ALS Ice Bucket Challenge Funds RNA-Seq Experiments

from Gizmodo by Jennifer Ouellette

Last year’s hugely popular “ice bucket challenge” saw celebrities pouring buckets of ice water over their heads to help fight Lou Gehrig’s Disease (ALS). Skeptics dismissed it as mere “slacktivism,” but researchers told us that the money led directly to a scientific breakthrough. Can slacktivism actually work?

Earlier this month, Nicholas Kristof wrote a rather gloating Op-Ed in the New York Times, chafing at the criticism that such campaigns are largely ineffective and meaningless. After all, some 17 million people participated in the challenge, and the ALS Association claims it raised $115 million in six weeks for the cause. Money doesn’t mean scientific discoveries follow, however.

But in early August, researchers at Johns Hopkins University announced a potential breakthrough therapy for ALS. JHU’s Philip Wong’s told the press that “The funding [from the ice bucket challenge] certainly facilitated the results we obtained.” That seemed to support Kristof’s claim, but could it really be that simple? We wanted to know more.

First, just what is this big breakthrough that appeared in the journal Science? It centers on a particular protein, TDP-43, that is known to form clumps inside the brain cells of almost all people with ALS (97%), as well as in 45% of those suffering from dementia. But the exact function of this protein, or just what effects that clumping had, weren’t known.

The JHU researchers figured out that in healthy people, TDP-43 protects cells by ensuring that faulty RNA segments aren’t included in the “blueprint” for manufacturing other proteins. (As Francis Crick pithily observed: “DNA makes RNA, RNA makes proteins, and proteins make us.”) But when those clumps form, the TDP-43 no longer functions properly. It’s as if the protein isn’t present at all and the cells can’t read the “blueprint.” And without that protection, those brain cells start to die.

The JHU team even managed to salvage dying cells by plugging in a different, custom-designed protein to mimic the function of the defective TDP-43. And it worked! The damaged cells returned to normal. “We can for the very first time make these zombie-like cells where they don’t have any TDP-43 but they survive,” lead author Jonathan Ling told Gizmodo. “No one has ever shown that.” So there is now a path forward toward developing an effective gene therapy to combat ALS.

This is very exciting stuff. But can we really point to a direct cause-and-effect link between this new result and the funds raised by the ice bucket challenge? The answer is a bit more nuanced than that.

Breakthroughs don’t happen in a vacuum, despite what the headlines would have you believe. There are months, years, sometimes decades of toiling in obscurity before that big eureka! moment arrives. JHU’s research program on TDP-43 was already well underway before the lab received extra funding from the ice bucket challenge. It was the timing of the funds that seems to have made the difference, according to Wong’s statements to the press.

Ling confirmed to Gizmodo that the grant the lab received from the ALS Association “was a big help towards the end of the study. It was good to have that money come in at that time.” They had collected enough data to warrant a journal review process for their draft paper, but that takes several months. And reviewers inevitably want more experiments to be done before green-lighting a paper for publication, which takes money.

Ling acknowledged that they might have managed to pull a few strings and get more funding without the challenge, but there was no guarantee of success, especially since plenty of scientists were skeptical about their hypothesis. So much prior work had been done on this particular protein; surely if there was anything significant there, the reasoning went, someone else would have found it by now. “This is the problem with science,” said Ling. “Once people get set in their thinking, the onus is on you” to prove otherwise.

The technology used in this particular experiment is called RNA-seq (sequencing), which speeds up the process of sequencing genetic information. But it is also ridiculously expensive — and it still takes several months to process samples because there are long waiting lists to use these rare multimillion dollar machines. “It’s a huge risk to put all of your eggs into one basket,” Ling said. “If you try to engage in a high risk, high reward experiment, and it doesn’t end up working, then you’re out of money to do the work you’re supposed to do.”

So the ALS funds might not have led directly to this new therapeutic strategy, but that money accelerated the lab’s progress by allowing them to do a pricey experiment that they might otherwise not have been able to afford. Ling estimates it would have taken another two to three years at least without it. That’s not very long in the world of scientific research, but it is an eternity to someone suffering from ALS, which kills most patients within two to five years. So in that sense, we can call the ice bucket challenge a success.

Exciting though this experimental result may be, it is not a magical “cure” for ALS — or even a fully developed therapy. The pivotal experiment was done on lab-grown cells, not whole living organisms. The next step for the JHU group is to test their designer protein that mimics TDP-43 on mice. If that works, it must then be tested on humans. The good news is that TDP-43 functions the same in both mice and humans — indeed, in pretty much every higher-order organism, according to Ling. It just does its thing in different locations.

“Just because you see it in 97% of patients, we still don’t know whether it’s causing the disease or if it’s merely a symptom of the disease,” Ling said. “What we do know is that if you remove [TDP-43] from a neuron, that neuron will die. We may just be slowing things down.” The only way to know for sure is to conduct a clinical trial. And clinical trials are expensive.

Hmmm. It might be time to break out the ice buckets again.

Ling, JP et al. (2015) TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349(6248): 650-655. [abstract]

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