If Taylor Swift and Justin Bieber Wrote a Grant, Would the NIH Fund It? — OR — How Much Outside-the-Box-Thinking Should the NIH Support?

By Guest Blogger Robert Dellavalle, MD, PhD, MSPH, Associate Professor of Dermatology and Public Health, University of Colorado and the Colorado School of Public Health

 

“To maintain our edge . . . we’ve got to protect our rigorous peer review system and ensure that we only fund proposals that promise the biggest bang for taxpayer dollars . . . that’s what’s going to maintain our standards of scientific excellence for years to come.” –President Barack Obama on the 150th Anniversary of the National Academy of Sciences, April 29, 2013

 

Peer review may be scientifically untested, expensive, unreliable, and biased [Guthrie et al. 2015; Ginther et al. 2011], but it’s the best we’ve got–so let’s not tweak it too much. That’s the gist of a recent New England Journal article examining current National Institutes of Health (NIH) peer review processes for reviewing grants [Lauer and Nakamura, 2015]. Support for the status quo defaults from the lack of acceptable proven alternatives. Alternative grant rewarding systems do exist: one example is awarding grants according to the past performance and creativity of applicants (as the MacArthur Awards do), and another example is creating milestone competitions to reach large end goals (as the Human Genome Project did). But the outcomes (number of publications, positive changes in clinical practice, etc.) of these alternatives have not been compared rigorously to the outcomes of selecting grants by peer review.

 

The NIH budget doubled 15 years ago. This expanded the number of science trainees, leading to more NIH grant applications from more people today. These applicants are also submitting more applications due to the increasingly competitive funding levels. This provides a dilemma for the NIH—with an ever-tightening budget, should it continue to fund high-risk projects that score highly with peer review or adapt other review systems that might better identify projects with greater scientific impact?

 

Black-and-white cat next to littterbox.
Fig 1. My cat, Spot, thinking outside the box.

Do you ever think outside the box (Fig.1)? My personal NIH funding history provides a case report of a high-risk proposal. At the start of my academic career my wife Lisa Schilling, like all good internists, was reading the New England Journal of Medicine in bed late one night and pointed out to me that a large randomized trial of statins for the prevention of heart disease noted a lower rate of melanoma in those receiving treatment. Ah ha! I thought—perhaps this was the magic bullet to cure melanoma—or at least a new chemopreventive agent. Since many large, high quality statin clinical trials had already been completed, I proposed examining the effect of statins using meta-analysis of individual patient data from those trials. I submitted the project to seventeen funding agencies and was reminded repeatedly of Alain de Botton’s quote “Most business meetings involve one party elaborately suppressing a wish to shout at the other: ‘just give us the money’.” In the end the NIH National Cancer Institute was the source of funding for my grant that found that statins were not the magic bullet for preventing melanoma [Freeman et al. 2006].

 

Subsequently my research has turned to another unconventional topic–educating tattoo clients about the risk of UV radiation for ruining their tattoos and the canvas for their body art (their skin). This time my collaborators and I have not considered another funder besides the NIH. So, given my experiences, I strongly favor the NIH funding high risk, outside-the-box projects despite the messiness. But the question of how best to achieve this goal will remain until rigorous methods compare alternative grant reviewing processes [Azoulay 2012].

 

 

References:

 

Azoulay P (2012) Turn the scientific method on ourselves. Nature 484:31–32.

 

Freeman SR, Drake AL, Heilig LF, Graber M, McNealy K, Schilling LM, and Dellavalle RP. (2006) Statins, fibrates, and melanoma risk: a systematic review and meta-analysis. J Natl Cancer Inst 98:1538-46. http://jnci.oxfordjournals.org/content/98/21/1538.long Accessed November 25, 2015.

 

Ginther DK, Schaffer WT, Schnell J, Masimore B, Liu F, Haak LL, and Kington R. (2011) Race, Ethnicity, and NIH Research Awards. Science 333:1015-1019.

 

Guthrie S, Guérin B, Wu H, Ismail S, and Wooding S. Alternatives to Peer Review in Research Project Funding 2013 Update. http://www.rand.org/pubs/research_reports/RR139.html Accessed November 25, 2015.

 

Lauer MS and Nakamura R. (2015) Reviewing Peer Review at the NIH. New Eng J Med 373:1893-4.

 

 

 

The Secrets of Insect Skin

By guest blogger Clint Penick, North Carolina State University

Clint-Penick
Clint Penick

Insects wear their bones on the outside of their bodies. Their so-called “exoskeletons” provide rigid support and structure for muscle attachments similar to our own skeletons. But the exoskeleton also performs functions similar to our skin. Like skin, the exoskeleton is composed of multiple layers with pores and hairs that create a buffer between the inside of an insect’s body and the outside world (Fig. 1). With literally millions of insect species on Earth, the unique properties of insect “skin” are only beginning to be explored.

A drawing of ant cuticle and human skin

The first clue that insect skin (or, cuticle) could offer new insights into the way we think about body coverings comes from studies on the Namib Desert beetle, Stenocara gracilipes. The Namib Desert is one of the driest places in the world, but the air above the desert floor can be saturated with fog that blows in from the ocean. When fog blows in, the Namib beetle stands on its head to expose small bumps on its abdomen that attract water. The rest of the abdomen is covered with waxy grooves that channel the water to the beetle’s mouth. Engineers have now mimicked this process to build new devices that pull fresh water out of the air in regions where drinking water is scarce.

 

A more recent discovery related to insect skin comes from studies on the Saharan silver ant, Cataglyphis bombycina. The silver ant forages at temperatures that would kill most other insects, but silver ants are able to withstand the heat using a special coat of hairs (yes, insects have hair, though insect hairs are somewhat different from those in mammals). The hairs of the silver ant reflect most wavelengths of light but are nearly transparent to mid-infrared radiation—the wavelength ants emit as heat. This trick allows silver ants to reflect heat when they are in the open and then shed excess heat when they find a patch of shade.

 

Over the past semester, a group of students I have been working with at North Carolina State University have also become interested in the body coverings of ants. For hundreds of years, scientists have used differences in ant cuticle patterns to tell species apart, but very little is known about what these patterns do for the ants. We had a hunch that differences in ant cuticle could affect how species deal with pathogens, and we are now studying this in a genus of Australian ants that wildly differ in their cuticle structure (Fig. 2). We are extending this project to work with students from arts and design to make a catalog of different cuticle patterns. This is the first step in what we hope is a deep investigation into the properties of insect cuticle.

Ant po9rtraits showing broad differences in cuticle structure
Ant portraits, Credit: AntWeb (https://www.antweb.org.) These images are made available under a Creative Commons license.

 

 

References

Parker AR and Lawrence CR (2001) Water capture by a desert beetle. Nature 414: 33-34.

Shi NN, CC Tsai, F Camino, GD Bernard, N Yu, and R Wehner (2015) Keeping cool: Enhanced optical reflection and radiative heat dissipation in Saharan silver ants. Science 349: 298-301.

Predicting the Future – Hywel Williams, our Yogi Berra, Is at the Plate

Hywel
Hywel Williams

One of Yogi’s famous quotes — or misquotes — is that “it is very tough to make predictions, especially about the future.” Hywel Williams is one of Dermatology’s experts in explaining the present and predicting the future of health related events using quantitative data. He has been given the responsibility for directing the NIHR Health Technology Assessment Program for the UK National Health Service. Essentially all 400+ current major clinical trials within all medical specialties will be under his purview. A wonderful recognition of his analytical skills and his ability to put together large groups of investigators in endeavors such as the International Cochrane Skin Group systematic reviews and various national clinical trials within the UK Dermatology Clinical Trials Network, which he founded. Hywel likes to understand and predict events, so it is important to understand the path that brought Hywel to this next stage of his academic life.

Hywel-Dda-from-Wikipedia-CC-License-public-domain
Hywel Dda (Hywel the Good)

Even more important than Hywel’s horoscope, which is still being crunched by my supercomputer, is the name “Hywel.” “Hywel” is Welsh for ‘eminent’ or ‘remarkable’; thus he was given his life’s direction from the get-go by his family. Hywel comes from the small hillside village of Cymmer Afran in South Wales, and he attended a tiny comprehensive school there. Hywel Dda (meaning “Hywel the Good”) was a ninth century Welsh king whose major accomplishment was codifying Wales’ laws and customs and for ensuring equal rights for women. Yes, our Hywel has followed the direction of his namesake king and has given extraordinary service in codifying clinical trial data and global burden of disease, both in the United Kingdom and internationally.

Just go through Pubmed listings for HC Williams and you cannot help being impressed by the extent and breadth of his interests and accomplishments. In addition to the big picture items, Hywel’s most recent paper in the British Journal of Dermatology (2015) looks at the micro-level on how to improve teleconferencing; for him no issue is too big or too small to be studied and improved. His multiple accomplishments and awards are easily searchable on the University of Nottingham web site. When I was the Editor of the JID, Hywel was clinical trials Editor, and he improved the Journal‘s approach to clinical trial data and publication. His service to our specialty has been extraordinary and exemplary.

We know that the entire British National Health Service and the individuals it serves will benefit from having Hywel in his new position. Although Hywel comes from Nottingham, he is no Robin Hood and will be judicious in supervising the reviewing and awarding grants for clinical research. It is his nature and in his name.

Stem Cells at the Montagna Symposium on the Biology of Skin (Part II)

Photograph of Sancy LeachmanGUEST BLOGGER:  Sancy Leachman, Oregon Health & Science University

Welcome back to Montagna, 2015!  The conference keeps getting better and better!

The morning session, chaired by John McGrath, focused on stem cell-based therapies and innovative reprogramming technologies. In this session, it seemed almost possible to glimpse the future — a future where monogenic disorders of the skin like epidermolysis bullosa might be treatable!  John reported on remarkable responses to cell-based therapies which led to life-changing improvements in the quality of life for his patients. Angela Christiano followed with a story about the next generation of 3-D skin models that she is developing that include not only keratinocytes and fibroblasts, but also melanocytes, nerve cells, and even rudimentary hair follicles. Jakub Tolar, a bone marrow transplant (BMT) expert from the University of Minnesota then showed truly amazing responses in recessive dystrophic epidermolysis bullosa with BMT. He demonstrated that stem cells derived from the BMT donor were able to differentiate and populate the skin and that these cells were able to produce collagen VII and improve clinical results in patients. Finally, Tony Oro presented clinical trial results from the Stanford dystrophic EB trial and showed new advances being made in adenoviral-driven reprogramming of autologous cells for therapeutic benefit. Taken together, these talks demonstrate the progress that is being made on all fronts, through the use of stem cells, for the benefit of these patients. It is one of the most optimistic and hopeful times I have seen for this class of disease.

The meeting ended with a bang – in keeping with tradition. Xiao-Jing Wang, from University of Colorado, revealed her new mouse model for patient-derived xenografting. One of the major limitations of the PDX mouse models is the need to use immunosuppressed mice in order to prevent rejection of the human tumor grafts. The immunocompromise in the traditional model eliminates the possibility of investigating the role of the immune system in the cancer progression and does not permit the investigation of immunotherapies. Xiao-Jing has now not only xenografted immunocompromised mice with human squamous cell carcinomas, but also used stem cells harvested from the same donor to reconstitute (or humanize) the mouse immune system. The same patient’s cancer graft is then removed and re-transplanted into the matched humanized mouse. In short, this is a new personalized model of the patient’s own tumor and immune system and opens up the possibility for testing novel drugs and drug combinations to predict response of the tumor to therapy, even immunotherapy. This is truly a preview of personalized medicine.

The last elements of the meeting included a panel discussion that was very lively. Topics included how to compete more successfully for grants, how to publish successfully, and how to position yourself for getting the job of your dreams after you finish your post-doctoral fellowship. I hope the young students and investigators in the room “felt the love” – those more senior members in the room were clearly committed to helping them become a successful next generation of investigators!

The finale of the meeting was a Potlatch Northwest-Style Salmon Barbeque at the home of Drs. Diane and Jim Baker. Just like the science at the meeting, life doesn’t get much better than this!

 

How Does Science Happen? The Basal Cell Nevus Saga

image of a lightbulb with a brain inside

Was Newton sitting under an apple tree? Was Kekulé dreaming while snakes were forming benzene rings during his rapid eye movements? Hard to say, it was a long time ago. That is why it is especially interesting to have a contemporary scientific narrative told by one of the key movers within the story. The October 2015 issue of JID includes an editorial by Ervin Epstein, Jr., who has been thinking of, dreaming of, and exploring the secrets of the basal cell nevus syndrome in the laboratory. He has been a great networker, even before the notion of networking was named, and he has interacted with clinicians and basic scientists throughout the world, as documented in his editorial. He starts with thoughts induced by sleep — or possibly hypoxia — on a transcontinental flight, reading, and integrating models and information from other diseases. Key steps of interacting with drug companies and convincing the money managers that basal cell nevus syndrome is important and that it could help their bottom line are expounded. The story is still in progress, so it is useful for the historians who will be digging though his emails and laboratory notebooks that Erv has shared his narrative in this issue.

 

Credit: Image credit: copyright Macrovector on Shutterstock.com

Einstein’s Grandchildren Revisit Space and Time

Our last post explored the international space station and its effect on mouse hair growth. Now we go 1400 light years further into space — and the future — to Kepler 452b, a time and distance trip, with  blogger Paul Kantor. Time travel and prediction of the future of mankind is a popular genre — Thomas More’s “Utopia” (1516), Jules Verne‘s “Twenty Thousand Leagues Under the Sea” (1864), and George Orwell’s “1984” (1949) are just a few of the science fiction works popular with my generation in the 1950s. Describing the distant future requires both discussing a scientific and technical environment and the political and social structures of a new time and place. Aldous Huxley (“Brave New World”, 1932) would have appreciated the fate of flash drives and ‘bks’ in Kantor’s future earth.

Trip to Space Station Grows Hair on Male Mice

Some experiments are not easy to perform. Consider a recent publication reporting six mice sent to live 91 days on the international space station (ISS) while their control group was on earth. (Neutelings et al, 2015) Alas, one mouse did not survive lift off, and two others died during the mission. Do not criticize the investigators because of the small number of animals involved or the fact that they were all males. Instead, concentrate on the most interesting finding for those earthbound humans who are developing baldness: the increased number of anagen (growing follicles) in the mouse in space. Hence, the mouse exposed to microgravity and other environmental factors on the ISS had dramatically increased transcripts associated with growing hairs.

Homo sapiens in space commonly experience skin injuries. One human experiment in progress involves one twin on earth and one in the station. There are returning human astronauts, and their hair could be checked for anagen/telogen ratio (a rather benign test). It is unclear whether the cost of sending someone to sit in the station is a high price to trigger their hair into anagen. For some, more hair at any price may be worth it. More studies can determine if more hairs are entering anagen or whether they are not leaving anagen.

This is a set of experiments that should be followed closely, and maybe balding individuals can donate their dimes and dollars to sponsor experiments such as these during long voyages on the station — or even longer voyages to Mars.

References:

T Neutelings, BV Nusgens, Y Liu et al (2015) Skin physiology in microgravity: a 3-month stay aboard ISS induces dermal atrophy and affects cutaneous muscle and hair follicles cycling in mice npj microgravity doi:10.1038/npjmgrav.2015.2

No Hair Works Alone—Hair Plucking and Growth

Image of woman plucking eyebrow with tweezer

Plucking of mouse hair is often used in the laboratory to investigate the hair cycle and sometimes to remove the pelage covering the skin before applying chemicals, drugs, ultraviolet irradiation or other components of the experimental tool box. An article by a cross-disciplinary team composed of dermatologists, stem cell biologists, developmental biologists, immunologists, mathematical biologists, and tissue engineers have worked together from diverse regions including the US, Taiwan, People’s Republic of China, and the UK. The result is a stimulating article in CELL about a simple principle underlying the population regenerative behavior in a complex biological system (Chen et al., 2015).

Important points:

  • Plucking hairs stimulate regeneration of both plucked follicles and unplucked adjacent follicles at some distance by some signals sent out from plucked follicles.
  • The immune system plays an essential role in this regenerative process. Hair follicles produce proinflammatory cytokines, including the chemokine CCL2, which attracts inflammatory macrophages with tumor necrosis factor alpha. These macrophages are necessary for spreading the signal afar, achieving the two-step signaling propagation.
  • Mathematical modeling of this system is consistent with the process of quorum sensing. Quorum sensing behaviors are often seen in bacteria and social insects such as ants and bees. Here, hair regeneration is shown as an interesting and important quorum phenomena in a mammalian system. “Quorum” in such systems describes a condition in which numbers of individual cells, organisms, or organs (e.g., hair follicles) are necessary for a change rather than an absolute level of chemical mediator.
  • NF-kappa B is one of the important mediators that stimulate hair regeneration.
  • In addition to the detailed mechanism that functions after hair plucking, this article shows that mathematical modeling analyses can helps to reveal a deeper level of understanding of skin diseases.
  • The institutional origin of the investigators is a perfect demonstration of the importance of involving multiple disciplines in research, as well as the broad international nature of skin-related and all research.
  • As investigators use wax or plucking to remove hairs to study their own hypotheses, they must be cognizant of all the quorum processes going on beneath the skin surface.
  • Hair disorders and organs beyond the skin may be co-opting the evolutionarily conserved quorum sensing principles for health or disease.

References        

Chen et al (2015) Organ-level quorum sensing directs regeneration in hair stem cell populations. Cell 161:277-290

Wringing Warts Till They Blister

Image credit: TInus Beyers / Shutterstock.com

For over two thousand years blistering beetles and their extracts have been used to remove noxious, noisome, persistent warts from skin. Research through 1960 (yes, before many of us were born), before keratinocyte culture, before PCR, before demonstrating autoantibodies in Pemphigus and Pemphigoid, was reviewed and worth a read, since it may yield clues pertinent even today (Bagatell & Stoughton, 1964).

Fast forward to last month.

At the Society for Investigative Dermatology meeting in Atlanta in May 2015, Li et al reported fascinating research in cultured human keratinocytes. Cantharidin, the active blistering component of blister beetle juice, specifically cleaved desmocollin (DSC) 2/3 both extracellularly and intracellularly, and DSC ectodomain fragments appeared in the culture media.. Even more interesting was that cantharidin caused intracellular cleavage of DSC . The extracellular cleavage was blocked by metalloprotease inhibitors, and a tyrosine kinase inhibitor, genistin, blocked both the extracellular and intracellular cleavage of DSC 2/3. Those interested in tyrosine kinases may let their imaginations run wild concerning new wart therapies.

Another major question beyond these very interesting mechanistic findings is whether the mechanism of acantholysis caused by cantharidin is a clue to the mechanism of acantholysis in some of the autoimmune blistering diseases.

 

References

Bagatell, F and Stoughton RB (1964) Vesication and Acantholysis chapter XXXI, in The Epidermis W. Montagna and WC Lobitz eds. Academic Press, NY, NY, pages 601-611.

Li, N, Liu, Z, Diaz, LA (2015) Desmocollin ectodomain shedding and cantharidin acantholysis Abstract Number 382, J Invest Derm 135:S65, 2015, page S65 (Abstract Number 382).

 

Conflict of Interest:

Your blogger in an Emeritus professor at UNC Chapel Hill where this research was conducted but had no role in the research.

Disney Is Correct: It Is a Small World for . . . Investigating Psoriasis

Christopher Griffiths, Head of Dermatology at the University of Manchester in the UK gave the plenary Eugene Farber lecture on “The Natural History of Psoriasis” at the Society for Investigative Dermatology annual meeting on May 7, 2015 in Atlanta, Georgia. I was stimulated in many dimensions:  by the excellent research and presentation style, the wonderful use of the King’s/Queen’s English, and the incredible organization of the UK Dermatology enterprise in generating and sharing data.

The English dermatologists have developed nationwide organizations for collecting, analyzing, and disseminating important clinical data. A little investigation showed that dermatologists around the world are contributing to similar big data sets for the benefit of patients.

Examples are within an alphabet soup of acronyms; it should be noted that the BAD, the British Association of Dermatologists, is a key mover in this process. UK-TREND (UK Translational Research Network in Dermatology), a membership organization started in 2013, is one example of the BAD’s commitment to facilitating translational research in skin biology and disease to improve patient care.-

 

image credit: www.shutterstock.com / 903418000Other examples include:

BADBIR – British Association of Dermatologists Biologic Interventions Register

BADGEM – British Association of Dermatologists Dermatology and Genetic Medicine

PSORT –  Psoriasis stratification to optimize relevant therapy

 

Another international group collecting data, including data on adverse events is:

PSOLAR – (Psoriasis Longitudinal Assessment and Registry) is a multinational group of investigators collecting important data on longitudinal fashion on now over 1,496 patients (Kalb et al, 2015) in the US (74.3%), Canada (13.7%), and the rest in other regions of the world.

 

All of these groups address important research and clinical issues, and several have industry support.

Data from these groups will lead to relevant information for patient management.. The stratification studies can also lead to choosing between apparently equivalent therapies that may be more beneficial for one subset of patients compared with others.

 

REFERENCE:

RE Kalb, DF Fiorentino, MG Lebwohl, et al (2015) Risk of serious infection with biologic and systemic treatment for psoriasis. JAMA Dermatology   doi: 10.1001/jamaddermatol.2015.0718