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UCL iGEM 2016 | BioSynthAge

The experts

Talking to researchers that are in the ageing field. To start our story, we want to build the foundation of our ideas by talking to the experts and reknown biologists that are in the field, to get an experts opinion on our ideas.

Skype meeting with Aubrey de Grey

On July 14th, we held a Skype meeting with Dr. Aubrey de Grey, who’s a prominant researcher on gerontology, ageing and regenerative medicine and is known for his work all over the world. He has lead many TED talks about healthy ageing as well as being a member of the SENS research foundation. We discussed a variety of topics, including oxidative stress as a route to tackle ageing, using probiotic bacteria as a means of delivering therapeutic products, and the feasibility of creating a synthetic human genome. 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 a 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 where to focus on our research. We received a lot of help into how we can do some characterisation experiments on our lycopene idea, which Aubrey said was a good idea, if we can prove (through experimental data) that Lycopene can survive in the gut aswell as being successfully secreted from the bacteria. Specifically, we will now look into adsorption of lycopene by the cells to make it suitable for the gut. He also mentioned that we need to think about whether the bacteria can survive in the gut envriorment and that we should consider modifying the bacteria so that they would survive under low pH of the digestive tract. Aubrey was able to provide us with alot of points to consider, thing that we may have not thought about. He mentioned that oxidative stress does not only differ significantly 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 spectical – primarly because synthetising the genome itself is note sufficient for it to work. A lot of effort would have to be put to add methylatons, and histone modifications, and that 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 further ways that we can charactorise Lycopene and prove that the gut microbiota will benift from lycopene. We are hoping to design further charactorisation tests that we are going to use. We got a huge insight to current ageing research and also provided us with tips for 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 (we possible cant do anything thats already be done within our project). In response to his perspective on senescence and synthetic biology, we are hoping to speak to Maximina who is currently doing research on Salamander and senescence. Through this meeting we can hopefully gain another perspective about our senescence idea.

Filipe Cabreiro from UCL institute of ageing

On July the 18th, we met with 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 interactions, 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, feasibility of the bacterial probiotics, and challenges relating to those, including stability of both the microbe and the our product, the difference 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 patern 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 adsorption and degradation pathways need to be checked experimentally. However, Filipe said that antioxidants as an entreprenerial idea, can become a hot topic within healthy ageing research: ‘’From the comercial 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 occuring naturally in the gut.

Finally, Filipe also raised the issue of stability and transferability of our lycopene product from model organisms to humans is of utmost importance. As most of the cutting edge research to do with ageing is all being proved in mice and not humans, it may be difficult to prove that the same effect will occur in humans as mice and humans have different microbiota. This all goes down to the same point raised by Aubrey de Grey - that we need to think about how to create a compelling proof of concept for our casettes and to get enough evidence from the experiments that show that the Lycopene secretion will not be effected by the gut and that Lycopene will not effect the gut microbiota.

Filipe also provided us with some useful thoughts about doing somethng 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 alot of ideas that we could look into more detail and that we are hoping to research in more depth.

Maximina interview Thursday 21st July

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. Which 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 SOD or low concentration of it, 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 of 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 she 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 into enzymes related to lycopene and reactive oxidative species (ROS), to look at the interactions between them. Max also pointed out a company called Catapult, which is involved in gene therapy clinical trials, which could help us with our idea of gene therapy. Such therapy could involve haematopoetic cells, which would be less risky, as it would only target one system only. As a result, we are going to contact the company for more information, as well as to obtain a more detailed opinion of the feasibility of our SOD gene therapy idea.

As 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 already encountered, is 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. Not only that, 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 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)!

We also mentioned the possibility of developing a gene therapy that would allow the cells to make synthetic telomeres that 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 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 the 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 and how the organism became and that Its not just about making an organism live longer, its 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. Specifically, he believes that if regenerative medicine aims to repair the body in disease, why not repair the problems of ageing as well. His work is mainly focused on several areas of chemical aspects of ageing that are potentially tractable to treatment and are being ignored by mainstream medicine. Below are his responses to the questions we asked during the discussion.

A) We told William about out our SOD gene therapy idea and the lycopene probiotic which are focused on tackling oxidative stress to increase healthy lifespan.

I think that the SOD therapy idea is interesting. For the lycopene idea, we should think about how our probiotic is better than just taking lycopene supplements. A probiotic can be interesting and its where the synthetic biology part comes in, because if there can be several different sorts of oxidative stress and different sorts of antioxidants that can counteract that and if you could have several sensors that and a genetic logic circuit that then produces the right combination of antioxidants to treat a particular thing. Then that can be a cooler synthetic biology project and I think that would be the advantage. The difficulty with that is that our probiotic only addresses the gut and for most old people that they have gut problems but its more related to incontinence than oxidative damage in the gut itself and this will be in the large intestine as this is where most of the bugs live. So you’re not going to be able to fix damage to the stomach using the probiotic as it won’t survive in the stomach. When you eat the probiotic it will go through the stomach but it won’t actually be active in the stomach – it will go into the large intestine.

I think that the gene therapy approach is much more radical, much more interesting and it’s the sort of thing that the judges are going to say “well you’re not going to be allowed to do that”. To which my response is no that is entirely right under conventional regulation. But if I’ve got a millionaire old person that doesn’t want to be old then they are going to say forget the regulation - I’m going to do it on my yot off shore. Then the regulation aspect is less of a problem then you think.

Replacing SOD in the lungs was interesting and I haven’t heard of it before as the lungs is the most oxidative part of the body. Maybe check whether older people are genetically deficient in SOD or whether it’s just found that there are low levels of SOD in older people and you should explore whether this is a correlation or a causation.

SOD is not the only defence against oxidative damage and a problem with repairing any one of these. If you have three or four defences against oxidative damage, and if you boost one of them up and the others are still not working properly so you still get a lot of damage. So we need to think about what the whole system that defends against oxidative damage and maybe incorporate 2 or three things possibly that decline with age and possibly put them into a virus.

I think that having it expressed in induction of oxidative damage is a good idea. And the reason is that these enzymes and proteins are going to have adverse effect on the body in some way even if you get the human enzyme and express it in a virus, human cells, human body there is going to be a bad thing it does. So if you can turn it on when you need it then it’s a good thing. Have you looked into how you are going to detect oxidative stress?

CEO of Signum Biosciences

We were also very lucky to have spoken to the CEO of Signum Biosciences, Maxwell Stock and Antonino Chetta (director of communications) in a skype interview. 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 explaining 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 is interesting and a good idea. He believes that the microbiome is the key to ageing and that it is ignored in a lot of medical communities and a much better path. “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 when compared to other people.

Maxwell also said that he believes that the western culture has made the microbiome less diverse which has had a negative impact on ageing in humans also lowering the immune system.

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.

He said that these systems can be complex and just producing lycopene might not be the answer to ageing and that we should think about this in a system wide approach and see how it will impact other parts of the microbiome and gut. With the work Signum Biosciences do, they look 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 with ageing of human cells. Max said that mitochondrial dysfunction is clearly is 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.

In conclusion from the chat…

Think about the impact that lycopene will have on the whole microbiome
Think about the mode of delivery, is faecal transplants a good way?
We also need to start to think not only about the benefits but also the negative implications of the ideas.

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. 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.

In conclusion from the chat…

Contact gene therapy companies to find out what issues they face with safety
Look into UK laws associated with GM and how this may change after Brexit, possibly talk to a politician about this.
Think about safety in terms of the design of the project. Do people want to have an injection? Pill? Inhaler? Are certain delivery routes less safe than others?

Team:UCL/Human Practices/Experts