We’re proud to announce that this weekend we submitted our proposal to the Assay Depot Rare Disease Challenge, partnering with an outstanding team of researchers to propose the creation of stem cell lines that will be instrumental in achieving our research goals.
Here’s the essence of our proposal. Prion Alliance President Sonia Vallabh, a carrier of the FFI mutation, will donate skin cells to be transformed into induced pluripotent stem cells. Then we’ll use a zinc finger nuclease to correct the single base (G->A) mutation that causes FFI. This way we’ll have two stem cell lines that are completely genetically identical except for this one base, which gives us an incredibly well-controlled platform to explore how this mutation causes disease. We also plan to create two other variations on these stem cell lines: one which is homozygous for the FFI mutation and so presumably more prone to disease, and one which has the entire PRNP gene knocked out, so that we can study the effects of this knockout in human cells – something that has never been studied before. We also plan to create similar sets of stem cell lines from the existing FFI knock-in mice so that we can study human and mouse cells in parallel.
We estimate that if we win the competition, the $10,000 cash prize plus the free custom-designed zinc finger nuclease being donated by Sigma Life Science (normally $25,000), along with several other donated services, will be enough to get all these stem cell lines created, differentiate them into neurons and do a few basic experiments to demonstrate how they behave differently. All that should position us well to win further grants and build on this early success.
Which brings us to the awesome part. Creating these stem cell lines is just the beginning of our broader research agenda. We want to measure everything we can about these cells – gene expression, morphology, epigenetics and more – to find subtle ways that the FFI stem cells are different from their healthy counterparts. That will give us clues as to the molecular mechanisms by which the FFI mutation causes disease and, perhaps more importantly, will give us ways to measure the efficacy of different potential drugs we’d like to test. And once we’ve developed hypotheses or identified drugs we think might work, we’ll be able to test them in FFI knock-in mice.
This is all cutting-edge stuff and we believe what we’re doing will prove useful not just for advancing science on FFI but for all prion diseases and hopefully other neurodegenerative diseases as well. Most people who study prion disease in cell culture today use mouse brain cancer cells infected with rodent strains of scrapie. This model has been a useful tool so far, but it’s limited, for instance because it relies on infection rather than spontaneous disease and on rodent rather than human strains of prions. We believe that studying human stem cells in tightly controlled experiments will give us much better insight into what’s really going on in prion disease. In order to make our impact as broad as possible, we also plan to open source this project, providing the stem cell lines as a tool for other researchers to use and opening up our data for others to analyze.
Hats off to Prion Alliance Director Greta Beekhuis, who pulled together an amazing team to do this research:
Dr. George Carlson, director of the McLaughlin Research Institute in Great Falls, Montana has signed on as Principal Investigator for this project. Dr. Carlson has been doing valuable prion research for three decades – in the 1980s he teamed with Stanley Prusiner to provide some of the earliest evidence for the ‘prion hypothesis’ – the now widely accepted idea that infectious proteins are the cause of disease in animal scrapie and in human CJD, FFI, etc. He’s been an innovator in using stem cells for this research and in 2005 he created the first mouse embryonic brain cell model of prion disease. We admire his research and we also love that he’s a big believer in open source – he co-led the team that did the first large systems biology study of prion disease [Hwang 2009] and open sourced all of its data at prion.systemsbiology.net. In this project Dr. Carlson will oversee all of the experiments to tease out the molecular differences between FFI and control stem cells and see how they respond to different stresses and drugs. He’ll also house the FFI knock-in mice – McLaughlin has one of the best and most efficient mouse facilities in the United States – and oversee all of the followup experiments on them.
Dr. Irving Weissman, director of the Stanford School of Medicine Institute for Stem Cell Biology and Regenerative Medicine, is on board to create and differentiate the stem cell lines. Dr. Weissman is in fact a founding father of the whole stem cell field: he was the first to isolate blood-producing stem cells from mice and from humans and to chart out the lineage of how these cells differentiate into different types of blood cells, laying the groundwork for much of stem cell science today. He has continued to innovate and is now at the leading edge of figuring out how to use reprogrammed stem cells in therapeutic transplants.
Dr. Bruce Aronow, co-director of the Computational Medicine Center at Cincinnati Children’s Hospital, is a leader in using big data to advance biomedical research. His work fuses genetic, systems biology and high-content image analysis approaches to uncovering the roots of human disease. This entire research project has been his vision, and he will lead the work of analyzing all the data we gather from the cells.
Dr. Walker Jackson, group leader at DZNE, is the creator of the FFI knock-in mice and a master molecular biologist and mouse geneticist with decades of experience in neurodegenerative disease. He will provide mice for this project and participate in efforts to characterize the differences between the FFI and control cells and mice.
We are incredibly honored to be part of such an outstanding group of researchers. Going forward, this project will be our focus and top priority.
This competition is a perfect start for us for two reasons. First, it presents us with a great opportunity to mobilize you, our supporters, to help us out. The scientific judges for the Rare Disease Challenge will choose finalists by February 28, 2013 and the winner of the cash prize will then ultimately be chosen by Facebook voting, for which we’ll ask for your support once it gets started.
Second, if we win, this competition will provide us with enough seed money to get this project off the ground and make us competitive for grants. But more importantly, it’s already gotten us organized and teamed with a crack team of researchers, and now we are determined to move this project forward whether we win or not.
The cash prize is $10,000 and we’ve also applied for a number of donated services, all of which would be a huge boost to our project. The cornerstone of our plan, though, is the use of a custom zinc finger nuclease which will let us target and edit the exact part of the genome that we want to change. These sell for $25,000 normally. Our goal, then, will be to raise $35,000 by the end of March 2013 so we can get these stem cell lines started no matter what – and if we do win, then we can move that much faster and do that much more.
Cheers to everyone who has chipped in already – you guys are amazing – and to those who have promised to send checks before the end of FY2012. If you haven’t donated yet, and if you think this research project sounds awesome, then donate now to help make it a reality.