By borrowing a system found in plants, researchers can turn off sperm production in an inducible, reversible, and non-toxic manner

Let’s say you want to study how your favorite gene affects aging. You pick Caenorhabditis elegans for your study because it is one of the most important models of aging, and you put some of the worms on a plate—but within days, they multiply, and suddenly your plate is a random mix of worms young and old! How are you supposed to study how long these nematodes live? A new system reported in G3: Genes|Genomes|Genetics provides a handy solution: a reversible way to sterilize your worms at the start of the experiment.

Kasimatis et al. set out to create a system for inducing sterility in C. elegans so that mating can be precisely controlled in the lab—whether for aging experiments or for studies in which controlling the timing of mating is beneficial, such as investigations of sexual reproduction itself. While methods like treatment with the chemotherapy agent FUdR have been used for some time, these systems are typically toxic and have off-target effects.

To create a method that was inducible, non-toxic, and reversible, the authors used the auxin-induced degradation (AID) system, which originates from Arabidopsis thaliana. In plants, the hormone auxin causes TIR1 to mark other proteins for ubiquitin-mediated degradation by adding a degron tag. The authors generated worms that express plant TIR1 and have degron tags on the gene spe-44, which is crucial for production of sperm. In these worms, auxin treatment leads TIR1 to degrade spe-44, thus preventing the worms from making sperm.

C. elegans has two sexes: hermaphrodite and male, and the authors tested the AID system in both. Auxin treatment in their model induced self-sterility in both hermaphroditic and male worms, just as expected. Self-sterile hermaphrodites were still able to mate with wild-type males, though, because egg production was unaffected. Male worms treated with auxin as larvae regained their virility after auxin withdrawal in adulthood, demonstrating that the system is reversible. The authors also compared their system to the common FUdR system; the new AID system resulted in longer lifespans, demonstrating that it’s a less toxic approach.

This new system, while an improvement over previous methods, is not without its drawbacks. Worms with degron-tagged spe-44 that were not treated with auxin still showed a detectable, though statistically insignificant, decrease in fertility, likely because the function of spe-44 was affected by the degron tag. Still, the AID system is a big advance over chemically toxic methods and is less labor-intensive than separating out adult worms by hand, leaving researchers more flexibility in designing assays to study longevity and mating.

Citation:

Auxin-Mediated Sterility Induction System for Longevity and Mating Studies in Caenorhabditis elegans

Katja R. Kasimatis, Megan J. Moerdyk-Schauwecker, Patrick C. Phillips

G3: GENES|GENOMES|GENETICS August 2018 8: 2655-2662; https://doi.org/10.1534/g3.118.200278

http://www.g3journal.org/content/8/8/2655

A reanalysis of genes tied to life span in mice reveals only a select few affect aging.

Like it or not, you are always getting older. The mechanisms responsible for this fact of life, non-negotiable as it is, remain poorly understood. To identify genes that drive the aging process, researchers typically look for those that affect lifespan. On the surface, interpreting such studies might seem simple: if animals with a mutation live longer or shorter than their wild-type counterparts, the mutation must have some effect on aging, right? Not necessarily; many mutations change the rate at which animals die, not the rate at which they age. In a report in GENETICS, de Magalhães et al. demonstrate the importance of this distinction by reanalyzing a set of genes previously connected to aging in mice. Their results have broad implications for interpreting studies of longevity.

To reevaluate these genes, the authors calculated the “demographic” rate of aging in the corresponding mutants, which reflects age-dependent mortality. The Gompertz-Makeham law of mortality states that the effective human death rate is made up of both age-dependent factors (e.g. heart disease) and age independent-factors (e.g. lightning strikes). When the age-independent factors leading to death are rare (like with laboratory mice), the law can be simplified into just the Gompertz equation. This equation describes the exponential increase in mortality rate with age, and by applying it to data from previous mouse studies, the authors were able to determine which genes affect the demographic rate of aging.

Most of the genes the authors analyzed turned out to affect mouse longevity in an age-independent manner. Only two out of 30 genes that increased lifespan did so by decreasing the demographic rate of aging. Similarly, only five out of 24 genes that shorten mouse lives increased the demographic rate of aging. While all of these genes are undeniably important for lifespan, the select few identified to influence the aging process are better candidates for studying the details of how organisms change as they age.

The authors also offered some insight into how studies of aging and longevity in mice are conducted, noting significant variation in the life span of control animals from study to study. This variation suggests that differences in how animals were housed and cared for, as well as other random factors, could be influencing the results of aging studies. Such variation must be taken into consideration as future studies attempt to unravel the biological complexities behind getting old.

CITATION:

A Reassessment of Genes Modulating Aging in Mice Using Demographic Measurements of the Rate of Aging

João Pedro de Magalhães, Louise Thompson, Izabella de Lima, Dale Gaskill, Xiaoyu Li, Daniel Thornton, Chenhao Yang, Daniel Palmer

GENETICS April 2018; 208: 1617-1630. DOI: 10.1534/genetics.118.300821

http://www.genetics.org/content/208/4/1617

Multiparental populations (MPPs) have brought a new era in mapping complex traits, as well as new analytical challenges. To face these challenges and encourage innovation, the GSA journals launched the ongoing Multiparental Populations series in 2014. This month’s issues of GENETICS and G3 feature a bumper 16 MPP articles, timed to celebrate a new easy-to-use site for browsing the series. In line with our goal of encouraging communication across disciplinary boundaries, the “MPP People” profiles aim to introduce series authors working in a wide range of systems.

Not all sand field crickets can fly. The “short wing” morph of this species is grounded by its stumpy wings and feeble flight muscles. But because female short-wings don’t need to sink their limited resources into the costly trappings of flight, they are champion reproducers. In contrast, the “long wing” morphs can fly to new and better habitats, but produce substantially fewer eggs than their Earth-bound peers.

Libby King has long been fascinated by such dramatic tradeoffs in how organisms allocate their limited pool of energy to key traits, particularly in how they coordinate their allocation strategy with the nutritional environment.

“If they have a lot of resources and a big pool of energy, then there might be one optimal way to divvy up that pie, but if they’re really resource limited, then there might be another, better way,” says King.

During her PhD research with Daphne Fairbairn and Derek Roff at the University of California, Riverside, King investigated how the proportion of long-wing to short-wing morphs in a cricket population is influenced by variation in resource availability across the landscape. From this ecological and evolutionary perspective, King was drawn to thinking about the mechanisms behind these patterns. What are the genes involved in strategy variation? There were no easy answers.

“That’s how I got pulled into the very hard problem of how to dissect a very complex phenotype,” says King. To work on such problems, she shifted focus in her postdoc research to fruit fly genomics.

Elizabeth G. King, University of Missouri–Columbia

“Libby is really talented and has already made big contributions to the field,” says her former postdoc mentor Anthony Long at the University of California, Irvine. “She is one of the rare people with a really deep appreciation for both classical quantitative genetics and more modern molecular approaches to the dissection of complex traits.”

Working with Long and Stuart Macdonald (University of Kansas), she played a key role in the development and testing of the Drosophila Synthetic Population Resource (DSPR), a pair of multiparental populations with high power and resolution for complex trait mapping.

The DSPR is derived from 15 founder inbred lines capturing fruit fly genetic diversity from around the world. Each of the two replicate DSPR populations was created by crossing eight founder lines (seven unique, one shared by both replicates) for 50 generations and then establishing more than 800 recombinant inbred lines (RILs) per population.

Some of the main advantages of the DSPR, says King, include the very high mapping resolution and the fact that initial trait mapping requires only phenotyping of the RILs because the genome sequence of each can be imputed. During her postdoc, King developed a Hidden Markov Model method to infer the RIL sequences using dense genotyping with RAD markers and the known genome sequences of the founders.

Inbred lines also enable testing multiple phenotypes across the same genotypes. This last feature is particularly important for King now that she has established her own lab and is using the DSPR to investigate resource allocation in Drosophila.

“These are pretty complex traits that encompass all sorts of other traits, so it’s really useful to be able to measure phenotypes at those multiple levels of organization,” she says.

In a paper published in the MPP series in the June issue of GENETICS, King’s group, led by graduate student Patrick Stanley, examined a widespread resource allocation pattern: in many eukaryotes, individuals tend to live longer and reproduce less when nutrients are scarce. This is hypothesized to help conserve resources for survival while the individual waits for conditions to improve.

One potential avenue for the evolution of this pattern is the highly conserved insulin/insulin-like growth factor/Target of Rapamycin (IIS/TOR) pathway. In many models, knockouts for genes in this pathway live longer than wild-type, and there is substantial evidence that the pathway is involved in coordinating growth and metabolism with nutritional conditions. Changing expression of these IIS/TOR genes is often hypothesized to drive the lifespan/reproduction shift seen in low nutrient conditions.

Stanley et al. used the DSPR to investigate the link between this pathway and the nutrient-induced lifespan shift by focusing on 56 core IIS/TOR genes. They assayed how expression of these genes changed on three different diets, mapped genetic variation influencing these responses, and then measured lifespan of a subset of flies under these conditions.

As expected, most genes in the pathway changed expression between diet conditions. The team successfully mapped the genetic basis for these changes, including two trans QTLs that likely represent transcription factors that respond to diet.

But, consistent with mixed results emerging elsewhere in the literature, the results do not provide strong evidence that IIS/TOR gene expression changes drive the lifespan response to diet. They observed relatively small expression changes in most genes, rather than strong changes at a few key genes, and these were not in the direction you would predict based on knockout mutant phenotypes. “There is a change in global gene expression in response to diet, and this may well be partially driving what’s going on, but it’s clearly not the whole story,” says King.

Detail from the cover of the July 2012 issue of GENETICS, which included an article describing the properties of the Drosophila Synthetic Population Resource (DSPR). The center image represents the 15 inbred founder lines used to create the DSPR (blue = A population, red = B population, center purple fly representing the founder line shared between the populations). The background shows a sample of 100 RILs with the colors representing the founder ancestry across the genome. White areas represent an uncertain founder assignment.

A second MPP paper by King and Long in the June issue of G3 uses simulation to explore how an important bias affecting QTL mapping applies to large panels like the DSPR. This bias, known as the Beavis effect, is the tendency of significant QTLs to have overestimated effect sizes. This is because a test with an overestimated effect size is more likely to be found significant than one with an underestimated effect.

This phenomenon is one reason that, even for a true hit, validating a significant locus in a second population can fail if the experimental design lacks the power to detect the QTL at its true effect size. Although the Beavis effect is well established for traditional two-way QTL mapping, its importance is unknown for multiparental designs and association mapping, which can involve millions of tests.

The study revealed that the most important factor affecting the strength of the Beavis effect is the sample size, with the detail of the mapping design mattering much less. In essence, the more lines that are phenotyped, the weaker the Beavis effect becomes and the more accurate the QTL effects estimates become. Using only a few lines from the DSPR would make it is highly likely that the effect sizes of significant QTL are overestimated, and they may be difficult to validate in replicate experiments or cross-validate between different mapping designs. King and Long use their results to provide guidelines on the sample sizes needed to accurately estimate the percent effect variance of an identified QTL and the conditions under which a mapped QTL is likely to be successfully replicated.

King’s work with the DSPR has not only provided her the means to pursue her interest in the evolution of resource allocation strategies. It has also enriched the field as a whole, providing a powerful new component to the Drosophila toolkit for unraveling the molecular mechanisms of complex traits.

Read other MPP People profiles.

Browse the GSA Journals MPP series.

MPP AUTHOR:

Elizabeth G. King, University of Missouri–Columbia

MPP ARTICLES:

The Beavis Effect in Next-Generation Mapping Panels in Drosophila melanogaster

Elizabeth G. King and Anthony D. Long

Genetic Dissection of Nutrition-Induced Plasticity in Insulin/Insulin-Like Growth Factor Signaling and Median Life Span in a Drosophila Multiparent Population

Patrick D. Stanley, Enoch Ng’oma, Siri O’Day, and Elizabeth G. King

The genetic architecture of methotrexate toxicity is similar in Drosophila melanogaster and humans

Galina Kislukhin, Elizabeth G. King, Kelli N. Walters, Stuart J. Macdonald, and Anthony D. Long

Fine-Mapping Nicotine Resistance Loci in Drosophila Using a Multiparent Advanced Generation Inter-Cross Population

Tara N. Marriage, Elizabeth G. King, Anthony D. Long, and Stuart J. Macdonald

Using Drosophila melanogaster to identify chemotherapy toxicity genes

Elizabeth G. King, Galina Kislukhin, Kelli N. Walters, and Anthony D. Long

Properties and power of the Drosophila Synthetic Population Resource for the routine dissection of complex traits

Elizabeth G. King, Stuart J. Macdonald, and Anthony D. Long

Restricting calorie intake seems to promote longer lives in a wide range of organisms, from microbes to mammals. Some determined youth-seekers are already adopting reduced-calorie diets in an attempt to extend their lifespans. But it’s not clear yet that these anti-aging effects apply to humans, and the mechanisms by which they work in other organisms are not fully understood.

In the March issue of GENETICS, David McCleary and Jasper Rine delve into the complex relationship between calorie restriction (CR), chronological aging, and the histone deacetylase Sir2. Some work suggests Sir2 lengthens lifespan in low-glucose conditions in yeast, while other work finds no such effect. The researchers made a clever observation that allowed them to resolve these conflicting results: almost all yeast are grown on 2% glucose, which they suggest is actually borderline CR, since natural yeast substrates contain substantially more glucose. They employed a broader range of glucose concentrations to more fully capture the range of effects of Sir2 and CR on aging in yeast.

McCleary and Rine found that the effect of SIR2 deletion depended on both glucose level—high or low—and the media type—rich, which is full of assorted nutrients and peptide fragments, or minimal, which contains a precise but simple combination of amino acids and nutrients. Deletion of SIR2 extended lifespan only in high-glucose minimal media. But in rich media, deletion of SIR2 had little effect in high glucose and decreased lifespan in low glucose. In search of a mechanism, the researchers considered the cellular function of Sir2: to deacetylate specific sites on histone tails, leading to heterochromatin formation and gene silencing at the affected locus. They found that Sir2-dependent silencing at one such site, the HML locus, was affected by the media—the silencing was destabilized by high glucose in rich media, but the opposite was true in minimal media.

These results suggest a role for Sir2 as a regulator of yeast aging, lengthening or shortening lifespan depending on the environment. It’s certainly conceivable that in lean times, a longer chronological lifespan would be handy, allowing for reproduction to be put off until conditions improve. But what benefit could there be for a single-celled organism to shave time off its life? It’s possible that the shortened lifespans seen in nutrient-rich environments simply result from faster metabolism, more activity, and more risk of cellular damage, causing aging. But another intriguing possibility is that group selection is at work—if a population of yeast consists of genetically close individuals, killing off some individuals would free up nutrients and space for the next, possibly even better-adapted, generation.

CITATION:

McCleary, D.; Rine, J. Nutritional Control of Chronological Aging and Heterochromatin in Saccharomyces cerevisiae.
GENETICS, 205(3), 1179-1193.
DOI: 10.1534/genetics.116.196485
http://www.genetics.org/content/205/3/1179

New Faculty Profiles showcase GSA members who are establishing their first independent labs. If you’d like to be considered for a profile, please complete this form on the GSA website.

Jennifer Garrison

Assistant Professor
Buck Institute for Research on Aging
Lab website

Research program:

We study the relationship between the anatomy of neural circuits and the neuromodulators that functionally reconfigure them. We use both C. elegans and mouse model systems to understand how the behavioral outputs of a neural circuit are encoded by the diversity of neurotransmitters that they express—and in particular to investigate the cellular and molecular mechanisms that govern neuropeptide signaling in behavior and aging.

Outstanding, inquisitive scientists are invited to apply for postdoctoral positions in the Garrison lab. Prospective postdocs should send a cover letter describing research interests, CV and three letters of reference to Jennifer Garrison at jgarrison@buckinstitute.org. 

How has being a member of GSA helped you advance in your career? Why do you think societies like GSA are important? 

Absolutely! Professional societies like GSA are essential for many aspects of my career in science because they facilitate interactions with others in my field through conferences and publishing journals.

Previous training experiences:

Postdoctoral Fellow, The Rockefeller University
Laboratory of Neural Circuits and Behavior
Advisor: Dr. Cornelia Bargmann
Exploring neuromodulatory signaling and behavior in C. elegans

Graduate Fellow, UCSF
Advisor: Dr. Jack Taunton
Defining the mechanism of action of a small molecule inhibitor of protein biogenesis

New Faculty Profiles showcase GSA members who are establishing their first independent labs. If you’d like to be considered for a profile, please complete this form on the GSA website.

Xantha Karp

Assistant Professor of Biology
Central Michigan University
Lab website

Research program:

During aging, stem cells gradually become less effective at renewing tissue, leading to an overall decline in health. We are studying the mechanisms that maintain multipotent cell fate during quiescence (reversible cell cycle arrest) using C. elegans as a model for aging stem cells. When young C. elegans larvae are cultured in adverse environmental conditions, they pause their development by entering dauer quiescence—an arrested, non-aging and stress-resistant stage. If conditions improve, dauer larvae recover and complete development normally. Therefore, progenitor cells in wild-type dauer larvae maintain their ability to give rise to all proper cell types. The maintenance of multipotency during dauer is an active process involving at least two molecular mechanisms. First, we find that microRNA activity is modulated during dauer in order to regulate cell fate. Second, we find that DAF-16, the FOXO ortholog, is important for maintaining multipotency during dauer. Current projects are probing the intersection of these players with developmental pathways in two cell types in C. elegans dauer larvae.

The Karp lab currently has openings for MS students starting fall 2016. Qualified applicants will be provided year-round support (tuition waiver and stipend) via a combination of teaching and research assistantships. Students will use genetics combined with molecular biology in their research projects and will present their research at regional and international meetings. The goal will be for each student to be an author on at least one peer-reviewed publication. In 2016, we will be moving to the new state-of-the-art Biosciences building. This building will also house the two other C. elegans labs on campus, enhancing our vibrant worm community at Central Michigan University. Applicants should send an email with a statement of interest, a cv, and an unofficial transcript.

How has being a member of GSA helped you advance in your career? Why do you think societies like GSA are important? 

The GSA is important to me individually, to the field, and to society as a whole. First, going to the worm meeting is always a highlight of the year, and is an important way for me to stay connected. Second, I think the GSA journals play an important role in the field, and I have very much appreciated their high quality, both as an author and a reviewer. I am also excited for the adoption of WormBook in GENETICS. WormBook is an invaluable resource for the community, and I am happy that it will be able to continue in the future because of this new form. Finally, the education and advocacy missions of the GSA are extremely valuable to inform citizens and lawmakers about the importance of basic research.

Previous training experiences:

• Undergraduate at University of Toronto (research advisors Maurice Ringuette and Theodore Brown)
• PhD in Genetics and Development at Columbia University (advisor Iva Greenwald)
• Postdoc at Dartmouth Medical School and University of Massachusetts Medical School (advisor Victor Ambros), and Columbia University (advisor Iva Greenwald)

Teaching:

I teach undergraduate and graduate courses, primarily in the areas of genetics and cell biology.

Today’s guest post is contributed by Todd Plummer, a Research Associate in Gordon Lithgow’s lab at the Buck Institute for Research on Aging. Todd is a certified California Naturalist interested in the ecological relationships that affect wild strains of worms used as model organisms. Follow him on Twitter: @plumtodd 

This post first appeared on SAGE, a blog focused on the science of aging, founded by Postdocs at the Buck Institute. 

Adult Caenorhabditis elegans (Image source Wikimedia)

“What do you like about studying C. elegans?”

This was the question posed to attendees (myself included) by long-time scientists/entertainers Morris Maduro and Curtis Loer at the Genetics Society of America (GSA)’s 20th Annual Worm Conference hosted at UCLA this past June. Out of all the worm conferences around the nation each year, this is the only one referred to simply as “THE Worm Meeting.”

The emcees of the ever-popular, conference-ending variety show (the Worm Show) asked attendees of the conference what they enjoyed the most. By far the most popular answer was “the community.” One couldn’t help but feel caught up in something big and cohesive, held intact by the youthful stringiness of the field: most of the pioneers are still alive and kicking with webs of prodigy scientists succeeding and spreading the worm gospel.

This year the organizers overtly recognized the history of our biomedical research niche in which C. elegans nematodes are used as a model organism (see our SAGE blog on how C. elegans models are used to study aging). The genesis of Caenorhabditis in research dates to ideas put forth by Sydney Brenner in 1963 in a letter to Max Perutz. The idea took off and led to major breakthroughs in genetics, molecular science, and pharmacokinetics in the 1970s.

I’m relatively new to worm research, with previous experience as a technical writer, wildlife biologist, and nonprofit development officer. After working in administration and development at the Buck Institute for 6 years, I got an offer I could not refuse: to work in the lab of Dr. Gordon Lithgow. I jumped at the chance, and am now a technician on a consortium project between the Lithgow lab and the labs of Monica Driscoll (Rutgers) and Patrick Phillips (Univ. of Oregon). We are using worms to screen healthspan-enhancing compounds and to develop controlled methods for broad experimental reproducibility.

Stepping from the microcosm of our lab into the macrocosm of Worm People was like emerging from a thin trickle into the rush of a whitewater rapid. I was blown away by the energy, community, and mutual affection of worm folks. Names on journal pages became faces with eureka stories, friendly jibes, and advice for newer researchers – names like Nobel laureates Marty Chalfie (co-developer of GFP techniques) and Craig Mello (co-developer of RNAi technology).

It wasn’t long after I arrived that I started to hear the hive buzz among the thousand-plus audience members during the plenary talks in the beautiful Royce Hall on UCLA’s main campus. It sounded like a collective call-to-action: “One of us! One of us!”

The conference ran for five days with large plenary talks interspersed with breakout discussions on diverse subjects (physiology, neurology, cell development, gene regulation, etc.) I stuck mainly to sessions on stress, aging, and worm tracking and image capture. Keeping an eye on worms and their activity is a lot easier when one doesn’t have to look at them through a scope and poke them with a sharp wire to see if they are alive. On my project (the Caenorhabditis Intervention Testing Program or CITP), we use modified scanners and image-analysis software to assess worms on a touch-free system over their entire post-reproductive lifespan. This so-called “Lifespan Machine” was developed by Nick Stroustrup in the Fontana lab at Harvard Medical School. I heard his presentation on the technology and enjoyed learning about other competing platforms.

CITP worms on the Lifespan Machine. Photo credit: Todd Plummer

It’s impossible to describe the whole elephant – to capture the enormity of the hundreds of posters, talks, and conversations of the Worm Conference. So here are a few snapshot moments that stand out from my experience:

• Meeting several of my collaborators from other institutions face-to-face for the first time and really liking them as people. I prefer face-to-face contact. It’s way better than busy, tweaky conference calls and nuts-and-bolts emails.

• Hearing inspirational talks from the aforementioned Nobel laureates, especially Craig Mello. He really got me when he used the Hubble Ultra Deep Field image as a metaphor for the value of looking ever deeper into areas of inquiry that may seem “picked-over” or absent of interest. In that image taken of a tiny slice of dark sky devoid of visible stars, Hubble imaged something like 10,000 galaxies.

• Realizing that I could learn something from every talk, no matter how unfamiliar the subject matter seemed to be.

• Getting locked in my dorm bathroom at 4:30 in the morning. Luckily for me, the guy in the room on the other side of the shared bathroom was a worm scientist studying sleep (ha!) and wasn’t too cross when I had to pound on his door to get help. So we sat in his room – both in our jammies – and chatted about worms until help came to let me into my room. I never saw him again.

• Seeing former colleagues from the Buck, like Di Chen (Kapahi lab) and Pedro Rodrigues (Lithgow lab) who have gone on to other labs.

• Learning about the recent discovery of C. elegans’ so-called “sister species” – Species 34 – by Gavin Woodruff in Okinawa.  Species 34 lives on living figs visited by a certain species of fig wasp, unlike most Caenorhabditis which prefer rotting fruit in compost or on top of soil. Gavin was working at FFPRI at Tsukuba but now works with CITP collaborator Patrick Phillips.

• Worm art

• Seeing this amazing “rainbow cloud” during a break between sessions. While the Rainbow image seemed especially poignant in light of the recent Supreme Court decision on gay marriage, I think that it also reflects the many voices, talents, and experiences of the river of Worm People.
  

  Outside Royce Hall, UCLA. Photo credit: Todd Plummer

I’m definitely looking forward to the next Worm Conference!

By the time President Obama announced the Precision Medicine Initiative in January 2015, the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort was already a trailblazing example of this new approach to medical research.

GERA is a group of more than 100,000 members of the Kaiser Permanente Medical Care Plan who consented to anonymously share data from their medical records with researchers, along with answers to survey questions on their behavior and background. Participants also shared their DNA—via saliva samples—to help with the project.

The result is a treasure trove of data, says GERA co-principal investigator Neil Risch (University of California, San Francisco). The study links genotype data from the saliva to environmental and lifestyle data from the surveys to clinical, pharmacy, imaging, and diagnostic laboratory data from electronic medical records—all derived from a large, ethnically-diverse population.

GERA was formed in 2009 by a collaboration between the Kaiser Permanente Northern California Research Program on Genes, Environment, and Health (RPGEH) and the Institute for Human Genetics at UCSF, and is led by Risch and RPGEH Executive Director Catherine Schaefer.

Today, in a series of three papers published Early Online in GENETICS, the research team formally describes the GERA resource, including the population structure and genetic ancestry of the participants, telomere length analysis, and details of the innovative methods that allowed them to perform the genotyping within 14 months.

Genes to Genomes spoke with Dr. Risch about GERA and the team’s research:

What makes the GERA data so useful?

In my view, it’s Kaiser’s incredibly comprehensive electronic health record system. They’ve been way ahead of the game. The records include pharmacy records, what procedures were performed, scans, lab tests, you name it, it’s all there. Really, the only thing missing is dental. And it all goes back twenty years to 1995. Kaiser places a big emphasis on prevention, so there are lots of screening results that greatly enhance the information on risk factors. Once you attach genetic information to data like this, it enables analysis of so many different phenotypes.

And it’s not just genetics. From their survey responses we learn about patients’ behavior and lifestyle, and from their addresses we can infer all kinds of things about their risk exposures, air quality, water quality, social environment, built environment, income, etc.

Historically, the way we’ve done genetic studies is to start from scratch. We would recruit a study population, collect all the information, and measure a few things—like disease status or biomarkers—at one specific point in time.

But when we instead use data that is routinely collected as part of care, we have a much richer dataset, often over many time points. For example, I’m interested in lipids. You might think if we have a cohort of 100,000 people, that translates to 100,000 lipid panels. In fact it’s 1.1 million because the average person in the cohort has records from 11 lipid panels. That means we can look at changes over time with age.

Because these records are also linked to the pharmacy database, we also know what each of those people has been prescribed. So we’ve been able to analyze how people’s LDL cholesterol levels change after they start taking statins. And then we can look at side effects and so on. We don’t have to create a proposal for each of those questions, we just go back to the database.

And better still, a cohort like this only gets more valuable over time, because the records get updated every night. That means we can now do prospective, rather than retrospective analysis [prospective studies follow clinical outcomes in a cohort after enrollment in the study; retrospective studies record outcomes and risk factors in the cohort before enrollment. They suffer from more bias and confounding factors than prospective studies].

Skeptics thought electronic health data would turn out to be less reliable than targeted measurements, but that’s wrong. Over and over again, we’ve validated that electronic records are actually fantastic for these kinds of studies. In fact, I see this as a phase shift in the way genomics research will be done.

What findings has the GERA data yielded so far?

We have findings for prostate cancer, allergies, glaucoma, macular degeneration, high cholesterol, blood pressure—and those are only a few examples. It’s not just diseases either. For example, we have the results of PSA tests [prostate specific antigen screening tests for prostate cancer risk]. So we were able to find up to 30 novel variants that influence PSA levels.

The beauty of this resource is that no matter what phenotype we look at, we find associations—everything we touch! These are subtle effects, but in this cohort, if they exist, you’re going to find them. Even though people complain that the risks detected by GWAS are modest, I argue that this simply reflects reality—not everything is a Mendelian disorder. Model organism geneticists have known this for years: these traits are polygenic and there are many genes involved.

What did you learn from the population structure analysis?

Traditionally there’s been a bias in research participation from people with Northern European ancestry. To make up for that bias, we had a mandate to maximize minority representation when we selected participants. In the end, around 20% of the cohort were from a minority ethnicity/race/nationality.

We were particularly interested in people who checked more than one box on the ethnicity questionnaire. More and more people are identifying as multi-ethnic, which can pose some technical challenges for genomic studies in terms of complexity. At the same time, it also presents opportunities for analyzing genetic and social contributions to disease differences between groups.

Yambazi Banda (UCSF), first author of the population structure paper, is very interested in the relationship between genetic ancestry and how people self-identify. We found that the relationship is very strong, and the way people describe their backgrounds generally matches their genetics.

One interesting aspect of the data is that we ended up with related individuals among the cohort, including around 2,000 pairs of full siblings. That meant we could tell whether these siblings described their ethnicity in the same way as each other. Most did, but those who reported different ethnicity from their siblings tended to be multi-ethnic. Multi-ethnic people also tended to be younger, which probably reflects social changes and increased intermarriage across racial and ethnic boundaries.

How and why did you genotype the samples so quickly?

Around 2008 we had 85,000 saliva specimens and consent to use them, but we needed funding. This was around the economic recession, and, it turns out, when Arlen Specter and Congress pushed for 10 billion dollars in extra funding for the NIH, as part of the economic stimulus package. We received Grand Opportunity Project funding from the National Institute for Aging (NIA) because the average age of the cohort was 63, and the NIA was interested in funding genomic analyses of age-related diseases. But we needed to finish the work in two years, or just 14 months in the lab.

In 2009, it was a big deal to do something like this so fast. We were under the gun to get this data, with assays running 24/7. Thankfully we had a lot of hands-on help from Affymetrix [manufacturers of the genotyping chips]. And Mark Kvale, our lead scientific programmer, and postdoc Stephanie Hesselson, and Pui-Yan Kwok, who directs the genomics core, did a huge amount of work to make the project a success.

Part of our solution to the time crunch was developing real-time turnaround in the data analysis. So within three hours after the results came out of the GeneTitan [the genotyping array processing stations], we knew if anything was going wrong. Working in this way probably saved us hundreds of thousands of dollars.

We also improved the way the genotypes were called [inferred], realizing that Affymetrix’s historical method was suboptimal for rare variants. The upshot is that Affymetrix has since changed its protocol and has used a lot of the lessons that we learned with the GERA project to benefit other very large genotyping projects using the same platform—for example, the Million Veterans Program.

It wasn’t just genotyping either. Liz Blackburn and her group were assaying telomere length in all the samples at the same time [Blackburn is a UCSF geneticist and won a Nobel prize for the discovery of telomeres]. No one had done anything with telomeres on this scale before. The first author on the telomere paper, Kyle Lapham, had to create a robotic system for these very tricky experiments. In the end it only took four months to do the assays. It’s quite an achievement!

The results confirmed that the data is sound—for example, we see that telomeres get shorter with age as expected. We also observed a sex difference, where women tend to have longer telomeres than men.

Remarkably, there was some evidence that telomere length is related to survival. For those under 75, younger people tend to have the longer telomeres; But for the over 75s, there’s a reversal; the oldest people tend to have the longer telomeres.

What’s next for GERA?

We’re working on publishing more of the results; there are so many phenotypes that are just begging for analysis! At this stage we’re operating largely as a resource for other scientists. Researchers can apply for data access via Kaiser Permanente [the Kaiser Permanente Northern California Research Program on Genes, Environment, and Health] or via NIH’s database dbGap.

The field is moving away from SNP genotyping and in the direction of sequencing, with the rationale that the SNP arrays don’t provide good coverage of rare variants. But in reality the amount of information you get from these arrays is vastly more than just the several hundred thousand sites on the array because you can impute the genotypes at other sites by using reference sequence panels.

Tom Hoffmann (UCSF), who helped design the GERA genotyping arrays, has done a lot of work on imputation in this cohort. For example, we’ve published analyses on a rare mutation in HOXB13 that causes prostate cancer. The carrier frequency in people with Northern European ancestry is only about 0.3%, but given we have 100,000 people in the cohort, we expect carriers among them. But how do we find them? That particular variant was not included on the SNP arrays.

We found we could identify carriers relatively well by imputing genotypes at the mutation site using reference sequence panels and the genotypes of surrounding SNPs. The beauty is, once we had identified those carriers, the health records allowed us to look at not only prostate cancer, but at all cancers. Sure enough, we showed that in fact this mutation is a risk factor for a lot of other cancers.

Using imputation, I believe it’s very realistic that the GERA cohort will end up with good coverage of variants with frequencies of around one in a thousand. That means we’ll have data on up to 50 million variants, rather than just the several hundred thousand on the array.

As you can tell, I’m enthusiastic about this project! At the beginning of a big project like this, you really don’t know it’s going to work. It’s gratifying that after such a major investment of time and effort, we ended up with a resource that is so valuable and exciting.

CITATIONS:

Characterizing race/ethnicity and genetic ancestry for 100,000 subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort

Yambazi Banda, Mark N Kvale, Thomas J Hoffmann, Stephanie E Hesselson, Dilrini Ranatunga, Hua Tang, Chiara Sabatti, Lisa A Croen, Brad P Dispensa, Mary Henderson, Carlos Iribarren, Eric Jorgenson, Lawrence H Kushi, Dana Ludwig, Diane Olberg, Charles P Quesenberry Jr, Sarah Rowell, Marianne Sadler, Lori C Sakoda, Stanley Sciortino, Ling Shen, David Smethurst, Carol P Somkin, Stephen K Van Den Eeden, Lawrence Walter, Rachel A Whitmer, Pui-Yan Kwok, Catherine Schaefer, and Neil Risch (2015). Genetics. Early Online June 19, 2015. doi: 10.1534/genetics.115.178616

http://www.genetics.org/content/early/2015/06/18/genetics.115.178616

Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

Mark N Kvale, Stephanie Hesselson,Thomas J Hoffmann, Yang Cao, David Chan, Sheryl Connell, Lisa A Croen, Brad P Dispensa, Jasmin Eshragh, Andrea Finn, Jeremy Gollub, Carlos Iribarren, Eric Jorgenson, Lawrence H Kushi, Richard Lao, Yontao Lu, Dana Ludwig, Gurpreet K Mathauda, William B. McGuire, Gangwu Mei, Sunita Miles, Michael Mittman, Mohini Patil, Charles P Quesenberry Jr, Dilrini Ranatunga, Sarah Rowell, Marianne Sadler, Lori C Sakoda, Michael Shapero, Ling Shen, Tanu Shenoy, David Smethurst, Carol P Somkin, Stephen K Van Den Eeden, Lawrence Walter, Eunice Wan, Teresa Webster, Rachel A Whitmer, Simon Wong, Chia Zau, Yiping Zhan, Catherine Schaefer, Pui-Yan Kwok, and Neil Risch (2015). Genetics. Early Online June 19, 2015, doi: doi:10.1534/genetics.115.178905

http://www.genetics.org/content/early/2015/06/18/genetics.115.178905

Automated assay of telomere length measurement and informatics for 100,000 subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Kyle Lapham, Mark N Kvale, Jue Lin, Sheryl Connell, Lisa A Croen, Brad P Dispensa, Lynn Fang, Stephanie Hesselson, Thomas J Hoffmann,Carlos Iribarren, Eric Jorgenson,Lawrence H Kushi, Dana Ludwig, Tetsuya Matsuguchi,William B McGuire , Sunita Miles, Charles P Quesenberry Jr, Sarah Rowell, Marianne Sadler, Lori C Sakoda, David Smethurst, Carol P Somkin, Stephen K Van Den Eeden, Lawrence Walter,Rachel A Whitmer, Pui-Yan Kwok, Neil Risch, Catherine Schaefer, and Elizabeth H. Blackburn (2015). Genetics. Early Online June 19, 2015 doi:10.1534/genetics.115.178624

http://www.genetics.org/content/early/2015/06/18/genetics.115.178624

Photo credit: John Goode  CC BY 2.0

Today’s guest post was contributed by Andreas Prokop, of the University of Manchester. Along with research on the cell biology of neurons during development and ageing, he is engaged in many science communication and outreach projects. Follow him on Twitter: @Poppi62

More than a century of intense research with the fruit fly Drosophila has arguably turned this little insect into the animal whose biology we understand the most. Work with Drosophila has had a seminal impact on the development of modern biology [1, 2]. Flies offer many practical advantages (see more here), and fly researchers capitalize on a well-organized community, a rich pool of molecular, genetic, and online tools, as well as technologies that tend to be at the forefront of the field. As Hugo Bellen nicely sums it up: “You get 10 times more biology for a dollar invested in flies than you get in mice.”

There is some evidence, however, that there has been a downturn in NIH and NSF funding for Drosophila research [3]. One explanation for this could be the worldwide political trend of reducing funding for basic science in favor of providing funds for more translational research — in an (arguably false) expectation of short-term returns on tax investments. Unfortunately, this strategy ignores the role fundamental biology plays as the lifeblood for translational research. A trend of decreased support for basic science may well have the opposite of its intended effect, gradually and eventually drying up the production line that feeds advances in biomedical application.

What can fly researchers do to address these issues? I would argue that education, science communication, and outreach initiatives are some of the most critical tools we have for maintaining a robust Drosophila community that can continue its important contributions to biology and biomedical research. In this blog post, I describe some existing outreach initiatives, and discuss what more we can do.

An increasing need for science communication and outreach

Photo: Untitled by Kim94109 (CC BY-NC-ND 2.0)

Ironically, despite the threat of decreased funding, Drosophila research is needed more urgently than ever, as “omics” approaches in human genetics release a flood of disease-linked genes — which are more often black boxes than known entities. Established model organisms like Drosophila will be key to understanding these genes and testing hypotheses about them quickly and efficiently.

Fruit flies are also powerful tools for facing other challenges generated by “omics” data and new technologies. The fly’s efficient combinatorial genetics are ideal for validating and understanding gene networks, and Drosophila can readily serve as an experimental pipeline to help iteratively build and test computational models [e.g. 4].

While flies are clearly not mini-humans, and there are limitations to using Drosophila for studying human diseases, Drosophila has a proven strength in pioneering research into unknown territories. Using efficient and cost-effective research in flies to explore these genes is a responsible and low-risk investment, and countless cases from the last decades have shown us that this investment pays off: knowledge gained in flies frequently inspires and enormously accelerates advances in mammalian and human research. This has been well documented in the article by Hugo Bellen and colleagues: “100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future” [5].

Does the community of drosophilists do enough to communicate these benefits of fly research to the general public, including politicians? We tend to be so occupied with our scientific activities that public communication of our work is easily overlooked (or intentionally sidestepped). At the outreach workshop of the last GSA Annual Drosophila Research Conference in Chicago, Allan Spradling also commented that fewer members of the public, especially the younger generations, seem to have encountered Drosophila in schools. I observe the same at museum events, where those who were taught about flies at school even decades ago, tend to respond with noticeably greater curiosity and interest about fly-related topics than those without such memories. Traditionally, flies were used in school lessons to teach classical genetics, but the enthusiasm for this strategy seems to have been widely lost. As a consequence, I notice that first year university students often have little appreciation of, and even a disregard for the usefulness of invertebrate model organisms. We can hardly blame them for this. On occasion, I wonder whether even our fellow scientists and clinicians are sufficiently aware of the opportunities fly research offers.

Clearly, science has moved on. Drosophila was once unrivalled in its status as a “boundary object”, i.e. a model in which genetic strategies could be used for the investigation of biological mechanism (for an enlightening article on Drosophila embryos as boundary objects, see [6]). But as the genetic methods for other organisms have substantially improved over the years, Drosophila now shares this key role with other important models (and even culture systems). The advent of CRISPR technology will further contribute to this trend. Arguments for supporting fly research are therefore less black-and-white than in the past, and need to be substantially refined. We need to creatively, but sensibly, highlight the speed, efficiency and cost-effectiveness of our research, as well as the depth of conceptual understanding, the high degree of genetic and mechanistic conservation, and the unique opportunities for newly arising research directions.

What can be done to address these issues?

Scientists and educators can do more to promote the public understanding and appreciation of invertebrate model organisms, including Drosophila. Ideally, such outreach initiatives should be:

1. multi-faceted, targeting audiences at all levels;
2. follow long-term strategic plans, and;
3. should be well coordinated within the Drosophila

Initiatives that address the first two aspects are starting to spread within the community:

• More than a decade ago Christian Klämbt started the visionary “FlyMove” project, a site dedicated to illustrating and explaining Drosophila developmental biology in simple terms, aimed at university students and teachers of developmental biology.
• Increasing numbers of school or university lessons are being published, as well as ideas for science fair displays (some examples).
• Bethany Christmann‘s blog “Fly on the wall” is an outstanding initiative to explain in lay terms trends in Drosophila.
• Originating from her participation in a 2011 workshop on Drosophila Neurogenetics (organized by Lucia Prieto-Godino and Sadiq Yusuf in Uganda), Isabel Palacios runs an increasingly successful series of Drosophila workshops in Africa. Together with the development of the TReND in Africa organization, which developed from the same workshop [LINK1; LINK2], these initiatives are successfully seeding an African biomedical research community which also capitalizes on Drosophila as an affordable model organism.

The Manchester Fly Facility has also developed a range of outreach activities and resources:

• Two entertaining films about Drosophila, “Small fly, big impact” (part 1 & part 2), which have proven popular and valuable online and in schools.
• Free-for-download lesson plans and the droso4schools support website, which grew from an initiative to establish flies as modern teaching tools at schools (for more see here and here].
• Thoroughly tested approaches for multi-stand science fair displays; for example a successful neurobiology fair where Drosophila researchers joined ranks with mammalian neurobiologists and neurosurgeons.
• Novelties for engaging young children, such as Hama bead patterns (PDF). These can also be used for science fair flyers that children can take home, ideal for using a “Trojan horse strategy” [7], in which we provide web links to lay resources on Drosophila that parents can investigate.
• The twitterbot @fly_papers, set up by Casey Bergman to provide an easy means to stay up-to-date with the fly literature [8]. This information pipeline has recently been joined by Thomas Brody‘s new twitter feed @interactivefly.
• The Drosophila genetics training package [9] including the “Rough guide to Drosophila mating schemes” [10], developed for training newcomers to fly research, is now being used worldwide.
• Strategies to implement this training package in university courses, including flexible methods to electronically assess learned skills (see below).

Drosophila expressionism. Drawn by Natalia Sanchez-Soriano and the author in a collaborative effort

Unfortunately, the third aspect, i.e. coordinating outreach activities within the Drosophila community, is presently difficult to achieve, and, as a community, we need to develop better means of communication. The visionary idea of the Drosophila Information Service to spread the word within the community and share good practice [11] needs to be translated into modern communication technologies, which can be as simple as a moderated newsfeed. Another strategy is to increase the visibility of existing materials. To this end, the Manchester Fly Facility has developed a website, complementary to FlyBase and The Interactive Fly, which provides a one-stop-shop for Drosophila science communication resources, also including growing lists of lay articles and material about the history of Drosophila research.

Long-term strategies: Targeting students
For our efforts to have profound effect, we need long-term strategies. One such strategy is to give flies a stronger prominence in biology school curricula. This strategy also has a lot to offer to schools. Flies provide exceptionally good conceptual understanding of biology and bring countless opportunities for exciting, low budget experiments with live animals that reflect contemporary research (see the droso4schools website).

Another long-term strategy is to increase Drosophila teaching of university students. This audience is unique because they are non-expert members of the general public but are also potential future scientists. For example, to address the “general public” side of students, we can adapt the Drosophila resources developed for schools. In my experience, starting at this fundamental level is a good way to engage university students. To address “future scientists,” the fly genetics training package we described in G3 [9] offers great opportunities.

Originally, this training was developed for use in Drosophila research groups, to teach the fundamentals of classical genetics and transgenics, as well as their application during mating scheme design. As explained in our more recent G3 paper [12], applying this training to university courses has a number of important advantages, including:

• Introducing students to the core strategies and concepts of genetic model organisms like Drosophila.
• Reflecting relevant training that students can directly apply if they choose to join a lab working with flies or other genetic model organisms.
• Improved learning by teaching the fundamental concepts of classical genetics in an integrated and applied way.
• Providing training in strategic thinking and representing active learning at higher order, both desirable goals in university education.
• Flexibility; it can be used either as a stand-alone unit or integrated into courses on other subjects, including genetics. Incorporating the module into genetics courses provides a potent means to address critical comments by Rosemary J. Redfield, who pointed out a need to change the focus of genetics courses away from classical topics and towards state-of-the-art molecular, genomics, and “omics” approaches [13]. Embedding the Drosophila training module in a genetics course alongside other modern techniques will ensure that basic classical genetics is taught in an efficient way that leaves space for other topics. The feasibility of this approach is demonstrated by our annual developmental genetics course at Manchester, where the fly genetics training has been successfully integrated [14].

Cartoon made using the Genotype Builder tool provided as supplement to Roote and Prokop (2013).

This developmental genetics course includes up to 65 students. Assessing such large numbers for mating scheme design skills is not trivial. To make assessment more feasible, we developed a hybrid strategy, in which students solve a mating scheme task first on paper, and the solution is then queried using standard multiple-choice or multiple answer e-assessment questions. As explained in our G3 paper [12], this method combines the advantages of paper-based and electronic assessments, so that exams are more fair, and provide the flexibility to assess a wide range of knowledge and skills, including virtually every aspect of mating scheme design and the underlying classical genetics, as well as the ability to translate between genotypic and phenotypic levels. As we point out, this strategy is not only suitable for genetics, but could as well be applied other disciplines requiring complex problem solving, such as mathematics, chemistry, physics or informatics. We used this assessment in three consecutive years, and have observed a reliable and realistic spread of marks that clearly highlights the stronger candidates. We are therefore confident that in-place strategies can be used to teach and assess Drosophila mating scheme design even to large cohorts of university students. Since the strategy is based on an interactive, interesting and unconventional method that engages students, it hopefully leads to a long-lasting and better appreciation of the usefulness of model organisms.

Conclusion

Drosophila plays a key role in the current research landscape, and there are many areas in which the fly can make major contributions in the future. But there are alarming signs that funding trends might not favor invertebrate model organisms. Better communication and active outreach is urgently required to address this trend, ideally making use of long-term strategies. Here, I have tried to provide an overview of the ways in which this can be achieved, hopefully inspiring more researchers to join in. As I have argued in an another blog post, scientists themselves can learn a lot from engaging with the public. In my own experience, outreach has helped enormously in developing better arguments and ways to communicate my research, and this has turned out to be extremely useful for grant applications and publications — all in all, a win-win situation!

References

[1] Kohler, 1994, Lords of the fly. Drosophila genetics and the experimental life, The University of Chicago Press.

[2] Brookes, M. (2002). Fly: The Unsung Hero of Twentieth-Century Science. Phoenix.

[3] Wangler, M. F., Yamamoto, S., & Bellen, H. J. (2015). Fruit flies in biomedical research. Genetics, 199(3), 639-653. doi:10.1534/genetics.114.171785.

[4] Shimizu, H., Woodcock, S. A., Wilkin, M. B., Trubenová, B., Monk, N. A., & Baron, M. (2014). Compensatory Flux Changes within an Endocytic Trafficking Network Maintain Thermal Robustness of Notch Signaling. Cell, 157(5), 1160-1174. doi: 10.1016/j.cell.2014.03.050.

[5] Bellen, H. J., Tong, C., & Tsuda, H. (2010). 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future. Nature Reviews Neuroscience, 11(7), 514-522. doi:10.1038/nrn2839.

[6] Keller, E. F. (1996). Drosophila embryos as transitional objects: The work of Donald Poulson and Christiane Nüsslein-Volhard. Historical studies in the physical and biological sciences, 313-346.

[7] Sumner, J., & Prokop, A. (2013). Informing the general public about cell migration-an outreach resource. doi: 10.6084/m9.figshare.741264.

[8] Gibney, E. (2014). How to tame the flood of literature. Nature, 513(7516), 129-130. doi:10.1038/513129a.

[9] Roote, J., & Prokop, A. (2013). How to design a genetic mating scheme: a basic training package for Drosophila genetics. G3: Genes| Genomes| Genetics, 3(2), 353-358. doi:10.1534/g3.112.004820

[10] Prokop, A. (2013). How to design a genetic mating scheme: a basic training package for Drosophila genetics, supplementary materials. figshare. doi: 10.6084/m9.figshare.106631

[11] Kelty, C. M. (2012). This is not an article: Model organism newsletters and the question of ‘open science’. BioSocieties, 7(2), 140-168. doi:10.1057/biosoc.2012.8

[12] Fostier, M., Patel, S., Clarke, S., & Prokop, A. (2015). A Novel Electronic Assessment Strategy to Support Applied Drosophila Genetics Training on University Courses. G3: Genes| Genomes| Genetics, 5(5), 689–698. doi:10.1534/g3.115.017509.

[13] Redfield, R. J. (2012). “Why do we have to learn this stuff?”—a new genetics for 21st century students. PLoS biology, 10(7), e1001356. doi: 10.1371/journal.pbio.1001356.

[14] Prokop A. (2013). 2nd year Drosophila Developmental Genetics practical. figshare. doi: 10.6084/m9.figshare.156395

Fruit flies suffer from an image problem. Maybe it’s the alliteration in the name, or the association with bananas, but Drosophila have become a go-to target for politicians looking to ridicule wasteful public spending. In February, presidential candidate and US Senator Rand Paul (R-KY) questioned the NIH for spending:

“…a million dollars trying to determine whether male fruit flies like younger female fruit flies. I think we could have polled the audience and saved a million bucks.”

Of course, there’s a lot more to the study, which was really about how the process of aging is regulated. In fact, because many mechanisms of aging are broadly conserved across animals, including Drosophila, research on the signaling networks that regulate this process could eventually have profound impacts on the treatment of age-related diseases like Alzheimer’s.

Fortunately, the spirited mood among the more than 1,500 fruit fly geneticists gathered in Chicago in March for the 56th Annual Drosophila Research Conference suggests the community is prepared to take up the challenge of explaining the value of Drosophila research.

In a passionate keynote address at the Fly Meeting, Allan Spradling argued that Drosophila research is actually among the most productive ways to spend NIH dollars.

#DROS2015 Model organism-centered research has EXPLODED our knowledge base in the last 50 yrs. great message cool data. Mind. Blown.

— Hannah Gordon PhD, MSCI (she/her) (@brieski) March 5, 2015

Spradling attributed most of the recent explosion in genetic knowledge and tools to the post-1950s expansion of NIH funding for research that sought to understand the fundamental principles of biology. And much of that progress was fueled by work on model organisms like Drosophila.

Spradling described many examples from his own research demonstrating the unexpected similarities between the biology of Drosophila and that of mammals, concluding that although conservation of the basic mechanisms of life was one of the most spectacular (and useful) lessons of modern biology, scientists have failed to communicate this message to the public. This failure makes it harder for the public to understand the value of model organism research, which in turn threatens its funding.

One of the great (under appreciated) discoveries of biology: deep conservation across organisms of genes, pathways, & physiology. #dros2015

— Tera Levin (@tera_levin) March 5, 2015

Funding woes have preoccupied most biomedical researchers in recent years, but those working on Drosophila may have it worse than average, argued Michael Wangler, Shinya Yamamoto, and Hugo Bellen in a Perspectives article published in the March issue of GENETICS and distributed as a reprint at the meeting.

According to Wangler et al., NIH funding for Drosophila research has dropped by around 30% over the past five years, compared to a 15% decline for all fields combined. That’s despite the many contributions of the Drosophila model to understanding mammalian biology — like the chromosomal basis of inheritance, genetic linkage, body plan development, the molecular basis of innate immunity, circadian rhythms, and more. Try imagining medical research today without knowledge of Hox genes, Toll-like receptors, or TRP channels, for example, or Notch, Wnt, Hedgehog, and BMP/TGFβ signaling.

The NIH should increase its funding for fruit fly research, the authors of the GENETICS Perspective propose, in part because there is such an unmet need for functional annotation of the human genome. The wealth of Drosophila resources and knowledge make it a powerful tool for accelerating our understanding of gene function, and the authors encourage greater collaboration and communication between fly biologists, human geneticists, and clinicians.

But what about addressing the humble fruit fly’s image problem? Tackling that conundrum was one popular workshop at the meeting, “Communicating Your Drosophila Research to Scientific and Non-scientific Audiences.”

At the workshop, Joyce Fernandes and Raeka Aiyar discussed ways scientists can tailor their messages for different audiences and different goals, Andreas Prokop spoke about a Drosophila outreach project run by the Manchester Fly Facility, followed by Isabel Palacios on DrosAfrica, a project to foster the Drosophila biomedical research community in Africa.

I'm ready to tell everyone I meet about my research after the @GeneticsGSA workshop on communicating science! #DROS2015

— Jamie L. Wood, Ph.D. (@FlyDoc2015) March 6, 2015

Of course, the heart of the meeting was the amazing science shared in talks, at posters, and in conversations over coffees and beers. In many cases, the links to real-world applications were clear. For example, the meeting closed with an engaging talk from Ulrike Heberlein (HHMI/Janelia Research Campus) on using flies to understand the chronic and acute effects of alcohol consumption. Remarkably, fly behavior has become a valuable model for alcoholism.

Heberlein: 80-90% of Drosophila genes with ethanol-related phenotypes show same phenotypes in rodents #DROS2015

— Genetics Society of America (@GeneticsGSA) March 8, 2015

But much of the research at the meeting featured themes so fundamental that their value can’t be reduced to a single disease or application—like the many projects focused on how genomes work, or how to manipulate them, or how they evolve. To the public, this is precisely the kind of research that can seem frivolous or overblown. Invigorated by the science and conversations during the meeting, many attendees left feeling like ambassadors for Drosophila research, determined to tell everyone they meet what such research is truly worth.

Discussed the importance of fly research with the Lyft driver. #DROS2015 #flyoutreach

— Albert Mondragon (@amondragon) March 8, 2015

https://twitter.com/anna_zeidz/status/573875910459396096

Check out the program book and #DROS2015 on Twitter for meeting highlights. Those eager to share their enthusiasm for fly research can find many useful communication resources at the Manchester Fly Facility’s public outreach website. The Drosophila Communications Committee has also prepared some slides for researchers on “What you can do.” And GSA is working to develop a resource on the value of research with model organisms. Stay tuned!

CITATION
Fruit Flies in Biomedical Research
Michael F. Wangler, Shinya Yamamoto, and Hugo J. Bellen
Genetics March 2015 199:639-653; doi:10.1534/genetics.114.171785
http://www.genetics.org/content/199/3/639