The Centre for Personalised Immunology Tackles Lupus
Laura Campbell, photo credit = Rory Gillen
"The mental real estate required to manage and maintain a chronic illness is incredibly high.”
October is Lupus Awareness Month in Australia.
At the age of 18, after a sunny week outdoors celebrating the end of year 12, Laura Campbell suddenly became very ill and was hospitalised. Initially doctors thought she had contracted the Ross River virus. Her condition worsened, and doctors revised the diagnosis to pneumonia. Unable to keep up with the fluid collecting in her chest and lungs, and mystified by other symptoms, they intubated her and sent her by air ambulance to the Royal Melbourne Hospital. There, blood tests finally revealed the clues that led to the correct diagnosis, and to treatment that saved her life: Laura had lupus. It took her two months in the hospital to wean off of supplemental oxygen and learn to walk again.
Nearly seven years later, Laura is a fourth year student at the Australian National University pursuing honours degrees in Psychology and Law. Typically she takes nine medications a day. On a good day, she says, she can take deep breaths, and can walk and talk with ease. Her pain and fatigue levels are moderate, so she can go to classes, go to the gym, and cook dinner. On a bad day – if perhaps something unexpected came up the day before and she walked too far in the wrong shoes – she is short of breath, every muscle feels bruised, her feet swell, and her fingers swell and lock in a curled position. To avoid the bad days, she says “There’s no room for recklessness and disorganization. The consequences are too great.” Articulate and capable, she also admits that living as a young person with a disability is extremely isolating. “It’s by far the loneliest experience I’ve known. People in their 20s think they’re invincible.” She goes on “The mental real estate required to manage and maintain a chronic illness is incredibly high.”
Laura calls herself lucky: her disease was diagnosed at its start, which is not true of all lupus patients. Lupus is an autoimmune disease that can strike anyone, but most often strikes women between the ages of 15 and 45. It occurs when the immune system produces extra antibodies that cause inflammation in various structures in the body – such as joints or skin, or in organs including the brain, kidneys, heart, or lungs. Symptoms vary from patient to patient, so the disease may be difficult to diagnose. The onset of the disease seems to have environmental and hormonal triggers. Sibling and twin studies have shown that it also has a strong genetic component. Lupus is a chronic disease which flares and subsides, and it may prove fatal – for example if it affects a patient’s kidneys or lungs. The cause of the immune system attacking healthy tissue is unknown, and while various treatments address the symptoms of lupus, there is currently no cure.
“We think that autoimmune diseases like lupus can be caused by rare gene variants in the individual,” says Professor Carola Vinuesa, co-Director of The Centre for Personalised Immunology (CPI). “Our current work shows from one to three rare variants can cause disease.”
CPI, housed at ANU, is identifying changes in genes that lead to lupus. Beyond discovering the correlation of each rare gene mutation to lupus, its researchers are tracking down exactly how these mutations affect the cells and biochemical pathways within each patient. For example, if an abnormality in a person’s DNA causes a protein in the body to be manufactured incorrectly, the protein may not function as needed in the cell leading to symptoms of the disease. By learning the specific pathway that causes lupus in each patient, a disease which varies so much from patient to patient, researchers can then target treatment to individuals, using drugs to interrupt the disease process rather than merely treating the symptoms.
This ambitious approach starts and ends with individuals.
- Clinicians identify patients with extreme cases of lupus. These are the patients who are likely to be genetically predisposed for contracting the disease.
- Specialists analyse the patient’s blood for biomarkers, to discover which types of auto-antibodies and white blood cells are being produced as part of their particular disease pathway
- DNA is extracted from the patient’s blood, and undergoes DNA sequencing to map the whole genome for that patient.
- Bioinformaticians use sophisticated data analysis to identify rare mutations in the genome that are suspects for contributing to the disease. Comparisons with other patients may or may not uncover other individuals with similar gene mutations and symptoms.
- Using CRISPR/Cas9 genome editing, researchers insert the suspect mutation into the DNA of mouse models and human cell lines the lab, so they test its function in isolation to confirm whether the mutation causes similar disease traits in mice and abnormalities in cell processes. By tracking exactly how the mutation affects cells and molecules, they can discover the pathway whereby the mutation leads to the disease.
- Once the pathway is understood, researchers seek drugs that can specifically address the process that has gone wrong.
- The drugs are tested. If they safely and successfully treat the disease, they can be made available to individuals where the same pathway is affected, by matching the particular genetic mutation and matching biomarkers in their blood as the original patient.
CPI uses this strategy to address other immune diseases as well as lupus. The effort involves a masterful coordination of techniques that have only become available in the past few years, using high-tech facilities and expertise at ANU including the National Computation Infrastructure and Australian Phenomics Facility. The Centre has developed a network of clinicians and their patients from around the world and established a joint centre at Renji hospital in Shanghai.
Although helping patients like Laura is reason enough to launch such an ambitious effort, the Centre’s exploration of lupus can potentially “beat a track” toward solving the mysteries of other diseases that have genetic components. With each success, CPI will share its techniques and processes with specialists across Australia and the world. The development of personalised medicine for patients with lupus can serve as a model for addressing other conditions.
If you’d like to help researchers find the best treatments for lupus or other immune diseases, you can donate here.
CPI is also seeking healthy blood donors to assist their research. Visit here to learn more.