GDF11 controversy – my antibody better than yours!

by Alexey Bersenev on May 20, 2015 · 2 comments

in open science

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As you may heard Yesterday (read good coverage by Nature and Science and the Scientist), David Glass from Novartis has challenged a significance of highly profiled “rejuvenating factor” – GDF11. In particular, the results of his study showed that some conclusions from famous Amy Wagers paper, may be wrong. Contrary to Wagers, Glass demonstrated that GDF11 actually increase with age and negatively impact muscle regeneration. In the heart of controversy – antibody!

First, Glass repeated Wager’s experiment, using the same antibody. He demonstrated that the antibody was non-specific and cross-reacted with GDF11 analog – myostatin. Using specific antibody, researchers got different from Wagers group results. Wagers comment on Glass findings:

Harvard stem cell biologist Amy Wagers, who led much of the original work, says the Novartis data on GDF11 levels are not persuasive. And although they “appear to conflict with” her group’s, “we are actually very excited to see the Novartis data,” she says. “We remain convinced that at least one form of GDF11 declines in blood with age and that maintaining GDF11 levels in an appropriate physiological range is essential for muscle health.”

Wagers sticks by her data, noting that her group’s Science paper also found a drop in GDF11 with age using a different antibody that distinguished GDF11 from myostatin. And she says the Glass team’s injury experiment cannot be compared to hers because they used young animals and a dose of GDF11 three times higher. (Glass did this in part because he did not see any effect in old mice at the dose Wagers used.) The signaling pathway in which GDF11 lies “is notoriously dose-sensitive,” and low and high doses can have different or opposite effects, she says. Moreover, she says, the Novartis team’s muscle regeneration test was not comparable to hers—the Harvard team made the injury by freezing tissue, which is less likely than a toxin to kill muscle stem cells needed for regeneration.

Wagers says new data from her group will show that “there is a very compelling biological explanation for the apparent discrepancies.”

So, whose antibody is better? Antibody is the biggest possible reason for lack of reproducibility in biomedical research. Conclusions of many “hot” stem cell papers, solely based on use of antibodies. However, most researchers seem to be not bothered by comparative validation of antibodies quality. Why don’t researchers talk to each other? Write reviews, rank antibodies and freely share results of titrations/ validations! After all, Wagers and Glass go to the same bar to drink (theirs institutions just “across the road”), why not discuss antibodies before conduct experiments? Yet another issue is considerations for multiple isoforms or analogs of studied factor.

Coming back to reproducibility of the muscle injury experiment. I noticed that different rGDF11 were used (from PeproTech vs. R&D) by both Wagers and Glass groups. Even though Wagers said that injury models were different (btw, supplement to Wagers paper says cardiotoxin was also used for muscle injury), GDF11 administration and time points of experiments were the same. Would muscle injury model dramatically change conclusions? I doubt it.

Ok, we got one more interesting controversy here. The future excitement about “rejuvenating factor GDF11” now will depend on new data from Wagers lab. It seem to me, that controversy could be easily resolved if researchers would agree to run parallel experiments with the same reagents. See examples of it here and here.

{ 2 comments… read them below or add one }

Mike May 26, 2015 at 7:59 pm

There is obviously significant issues with getting consistency with antibodies. I will shout at the rooftops that the major contributor to this is the relabeling of antibody by the hands of dozens of suppliers that researchers purchase from everyday. You could identify one company selling a bad antibody, but you can’t stop it from being sold by 10 other companies who are reselling it under their own brand.
One World Lab has taken a different approach by forming legally binding contracts with original manufacturers to exclusively sell only their unique products and make them all available at $50 aliquots. Now researchers have the purchase power to test antibodies against the same antigen in the same experiment without the fear of duplicitous testing of the same material unknowingly. Now we just need to put the reviews next to the products and the oneworldlab.com offering will be complete.

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Kate August 21, 2015 at 11:04 pm

Sure there remains discrepancies between the constants of the labs, but how do we even know that Wager’s dosage is the correct one? Just because her and her team have pioneered this “anti-aging” field doesn’t mean they’ve done it accurately. Only the test of real time and real humans with detailed autopsies and studies can prove which anitbody/recombitant combats better. And that will take years and years.

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