Our type 1 diabetes research
Left to right: Nathan Zammit, Nazanin Beyzaie, A/Prof Shane Grey, Stacey Walters, Daniele Cultrone and Suzanna Pilgrim
A cure for type 1 diabetes (T1D) seems not only possible, but probable.
Our team is probing the molecular causes of this disease in the hope of creating new therapies.
We’re using state of the art gene analysis technologies, molecular biology techniques as well as experimental models of diabetes to help search for a cure. We have discovered novel genes that control how insulin-producing cells die when attacked by the immune system.
Using whole-genome sequencing to examine DNA has led to the discovery that most disease is linked to genetic mutations. Instead of trying to treat the symptoms of the disease, we can now aim to treat the mutations causing them.
Whole-genome sequencing gives our immunogenomics team the unparalleled ability to test families with a genetic risk for T1D, and diabetic complications like renal failure and hypoglycaemic unawareness. This leads to better prevention and more effective personalised medicine.
Read more about our functional genomics approach to type 1 diabetes.
Key areas of investigation
The role of genes
There is strong evidence that T1D arises when a certain combination of genes come into contact with a particular environmental influence. Past research has identified some good candidate genes, and raised suspicion on others. We know less about the particular changes in the genes, and how as a result, their function differ.
Our research uses new genome technologies to track and record gene changes in T1D. We’ve begun by sequencing the genomes of 50 individuals with T1D.
We’ve shown how changes in one gene called A20 (known to be a player in type 1 diabetes) contributes to diabetes susceptibility, and also enhances rejection in islet transplantation. This data will bring us closer to a better understanding of T1D and hopefully a cure.
Our team of senior researchers from Garvan includes clinical leaders from Westmead Millennium Institute and Royal Adelaide Hospital, experts from the Charles Perkins Centre, University of Sydney and the Australian National University, as well as international leaders from New Zealand, USA and Canada.
Preventing immune attack
In T1D, the immune system is unable to tell the difference between harmful invaders and the body’s own cells. One way to cure diabetes would be to persuade the immune system to accept pancreatic beta cells as part of the body.
Some of the immune system culprits are T cells. T cells develop in the thymus gland and are ‘educated’ to become helpers, warriors, or regulators. In T1D, the helper and warrior T cells work together to kill beta cells, while the regulators appear unable to stop this.
The Garvan team has worked up a vaccine, called BCMA-Fc, that redresses this imbalance. When given to mice with a disease similar to T1D, the vaccine increased the number of regulator T cells and reduced the warriors.
In a human trial of a related compound, rituximab, people retained the ability to produce insulin for up to 18 months. Further studies will test whether the drug can continue to maintain insulin production.
Islet transplantation surgery
One solution would be to replace the destroyed pancreatic beta cells with new ones. Isolated islets from a donor pancreas can be transplanted into another person, where they begin to produce insulin again.
These studies reveal an important new paradigm in transplantation
As part of the Australian Islet Transplant Consortium, we compared the gene signatures of transplants or ‘grafts’ with patient outcomes, seeing what constituted a good or a poor graft. Of the 17 patients who received new beta cells from a donated pancreas, seven have stopped using insulin completely. The others need less insulin, and have better diabetes control.
One problem with islet transplantation is that people need two or three donations, so fewer people can be helped. Recipients also need to take powerful immunosuppressive drugs, limiting the potential of this treatment.
We have also found that islets are full of inflammatory molecules (much like stressed or damaged tissue). However, islets are easier to manipulate than the immune systems of patients, and this lets us to treat islets with anti-inflammatory compounds before transplantation.
We’re also modifying these fragile beta cells genetically so they’ll survive the transplantation process. In mice, we’ve demonstrated that engineering an islet graft with anti-inflammatory compounds helps the grafts survive.
These studies reveal an important new paradigm in transplantation, whereby the islet graft can dictate T cell decisions. We’ve used this to develop the concept of a ‘death-defying islet’ which is protected from immune attack — and so do away with the need for immunosuppressive drugs.
T cells to the rescue
The Garvan Institute is embarking on a joint program with the Victor Chang Cardiac Research Institute and the University of Adelaide to investigate if we can train the body to heal itself from T1D. The program stems from the discovery that zebrafish can use their immune systems to repair and regenerate damaged organs and tissues, including the pancreatic beta cells destroyed in T1D.
Dr Kikuchi’s discovery opens the door to a new possibility that we can train the body to heal itself.
It may be possible to harness this same power and train the immune system of people with T1D to repair their own insulin-producing cells.
Dr Kazu Kikuchi, a co-investigator on the study, uncovered a surprising link between the immune system and heart regeneration in zebrafish. Dr Kikuchi studies zebrafish because their tissues can regenerate after damage. He found that T cells were needed for zebrafish hearts to regenerate – and that they supply crucial ‘regeneration factors’ in the process.
He also uncovered the possibility that T cells may kickstart regeneration in other tissues.
National and international collaborations
- Australian Islet Transplant Consortium including Westmead
- Hospital, Sydney; St Vincent’s Institute, Melbourne and Royal
- Adelaide Hospital, Adelaide, Australia
- Charles Perkins Centre, University of Sydney, Sydney, Australia
- Childrens Hospital, Westmead, Sydney, Australia
- Garvan Institute of Medical Research, Sydney, Australia
- Institute of Cellular Medicine, Newcastle University, UK
- John Curtin School of Medical Research, ANU, Canberra, Australia
- Kinghorn Centre for Clinical Genomics, Sydney, Australia
- National Computational Infrastructure (NCI), ANU, Canberra, Australia
- Scottish National Islet Transplant Programme, Edinburgh, Scotland
- Translational Genomics Transplant Laboratory, University of Virginia, Virginia, USA
- University of Adelaide, Adelaide, Australia
- Victor Chang Cardiac Research Institute, Sydney, Australia
- Wellcome Trust/MRC Institute of Metabolic Science, Cambridge, UK.