Post by: Peter Vitiello, PhD
Last week, HBO’s satirical comedy newsman, John Oliver, addressed how scientific studies can be misconstrued by the media, transforming their original findings into entertainment solely suitable for morning show banter. In addressing how junk science becomes overhyped, the episode did a great job exposing data replication issues limiting research investments.
(Click Here to View HBO's John Oliver Video Clip. Warning: Language may be inappropriate for some.)
Reproducibility became an important topic of discussion in 2012 when Amgen reported that they were unable to reproduce findings in 47 of 53 “landmark cancer papers” published in journals with an impact factor greater than five. Even when considering failure rates of pre-clinical studies, this 94% irreproducibility rate was shocking and served as the motivation for new standards. The US National Institute of Neurological Disorders and Stroke called for data reporting standards in regard to animal randomization, blinded assessment, sample-size estimation, and data handling and biological sex and reagent authentication have also been added to this list. However, there was also a clear delineation between how this rigor should be applied exploratory studies (early-stage observational tests) and more robust hypothesis-testing experiments.
In light of such issues, direct requests to access raw data and protocol details of published studies have increased. However, editors of the New England Journal of Medicine, which coincidentally has the highest retraction rate of any journal in the world, recently refereed to such scientists as “research parasites”. Casey Greene at the University of Pennsylvania Perelman School of Medicine used this opportunity to create the Research Parasite Award to recognize outstanding contributions to the rigorous secondary analysis of data (nominations are due by October 14). More transparent approaches for handling confirmatory and replicative studies performed by such “parasites” are being developed. Although Amgen’s 47 irreproducible studies remain anonymous, they recently released data on three failed studies through a new “Preclinical Reproducibility and Robustness” channel created by Faculty of 1000. Many other publishers are following suit as Elsevier recently announced a new “Invited Reproducibility Paper” as a new article type appearing in the data science journal, Information Systems.
In summary, I’m very excited to see greater data sharing and transparency through guidelines set by both funding agencies and publishers along with opportunities and respect for parasitic confirmatory studies. I hope that scientists embrace such expectations and do not use them as sole justification to dismiss creativity and novelty during peer review. My only fear is knowing that my harshest critics watch John Oliver and I’ll be expected to respond to these cynics at our next family gathering.
Category: Redox Biology
On October 21-22, SfRBM leadership held 12 meetings on Capitol Hill in Washington D.C. to introduce key Congressional offices to the society and discuss important issues impacting members, including increased NIH funding, diversity and public engagement in science.
SfRBM met with senior staff of the Senate Committee on Health, Education, Labor and Pension (HELP), which has jurisdiction encompassing most of the agencies, institutes, and programs of the Department of Health and Human Services including the NIH. SfRBM also met directly with Senator Chuck Grassley, Senator Joni Ernst, Congressman Dave Loebsack to name a few. One goal of these meetings was to build relationships between key Congressional offices and SfRBM. While SfRBM is a member of the Federation of American Society for Experimental Biology (FASEB), which does an amazing job raising awareness of legislation impacting the scientific community, they do not promote or raise awareness about SfRBM specifically.
SfRBM leaders and staff who participated included Neil Hogg, Rick Domann, Sruti Shiva, Eric Kelley, Kent Lindeman and Brent Carney, the society’s communications and public affairs partner.
In talking to members of Congress about ways to increase NIH research funding, there was pledged support for this initiative, however no real solutions laid out for how to fund it. Congressmen James Sensenbrenner’s office indicated they would not vote in favor of any NIH bill that did not clearly identify the funding source. Senator Robert Casey’s office stated that the pharmaceutical industry, who benefits greatly from the bench science resulting from NIH funding, doesn’t seem to prioritize the importance of NIH funding to support this research when they are speaking with legislators.
After meeting with the Senate HELP Committee, we came away with guarded optimism. The Committee is currently working on an “Innovation Bill” that will be the Senate companion to the 21st Century Cures Act which passed the House earlier this year. This bill will focus on three sectors, NIH research, FDA research and Health IT. While the bill is set to be introduced in the next couple weeks, making our visit extremely timely, it is unclear if it will contain increased funding for the NIH. Senator Patty Murray, in her role as Committee Ranking Member, indicated to us that such funding is a “must have” in the legislation.
Overall, we were thrilled with the reception we received and the opportunity this gives us in the coming years. Given the timing of the legislation in the HELP Committee and the FY2016 budget, our visit couldn’t have come at a more pivotal time. As one of the benefits you receive as an SfRBM member, we feel this representation in Washington was extremely beneficial for our organization, its members and the issues so many of us hold dear. We look forward to continuing to build the relationships that were started in DC last week, to the benefit SfRBM members in future years.
Neil Hogg, Ph.D.
Medical College of Wisconsin
Category: Redox Biology
To Experienced Mentors,
My principal investigator (PI) helped me with my writing, the postdocs in lab taught me bench science, and my fellow grad students helped me better communicate my science. I’m going to be in charge of training an undergrad on a project which will be an extension of my dissertation work. I’m excited, and my PI thinks I am ready for this responsibility, but I don’t know if I am going to be good at training as this is my first time as a science mentor. Should I be worried?
A Nervous New Mentor
Dear A Nervous New Mentor,
First off, congratulations on taking this leadership role in your lab. Training freshmen scientists is one of the most important steps in maintaining the success of not only individual research programs, but scientific progress in general. That being said, training a new lab member as a graduate student or even a postdoc for the first few times can be challenging because rarely will you have someone providing constructive criticism as you employ your own method of training.
Even though this is your first time in a training position, know that your PI trusts you at this point in your career to be able to handle this responsibility. This is not to say there won’t be speed bumps and some additional demands on your already busy lifestyle. But that is where you can utilize your mentors’ help. Never be afraid to ask for advice from your PI and other colleagues who have had the opportunity to train new lab members. Use their advice to mold your own personal training strategy, and over time with trial and error you can improve your mentoring strategy. Even seasoned investigators sometimes have to modify the way they teach based on the available resources and personal characteristics of the trainee.
So to answer your question, don’t be worried. Instead, utilize your skills as a scientist to be observant and know that some hardships and failures may come up that you will have to find solutions to implement.
An Experienced Mentor (who is still learning a few tricks)
Most of the SOD mimics thus far developed belong to the classes of Mn-(MnPs) and Fe porphyrins(FePs), Mn(III) salens, Mn(II) cyclic polyamines and metal salts. Due to their remarkable stability we have predominantly explored Mn porphyrins, aiming initially at mimicking kinetics and thermodynamics of the catalysis of O2− dismutation by SOD enzymes. Several MnPs are of potency similar to SOD enzymes. The in vivo bioavailability and toxicity of MnPs have been addressed also.
Numerous in vitro and in vivo studies indicate their impressive therapeutic efficacy. Increasing insight into complex cellular redox biology has been accompanied by increasing awareness of complex redox chemistry of MnPs. During O2− dismutation process, the most powerfulMn porphyrin-based SOD mimics reduce and oxidize O2− with close to identical rate constants. MnPs reduce and oxidize other reactive species also (none of them specific to MnPs), acting as reductants (antioxidant) and pro-oxidants.
Distinction must be made between the type of reactions of MnPs and the favorable therapeutic effects we observe; the latter may be of either anti- or pro-oxidative nature. H2O2/MnP mediated oxidation of protein thiols and its impact on cellular transcription seems to dominate redox biology of MnPs. It has been thus far demonstrated that the ability of MnPs to catalyze O2−dismutation parallels all other reactivities (such as ONOO− reduction) and in turn their therapeutic efficacies.
Assuming that all diseases have in common the perturbation of cellular redox environment, developing SOD mimics still seems to be the appropriate strategy for the design of potent redox-active therapeutics.
By: Dean P. Jones, Emory University
Metazoan genomes encode exposure memory systems to enhance survival and reproductive potential by providing mechanisms for an individual to adjust during lifespan to environmental resources and challenges. These systems are inherently redox networks, arising during evolution of complex systems with O2 as a major determinant of bioenergetics, metabolic and structural organization, defense, and reproduction. The network structure decreases flexibility from conception onward due to differentiation and cumulative responses to environment (exposome). The redox theory of aging is that aging is a decline in plasticity of genome–exposome interaction that occurs as a consequence of execution of differentiation and exposure memory systems. This includes compromised mitochondrial and bioenergetic flexibility, impaired food utilization and metabolic homeostasis, decreased barrier and defense capabilities and loss of reproductive fidelity and fecundity. This theory accounts for hallmarks of aging, including failure to maintain oxidative or xenobiotic defenses, mitochondrial integrity, proteostasis, barrier structures, DNA repair, telomeres, immune function, metabolic regulation and regenerative capacity.