Prof Cliona O’Farrelly is on a mission to find out why some people can block infection by hepatitis C, in a bid to improve treatment. She spoke to Dr Claire O’Connell.
Prof Cliona O’Farrelly is known for asking questions. Questions that others might consider a bit ‘out there’ or even downright ‘ridiculous’, in her own words.
But, by asking those questions, she has made exciting discoveries about the liver having its own special immune system, and now she is asking what antiviral strategies we can learn from women whose immune systems seem to block the hepatitis C virus from establishing an infection.
O’Farrelly, who is today professor of comparative immunology at Trinity College Dublin (TCD), spent a portion of her career at St Vincent’s University Hospital in Dublin in the 1990s, and it was there that her interest in the liver was piqued. “Vincent’s was the national treatment centre and they carried out the first liver transplant in Ireland in 1993,” she explained.
“I had done my PhD in immunology on coeliac disease, and I knew there was a lot of information coming out about the gut having its own immune system, so I wondered if the liver might, too. People thought I was mad to even think such a thing.”
But she persevered, and her work alongside clinicians found that the liver did indeed have its own unusual immune cells and responses, turning previous thinking on its head. “That is probably the work in my career that I am most proud of to date,” O’Farrelly told Siliconrepublic.com.
At around the same time, it emerged that groups of women in Ireland had been exposed to the hepatitis C virus (HCV), which attacks the liver, through a contaminated anti-D blood product they had received following pregnancy in the 1970s and again in the early 1990s. The scandal affected hundreds of women, many of whom developed hepatitis C, and some of whom died from the disease.
O’Farrelly was intrigued by the women who had received the contaminated anti-D and had been exposed to the virus, but who showed no signs of infection.
“I wondered what was going on there,” she recalled. “I thought maybe there was something different about their ‘innate’ response to the virus in the liver that meant they cleared it but, again, people thought that was a ridiculous notion.”
That train of thought started to rumble more loudly when O’Farrelly and TCD colleague Prof Nigel Stevenson dug into the biochemistry of how HCV disarms the immune system.
This spurred O’Farrelly on to apply for funding to compare the immune responses of women who had been exposed to HCV and who had developed an infection, and women who had been exposed to HCV but who had not developed an infection.
“I applied to Science Foundation Ireland and it took three goes to get the grant,” she said. “I was bitterly disappointed the first time, more philosophical the second and absolutely determined the third time.”
Going viral in the media
The next step was to recruit women who had received the contaminated anti-D, but O’Farrelly was advised against contacting them directly for bioethical reasons. So, she decided to put the word out publicly on traditional and social media. “We ran a campaign last year with newspaper stories and TV and radio and we got a massive response – more than 700 people contacted us over a couple of days,” she said.
A separate social media campaign on Twitter and Facebook gathered a few additional recruits, but was also important for building public awareness and trust, according to O’Farrelly.
Following telephone interviews, the team sent out 440 study packs and got a whopping 370 back. “We were delighted with the response rate,” she said.
Blood and liver cells
Following the campaign, they now have a group of volunteers who received HCV-contaminated anti-D and, crucially, among those are 33 women who did not develop an infection. The researchers are already looking at specific genes from those volunteers, though O’Farrelly suspects the sample size is probably too small to identify any strong genetic component.
They are also gearing up for more functional studies. “In one study, we are taking blood from volunteers and exposing cells in those blood samples to the virus to see what happens, and if there is a difference between the women who did get infected and those who did not get infected,” O’Farrelly explained. “We are collaborating with the Pasteur Institute in France, who have a wonderful system for challenging the samples.”
‘What we learn from this study could point the way to new drugs, or to tests that can tell us if a person has a high natural resistance level. We might even be able to design new vaccines to keep the virus at bay in the first place’
– CLIONA O’FARRELLY
Even more ambitiously, they are going to use stem cell technology to turn mature white blood cells from the samples into liver cells and see what happens to those cells when they are challenged by the virus. To do this, the TCD team is working with colleagues from the MRC Centre for Regenerative Medicine at the University of Edinburgh and Cambridge-based company Stemnovate, explained O’Farrelly.
“Obviously, liver biopsies are invasive so, rather than taking cells from the liver, we are going to take white cells from the blood samples and ‘reprogram’ them so they grow as liver cells in the lab. Then, we will expose these liver cells to the virus and compare the responses in the cells from the women who were infected and the responses in those who blocked the infection.”
O’Farrelly is keen to keep the wider public involved in the research and is planning another open session when the results of the blood sample challenges are in. “One thing I really picked up on from the social media campaign was that I think it helped people feel part of the team, and I want to keep that going,” she said. “I want to find out what people think we should focus on as the project develops.”
Ultimately, O’Farrelly hopes that the findings will tell us more about how to tackle HCV and possibly other viruses, too.
“We have new drugs to treat HCV now that were not around when the anti-D issue arose in Ireland, but these drugs are expensive and they may not be available to everyone who could benefit from them around the world,” she said.
“Ideally, what we learn from this study could point the way to new drugs, or to tests that can tell us if a person has a high natural resistance level and so could clear the virus themselves, and we might even be able to design new vaccines to keep the virus at bay in the first place.”
O’Farrelly’s enthusiasm for science and her work is obvious, and her engagement with students and postdoctoral researchers earned her a Mentoring Award from Nature in 2014.
Yet at school, she initially had her mind set on being an architect. “I grew up in Adare and I went to a boarding school in Athlone,” she said. “I did find as we went out on field trips to the bog that I was amazed by the creatures you could see in the water, and I think that probably sparked my interest in science.”
For current students, she encourages them to follow their interests and to not shy away from the more challenging subjects and questions. “Don’t be put off by something that seems difficult,” she said. “Having to work at something can bring its own satisfaction.”
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