretty close to being fully blind who have regained Vision. Several lines on the vision chart. these are very early patients trials yet we are seeing tantalizing evidence that this might work. This is true in other clinical trials in type 1 diabetes, and potentially in cardiac repair. A huge bunch of trials are planned over the coming years using embryonic stem cells. we have a lot of steps out as at the moment using cells either from bone marrow, or from cord blood, or from adipose tissue (fat) that is an interesting source of stem cells and actually quite a good one, because you get a lot of them, and in some cases they are better than from bone marrow. I think the whole field is moving to a realisation that cell based therapies they have a major impact on a lot of diseases which are age related in many cases but which there is currently very little therapy. These are therapies which may actually counteract the disease rather than just treating the symptoms.

20:31 Anastasiya

And that’s using stem cell-based therapies?

20:34 Stephen

Yeah not everything is working, and not everything we fully understand. For example we can make reasonably good bone from what are called mesenchymal stem cells, either from adipose tissue or from bone marrow, but we make relatively immature and not fantastic cartilage. it works ok if you really need cartilage replacement but it's not the but is not the best cartilage which our bodies make. but in other cases like from embryonic stem cells we think we can make heart cells that we think could be equivalent to the cells that are already in our heart. then there is Pete's work on retinal epithelium where he can produce the cells very easily and his clinical data already looking very very promising. the field is progressing rapidly. I don't know how many stem cell conferences there are now.

There is a lot of interest both from pharmaceutical companies and the investment community, but it is a long-haul. people worked on the t cell immunotherapy space for more than 25 years before they got success and if you asked people back before 2010 what are the chances that it would work roughly 99% of oncologist would have said that this is not going to work, and now it is the hottest thing under the sun.

22:11 Sion

Is there any research in the longevity space which looks especially promising?

22:18 Stephen

you know it's interesting, there has been a lot of froth, many silicon valley guys have set up longevity companies, and they have been generally very quiet about what they have been working on, and of course Aubrey de Grey and his SENS Foundation was set up around longevity and has attracted considerable funding. But I haven't seen anything yet that is really definitive in this space well I think someone has figured out a way to extend life or extend health life using a drug or using a therapy. so it's a new field and I think everyone is interested in it. The bottom line is that people are living longer because of better nutrition, better medical care and better antibiotics, having more medical specialists, having more specialised devices, and more preventative medicine.

I am a big proponent of longevity. I wouldn't be in this field if I wasn't. many of the therapies are essentially helping people to live longer, but if we don't deal with dementing illnesses such as Alzheimer's which I think is a time bomb, and/or macular degeneration, then what is the point of living longer if you are blind and/or demented? quality of life is still a major factor if you are going to live longer. I'm not sure we're going to find a drug to do that. I think it is a little more complex than that. I think we need to have a better understanding of the microbiomic environment our bodies live in, these guys who are with us all the time and vastly outnumber the human cells in the body. understanding both how they keep us well and also what causes us to get sick when the system becomes dysregulated. I think that is a big untapped area for understanding fundamental disease and pathogenesis. Could you have a bacterial based or fungal based transplant system that brings your gut back to normality? you can take patients you've had a really nasty bacterial infection in their gut caused by clostridium, That in its worst case is not treatable by any antibiotics, but if you give them a foecal transplant from someone who is healthy then more than 98% of these patients resolve in the absence of antibiotics. this is a disease which is generally not treatable. it is bug mediated.

then there is the whole impact of preventative medicine and healthy ageing. we are what we eat and how we exercise. there was another catastrophic disease that come in that is basically liver failure promoted by obesity. the only treatment for that at the moment is called Nash. roughly 400 or 500 livers are transplanted per year in the US, and many die awaiting transplantation. liver transplantation is not really the solution for this disease. there needs to be more emphasis on diet and nutrition.

27:11 Sion

Is that what you are working on with Educell and Biobanka in Slovenia?

27:16 Stephen

Educell and Biobanka are owned by a friend of mine, Miomir Knezevic. Mio has one of the oldest stem cell companies in the world, celebrating it's 21st anniversary this year. Mio is responsible in many ways for me coming to Slovenia. Basically he has a cell therapy production facility. he develops cells for a whole range of different therapies, and he works with hospitals here to develop cell based therapies for them, under very strict regulations. So my involvement with them is just as a cell therapy advisor, helping them develop their manufacturing capability and to look for new emerging clinical areas where it looks like cell based therapies going to work. For example, the Cancer immunotherapy space they are very interested in learning to Slovenia, as much as everyone is interested in bringing this to everywhere.

28:27 Sion

Are there any areas of the longevity industry which you think are overhyped?

28:37 Stephen

Well I'm not sure there's really an industry yet. There is a lot of stuff about relating to life extension, saying if you take this drug, with a few people out there promoting some snake oil type stuff. For example, there was a big interest not too long ago in extracts from red wine. Resveratrol. The protein target for that was sirtuin. Pharma companies invested heavily in that and it turned out to be a dead end. so it could be the same with other plants we put a plant extract on something and it looks interesting but when you cut it up into its constituent parts you find out it doesn't work as well as the whole extract does. maybe it's the same with red wine. I'm not sure there's a magic bullet that's going to be useful in aging. I think it's lifestyle. I think it's environments. I think it’s smoking, drinking, eating, exercise, sleep. I think it's your microbiome. I'm not sure there is a longevity programme you can plug in and follow. a lot of it is common sense. Obviously if you smoke is not going to be good but my mother is 82 and she's still smokes. And she appears to be pretty healthy. I'm dubious about a lot of things not just in the longevity space but in science in general, that is one thing is exactly what we are looking for and will solve all our problems. I don't think biology is that simple.

30:42 Anastasiya

Why did you decide to move to Slovenia? And why Ljubjana?

30:57 Stephen

Yeah, its not spelt Lyubyana. In Slovenia it’s got lots of J’s which are pronounced like Y’s. I think I've been going to Slovenia since 2003 or 2004. I met Mio my friend from Educell and Biobanka in Brussels. We were both on a review panel for the European Commission. We became good friends. He told me he was running a summer school in Slovenia on the coast, in a place called Piran, Would you come and give a lecture and I said sure. he promised me beach and sun. Over the years I came to visit and teach, and started going more and more. In 2009 I left Kings and joined GE and I was travelling like a crazy person for years and years. when I came out of GE in 2016 I spent a substantial amount of time in London and I discovered that I was tired of it. Big city, big life, smoke, dirt, bad air. All the bad things.

Then brexit happened and I was very very unhappy about brexit. I wouldn't claim to be a soothsayer but all my predictions about how catastrophic it is and how I think is going to have a massively bad effect on British Science, British universities, the NHS, British education, whether we are either going to have a deal is still tremendously up in the air. when the vote happened I was in the States watching it on TV in a bar and I told my British friend I'm going to leave. I'm a European I grew up in Europe and I can't stand the idea that the UK is not going to be in Europe. so I started looking around for a place to live and in early 2017 I was here for 3 months in Ljubjana. and I liked it so I start talk to my friends about what would be the reality if I try to move here. I had a European passport so about a year ago I slept coming here pretty much full time and at the end of the year I basically moved him lock stock and barrel. I spend 1 or 2 weeks every couple of months back in London but the rest of my time I'm here. it's a different atmosphere obviously you don't have the major universities you have back in London but the quality of science it is outstanding, the clinical environment is that standing. there is a well educated student population here and there is a big interest in cell therapy, gene therapy. I can walk everywhere, I don't need a car and the other super clean. We’re surrounded by mountains and forests. It's an hour from the sea. I probably wouldn't have done it except for brexit. I have a huge body of a really good friend here most of whom Are Scientists. good food good wine good beer. we will have dogs. I got a dog almost immediately after moving here. just a very different life here and very relaxed.

36:05 Anastasiya

Which universities or societies organisations in the UK on your opinion doing something that's breakthrough or transformative in a field of stem cell based therapies, anti-aging, and longevity?

36:42 Stephen

There is so much good quality science in the UK. I was at Kings, so I know Kings best of all. At Kings there is a lot of research into stem cells, and Kings is one of the leading transplant environments in all of Europe. Liver transplants, pancreatic transplants, and a lot of bioengineering and a lot of biomaterial research.

I think UCL has a tremendous bioengineering capability. Imperial on the other hand is very much more of a pure engineering environment with relevant to bioengineering. At Oxford you have professor John Bell who is leading this charge to develop Oxford as one of the leading biomedical environments in all of Europe. John has been tremendously successful in raising money and building Institute in Oxford, creating a real powerhouse there. Cambridge though, is silicon fen, and you have all these biotech companies.

I hope they scale out and look at other omics other than just dna-based omics. For example, in the microbiome. for many years we didn't really care about the microbiome, because we couldn't grow much in the gut, because these cells don't grow in oxygen, and we didn't understand anything about them. but we don't need to grow the things we just need to sequence them and identify based on homology to other known bacteria. so the Wellcome Trust genomic centre is one of the leading centres in the world.

And it isn't just the Golden Triangle of Oxford, Cambridge and London. there is a lot of great research in Edinburgh, in Glasgow, in Nottingham and there is just a lot of incredibly good British Science.

39:21 Sion

Do you think that ageing can be looked at as a disease in its own right?

39:27 Stephen

You know people talk about that, but it's a stage of life so far as I'm concerned, and we all go through stages of life. I'm in my early 60s and if I think back to when I was much younger and I think of the people I knew who it in their early 60s or 70s, and they were old, and now I think we're not. I have now friends in their 80s, who are still very active scientists. I think ageing is a very interesting concept. we age differently now than we did a few decades ago. in Japan now the median life expectancy of a woman alive now is 90. it was only 75 maybe a generation ago. so we are aging differently. I think our health is better as we get older than it used to be.

But I saw a statistic the other day, that in 7 states in the US 35% or more of the population is considered to be obese. that is huge. obesity is a disease. It's a lifestyle yes, but is also a disease, and it's impact is getting worse. Aging can be a lot of different things. How we age is very important. since I got here and I brought my dog, we go walking for an hour each day, and I can tell you it has mentally changed my life. I used to be fairly fit, but now I am much much fitter. I just feel completely different. I feel better than I have for maybe the last 10 or 15 years. And so I think exercise, mental attitude, mental stimulation, are very important. Being isolated, if you are not intellectually engaged in the world, you tend to do not as well as as if you are intellectually engaged in the world. so I think there is a whole host of things an impact on how we age. Ageing can go badly or it can go well. The funny thing about Ljubjana is that most people have one or both parents living until they are 90, despite the fact that they drink or smoke.

42:35 Anastasiya

We should all move to Ljubjana!

42:37 Stephen

I don’t want everyone moving to Ljubjana! My Slovenian friends are like shut up, don't talk about Ljubjana so much. But the funny thing is they were never really obese, and everyone here works incredibly hard. that's that thing. I walk through the markets at 6 a.m. and almost everyone is hauling food or drink around. everyone I know here is fit. I have friends who climb 2000m mountains every weekend. So these guys live to a ripe old age despite the fact that they drink and smoke. You can probably get away with a lot if you keep healthy and if you are not obese.

I don't think I agree that aging is a disease. I think it's a state of mind. there are some interesting things out there. so some people say there are senescent cells in the body, then if you can get rid of those you can reduce the impact of ageing. but I need to see more data.

43:49 Anastasiya

What about other therapies such as blood transfusion?

43:53 Stephen

The young blood stuff. some of the data is quite convincing, but the group at Harvard found that there was a single Factor called gdf11, well that first study didn't pan out. they have just raised a bunch more money to do another subsequent trial. the idea is that you take your blood when you are young and you store it then you reinfuse it when you are 60 or 80 or whatever. the mouse data tends to support that this works, but quite often what you do in the mouse doesn't translate well into humans. I think it's interesting but I'm not convinced. I'm not convinced that it is just blood. again people are looking for a panacea, but we will see. it's an interesting concept, and clearly the market is interested in this so we will see what happens.

45:10 Anastasiya

What are the latest innovations in regenerative medicine?

45:11 Stephen

Right now almost everything we are doing is cell based, and it piggybacks on conventional medicines. Then you have organ transplantation, which is really tough, because there are not enough organs with matching donors, and most people who do need a new organ do not do well following transplantation. so the idea that you could fabricate tissue, using additive manufacturing is attractive because in some cases you don't need a complete tissue. you only need a certain part of it, we think for example in patients with heart failure, where they have lost a substantial part of their left ventricle, you don't need the whole heart, you just need the left ventricle back. it is like having a pump, and you were missing part of the pump, so you put the part back. we are already doing stuff like this in some small we are already doing stuff like this in some small bags ways, but I think we could fabricate tissue for personalised medicine, which could more or less put organ transplantation out of business if we could make the equivalent issues but that is a Big if, and we are nowhere near being able to do that now.

Understanding better the interaction of cells in scaffolds, and being able to put in delivery systems to organise cells better. I think there's going to be a huge amount of engagement between tissues in cells and non-biological systems like electronics and sensors. I see this conversion between a whole bunch of different disciplines, engineering, electronics, and cellular biology all coming together , to create more smart devices.

48:07 Anastasiya

What is the biggest lack in the longevity space?

48:25 Stephen

Well I think, investment and funding on the one hand, is you have to ask what is your product going to be. Going back to immunotherapy, that I manufacture outside of the patient, put them back, and when it works, they are cured of cancer. that's an easy story to tell. what are you selling in longevity? I'm selling the ability for people to live longer. well how long, and based on what? Let's say you have something which will allow people to live until they are 100, what are you going to do about Alzheimer's disease and what are you going to do about blindness? Most people I talk to just poo-pa this away--oh we will deal with it. Well I have been in this field for over 30 years and we have made almost no progress at all--my Alzheimer’s friends would be unhappy to hear this--I don't think we fundamentally understand the disease. Until we deal with that I don't see that living longer provides any real benefit, given the huge numbers of people that ultimately dement. if lots of people live to 100, a huge proportion of those would be demented, or blinds, or both. so that's the big problem.

On the other hand he had a more accurate device that delivers insulin, or a better kind of pacemaker, that was more durable. Things like that do have a demonstrable impact on ageing. I think that's an easier sell. like most things in science I think it is funding, funding, funding. I don't think the regulatory environments is any less or more difficult than for any other therapy, so I don't think it's regulations per se. I think it really is probably the amount of money and investment that is going into it.


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