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A Young Blood Controversy

The recent revival of interest in the way that the blood from younger animals (and people?) can improve the health of older ones came bundled with a particular protein candidate for the effect, GDF11. Several papers appeared on its effects in vivo, but there were people who found that odd, according to Nature News.

Those results quickly made GDF11 the leading explanation for the rejuvenating effects of transfusing young blood into old animals. But that idea was confusing to many because GDF11 is very similar to the protein myostatin, which prevents muscle stem cells from differentiating into mature muscle — the opposite effect to that seen by Wagers and her team.
For GDF11, “You could imagine that when it came out last year that it helped muscle, it was quite a surprise,” says David Glass, executive director of the muscle diseases group at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts. “Did we miss something?”

Now in Cell Metabolism, Glass and co-workers are reporting that GDF11 does not, in fact, have the effects ascribed to it. If they’re right, this is (yet another) case of antibody trouble, because they report that the antibody used in the recent papers is not as selective as it’s supposed to be. Novartis has an anti-myostatin antibody in development as a therapeutic (which explains their immediate interest here) and they’re looking into whether it blocks GDF11 as well. Their paper suggests that that would be no bad thing, actually.
Amy Wagers and co-workers at Harvard, though, are apparently sticking to their guns, suggesting that there might be multiple forms of GDF11. That’s possible, to be sure, but it’s also (I hate to say this) the sort of rationale that one comes up with after one’s antibody has been called into question. I wouldn’t want to count the number of times that studies (large and small) have come undone because of antibody problems, and it’s almost always because they turn out to be less targeted than thought. There are a lot of proteins out there, and a lot of related proteins to any given target. Assaying an antibody against them can be quite tedious, but if you don’t, you run the risk of things suddenly getting the opposite of tedious, and not in a good way. We’ll see how the dust settles on this one.
If the Glass paper is correct, though, and GDF11 is not the answer, that throws the field wide open for someone to find out what the answer is. I would guess that several groups have held back getting into this area, thinking that the big prize had already been found, but if that’s not so, well. . .
Update: and as fate would have it, Nature News now has a feature on the problems of antibody reproducibility! Thanks to a post in the comments section for pointing this out.

19 comments on “A Young Blood Controversy”

  1. steve says:

    Hi Derek – Your Cell Metabolism link isn’t working. With regard to the studies, you’d think that if the antibody blocks the activity that Wagers was looking at, and if Novartis is right that it’s not GDF11, then it’s likely to be another cross-reactive member of the family. If I were Novartis I’d be doing a lot of immunoprecipitations with that antibody and try to find what else it brings down.

  2. Douglas Kell says:

    And also doing some epitope mining to see what other motifs/sequences provide good candidates. Worth checking out http://www.proteinatlas.org as well.

  3. Douglas Kell says:

    And also doing some epitope mining to see what other motifs/sequences provide good candidates. Worth checking out http://www.proteinatlas.org as well.

  4. Douglas Kell says:

    And also doing some epitope mining to see what other motifs/sequences provide good candidates. Worth checking out http://www.proteinatlas.org as well.

  5. Ron richardson says:

    We’ve known myostatin is an obvious target for muscle wasting diseases with billion dollar markets for ~15 years now. It’s clearly druggable with antibodies. Acceleron’s attempt at the pathway led to bleeding problems and other tox issues are known–has anyone shown any human data suggesting there are tolerable and effective ways to target this pathway?

  6. interested reader says:

    Note that the NIH has jumped all over the finding from Wagers. They came out with an RFA that appears to be specifically designed to fund her work:
    • Analyses of Human Datasets and Biospecimens to Characterize Aging-related Phenotypes Relationships to Circulating Polypeptides and Proteins that Reverse or Accelerate Aging Changes (R01) (RFA-AG-16-012) National Institute on Aging
    Application Receipt Date(s): July 09, 2015
    It will be interesting to see what happens to that RFA and to Wagers. This is not the first time that she has been involved in research that turned out to be irreproducible. See:
    http://blogs.nature.com/news/2012/08/ori-former-harvard-postdoc-guilty-of-misconduct.html

  7. Anonymous says:

    Also Nature *just* did a feature story on how unreliable antibodies contribute to irreproducibility
    http://www.nature.com/news/reproducibility-crisis-blame-it-on-the-antibodies-1.17586

  8. Anonymous says:

    Does anybody know what happens to RetractionWatch ? The website looks totally dead. I wonder if this is the consequence of lawsuits from “scientific” fraudsters…

  9. johnnyboy says:

    @7: this is a huge, huge problem in molecular biology and pathology. The Nature article sums up the issue well. It references some studies indicating that about 50% of all antibodies sold as reagents may essentially be crap, and to me that looks like a low-ball estimate. Which raises the inevitable suggestion that research published using crap antibodies is also crap.

  10. Derek Lowe says:

    #8 – Retraction Watch is having all kinds of trouble with their server today. There was a big blowup of a social science paper, and they broke the story, so their traffic is through the roof.

  11. lynn says:

    Seems like a problem parallel to that of using small molecule enzyme inhibitors as probes of cellular function without proving the selectivity of the inhibitor.

  12. Lane Simonian says:

    Young blood in old brains may not be a great idea. GDF11 appears to primarily work through epidermal growth factor receptors, which can lead to neurogenesis but when over-activated can lead to neuronal cell death and to the subsequent inactivation of these receptors.
    http://www.ncbi.nlm.nih.gov/pubmed/12546816

  13. pete says:

    @12
    “GDF11 appears to primarily work through epidermal growth factor receptors”
    – no

  14. Lane Simonian says:

    This is exactly what I would expect:
    That pathway has a variety of functions in adult animals, often centered on growth and repair. In the brains of adult mice, for example, TGF-β is upregulated after injury and seems to play at least a short-term role in repair and neurogenesis. Longer term, however, elevated levels of TGF-β have been reported to cause abnormal hippocampal remodeling and worsened cognition – See more at: http://www.dana.org/News/A_Fountain_of_Youth_for_the_Brain_/#sthash.YsnYzoGk.dpuf

  15. tangent says:

    “This is not the first time that she has been involved in research that turned out to be irreproducible. See:
    http://blogs.nature.com/news/2012/08/ori-former-harvard-postdoc-guilty-of-misconduct.html
    That was fraud by a supervisee, this is (proposed to be) poorly characterized reagent. What factor about Wagers are you proposing to be in common leading to both incidents?
    You know, your link gives me a higher estimation of Wagers’ integrity, not lower (relative to the “nothing” I knew about her beforehand).

  16. interested reader says:

    It is the responsibility of the PI to ensure that the data being generated and published by his/her laboratory are accurate and reproducible. That is true regardless of the cause of the problem. Not ensuring that data generated by a single graduate student and published in multiple high profile publication have been verified, or not verifying that antibodies or other reagents that are critical to extremely important results are correct, falls equally on the shoulders of the principal investigator.

  17. Lane Simonian says:

    Sometimes both sides can be right and wrong at the same time. Here is a short list of ligands, receptors and kinases that promote neurogenesis in the absence of oxidative stress but which during the aging/oxidative stress process can lead to the death of neurons:
    GDF11, receptor tyrosine kinases, non-receptor tyrosine kinases, g protein-coupled receptors, NMDA receptors, AMP-activated protein kinase, and protein kinase C.
    So Amy Wagers was right in her model; David Glass was right in his model.

  18. Matthew Dougherty says:

    Seems like a single protein is too good to be true. Nice fast route to a Nobel if you can find it, and to the cities of gold.
    It may turn out to be an un-patentable blend of amino acids or RNA. Considering various & recent papers on Arg, Cys, Ser, and Met supplementation, it may be that simple: supplementation or restriction as a function of age.
    Aborted proteins due to lack of substrate; lack of glutathione allowing H2O2 levels to rise causing chronic disruption of signaling, lipids, rna, structural failure; etc.
    Unbalanced AA levels as a function of age, what could go wrong?

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