Improving treatment options for people with ankylosing spondylitis
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Improving treatment options for people with ankylosing spondylitis
Ankylosing spondylitis (AS) is a serious form of spinal arthritis. Unlike most forms of arthritis, which generally affect older people, AS tends to affect people aged 15 to 45 years old. At the Schroeder Arthritis Institute and the University of Toronto in Canada, rheumatologist Dr Nigil Haroon is improving treatment options for AS and preventing the disease from causing lifelong, disabling symptoms.
Talk like a rheumatologist
Ankylosing spondylitis (AS) — a long-term condition in which the spine and other areas of the body become inflamed
Arthritis — a condition causing painful inflammation of the joints
Cytokine — a type of protein released by immune cells which serves as a messenger and can also cause inflammation
Immune system — a network of biological systems which protect an organism from disease
Inflammation — a defence mechanism that the immune system uses against infections and diseases
Major histocompatibility complex (MHC) — a set of genes that code for cell-surface proteins that are vital to the immune response
Rheumatology — the branch of medicine that investigates diseases which cause inflammation in the bones, muscles, joints or organs
RNA sequencing — a laboratory technique that can detect and analyse RNA molecules within cells
Ankylosing spondylitis (AS) is a form of arthritis that causes inflammation of the spine. It is a long-term health condition with symptoms including back pain, stiffness and joint swelling. While physiotherapy and medication can help slow the disease, there is no cure for AS, and it can stop individuals from living independently.
At the Schroeder Arthritis Institute, Dr Nigil Haroon is the head of a research lab focused on finding new cures and improving treatment options for those living with AS.
Who is affected by AS?
AS is about three times more common in men than in women, and usually occurs in people aged 15 to 45. It is often associated with inflammation of the skin, gut and eyes. “However, even with over 50 years of research into the genetic and immunological causes of AS, many mysteries remain,” says Nigil. “We still do not fully understand how this disease develops, why some individuals are at higher risk of complications or why only certain patients respond to existing treatments.”
A personalised approach
Nigil and his team are developing a personalised medicine algorithm to help treat AS. Personalised medicine involves tailoring treatments to the individual needs and characteristics of each patient. “The goal of personalised medicine is to improve treatments by considering the unique genetic and molecular profile of each patient,” says Mansi Aparnathi, a researcher in Nigil’s team.
Mansi’s algorithm will be able to predict which personalised treatment option is likely to be most effective for a patient. If successful, this would help bypass unnecessary treatments and speed up the treatment process.
To develop this algorithm, Mansi is studying which patients respond to specific treatments and comparing their immune cells using RNA sequencing techniques. “We then validate the data in a large cohort of patients to find patterns that differentiate between patients who will and will not respond to treatments,” explains Mansi.
Besides Mansi’s algorithm, Nigil and his team are exploring the potential of other treatment options and developing novel ways of studying AS.
What is TRABID inhibition?
Archita Srinath, a PhD student in Nigil’s team, is investigating the TRABID molecule, which plays a major role in driving inflammation in AS. “Previous research has found that TRABID can upregulate the expression of key inflammatory proteins called cytokines,” says Archita.
If Archita can find a way to limit the function of TRABID, she may be able to reduce the inflammation caused by cytokines, which contribute to AS. “My research focuses on testing a novel drug that can inhibit the function of TRABID and alleviate the symptoms of AS,” she explains.
What is macrophage migration inhibitory factor?
Shaghayegh Foroozan, another PhD student in Nigil’s team, is studying a cytokine called macrophage migration inhibitory factor (MIF). “MIF is a protein in our bodies that plays an important role in our immune system,” explains Shaghayegh. “Think of it as a coach who guides your immune cells, making sure they go where they are needed and stay there long enough to get the job done.”
The team discovered that people with AS often produce more MIF than people who do not have AS. “This suggests that MIF might be causing the inflammation and pain they experience,” says Shaghayegh.
The lab has already made major advances. “We have discovered that using a drug against MIF can reduce AS symptoms in mice” says Shaghayegh. “We aim to expand this research to humans to see if the results are reproduced.”
What is SEC16A?
To understand the role of SEC16A, we must first learn about major histocompatibility complexes (MHCs). MHCs are a group of genes that code for proteins found on the surface of cells. These MHC proteins help our immune system identify and destroy foreign substances.
SEC16A is a molecule that controls a cell’s ability to present these MHC proteins on its surface. “If those MHC proteins are not expressed at the cell surface, they accumulate inside the cell and cause stress,” explains Dr Fethi Khiter, a post-doctoral researcher in Nigil’s lab.
Nigil and his collaborators have discovered a pair of genetic mutations, one affecting SEC16A and another affecting MHCs, that can cause AS. “I am studying how these two mutations work together to induce the disease,” explains Fethi. “By understanding the underlying mechanisms, we can identify new targets for drugs that we can develop and hopefully use to treat patients with AS.”
How does the team study AS?
Mariia Korshko is a research technician in Nigil’s lab who uses a range of techniques to study AS. For example, she creates tiny 3D-models called organoids which she grows from stem cells in the lab. “These mini-organs mimic the structure and function of real organs, allowing us to study diseases more accurately,” she explains.
Reference
https://doi.org/10.33424/FUTURUM530
Another technique that Mariia uses is called immunohistochemistry (IHC) staining. “IHC staining involves using special dyes to highlight proteins in cells, making it easier to see and understand the changes happening inside the tissues,” she says.
What motivates Nigil and his team?
“Our team is dedicated and collaborative, driven by a shared passion for tackling the big questions surrounding arthritis,” says Nigil. “We are motivated by the chance to make a real difference in the lives of people affected by this condition.”
Thanks to the discoveries and dedication of researchers like Nigil and his team, people with AS may have access to better care and treatment options in the near future. “We are on the cusp of several truly exciting novel discoveries,” enthuses Nigil. “It is our mission to uncover these mysteries and improve the lives of everyone living with AS.”
Dr Nigil Haroon
Senior Scientist, Schroeder Arthritis Institute, Canada
Associate Professor, Department of Medicine, Institute of Medical Sciences, University of Toronto, Canada
Head of the Division of Rheumatology, University Health Network and Sinai Health
Field of research: Rheumatology
Research project: Investigating new treatment options for ankylosing spondylitis
Funders: Canadian Institutes of Health Research, Arthritis Society, Krembil Foundation, CFI, UHN foundation, SPARCC, SPARTAN, Schroeder Arthritis Institute, Krembil Research Institute
About rheumatology
Rheumatology is the branch of medicine that focuses on diseases and disorders which cause, or are caused by, inflammation. There are hundreds of these complex disorders, and many of them are closely linked to problems with the immune system. Inflammation is often an important part of the immune system’s response to injuries or infections. However, some immune system disorders cause inflammation to occur when it is not needed, leading to rheumatic diseases such as arthritis.
“Rheumatology is an intellectually stimulating and dynamic field of research,” says Dr Patricia Remalante-Rayco, a clinical researcher who works closely with Nigil and his team. “We try to discover how and why the body’s immune system attacks its own tissues, and then try to find out how to stop that.”
As a clinical researcher, Patricia is focussed on the experience of patients living with ankylosing spondylitis (AS). For example, it often takes a long time for patients to be diagnosed with AS, which can increase their suffering. “Back pain is common and can be caused by many things like bad posture or muscle strain, so it can be tricky to tell when someone’s back pain is caused by AS,” explains Patricia. “It may take as long as eight years for patients to be diagnosed with AS, but this is slowly improving as more people become aware of the disease.”
It is important that people are aware of the signs and symptoms of AS, as this can help them to get diagnosed sooner. “Catching patients as early as possible means we can treat them right away,” says Patricia. “This will help relieve their suffering, lessen the damage to their spine and improve the way their bodies move and function.”
Pathway from school to rheumatology
During high school, study chemistry, biology, mathematics and physics. To become a rheumatologist, you will need to complete a medical degree and residency training in internal medicine before going on to do further training in rheumatology. The Canadian Rheumatology Association has a page for medical students on training programmes across the country (rheum.ca/students).
“Rheumatology is a multifaceted speciality that incorporates many other disciplines such as epidemiology, genetics, immunology, molecular biology and biochemistry, to name just a few,” says Nigil. “There are many paths to the destination, and the best rheumatologist is one who embodies empathy, demonstrates integrity and makes wise, patient-centric choices.”
“Read everything you can get your hands on,” recommends Archita. “Read books, magazines, news articles, scientific papers and textbooks.”
Explore careers in rheumatology
The Canadian Medical Association Journal has an article explaining why rheumatology is becoming a popular career choice (www.cmaj.ca/content/187/10/E298).
The British Medical Journal has a brilliant guide about becoming a rheumatologist (www.bmj. com/careers/article/the-complete-guide-to-becoming-a-rheumatology-doctor).
“Seek out practical experiences like internships and lab work to gain hands-on knowledge,” advises Mariia.
Communication skills are crucial for a career in rheumatology. “The world of science has grown so vast that excelling alone is no longer feasible. Having the ability to connect and collaborate with colleagues is a vital asset,” says Nigil.
Meet Nigil
Physics and mathematics were my favourite subjects in school. I found joy in solving equations and algebra problems.
My dad has always been my hero. As a compassionate and skilled physician, he consistently goes above and beyond to ensure the comfort and care of his patients. His healing touch has earned him the admiration and respect of many, and I grew up witnessing the profound impact he had on others.
The clinical skills I developed in medical training, combined with the passion for research and excellence instilled in me during my rheumatology training under Dr Ramnath Misra and Dr Amita Aggarwal, have been pivotal in shaping my professional journey. The highlight of my training was during my PhD, where I had the incredible opportunity to learn under Dr Rob Inman, a brilliant clinician-scientist and an exceptional person. I learned invaluable lessons from him that continue to guide my practice.
Outside of my professional life, I am a keen wildlife photographer. My photographic adventures have allowed me to interact with people from all over the world, transcending geographic borders, landscapes, race and religion. It doesn’t take much to realise that we are all woven from the same fabric.
Nigil’s top tips
1. Don’t hold back. You are at an age where you can take risks.
2. Test out things before committing long term.
3. Connect with people that you admire, make friends and, most importantly, enjoy the journey.
Meet Mansi
Mansi Aparnathi
Position: Scientific associate, Schroeder Arthritis Institute, University Health Network
Field of research: Personalised medicine
As a teenager, I became interested in science, especially molecular biology, from reading detective novels and watching crime shows that involved forensic science. DNA technology was new back then and I found it fascinating how a tiny sample of DNA could solve the most complex crimes.
I completed my PhD in bone tissue engineering and my postdoctoral fellowship in cancer research. I was very happy when Dr Haroon offered me a position which suited my interests perfectly. My goal is to have my own lab in the future.
All the projects in our lab are designed with the aim of translating the outcomes from bench to bedside. It is satisfying to know that the work that we are doing is ultimately going to benefit the patients.
Doing science is like solving a puzzle, and when the experiments work, it is satisfying to see all the pieces falling into place. Having said that, not all experiments work on the first try or go the way you’ve planned. But, by seeking answers to what is unknown in the field, discovering something novel and contributing to society, it is worth all the hard work in the end.
It is okay to fail. What matters is learning from your failures and rectifying your mistakes.
Meet Archita
Archita Srinath
Position: PhD student, Institute of Medical Sciences, University of Toronto
Fields of research: Rheumatology, immunology, bone biology
As a teenager, I wanted to be everything from a journalist to a business owner to a doctor. However, something about science and human biology felt like my calling. To my surprise, I realised that as a scientist, I could still pursue my interests in writing, business and medicine.
I knew I wanted to work with my hands in a lab, and I also knew that my favourite topic from undergrad was immunology. Therefore, when I was looking for a summer research internship, I was looking for a supervisor that combined both aspects in their research programme and was very luck to find Dr Haroon!
Every day I get to come into the lab and work towards discovering something that nobody else in the world knows about. It is a very exciting feeling!
Archita’s top tips
1. A rewarding career in science takes a long time. Do not go into it unless you are truly passionate about it.
2. Knowing how to recover from failure and being persistent will bring you way more success than being the ‘smartest’ person in the room.
Meet Shaghayegh
Shaghayegh Foroozan
Position: PhD student, Institute of Medical Sciences, University of Toronto
Fields of research: Gut immunology, rheumatology
As a teenager, I liked reading fiction, and I spent countless hours immersed in novels. I was also really into mythology and folklore from different cultures around the world. These stories sparked my imagination and allowed me to explore different worlds, traditions and perspectives, enriching my understanding of human creativity and storytelling.
For my master’s degree, I worked on a specific form of cell death called autophagy and came across one of Dr Haroon’s publications about its role in AS. I became interested in his work and asked if he had any open PhD positions. He responded, interviewed me and offered me the position. I was amazed by his positivity and drive during the interview, so when he offered me the position, I was on cloud nine!
Shaghayegh’s top tips
1. Cultivate resilience and practice patience.
2. Avoid comparing your journey to others. Remember that everyone’s path is unique, and comparisons can lead to unnecessary stress and mental setbacks.
3. Seek mentorship and collaborate with peers for guidance and new perspectives.
Meet Fethi
Dr Fethi Khiter
Position: Postdoctoral research fellow, Schroeder Arthritis Institute, University Health Network
Field of research: Cell biology
When I was a teenager, I was interested in four things: listening to music, watching Doctor Who, playing video games and doing mathematics. Music and Doctor Who transmitted to me a beautiful and fascinating vision of the world around me. Video games challenged me and helped me achieve goals, and mathematics helped me to become more focused and rigorous. Much later, I realised that I could find all of these feelings in science.
I am a French pharmacist who then pursued a PhD in microbiology and basic research. At the end of my PhD, when I started to look at different job offers and saw one posted by Dr Haroon, I had the feeling that I wanted this position with all my heart. One CV and a cover letter later, Dr Haroon interviewed me and took me in!
Rheumatology is even more enjoyable when you are working with a lot of kind people like in Dr Haroon’s lab. When you can imagine, conceive and analyse together, that’s when the magic of science happens.
Fethi’s top tips
1. Follow your heart and always try to enjoy what you are doing.
2. Be curious and open minded.
3. Science is an art, and it can be difficult. But when you are struggling the most, the results of your work will be even more rewarding.
Meet Mariia
Mariia Korshko
Position: Research technician II, Schroeder Arthritis Institute, University Health Network
Fields of research: Mouse models, organoids
As a teenager, I wasn’t particularly drawn to science. Instead, I enjoyed drawing, playing music, dancing, hanging out with friends, staying out late and playing computer games. It’s interesting how my interests shifted over time, eventually leading me to a rewarding career in medical research.
After completing my master’s degree, where I extensively used intestinal organoids, I moved to Canada and began searching for a job. Nigil’s lab was having issues with establishing organoid cultures, so my background was a perfect fit. I feel fortunate to have found this opportunity and to be able to contribute to such important work.
What I find most rewarding about my work is the opportunity to make a tangible impact on medical research and potentially improve patients’ lives. Seeing the results of our experiments contribute to a deeper understanding of diseases is incredibly fulfilling. Additionally, the collaborative environment, where I get to work with passionate and dedicated colleagues, makes the job even more enjoyable.
Mariia’s top tips
1. Stay curious and always ask questions.
2. Find a team with good vibes — working with supportive and enthusiastic colleagues makes the journey more enjoyable and productive.
3. Use your enthusiasm and dedication to drive you to excel and make meaningful contributions to the world.
Meet Patricia
Dr Patricia Remalante-Rayco
Position: Clinical research fellow and incoming PhD student, Institute of Medical Sciences, University of Toronto
Field of research: Clinical rheumatology
When I was younger, I was very much into linguistics and art. I studied new languages, wrote in the school paper, joined writing competitions, created my own comic books and directed and acted in school plays.
I was born and raised in the Philippines, where I trained to become a rheumatologist and clinical epidemiologist. I came to Toronto three years ago to specialise in AS as a clinician, until Dr Haroon introduced me to his groundbreaking translational research programme and the amazing team behind it. I realised that the possibilities are limitless when you work with a collaborative group of people with the same passion, drive and interests.
I love my dual role of being a rheumatologist and a researcher. Diagnosing and treating rheumatic diseases can be quite challenging, so it’s rewarding to see patients get better and to make a significant difference in their daily lives.
Patricia’s top tips
1. Be curious and keep asking questions.
2. Find mentors and colleagues who inspire you and support your goals and dreams.
3. Science demands a lot of dedication, drive and time, so it’s important to keep your humanity through it all, and to always remind yourself why and for whom science exists.
Do you have a question for Nigil and his team?
Write it in the comments box below and Nigil and his team will get back to you. (Remember, researchers are very busy people, so you may have to wait a few days.)
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