This research was supported by BrightFocus
Doyle’s BrightFocus-funded Results
Inflammatory responses of the immune system typically are caused when tissue becomes infected by a bacteria, virus, or fungus. However, in some chronic conditions where a tissue or organ becomes self-damaged (perhaps due to genetic or environmental factors), a sterile type of unprovoked inflammation can develop, even in the absence of infection. This sterile inflammation is linked to the progression of AMD through a rise in immune factors that trigger an inflammatory cascade. Doyle and colleagues hypothesized that this reaction is due to uncontrolled activation of immune system sensors known as toll-like receptors (TLR). Their investigation of this pathway could lead to the targeted development of new AMD treatments.
Results will be presented at an ARVO poster session on Wednesday, May 4, 11 am-12:45 pm, (Abstract No. 5010, Poster #B0216).
In just a few days’ time, 13,000 of the world’s vision researchers will arrive in Seattle for the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), the world’s largest gathering of its kind.
Being singled out for special recognition this year is 2013-16 BrightFocus grantee Sarah Doyle, PhD, of Trinity College Dublin (TCD), who’s been selected to receive a Genentech Age-related Macular Degeneration Fellowship from the ARVO Research Foundation. The fellowship is one of two given yearly to noteworthy young investigators under the age of 40, and carries a research stipend.
The award was given to further Doyle’s outstanding basic investigation into the inflammatory triggers of AMD. “The proposal [for the fellowship] was to look at the relationship between retinal pigmented epithelium (RPE) metabolism and unchecked triggering of the inflammasome,” Doyle said. “I'm trying to get to the root cause of inflammasome activation—what starts it off?”
That’s also the aim of Doyle’s current BrightFocus project, where she’s looking at how immune sensors known as toll-like receptors (TLR) become activated and contribute to the AMD disease process. Normally TLRs serve as the main sentries and scouts of the eye’s immune system. They are there to recognize the entry of a virus or bacteria, and initiate a defense against infection. However, in AMD they trigger an inflammatory response for no apparent reason.
Doyle will be sharing the latest results of her BrightFocus-funded investigation at ARVO (see details nearby). It’s one of more than 100 presentations of BrightFocus-funded research being featured at this year’s ARVO. Look for coverage ahead.
Team’s Earlier Research Spurred Controversy
If Doyle’s name sounds familiar to you, it’s because she has been in the limelight before. In the recent past, she and coinvestigators at TCD, including Matthew Campbell, PhD, and Luke O’Neill, PhD, collaborated on an earlier, 2011-13 BrightFocus grant to Peter Humphries, PhD. Under that grant, they discovered that not all inflammatory molecules are equal, and that increased levels of one naturally occurring inflammatory cytokine known as interleukin 18 (IL-18) may serve a protective role that could have therapeutic relevance. Their widely-published results advanced the hypothesis that increases in Il-18 actually help, rather than hinder, the eye’s recovery from choroidal neovascularization (CNV), which is the growth of wet, leaky blood vessels seen in wet AMD.
[Watch a video on their discovery: https://www.youtube.com/watch?v=QkjDkH5yDe4.]
These results seemed counterintuitive, as inflammatory factors had been considered uniformly harmful to the RPE cells of the eye, which nourish and maintain the retina. The work met with skepticism in some circles, and continues to be debated at researcher forums.
Nonetheless, the team’s ongoing investigation into IL-18 continues to support the hypothesis that it confers protection against CNV. That work has progressed to the stage of preclinical testing in non-human primates, and only a few hurdles remain before they’ll be in a position to seek FDA approval to conduct Phase 1 clinical testing in humans. Summaries of the work have been posted on the BrightFocus website: “Promising Research Looks to Clinical Uses of IL-18 to Prevent Wet Age-Related Macular Degeneration (AMD) (April 2014)” and “Results Published on Potential New Treatment for Wet AMD” (August 2015).
The intense scrutiny given their earlier work has made it all the sweeter for Doyle to be honored with the Genentech fellowship. She admitted that she is beyond pleased, and told BrightFocus that “affirmation is the right word for it!”
Close-up: The Husband-Wife Research Team of Matthew Campbell and Sarah Doyle
Trinity College Dublin researchers Sarah Doyle, PhD, and Matthew Campbell, PhD, have spent their married life doing research together. Below, they talk about how their partnership began, what continues to drive them, and the surprising turns their work has taken at times.
Q Did you two happen to meet in the laboratory—or where?
A We met when we were 17, in the south of France on holiday. As it turned out we lived within 10 minutes of each other in Dublin and had common friends, but we had never met!
Q Where did you grow up, and what led you into research?
A We grew up in a suburb of Dublin called Castleknock (Ireland). I seemed to take a natural route into research, I was always interested in the natural world growing up. After two years in natural sciences in Trinity, I knew I wanted to pursue molecular biology. I chose to study biochemistry for my degree and molecular immunology for my PhD. I still love asking questions and designing experiments to answer them. My parents weren’t surprised at all that I ended up as a scientist, apparently I never stopped with the “why” “where” and “how” questions!
Q What’s the best part about working together as scientists?
A I think we have a great understanding of what we each do and the various pressures that our jobs can entail. Speaking about our research and what we did that day without using technical jargon is difficult, so its nice that we know what each other is talking about all the time!
Q And the hardest?
A We have to decide who gets to go to which meetings, and who will watch the children when we both go to ARVO!
Q What are the special talents each of you brings to a research collaboration?
A Aside from the obvious difference in our expertise, Matt is much better at explaining what he and we do in ordinary language. He speaks really well and engages with his audience. I think writing comes more easily to me though!
Q Does either of you have any irritating lab habits?
A I’m not sure…thankfully we each have our own labs in separate buildings.
Q [to Matthew] A couple years back you were awarded the President of Ireland Young Investigator award from Science Foundation Ireland. What was that like?
A It was a huge honor to receive this award. The grant gave me an incredible platform to establish my own laboratory here in Trinity and has allowed me to recruit some seriously talented PhD students and postdoctoral researchers. I was presented the award by Michael D Higgins, the President of Ireland at a ceremony in his house (Áras an Uachtaráin). Quite the privilege!
Q [to Matthew]: We mostly know you as a “vision” researcher; however, last year you applied for and received a BrightFocus grant to study Alzheimer’s. What led you in that direction?
A My lab is focused on understanding the biology of blood vessels associated with neural tissues so we have a very keen interest in brain as well as retinal diseases. In fact the retina is an external part of the brain that just happens to be light sensitive. Current projects are focused on traumatic brain injuries (TBI), schizophrenia and Alzheimer's disease (AD). My work on Alzheimer's is primarily focused on how the brain rids itself of junk and our work has already led to some intriguing findings. We've shown that toxic material called amyloid, that builds up in AD patients brains, can squeeze between the cells that line blood vessels in the brain. If we can better understand how toxins are cleared from the brain, it may lead to new forms of therapy that can facilitate the process.
Q (to Matthew) Are your eye and brain research complementary?
A Yes, there’s a similar process occurring with drusen in AMD, with the eye’s inability to get rid of waste material, so it accumulates and starts to affect other tissues. The eye, too, has an eye-blood barrier, and AMD also appears to be, in part, a disease of aberrant clearance.
Q How will your research contribute to new AMD treatments?
A The more we understand about the disease processes underlying AMD, the better placed we'll be to contribute to new AMD treatments. Our work with IL-18 as a therapeutic for wet AMD is ongoing, and we are hopeful that from our basic research started in 2011 that we will have a new tool for treating this condition.
[Watch a video on their discovery: https://www.youtube.com/watch?v=QkjDkH5yDe4.]
Q What are the next big ideas you’d like to pursue?
A We have some intriguing data relating to the development of geographic atrophy, the end stage of dry AMD. We are still in the process of compiling all of our results but we think we may have stumbled upon a new series of therapeutic targets for the disease. Hopefully we'll be ready to publish these data by the end of the year!
Q What would you say to the BrightFocus donors who have sponsored your research?
A Thank you, thank you, thank you! You really have allowed us to explore some research questions that could be termed ‘high risk’ and that might have difficulty getting funding elsewhere. Hopefully, in tandem with increasing our knowledge about AMD pathology, we can improve treatment for AMD in the future.
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