Mittwoch, 4. Februar 2015

Two inspiring Stories suggest how to do better Science: Parabiosis and Super Resolution Microscopy


Parabiosis
Nature has a fascinating background story on this type of research (6), but other reviews are recommended as well (7). Parabiosis was invented in the 19th century and became popular around the 1970s before interest waned again. Then some 10 years ago it was rediscovered by the biogerontology community. What I would like to emphasize is that the ebb and flow in research interest isn't uncommon. One has to wonder how many other gems are there to be found in papers from 1900-1960?
An example that I recall is research on medial calcification, which was pioneered by Blumenthal and Lansing. Although, interest in (medial) calcification has steadily risen, few studies have revisited the exact pathology they described and the idea to tackle this pathology is rather new (1).
What immediately jumped out from the Nature article was the name Clive McCay, the godfather of calorie restriction research. McCay was the first to study parabiosis in the context of rejuvenation and aging research. I find it troubling, almost ironic, that his parabiosis research was ignored, while Walford, Weindruch and Masoro were (re-)discovering and validating adult-onset calorie restriction in the 1970s and 80s (3). Their studies showed that one has to take seriously McCay's research and what happened? For another 20-30 years, nothing happened and the eventual rediscovery of parabiosis by the biogerontology community had nothing to do with McCay, Weindruch, Walford or Masoro.

Around the turn of the century, Amy Wagers was studying stem cell migration using the parabiosis approach and serendipitously one thing led to another (6):
In 2002, Irina Conboy, a postdoctoral fellow in Rando's lab, presented one of Wagers' papers at a journal-club meeting. Michael Conboy, Irina's husband and a postdoc in the same lab, was dozing in the back of the meeting room.
The mention of stitching mice together jolted him awake. “We had been in discussion for years that ageing seems to be all cells in the body, that all tissues seem to go to hell in a handbasket together,” says Michael. Yet they had been unable to think of a realistic experiment with which to investigate what coordinates ageing throughout the body.
Inevitably the path science takes sometimes is rather labyrinthine. In this case, it could have been much easier, however. We lost 50 years of productive biogerontolgy research and if we can identify how we could have screwed up like that, we may learn how to avoid these mistakes in the future.

A short detour: Clive McCay
I want to briefly comment on a review article written by McCay (2) to add some context on his thinking and the valuable research that could have come from it: he seems to have had the mindset of a modern scientist, many of the questions he wanted to address have yet to be answered or it was only recently that good evidence became available:
At present man is not only making little use of animals for the study of aging, but he is neglecting important opportunities for controlled and non-injurious experiments upon man himself.
A few examples of the many problems that could be attacked easily in institutions are the effect of long continued use of sugar upon old age, the level of calcium needed in the diet to maintain bones, the effects of different levels of fat in the diet, the relative merits of vegetarian versus omnivorous diets, the effect of sterols upon cardiovascular diseases, the effects of the long continued ingestion of alcohol, the effects of diets rich in milk, imbalances in nutrition between trace elements, vitamins, essential amino acids and unsaturated fats and the effects of various levels of dietary protein.
When he says institutions, this means prisons or mental hospitals. And, no, experiments along those lines are not unethical per se. Since the treatments tested would be non-harmful acquisition of reasonable consent would be almost trivial (in many cases), but to this day there are too few such experiments. He also tried to select for long-lived rats and to find out if small animals live longer, two research avenues that have been successfully explored not too long ago, e.g. Michael Rose did successful drosophila selection.
Generally, he attributed calorie restriction to growth delay. McCay mentions that the inspiration for CR research dates back to Moreschi 1909, while he published the first CR study in 1935; again a period of 20 years passed between these two pivotal studies. He successfully identified the shortcomings of many contemporary studies, e.g. malnutrition and husbandry.

Super Resolution Microscopy
To round off our discussion on how to improve science, this Betzig and Hess video (4) reminds us that it's not easy to be successful, even if your work eventually leads to a Nobel prize. Lack of funding for interesting ideas; overhyping and overselling of existing ideas are certainly problems; the rigidity of academic structure; it all can be very demotivating.

Alas, the best we could do involves paying higher salaries and investing more into science. Many recommendations for more efficient use of resources have been proposed and reviewed as well, in particular by Ioannidis (5). A very rough selection from my ideas and from (5), e.g. publishing of negative results and incentives to replicate studies, less incentives to climb the hierarchical totem pole, higher punishments for misconducts, minimum standards for data disclosure, minimum standards for experiemental design (sample size, blinding, allocation concealment, limits on re-testing hypotheses, etc.), extending trial registration to smaller studies/animal work + mandatory publishing, better training of critical thinking/statistics at Universities, improved animal husbandry.

References
1. Blumenthal and Lansing reported on a universal, age-related, (probably) diffuse rise in medial calcium content. Most modern publication, however, deal with intimal atherosclerotic calcification, Mönckeberg's sclerosis or mouse models of extreme vascular calcification. More at: http://biogerontolgy.blogspot.co.at/2012/10/a-draft-pathologic-and-cardiovascular.html

2. Experimental Prolongation of the Life Span. Bull N Y Acad Med. 1956 Feb; 32(2): 91–101. Clive M. McCay, Frank Pope, and Wanda Lunsford
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1805858/

3. J Nutr. 2010 Jul;140(7):1205-10. doi: 10.3945/jn.110.122804. Epub 2010 May 19. Honoring Clive McCay and 75 years of calorie restriction research. McDonald RB1, Ramsey JJ.

4. "Eric Betzig and Harald Hess (Janelia Farm/HHMI): Developing PALM Microscopy"
https://www.youtube.com/watch?v=GcQ24khZzvU

5. Circ Res. 2015 Jan 2;116(1):116-126.Reproducibility in Science: Improving the Standard for Basic and Preclinical Research.Begley CG, Ioannidis JP.

6. http://www.nature.com/news/ageing-research-blood-to-blood-1.16762

7. Eggel, A., & Wyss-Coray, T. (2014). Parabiosis for the study of age-related chronic disease. Swiss Medical Weekly, 144, w13914. doi:10.4414/smw.2014.13914

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