30 years of research
To mark the 30th anniversary of our research institute, ANRI, we’re looking back at some of our major research achievements that have helped more people survive and thrive after a stem cell transplant.
Behind every stem cell transplant from a donor, lies the genetic matching that makes it possible.
To give a transplant the best chance of working, doctors search for a donor who is well matched to the patient based on their HLA type – determined by genes that are crucial in how the immune system works. If these genes are not well matched, there is a higher chance of serious complications.
Over decades of work, scientists have improved their understanding of the genetics of the immune system to allow even more accurate matching between patients and donors. Research at the Anthony Nolan Research Institute (ANRI) has made fundamental contributions to our global understanding of what makes an ideal match for a transplant. This ultimately means more patients living longer and with fewer complications after their transplants.
The genes behind transplant matching present us with an enormous, ever evolving puzzle. So how has our research helped us solve this puzzle, and what is left to discover?
The HLA genes: A puzzle of unmatched complexity
The HLA genes are the most varied collection of genes known to humanity.
You inherit a set of HLA genes from each parent, meaning you have two versions (known as ‘alleles’) of each HLA gene. The scientific community has discovered thousands of different alleles of the HLA genes so far, with theoretically millions more undiscovered alleles across humanity.
Your ‘HLA type’ is the particular combination of alleles that you’ve inherited. Currently, transplant matching focuses on six HLA genes (although there are many more).
Because of the way your HLA genes are inherited, your chance of having the same HLA type as an individual sibling is one in four. You will almost never have the same HLA type as your parents, because they will each have given you ‘half’ of their own HLA type. For these reasons, often people in need of a transplant don’t have a match in their family, and look for an unrelated donor on stem cell registries.
The reason for this puzzle piece-like complexity in the HLA genes comes down to evolution. The HLA genes help our immune system tell friend from foe, enabling it to target infections and disease. The more versions of the HLA genes we have across humanity, the better we are, collectively, at recognising and destroying potentially dangerous viruses and bacteria. While crucial for the survival of our species, this also means that most people’s immune systems are not fully compatible with each other – creating a difficult challenge for healthcare professionals looking for matches for people in need of a stem cell transplant.
And HLA genes continue to evolve and mutate, constantly throwing new variants and combinations into the mix. Keeping up with this dynamic puzzle is a monumental task – one which the researchers at Anthony Nolan are well acquainted with…
HLA is a very exciting field to work in, and it often feels like HLA has a consciousness that is working against me trying to foil my plans. I like puzzles and solving problems… I want to beat HLA at its own game.
Dominic Barker, Senior Bioinformatics Research Scientist
The IPD-IMGT/HLA Database: Building a library of puzzle shapes
Dominic is one of the scientists who currently maintains the IPD-IMGT/HLA Database – the official global resource for all the known variants of the HLA genes. Essentially, the database is a library of the different ‘puzzle shapes’ that the HLA genes can take, down to the tiniest variations – allowing us to identify each piece of the HLA puzzle with more accuracy.
This database underpins transplant science and provision around the world, helping scientists and clinicians work from the same library of ‘puzzle shapes’ when researching the HLA genes, or looking for a patient’s perfect donor match.
A small team at Anthony Nolan has managed this database, hosted by the European Bioinformatics Institute (EMBL-EBI), since Professor Steven Marsh and Dr James Robinson took it online in 1998 – moving from floppy discs to the internet. Now, Dr Robinson leads the team of bioinformaticians who are responsible for curating and uploading new HLA variants to the database, while also ensuring its continued smooth running and implementing upgrades and improvements.
As the database expands, we gain a better understanding of the different ‘puzzle shapes’ that HLA can take, and ultimately it will help us find more accurate matches between patients and donors.
I can look back on my career and I realise that every transplant that has happened within the world, somehow I can link it back to the work of the database – it’s that fundamental to the work of clinical transplant.
Dr James Robinson, Director of Bioinformatics Research
The Patient/Donor Programme: Discovering how the pieces fit together
With the HLA ‘puzzle shape’ database providing a foundation for global research, the major question we must answer next is: which shapes fit together the best for a successful stem cell transplant?
This, unfortunately, doesn’t turn out to be as straightforward as slotting two simple puzzle pieces together. For example, a patient might have a donor who appears well matched when we look at how the puzzle pieces slot together, but the transplant doesn’t go as well as expected. Or, a patient might have a mismatched donor where the pieces don’t quite appear to align, but the transplant is a major success. Essentially this means we have more to understand about how our HLA puzzle pieces fit and don’t fit.
The Patient/Donor Programme, running for over 30 years at Anthony Nolan, is our most long-term and arguably most impactful research programme – helping us get to the bottom of how exactly the HLA genes fit together best for a transplant.
Over the years, our scientists have collected thousands of blood samples from patient and donor pairs who have undergone a transplant. By linking factors like their genetics and the long-term success of the patient’s transplant, the team can learn what factors are most important for a good match.
Findings from the Patient/Donor Programme have made a huge impact for how stem cell transplants are performed around the world. Most notably, in 2003 the programme discovered the importance of a sixth HLA gene in transplant matching in the UK, HLA-DPB1, which is now used widely in transplant centres across the world, reducing the likelihood of negative side effects.
In 2017 the Programme confirmed that, in the UK, younger donors improve the chance of survival for patients. This research reinforced Anthony Nolan’s decision to become the first register to lower recruitment to 16, helping provide patients with more options for a well-matched donor.
The Patient/Donor Programme is crucial in bringing clinical improvements to transplant matching in the UK. The programme is unrivalled in the size of its data set, and the speed with which new findings can be brought into clinical practice. It will continue to improve and refine patient/donor matching, and is currently investigating new genetic factors in transplant matching as well as which types of mismatch are better tolerated for patients who do not have access to a fully matched donor.
Ultimately, the goal of the Patient/Donor Programme is to figure out exactly what picture is on the front of the box of the HLA ‘puzzle,’ allowing us to fit all the pieces together as best as possible.
We are able to improve survival rates for patients through the Patient/Donor Programme, because we are able to study the individuals who have gone through the transplant process, and understand which factors have made them successful and which factors potentially have led to poor outcomes. Using that, we can inform how we change the future practice for patients.
Dr Neema Mayor, Director of Immunogenetics and Research Services
Our collaboration with DATRI: Adding more matching puzzle pieces to the box
Understanding which donor matches are best is one thing; but making sure we have enough donors with matching HLA types is another. This could be compared to making sure we have many different kinds of possible puzzle pieces in our enormous HLA puzzle.
In the UK, people from minority ethnic backgrounds are more likely to have a rare HLA type compared to people from White, Northern European backgrounds. By recruiting more donors who have less well-represented HLA types, therefore providing more donor options for people with relatively rare HLA types, we can start to address this particular inequity.
We have developed an NIHR-funded pilot project together with an Indian stem cell register, DATRI, to recruit more potential donors with HLA types that are underrepresented in the UK and internationally. Anthony Nolan scientists are working to identify areas of India where people are more likely to possess these HLA types, so recruitment can be targeted to those areas.
The ultimate goal is to improve the variety of HLA types seen on international registries, especially for patients with South Asian heritage who may struggle to find a matching donor due to having relatively uncommon HLA types on the international register.
If this pilot project is successful, similar approaches could be used in other parts of the world to further enrich the global representation of HLA types – working towards having a more ‘complete’ collection of HLA puzzle pieces in the box, and striving towards more equity in transplant matching.
Meeting the challenge
The puzzle of matching the HLA genes for stem cell transplants is a complex and compelling one. Solving it promises to improve transplant outcomes and help more patients survive and thrive. And while its complexity can be daunting, we’re ready to meet that challenge.
This is work that could continue for decades – and it requires your support. You can donate to help support our research here.