Team:UCL/HP/Silver/Experts
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THE EXPERTS
Laying the foundation to our ideas
OUR MOTIVATION
To start our story, we want to build the foundation of our ideas by talking to experts and renowned biologists whose research is related to ageing. We believe that the experts can help us build better therapies that approach the complex problem of ageing. Ageing is not well understood to this day and it is believed to be a multidimensional process that is caused by many different factors. We approached experts to find out what they think is the best way to target healthy ageing and what synthetic biology could do. The aim was to talk to as many researchers as we could to try to understand how we could make our therapies safer and controlled. We also talked to biotech companies and gene therapy companies to get an idea of how we can translate our processes commercially.
Aubrey de Grey
We were extremely excited to skype with our main inspiration for our healthy ageing project, Aubrey de Grey. Aubrey is a prominent researcher on gerontology, ageing and regenerative medicine and is known for his work all over the world. He has led many TED talks about healthy ageing as well as he is a member of the SENS research foundation which pioneers novel therapies for the ageing population. The full skype interview can be seen below.
We started off by explaining that we are hoping to build some solutions to healthy ageing in humans and that we are hoping to do this by focusing on the effect that oxidative stress has on the cells. While Aubrey thought it was an interesting idea, he gave us some useful insights as to what to focus our research on.
We received a lot of help with how we can experimentally characterise the effects of lycopene on decreasing oxidative stress. Aubrey said it was a good idea if we can prove (through our experimental data) that lycopene can survive in the gut as well as be successfully secreted from the bacteria. He mentioned that oxidative stress not only is significantly different within different parts of the body but also in different parts of cells, and that a targeted delivery of the desired compound is vital. A targeted delivery would also allow to broaden our biobrick to Crohn’s disease, for example.
Besides our project, we asked Aubrey what his thought were regarding creating a synthetic genome, and subsequently creating ‘’synthetic humans” that could even be automated by robots. While he considered it interesting, he was quite sceptical – primarly because synthesising the genome itself is not sufficient for it to work. A lot of effort would have to be put to add methylatons and histone modifications, and that it is particularly labourious and challenging. Aubrey said that ”instead of creating the genome from scratch, it would be more efficient to cut out certain faulty genes”.
The interview with Aubrey allowed us to explore new ways of characterising lycopene and proving that the gut microbiota will benefit from lycopene. We are hoping to design further characterisation tests that we are going to use. Aubrey gave us a valuable insight into current ageing research and also gave us tips related to our project. He also suggested that senescence and ageing would not be a good route to go down as the genes have already been established (our project can not copy existing approaches). In response to his perspective on senescence and synthetic biology, we talked to Maximina who is currently doing research on salamander and senescence. Through this meeting we can hopefully gain another perspective on our senescence idea. Have a look at our human practice's gold page to find out how Aubrey has influenced our project.
Filipe Cabreiro from the UCL Institute of Ageing
We interviewed Dr Filipe Gomes Cabreiro, a researcher from the UCL institute of Ageing. His research focuses on the role of metabolism on ageing and interactions between host-microbiota-drugs, so he really gave an interesting perspective to our project as we are hoping to create a probiotic oxidative stress mop (Lycopene antioxidant). In our meeting, we discussed, among others, the feasibility of the bacterial probiotics and challenges relating to them, including stability of both the microbe and our product, the differences in gut conditions between humans and model organisms, and efficiency of our process.
During the meeting, we discussed how lycopene may interact with the microbiome, its stability, degradation pattern and how it could be absorbed. Filipe suggested that we needed to make sure lycopene does not influence any other microbes in the gut – that means absorption and degradation pathways need to be checked experimentally. However, Filipe said that antioxidants as an entrepreneurial idea can become a hot topic within the healthy ageing research community: ‘’From the commercial point of view, though, there is a huge market for anti-oxidant based products and they would very likely sell well”. However, a challenge could be licensing a GM product, and so majority of research focuses on using bacteria occurring naturally in the gut.
Finally, Filipe also raised the issue of stability and transferability of our lycopene product from model organisms to humans - it is of utmost importance. As most of the cutting-edge research related to ageing is done in mice and not humans, it may be difficult to prove that the same effect will occur in humans and mice as different species have different microbiota.
Filipe also provided us with some useful thoughts about doing something with the mTOR and insulin signalling longevity pathways which may be a more efficient way to tackle healthy ageing. Filipe and Aubrey de Grey also mentioned the same points of the microbial probiotic having potential in treating Crohn’s disease. The meeting resulted in Filipe providing us with a lot of ideas that we could look into in more detail and that we are hoping to research in more depth.
Maximina: Senescence – is it going to work?
Willing to dig deeper into senescence and ageing, we met Dr Max Yun, a Senior Research Associate in the UCL’s Division of Biosciences. Max’s research focuses on regenerative biology; aiming at understanding how regenerative capacity decreases with age, as well as looking into the impact senescent cells have in salamanders and humans. As someone in the field of ageing research, we really wanted to see what her opinion on our project ideas are and to get some feedback.
In the meeting, we discussed the potential of the SOD pathway as a method of removing oxidative stress in the lungs. Max really liked the application of using an inhaler which would direct the virus containing the SOD gene to the lungs - this would be a targeted gene therapy that would work on removing oxidative stress specifically in the lungs. She also suggested that we could use RNAi in cells containing no or little SOD to see how the cell reacts in the lab. As a result, we are now going to research the SOD pathway, as well as links between its over-expression and ageing.
Max also said that ’A product releasing lycopene would require a tight control of dose', highlighting the isssue with a probiotic that removes oxidative stress in the gut. Moreover, we found out that oxidative species are required for regenerative responses, and communication between cells so mopping these out might be damaging for the cells. Different tissues and cells may respond differently to lycopene, and Max also pointed out that oxidative stress can also be a good thing for the cells as well as bad. As a result, we will now look into enzymes related to lycopene and reactive oxidative species (ROS) to understand the interactions between them.
Max also mentioned a company called Catapult, which is involved in gene therapy clinical trials and could help us with our idea of gene therapy. Such therapy could involve haematopoetic cells, which would be less risky as it would target one system only. As a result, we contacted the company for more information, as well as to obtain a more detailed opinion of the feasibility of our SOD gene therapy idea.
In regards to the relationship between senescence and ageing, Max underlined the complexity of the topic: while a lot of research is being carried out at the moment, tackling senescence is incredibly ambitious also because there is no single senescence marker discovered yet. However, we were suggested to look into the inhibition of the mTOR pathway, which also decreases levels of senescent cells. Another challenge that we have encountered previously was the difficulty in measuring concentrations of senescent cells. While it can be done in vitro using a fluorescence assay, it is more challenging in vivo – a nanoparticle system doing that has recently been developed by Max herself.
Max also mentioned that using p16 as a marker for senescent cells is not 100% accurate and reliable as p16 can also be found in other cells. Additionally, she also mentioned that there is no surface marker that has been found only in senescent cells that can be used as a biomarker, and that researchers in the field are currently still trying to find one. Therefore, making a biosensor for senescent cells is difficult and not very accurate. Max joked that if we could find a surface marker then we could become Nobel prize winners (outlining the difficulty in this field)! Max really has shaped the way we have developed our project, find out more on our gold page.
We also mentioned the possibility of developing a gene therapy that would allow the cells to make synthetic telomeres which would prevent the telomeres from getting short. Critical shortening of telomeres in cells is a cause of ageing and cell death. Max said that ‘’the idea of engineering telomeres is of high risk due to cancer, as well as issues related to genome stability” . While we are still considering this idea, we might now give it a second thought as we would need to consider how a single change in the human genome would affect the whole system (whether this would cause more problems than it solved).
This meeting with Max provided us with a lot to consider and think about when it comes to the impact that our ideas would have on the human genome as well as other complications – not only do the causes of ageing have a negative impact on the cells but they can also have small positive impacts. For example Max raised the issue of reactive oxidative species being necessary for regenerative cells as well as damaging to DNA and causing ageing completions. After hearing all our ideas, we asked Max what she thought of our project overall. She mentioned that if there is a strong link between lung damage as we age and depletion in SOD enzymes, then there is a good and interesting case for gene therapy solutions.
We also asked Max what made her want to work within the ageing research - she said that she is interested in what makes an organism and how the organism develops, and that it is not just about making an organism live longer: it is about making them live healthier. Her interesting perspective will hopefully provide us with more of the scientific foundation and the feasibility of our ideas.
William Bains
We reached out to William Bains, who is a scientist, entrepreneur and teacher in the life sciences. He has an interest in regenerative medicine and ageing research. His work is mainly focused on several areas of chemical aspects of ageing that are potentially tractable to treatments and are being ignored by mainstream medicine. William suggested that we should try to consider how our probiotic is better than just taking lycopene supplements. He suggested that we should make a genetic logic circuit that releases many antioxidants in response to many types of oxidative stress, to make our system have a larger impact to healthy ageing.
At this point, our SOD3 antioxidant idea had evolved into a gene therapy approach, and we wanted to find out whether it was feasible and what the experts thought. William was really enthusiastic about our SOD3 gene therapy and said that its much more radical, much more interesting. He mentioned that some people are willing to do anything to feel younger, putting it as “a millionaire old person that doesn’t want to be old is going to say forget the regulation - I’m going to do it on my yacht off shore.” Surprisingly, William mentioned that he hadn’t heard of a SOD therapy before, and that it’s a good idea because the lungs are the most oxidative part of the body.
Through talking to other researchers, we noticed that there is a general feeling that low levels of oxidative stress are good for the human body - hence our strategy of removing oxidative stress may not be safe. William suggested that we should think about putting an oxidative-stress-induced promoter which induces the expression of our antioxidants only when enough oxidative stress is present. Our interaction with William has been by far the most useful, as his suggestions have greatly improved our SOD3 gene therapy idea. The full discussion can be seen on our gold page.
Signum Biosciences: Insight to the ageing industry
We also skyped the CEO of Signum Biosciences, Maxwell Stock and Antonino Chetta (director of communications). Signum Biosciences is a spin-out of Signum Dermalogix who are focused on developing dietary supplements for enhancing brain health and promoting overall better health. We wanted to find out what they think of out project and how the work they do fits in with promoting healthy ageing.
After we explained details of our project and what iGEM is, Maxwell commented that our project ideas are very good and he particularly likes our lycopene probiotic route, and even said that they have thought about this idea within their biotech company. Maxwell also said that expressing a vitamin (lycopene) is interesting and a good idea. He believes that the microbiome is the key to ageing and a much better path, and that it is unfortunate that it is ignored in a lot of medical communities. “People who live for 100 years have a good diet and a robust microbiome so a robust microbiome is the most important thing in ageing”. He went onto explain that people who have a diverse microbiome also have a lower incidence of neurodegenerative diseases and ageing diseases compared to other people.
Maxwell mentioned that we need to think about the route of delivery of the probiotic and believes that the route of delivery of the drug is the most important part. He suggested that we look into body faecal transplants where you take the faeces of one person and put it into another person to change the microbiome of the gut. He believes that seeding the microbiome can be a lot easier and better. Someone with a severe neurological condition can get a faecal transplant and recover.
As a part of the work Signum Biosciences do, he looks into the link between the microbiome and the brain and believes that the microbiome controls the brain. “There’s more of you in bugs than there is in eukaryotic cells and bugs dictate the health of you teeth and you”. Maxwell personally believes that gene therapy is hugely difficult and it’s for that reason why he prefers the lycopene probiotic route over the SOD gene therapy route.
We then asked what he thinks about the role of oxidative stress in ageing of human cells. Max said that mitochondrial dysfunction is clearly a problem but what’s not clear is the antioxidant approach. Antonino Chetta then mentioned that oxidative stress levels changes with the seasons, and microbes change with the seasons, and that high levels of oxidative stress may be good for the body for that short time until the levels go down later. He also mentioned that removing oxidative stress can be a negative approach as it may be promoting cancer so we need to take a systems-wide approach with our project and think about the implications and benefits.
The same question arises every time: how do we ensure our therapies are safe and do not cause any other unwanted side effects like cancer? Which is why after talking to so many experts we really wanted to integrate safety deep into all of our devices.
Piers Millet
Piers Millett’s work focusses on preventing biotechnology and life sciences from being used as a weapon. He is an international policy specialist and his research focuses on the security implications of, and policy responses to, the deliberate malign use of modern biology and biotechnology. We were keen to find out how we could make our project safer and to reduce its misuse once it becomes a therapy to treat ageing.
After explaining our project, Piers said that it’s great that we are tackling ageing as an issue and that it’s interesting that we are looking at both inhalational and oral routes. Piers went on to say that he is interested to see whether we look into some of the materials the big pharma companies are doing in that space and how they are looking at inhalational drugs and probiotics and what is happening in pharma that influences our design choices.
We then asked Piers what issues he sees with our project from a safety perspective. Piers said that the only issues would be with future applications of our ideas as we are putting GMO’s into the body. He mentioned that if we follow the UK rules and regulations of gene therapy then we will come across no safety concerns. However, Piers mentioned that he read an article that said that Brexit may lead to the UK taking a slightly different approach to GM than Europe, which may become a barrier for us if we want to make this a therapy in the UK -hence why we decided to explore how public policy and law can influence our project.
Piers suggested that we should look deep into the current market of ageing therapies and see what existing companies do to tackle safety and other issues such as the preferred delivery route of the therapies, do people prefer injections over oral route etc. Piers allowed the team to start thinking about the route of delivery more, so we contacted the gene therapy Catapult as a result.
Catapult gene therapy company: From lab bench to industry
As novel gene therapies for cystic fibrosis are moving smoothly through clinical trials, gene therapy has never been so exciting. We were interested to find out what we needed to do to get our SOD3 gene therapy into the market, what the manufacturing challenges were and what other difficulties gene therapies face now.
Maximina was able to put us in contact with Eugenio Macchiarulo, who is an industrial viral vector lead at Catapult gene therapy. During our phone conversation, we were able to explain our overall project, our SOD3 gene therapy approach and to ask Catapult some interesting questions about processing both small and large scale.
Eugenio said that our project is interesting. However, like many other experts we have interacted with, Eugenio expressed his concerns over safety. He mentioned that the reason why gene therapy is not being used right now is because they are trying to ensure that these gene therapies are safe for the human body and that they do not cause any long term side effects. Eugenio said that we need to think about where our lentivirus backbone will integrate into. Whilst the lentivirus is being inhaled, it may not just transfect the cells you want it to. We should think about the consequences of the virus transfecting other cells. Eugenio also mentioned that it costs around $1000 per dose through gene therapy. This means that there is a huge need for better manufacturing and bioprocesses in order to decrease this cost.
We also asked what the biggest challenges with gene therapy are right now, and Eugenio mentioned safety, lack of platform technologies available, scaling down and the general public forming a major barrier for the development of gene therapies. He said that there is a major conflict with the public, and a huge misunderstanding and misconception about genetically modifying organisms. Eugenio believes it’s the lack of knowledge related to gene therapy that makes people so against it. It’s for this reason why our iGEM team wanted to increase the knowledge base of genetically modified organisms to the wider world. See our public engagement and education page for more.
What have we learnt?
See our human practices gold for how our interactions with the experts have influenced out design.
