Led by Drs Aida Martinez-Sanchez and  Prashant Srivastava at Imperial College London, along with Dr Teresa Rodriguez-Calvo at Helmholtz Zentrum Munich, this project will investigate how tiny molecules called microRNAs change the function of insulin-making beta cells. Studying how these molecules are different between beta cells from people with and without type 1 diabetes, and in those grown from stem cells, could help to improve the effectiveness of beta cell transplants. 

Background to the research project – every beta cell is unique

In type 1 diabetes, insulin-producing beta cells are destroyed by the immune system. Beta cells are all unique, and some are more prone to the type 1 immune attack. This uniqueness is known as heterogeneity and plays an important role in how type 1 diabetes develops. 

MicroRNAs (miRNAs) are tiny molecules in our cells that switch different genes on and off and change how the cell works. They’re important in beta cell development and function, and differences in beta cell miRNA could be key to why some beta cells are more vulnerable to the type 1 attack. 

Drs Aida Martinez-Sanchez and Prashant Srivastava think that beta cells grown from stem cells – which are being developed as potential treatments for type 1 diabetes –   might have different miRNAs than beta cells found in humans. This could explain why stem cell-beta cells don’t function as well as human beta cells and are often rejected after transplantation if they’re not destroyed by the immune system first. They also suspect that there are differences between beta cell miRNA in people with and without type 1 diabetes. 

What will the team do in this project?

Drs Martinez-Sanchez and Srivastava want to examine differences in the miRNA of different kinds of beta cells. There are two main parts to the research: 

1. In beta cell and pancreas samples from donors with and without type 1 diabetes, they’ll investigate which genes are switched off by miRNAs with a method called AgoTRIBE. This works by ‘tagging’ switched off genes in individual beta cells. They’ll also use an advanced microscope to look for the tags, helping them to find out more about miRNA and how it impacts beta cell function. 
2.  Next, they’ll use AgoTRIBE to understand whether miRNA in beta cells grown from stem cells is different to that in beta cells from donors. They’ll also use a technique that will help them understand more about the role of miRNAs in beta cell survival and healthy functioning. 

How will this research help people with type 1 diabetes?

Understanding how miRNAs influence the behaviour and survival of beta cells could help scientists to develop healthier, longer-lasting lab grown beta cells. This could help to improve the effectiveness of beta cell transplants by making sure the transplanted cells are tougher and less likely to be rejected, which in turn would reduce the need for insulin injections.  

This research could also shed more light on how to protect beta cells from the immune attack, potentially preventing or slowing down the progression of type 1 diabetes.  

Dr Aida Martinez-Sanchez said:

“MicroRNAs are tiny molecules essential for keeping insulin-producing beta cells alive and well. However, not all beta cells are the same—some are more resistant to immune attack, while others are more vulnerable. Also, some beta cells are better at releasing insulin than others. In this project, we will use pioneering molecular and cellular biology techniques to explore whether microRNAs contribute to these differences.

“Identifying which miRNAs to manipulate could help us to grow the very best beta cells in the lab. The complex methodologies we’re developing have the potential to form the basis of future research in other important aspects of beta cell biology, such as how to reduce the risk of transplant rejection, or delay or prevent beta cell destruction in type 1 diabetes.”

Led by Professors Shoumo Bhattacharya and David Hodson at the University of Oxford, this project will take inspiration from tick saliva to develop a defence mechanism for beta cells transplanted into people with type 1 diabetes. This research could reduce the need for immunosuppressing drugs, leading to longer-lasting and more successful beta cell transplants.  

Background to the research project – taking evasin action

Some people with type 1 diabetes can have insulin-producing beta cells (taken from donors or grown from stem cells) transplanted into them, which replace their own cells that have been destroyed by their immune system. But the immune system often tries to destroy these as well. This means that transplant recipients need to take strong drugs that dial down their immune system, called immunosuppressants.  

And even with immunosuppressants, the immune system still eventually kills off the transplanted cells and most people end up needing insulin again after a few years. 

Transplanted beta cells release chemical signals called chemokines, which act like beacons that lead the immune system to attack them in type 1 diabetes. Researchers have struggled to find ways to block these signals, because there are so many different types of chemokines. 

Parasitic ticks have evolved proteins called evasins which can block a wide range of chemokines, allowing them to bite through skin and feed on blood without being detected by the immune system. Professors Shoumo Bhattacharya and David Hodson think evasins could unlock new ways to block chemokines released by transplanted beta cells, helping them to evade the type 1 immune attack and survive and thrive for longer after transplantation, without immunosuppressants. 

What will the team do in this project?

Professors Shoumo Bhattacharya and David Hodson have already identified the part of the tick evasin that’s responsible for blocking chemokines, called a peptide. In this project, they plan to make its blocking power stronger by adding chemicals to it in the lab. 

Next, to make the peptide last longer in the body, they’ll attach it to parts of antibodies (proteins that protect the body from harm), creating what they’re calling a ‘nanobody’. They’ll also experiment with adding the peptide to other substances to improve its stability and effectiveness. 

After this, they’ll engineer beta cells to produce chemokine-blocking peptides of their own, and test if they’re working by exposing them to chemokines in the lab, and checking whether immune cells spot and attack them. Lastly, they’ll verify all their lab-based findings in mice with type 1 diabetes. 

How will this research help people with type 1 diabetes?

The peptides developed from tick evasin in this project could improve the success of beta cell transplants for people with type 1 diabetes, by giving them a built-in defence mechanism against the immune system. 

They could reduce the need for immunosuppressing drugs, which can make it harder for people to fight off infections, and can even increase the risk of developing cancer. Lowering the risk of side effects from immunosuppressants could ultimately lead to better outcomes for people with type 1 diabetes. 

Professor Shoumo Bhattacharya said:

“Our lab is looking to nature for new ways to treat inflammatory diseases. Ticks have evolved over millions of years to block inflammatory signals called chemokines. Chemokines cause beta cell inflammation which is important in the development of type 1 diabetes and can cause transplanted beta cells to fail.

“We are very excited to receive funding from the Grand Challenge, with which we aim to develop tick-inspired treatments to help people with type 1 diabetes. These treatments could improve the success of beta cell transplants, and prevent type 1 diabetes from developing.”

Led by Drs Craig Beall and Thomas Piers at the University of Exeter, this project will explore whether a type of cell found in the brain can help beta cells to make more insulin while hiding them from the immune system’s attack. Using ‘organ-on-a-chip’ devices, their approach could improve the outcomes of beta cell transplants. 

Background to the research project – brain cells for beta cells 

In type 1 diabetes, the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. But beta cells aren’t the only cells that make insulin, and the pancreas isn’t the only place in the body where insulin is made. 

Insulin is produced in the brain. There are at least six different types of brain cells that make insulin, and in type 1 diabetes these are hidden from the immune system attack. The cells all have different functions but the insulin they produce isn’t released in the right place or in high enough quantities to help manage blood sugar levels in type 1 diabetes.  

Dr Craig Beall and Dr Thomas Piers are investigating if a type of brain cell can be engineered to work together with beta cells to make lots of insulin, out of sight from the immune system. The hope is that this could help improve the effectiveness of beta cell transplants in people with type 1 diabetes.  

What will the team do in this project?

In the lab, Dr Beall and Dr Piers will grow clusters of insulin-producing brain cells and beta cells on a special plate called an ‘organ-on-a-chip’ device. They’ll recreate the conditions of type 1 diabetes, and test how these clusters react to sugar, nutrients, and treatments, compared to clusters of beta cells from human donors. 

They’ll also test how well blood vessels form around them on the organ-on-a-chip device as this will be important for keeping the cells alive when transplanted. 

How will this research help people with type 1 diabetes?

In current beta cell transplants, the immune system tends to attack transplanted beta cells, meaning some of the benefits of transplants are short-lived. Or people who’ve had transplants need to take drugs that dial down their immune system, called immunosuppressants. Dr Beall and Dr Piers’ project could lead to the development of new or improved beta cell therapies that can help people with type 1 produce insulin for longer periods without the need for immunosuppressant drugs. 

Dr Craig Beall said:

“We are really excited to have this funding from the Type 1 Diabetes Grand Challenge. This scheme really pushed us to harness brainpower to come up with the best possible ideas and to look for creative new concepts. The moonshot we’re aiming for is a cure that frees people with type 1 diabetes from insulin injections and immunosuppression, and this is the next step in that journey.“

Led by Professor David Hodson, at University of Oxford, Dr Ildem Akerman, at University of Birmingham, and Dr Johannes Broichhagen, at Leibniz FMP, this project will pioneer new approaches to make better beta cells ready for transplantation, protect the beta cells from an immune attack, and to regrow beta cells inside the pancreas. This research could speed up progress to making life-changing beta cell therapies available for people with type 1 diabetes.

Background to the research project

For people living with type 1 diabetes, a cure is likely to mean a combination of different treatments. We need to replace insulin-making beta cells that have been destroyed by the immune system, so people can start to make their own insulin again. And we need to protect new cells from an immune system that is primed to seek out and destroy them.

To reach this goal, scientists are pioneering methods to grow new beta cells in the lab and transplant them into people with type 1 diabetes. Scientists can do this using stem cells. Stem cells have the special ability to become just about any cell in the body, including beta cells. But at the moment, beta cells made from stem cells just aren’t as good at controlling blood sugar levels as real beta cells and don’t survive for long enough. Because of these challenges, scientists are also exploring treatments that could trigger new beta cells to regrow directly inside the pancreas.

Once we can give people with type 1 working beta cells, we also need to protect them from the type 1 immune attack. Treatments, called immunotherapies, are designed to do this by retraining the immune system.

Professor Hodson, Dr Akerman and Dr Broichhagen are hoping to make transformational progress in all three of these areas with the help of two molecules known as incretin receptors. These receptors are found on the surface of beta cells and act as on-off switches to help control the release of insulin. Scientists have already harnessed their potential and developed type 2 diabetes drugs that target the receptors, to help people lower their blood sugar levels. They think the receptors could be key to unlocking major progress in type 1 diabetes beta cell therapies too.

What will the team do in this project?

1. Produce better functioning and longer lasting beta cells made from stem cells.

The team has previously discovered that around 20% of lab-made beta cells have incretin receptors on their surface, and that these are better at producing insulin than beta cells without it.

First, the team will develop a way to find the cells that have the receptors, using a technique called cell sorting. If this method was used to analyse a smoothie it would be able to tell us what fruits were used to make it and locate them. Then to check how well they are working, they’ll transplant the receptor beta cells into mice with type 1 diabetes and test if they work better than beta cells without these receptors.

2. Deliver an immunotherapy straight to the surface of the beta cells, to help better shield them from an immune attack.

The team will design an immunotherapy that will seek out and bind to incretin receptors at the surface of beta cells, so the treatment goes straight to where it’s needed. They’ll investigate if this precision delivery makes the immunotherapy more effective at slowing or stopping an immune attack, and brings fewer side effects, in mice with type 1 diabetes.

3. Coax other cells in the pancreas, called alpha cells, to transform into beta cells.

Alpha cells produce a hormone that raises blood sugar and are left unharmed by the type 1 immune attack. They carry incretin receptors on their surface. The research team will modify existing drugs that target incretin receptors to carry cargo that works to change the identity of an alpha cell into a beta cell.

How will this research help people with type 1 diabetes?

Beta cells therapies have the potential to transform how we treat type 1 and to form part of a cure. Selecting for the top performing lab-made beta cells and arming them with a protective immunotherapy will be key in moving transplants from the lab towards the clinic. While enticing new beta cells to grow inside the body could give us another way of restoring people with type 1’s own insulin production.

Bringing back beta cells would allow us to say goodbye to insulin injections and pumps, reduce the need for constant blood sugar monitoring and help prevent diabetes complications.

Professor David Hodson said:

“During the past decade, a lot of our work has focused on insulin-boosting molecules found on beta cells, called incretin receptors, which have become major drug targets for type 2 diabetes and obesity therapy. Using our knowledge and innovative technologies, we will now translate our work in type 2 diabetes and leverage the potential of incretin receptors in the type 1 diabetes space.

“We’ve developed an ambitious three-prong research programme that spans beta cell replacement, protection and regeneration, so as to give us the best chance of driving discoveries that could make these treatments available for people living with type 1 diabetes.”

Professor Francesca Spagnoli and Dr Rocio Sancho at King’s College London, together with Professor Molly Stevens at University of Oxford, hope to unlock the full potential of transplants of insulin-making beta cells. They’ll innovate ways to keep cells safe from harm once they’re transplanted into someone with type 1, so we can move closer to the day when beta cell transplants can free people from the relentless task of managing type 1 diabetes.

Background to the research project

Scientists are using stem cells to develop treatments to replace the beta cells that have been destroyed in people living with type 1 diabetes. Stem cells have the special ability to shape-shift into other types of cells in the body, including beta cells.

Small clinical trials of stem cell-turned beta cell transplants are now underway and are showing early promise. But after being transplanted into people with type 1 diabetes, new beta cells struggle to survive and gradually lose their ability to make enough insulin and tightly control blood sugar levels.

Using expertise from different fields including biology, immunology and engineering Professor Spagnoli, Dr Sancho and Professor Stevens will lead a team to tackle these challenges and give lab-grown beta cells the tools they need to survive and do their job after transplant.

What will the team do in this project?

The team will explore ways to both create tougher beta cells that can better withstand their post-transplant environment, and to make this environment friendlier.

1. 1. They’ll replicate the supportive environment found in a healthy pancreas by coating their lab-grown beta cells with protective gels that can help them stay safe and strong.
   2. They’ll use nanoparticle technology to deliver ingredients that can give the cells a survival boost after transplantation and protect them from an immune system attack.
   3. They’ll develop a transplantation device that beta cells can live inside. This protective ‘cage’ will provide the cells with the right levels of oxygen they need to survive and make them more resistant to their hostile surroundings. They’ll transplant this device containing their reinforced beta cells into rats with type 1 diabetes to investigate if the cells manage to survive long-term and produce enough insulin to control blood sugar levels.

How will this research help people with type 1 diabetes?

Creating the ideal conditions that keep transplanted beta cells alive and kicking could help us move quicker towards a new era in type 1 diabetes, where people are free from the burden of taking insulin, the fear of hypos and complications, and the mental load of self-managing their blood sugar levels.

Professor Francesca Spagnoli said:

“The Type 1 Diabetes Grand Challenge funding means we can explore new avenues in diabetes research. We’ll be able to start moving some of our discoveries closer to clinical applications and drive improvements in cell replacement therapies, which could ultimately cure type 1 diabetes.”

Professor Shareen Forbes, at University of Edinburgh, and Dr Lisa White, at University of Nottingham are exploring better and more innovative ways to transplant islets, clusters of pancreas cells, into people with type 1 diabetes to enable them to make their own insulin. This could pave the way for wider use of this life-changing treatment, while also making islet transplants much more effective.

Background to the research project

In an islet transplant, clusters of cells (called islets) from a donor pancreas are transplanted into someone with type 1 diabetes and start to produce insulin. They’re currently offered to some people with type 1 diabetes who have severe hypos and no awareness of them. However, usually about 60% of the donor cells die soon after transplant.

This means lots of donor islets are needed to have an impact on blood sugar levels. But with a limited number of donor pancreases available for islet transplantation, very few people with type 1 diabetes can currently benefit.

What’s more, islet transplants aren’t as effective as they could be. They rarely allow people to produce enough insulin to stop insulin therapy. And people need to take anti-rejection drugs to prevent their bodies rejecting the donor cells, which can bring serious side-effects.

Scientists are looking at ways to improve the benefits and availability of islet transplants, so they can become part of a cure for type 1 diabetes. Professor Forbes and Dr White think drugs packaged inside microparticles could provide an answer. Microparticles are tiny particles that help to protect a drug from the harsh environment in the body and deliver it to exactly where it’s needed. If drugs that keep islets healthy and protect them from the immune system could be transplanted alongside islets, it could help them to survive and thrive for longer.

What will the team do in this project?

Professor Forbes and Dr White will package microparticles with immune-altering and other drugs to improve the survival of transplanted islets. They will test different combinations of drugs in islet transplants in mice, to see which work best to help islets survive and control blood sugar levels.

The team will then run experiments to investigate how to scale up the dose of the drugs and how the treatment might work in humans.

Finally, they will check if the most promising drug microparticle combinations also work to protect beta cells that have been grown in the lab from stem cells.

How will this research help people with type 1 diabetes?

At the moment only a tiny fraction of people living with type 1 diabetes are eligible for islet transplants. And they’re far from a permanent or perfect fix.

If the team can improve the survival of donor islets it could unleash the benefits of islets transplants – making them much more effective at managing blood sugar levels, eliminating the need for anti-rejection drugs and opening them up for more people with type 1 diabetes.

In the longer-term, their discoveries could also be used to radically improve transplants of lab-made beta cells. This would entirely remove the supply problem of using donor cells, so that in the future everyone with type 1 diabetes could benefit from transplants.

Professor Shareen Forbes said:

“I hope the Grand Challenge’s investment will give people living with type 1 diabetes hope that a cure can be achieved in their lifetime.

“The funding has allowed scientists from diverse fields to come together in this project with a common goal of doing some truly innovative research that will advance the field. By improving the benefits of human pancreas cell transplants, and in time transplants using stem cells, we hope to contribute towards a future where people with type 1 diabetes can live a life free from insulin injections.”

Professor Shanta Persaud and Professor Aileen King are world-leading experts at studying how insulin-producing beta cells work and develop in humans. They’ll use their specialised knowledge to run state-of-the-art experiments and find ways to improve methods to engineer new beta cells in the lab, so they act and react more like real human beta cells. This project could help to accelerate progress towards life-changing new treatments that restore insulin production in people with type 1 and bring us closer to a cell-based cure for the condition.

Background to the research project

People with type 1 diabetes rely on insulin injections or pumps to replace what the immune system has destroyed. While insulin therapy is lifesaving, current insulins don’t come close to the minute-to-minute adjustments that beta cells make to manage blood sugar levels.

Scientists have been trying to find ways to give people with type 1 new beta cells, by making them in the lab from stem cells and transplanting them inside the body. Although lots of progress has been made in recent years, lab-made cells just aren’t as good at producing insulin or responding to changing blood sugar levels as real beta cells are.

Lots of what we know about turning stem cells into beta cells is based on how beta cells develop in mice. But Professor Persaud and Professor King have been studying human pancreas development and want to harness this knowledge to make better performing beta cells that are well equipped to survive transplantation.

What will the team do in this project?

Professor Persaud and Professor King will lead a team to:

1. Improve the process of turning stem cells into beta cells.

They’ve discovered that cells that support nerve cells (called Schwann cells) may also help support beta cells. They will carry out tests to see if Schwann cells could improve the ability of stem cells to transform into functioning beta cells.

2. Make sure lab-grown beta cells produce the right amount of insulin.

Once beta cells have been made, the team must make sure they are an elite class of insulin producers. They’ll run tests to see what type of support, nutrients and special molecules can help the newly made cells work even better.

Next, they’ll use state-of-the-art techniques to rigorously test if the lab-made beta cells are really acting like real beta cells. This includes looking at how the lab-made beta cells use oxygen, store insulin and respond to rising blood sugar levels.

3. Give lab-grown beta cells the best chance of surviving after transplantation.

The team will coat clusters of lab-grown beta cells with survival boosting molecules, by a process called nanoencapsulation, and test if this helps them survive transplantation better.

How will this research help people with type 1 diabetes?

Having an unlimited supply of elite beta cells ready for transplantation could mean a future where people with type 1 diabetes never have to think about their blood sugar levels or insulin, because their beta cells are doing it for them. While transplants would also help to reduce the risk of developing diabetes complications.

If successful, this project will turbo charge progress towards clinical trials of transplants using new and improved lab-grown lab cells, and move us closer to a cure.

Professor Aileen King said:

“People with type 1 diabetes have to constantly think about their blood glucose levels and adjust their insulin doses in response. Our aspiration is to produce fully functioning beta cells suitable to implant into people living with type 1 diabetes, which do this on their behalf.

“This would be transformative for people with the condition, as it would restore the body’s minute-to-minute insulin production that is required to carefully control blood glucose levels – reducing the risk of dangerous blood sugar lows and long-term diabetes complications, while also reducing the huge psychological impact of living with diabetes.”