When I first met Professor Carola Vinuesa, she invested well over an hour of her time to explain her work at the Centre for Personalised Immunology (CPI) to me. She speaks with such urgency, and passion, that this would be like three hours at normal speaking rate. She even drew on the whiteboard. I remember a stick figure and then an arrow pointing to a drawing of a mouse and then back again to the person.
The science of it is mind-bending for a lay-person: you edit the DNA of a mouse (!) so that it has the identical genetic mutation of a particular human (!) suffering from an auto-immune condition. And then, using the mouse model, you can develop specific treatments just for that person.
“So, if I was a patient,” I asked. “There would be a ‘mouse-me’ somewhere in the lab?”
“No,” she said. “There would be many ‘mouse-yous.’”
When I met Penny, a patient at the CPI, I was extremely eager to ask about her mouse model.
She looked confused.
“What mouse?” she said.
Sometimes it’s hard to see the most important part of a story.
When Penny was in her mid-20s, things started to go wrong. She got chest infections, one after the other, and then so often that it left scarring on her lungs.
She couldn’t play with her kids, and would be left breathless just from hanging out the washing. After a year had passed, she realised she had been sick for 11 of those months. And that’s how every year went for the next five years.
She went from doctor to doctor looking for answers, and regularly turned up at the emergency department.
“They were telling me it was all in my head and I started to believe them,” Penny remembers. “I thought, this can’t be real.”
Finally, after specialist Professor Matthew Cook noticed a problem with Penny’s immune system, she was diagnosed with common variable immune deficiency (CVID). This was even more complicated because Penny has immune deficiency plus lung inflammation even when she did not have infections.
This should be the part of the story where I tell you that thanks to a medical breakthrough at the CPI, Penny is cured. But if you know anything about immune disorders, you’ll know this story is not going to end any time soon.
Diagnosing immune disorders can be very difficult, and it is not unusual for the process to take years, as in Penny’s case. The category includes conditions as varied as rheumatoid arthritis, lupus, inflammatory bowel disease, multiple sclerosis, type 1 diabetes and psoriasis, which all present with vastly different symptoms, overlapping with symptoms for many other conditions.
Dr Simon Jiang is a researcher with the CPI and also a Canberra Hospital specialist in one of the conditions the CPI is investigating: autoimmune kidney disease. When he sees patients, he says they have usually been experiencing vague symptoms such as low energy and appetite, or more telling symptoms like rashes and swollen joints for months, or longer, before ending up in hospital.
“The general presentation is people feeling profoundly unwell, like the worst case of flu you’ve ever had, but it never goes away. Some of the more catastrophic presentations are people coming in coughing up blood, or unable to use their arms, their legs.
“It’s incredibly tough to treat people based on an incomplete understanding of what is affecting them.”
While eventually securing some kind of a diagnosis comes as a relief for many patients, it doesn’t end the journey of uncertainty, but starts another, equally frustrating, journey of treatment.
Immune disorders manifest differently in each patient, so there are no effective umbrella treatments even once you know what is wrong is with you. Instead, therapies—some with extremely toxic side effects—must be tried one after the other in each patient until something works, or all options are exhausted.
“I can tell you there’s nothing more heartbreaking than going through every drug that’s available and having your patient come to see you at the clinic and ask ‘What’s next?’ and to have no good answer for why things are slowly getting worse,” Dr Jiang says.
“As a doctor, it’s my worst nightmare.”
Penny knows a thing or two about nightmares. Even worse than her own illness, and the powerlessness to know what was wrong with her and how to treat it, is that her son also has chronic health problems. He has eczema which is so bad it cracks and bleeds, rendering him susceptible to infections. Sometimes he can’t use his hands to even feed himself, and sometimes he can’t walk.
She has shepherded him through the medical system on his own journey of uncertainty: why is it happening, and why isn’t there any effective treatment?
Now we can talk about the mouse models. Not because it’s mind-bending science, but because of what the science actually means for patients like Penny and doctors like Simon.
“We have previously focused on mice to start the research into immune diseases,” Professor Vinuesa says, standing at the whiteboard.
“But because we didn’t have mice that had the precise disease we find in humans, none of those mouse models really had the same mutations we would find in patients. So this hasn’t translated into better drugs.
“Now we are starting the research with a specific patient, sequencing their genome and looking at the many mutations that a patient has to see which one is the cause for the disease.”
This is how the CPI found the actual cause of Penny’s health problems. Instead of pointing to a blanket immune disorder, they were able to isolate a specific cause: a subset of CVID, caused by a genetic variant in the gene CTLA4. They were also able to find the cause of her son’s eczema: the exact same genetic mutation.
The CPI can now take this new information about the patient, and apply it to the mouse, as per the arrow on the whiteboard diagram.
“Using CRISPR, we can then edit the DNA to very easily generate a precise mouse model that replicates the specific mutations that the patient has,” Professor Vinuesa says. These mouse models help us understand how the mutated gene cause disease.
Treatments can then be trialled on the real disease in the mouse, until an effective one is identified and applied not just to the specific matching patient, but to all patients who have the same molecular markers.
“It’s a huge conceptual advance,” she says. “Instead of mouse to human, it’s human to mouse to human.”
“For the patient, it’s an extraordinary thing,” Dr Jiang says. “Years into their illness, with no clear explanation for what is causing them to be so unwell, to be able to give them an idea as to what is going on and being able to affect some change, it’s phenomenal.”
Penny has only recently received the results of her DNA sequencing, and has yet to start targeted treatment for her specific genetic mutation, but she says her outlook has already changed. She has been put in touch with another woman, in Perth, whose family is also affected by the same genetic condition to pool knowledge and share experiences, and she has hope for the future.
“There’s only five families in Australia with this mutation,” she says. It’s rare, but it’s real.
While each causative genetic mutation might not be common, when considered together, auto-immune diseases are estimated to affect five to ten percent of the world’s population.
“The fact that the CPI now has people sending difficult, complex cases from across the globe to us gives you a sense of the value it has to clinicians and patients around the world,” Dr Jiang says.
“For most patients, it’s hope they haven’t seen in a number of years, and an avenue forward that would otherwise not exist.
“To be able to help these people in a way that hasn’t been offered before, that’s a real ‘pinch yourself’ moment.”
Is it too much to say it's 'revolutionary'? I ask him, starting at the top of the list of superlatives and expecting to be talked down to 'important'. I am used to scientists and doctors preferring measured, cautious words that don't make great headlines.
"No." Dr Jiang says, immediately. And then he laughs.
"You can say that. Because it is. It is revolutionary."
The Centre for Personalised Immunology is part of the John Curtin School of Medical Research at ANU, Australia’s national medical research institute. Patients’ DNA is held at NCI, the Southern Hemisphere’s fastest supercomputer, also housed at ANU. Professor Carola Vinuesa has been awarded the Elizabeth Blackburn Fellowship for the NHMRC’s top female researcher in biomedical science in Australia – twice.