Jayden Smith studied chemistry and computer science and currently works at CITC Ltd as a Senior Research Associate. He works on several projects, one of which involves the development of induced neural stem cells for the treatment of neurological disorders.
Q: Can you describe in one sentence what this project is about?
We want to express and characterise a human-derived enzyme that has potential anti-cancer applications.
Q: How did the idea for the project come about?
It came from a collaboration between our company and the University of Cambridge. Through this collaboration we discovered that extra-cellular vesicles are secreted by neural stem cells, that these vesicles function as independent metabolic units and are able to consume the amino acid asparagine. When we looked into this in more detail, we found that this activity could be attributed to a particular enzyme called asparaginase-like protein 1 (Asrgl1).
Bacteria have been found to produce asparaginases that can deprive cancers of essential asparagine, for instance in acute lymphoblastic leukaemia (ALL). This is currently the gold standard for ALL therapy. However, there are issues with tolerability to this therapy due to the fact it is of bacterial origin. Moreover, there are issues with toxicity due to off-target effects.
Asrgl1 is a promising candidate because it is of a human source. It has good specificity for asparagine and therefore might be a good alternative therapy. At the moment, particular types of cancer such as several types of leukaemia are our main goal with regards to using the enzyme as a cure. However, asparagine plays a role or is thought to play a role in many other types of cancer too, such as breast cancer and particularly metastases from breast cancer, so there is room to expand the potential therapeutic use of this enzyme.
We recently got funded by InnovateUK and are starting off the project now.
Q: Can you explain the project in more detail?
The foundation of the project is that we want to express this enzyme, Asrgl1, in a yeast platform. Ideally you would get an enzyme of interest straight from the source, such as from humans or other animals that are sufficiently similar in this aspect. However, this is quite difficult to do, especially if you want to obtain more than a very small amount of the enzyme. Most recombinant proteins are expressed in bacteria because the genome of bacteria can easily be manipulated and these bugs quickly grow to very large numbers. However, bacteria do not have the same set of modifications for the proteins they generate, so you may not get exactly the same protein (in our case, an enzyme) as you would get from the human source. Yeast is a compromise for these two other options as their protein-modification machinery is more similar to humans, but yeast cells are much easier to grow in large quantities than human cells. Yeast is thus more relevant for industrial applications.
The InnovateUK fund is for the proof of concept. The first step of this project is expression of this enzyme in yeast, and then we want to generate larger amounts of the enzyme so we can study its functioning. We are keen to study its activity, kinetics, stability in various conditions, and we also want to look at its in vitro anti-cancer properties.
What we expect is to find out which properties of the enzyme are amenable to therapeutic use and which are not. We’ll be doing all of this project in Biomakespace. Off the back of this, in future projects, we want to see how we can develop this system further, for instance, for production and characterisation of other enzymes.
Outline of the project to study Asrgl1: Yeast cultures will produce the enzyme (shown as ASNase); after purification, the enzyme’s activity and kinetics, stability, and potential anti-tumour effects will be studied.
Q: Do you currently have all the experience/skills you need to start (and complete) this project or are you planning to learn these through Biomakespace?
I have quite some experience in research but there is always room to learn more. For instance, I only have a basic understanding of some of the areas of the project, so we have hired a technician to help us out.
Q: Are you looking for others to join you on this project?
I think we are all set at the moment for this project. If this project is successful, in the future we would want to expand our team.
Q: I know this is a tough question, but what is your current timeline?
Since the project is funded by an InnovateUK grant, we have 12 months to work on it. The project is due for completion at the end of April 2020. We have identified four key steps:
· expression of the enzyme in yeast
· characterisation of its activity and kinetics
· characterisation of its stability
· investigation of its anti-cancer activity.
The 12-month time frame is split about evenly over these four stages. We have to report to the grant provider regularly to discuss progress so this will hopefully keep us on our timeline.
Q: What do you expect from completing this project?
We want to look at the strengths and weaknesses of this enzyme and then see whether it is a good candidate to develop further into a potential therapy.
Q: Could you provide some resources to more information on the topic of your project?
Yes, the original research paper describing the behaviour of the enzyme in extra-cellular vesicles: