A field guide to cultivating computational biology

Evolving in sync with the computation revolution over the past 30 years, computational biology has emerged as a mature scientific field. While the field has made major contributions toward improving scientific knowledge and human health, individual computational biology practitioners at various institutions often languish in career development. As optimistic biologists passionate about the future of our field, we propose solutions for both eager and reluctant individual scientists, institutions, publishers, funding agencies, and educators to fully embrace computational biology. We believe that in order to pave the way for the next generation of discoveries, we need to improve recognition for computational biologists and better align pathways of career success with pathways of scientific progress. With 10 outlined steps, we call on all adjacent fields to move away from the traditional individual, single-discipline investigator research model and embrace multidisciplinary, data-driven, team science.

Do you want to attract computational biologists to your project or to your department? Despite the major contributions of computational biology, those attempting to bridge the interdisciplinary gap often languish in career advancement, publication, and grant review. Here, sixteen computational biologists around the globe present "A field guide to cultivating computational biology," focusing on solutions.

Biology in the digital era requires computation and collaboration. A modern research project may include multiple model systems, use multiple assay technologies, collect varying data types, and require complex computational strategies, which together make effective design and execution difficult or impossible for any individual scientist. While some labs, institutions, funding bodies, publishers, and other educators have already embraced a team science model in computational biology and thrived [1–7], others who have not yet fully adopted it risk severely lagging behind the cutting edge. We propose a general solution: “deep integration” between biology and the computational sciences. Many different collaborative models can yield deep integration, and different problems require different approaches (Fig 1).Open in a separate windowFig 1Supporting interdisciplinary team science will accelerate biological discoveries.Scientists who have little exposure to different fields build silos, in which they perform science without external input. To solve hard problems and to extend your impact, collaborate with diverse scientists, communicate effectively, recognize the importance of core facilities, and embrace research parasitism. In biologically focused parasitism, wet lab biologists use existing computational tools to solve problems; in computationally focused parasitism, primarily dry lab biologists analyze publicly available data. Both strategies maximize the use and societal benefit of scientific data.In this article, we define computational science extremely broadly to include all quantitative approaches such as computer science, statistics, machine learning, and mathematics. We also define biology broadly, including any scientific inquiry pertaining to life and its many complications. A harmonious deep integration between biology and computer science requires action—we outline 10 immediate calls to action in this article and aim our speech directly at individual scientists, institutions, funding agencies, and publishers in an attempt to shift perspectives and enable action toward accepting and embracing computational biology as a mature, necessary, and inevitable discipline (Box 1).Box 1. Ten calls to action for individual scientists, funding bodies, publishers, and institutions to cultivate computational biology. Many actions require increased funding support, while others require a perspective shift. For those actions that require funding, we believe convincing the community of need is the first step toward agencies and systems allocating sufficient support

1. Respect collaborators’ specific research interests and motivationsProblem: Researchers face conflicts when their goals do not align with collaborators. For example, projects with routine analyses provide little benefit for computational biologists.Solution: Explicit discussion about interests/expertise/goals at project onset.Opportunity: Clearly defined expectations identify gaps, provide commitment to mutual benefit.
2. Seek necessary input during project design and throughout the project life cycleProblem: Modern research projects require multiple experts spanning the project’s complexity.Solution: Engage complementary scientists with necessary expertise throughout the entire project life cycle.Opportunity: Better designed and controlled studies with higher likelihood for success.
3. Provide and preserve budgets for computational biologists’ workProblem: The perception that analysis is “free” leads to collaborator budget cuts.Solution: When budget cuts are necessary, ensure that they are spread evenly.Opportunity: More accurate, reproducible, and trustworthy computational analyses.
4. Downplay publication author order as an evaluation metric for computational biologistsProblem: Computational biologist roles on publications are poorly understood and undervalued.Solution: Journals provide more equitable opportunities, funding bodies and institutions improve understanding of the importance of team science, scientists educate each other.Opportunity: Engage more computational biologist collaborators, provide opportunities for more high-impact work.
5. Value software as an academic productProblem: Software is relatively undervalued and can end up poorly maintained and supported, wasting the time put into its creation.Solution: Scientists cite software, and funding bodies provide more software funding opportunities.Opportunity: More high-quality maintainable biology software will save time, reduce reimplementation, and increase analysis reproducibility.
6. Establish academic structures and review panels that specifically reward team scienceProblem: Current mechanisms do not consistently reward multidisciplinary work.Solution: Separate evaluation structures to better align peer review to reward indicators of team science.Opportunity: More collaboration to attack complex multidisciplinary problems.
7. Develop and reward cross-disciplinary training and mentoringProblem: Academic labs and institutions are often insufficiently equipped to provide training to tackle the next generation of biological problems, which require computational skills.Solution: Create better training programs aligned to necessary on-the-job skills with an emphasis on communication, encourage wet/dry co-mentorship, and engage younger students to pursue computational biology.Opportunity: Interdisciplinary students uncover important insights in their own data.
8. Support computing and experimental infrastructure to empower computational biologistsProblem: Individual computational labs often fund suboptimal cluster computing systems and lack access to data generation facilities.Solution: Institutions can support centralized compute and engage core facilities to provide data services.Opportunity: Time and cost savings for often overlooked administrative tasks.
9. Provide incentives and mechanisms to share open data to empower discovery through reanalysisProblem: Data are often siloed and have untapped potential.Solution: Provide institutional data storage with standardized identifiers and provide separate funding mechanisms and publishing venues for data reuse.Opportunity: Foster new breed of researchers, “research parasites,” who will integrate multimodal data and enhance mechanistic insights.
10. Consider infrastructural, ethical, and cultural barriers to clinical data accessProblem: Identifiable health data, which include sensitive information that must be kept hidden, are distributed and disorganized, and thus underutilized.Solution: Leadership must enforce policies to share deidentifiable data with interoperable metadata identifiers.Opportunity: Derive new insights from multimodal data integration and build datasets with increased power to make biological discoveries.

     

Physiological and biochemical mechanisms of the ornamental <Emphasis Type="Italic">Eugenia myrtifolia</Emphasis> L. plants for coping with NaCl stress and recovery

Main Conclusion

We studied the response of Eugenia myrtifolia L. plants, an ornamental shrub native to tropical and subtropical areas, to salt stress in order to facilitate the use of these plants in Mediterranean areas for landscaping. E. myrtifolia plants implement a series of adaptations to acclimate to salinity, including morphological, physiological and biochemical changes. Furthermore, the post-recovery period seems to be detected by Eugenia plants as a new stress situation. Different physiological and biochemical changes in Eugenia myrtifolia L. plants after being subjected to NaCl stress for up to 30 days (Phase I) and after recovery from salinity (Phase II) were studied. Eugenia plants proved to be tolerant to NaCl concentrations between 44 and 88 mM, displaying a series of adaptative mechanisms to cope with salt-stress, including the accumulation of toxic ions in roots. Plants increased their root/shoot ratio and decreased their leaf area, leaf water potential and stomatal conductance in order to limit water loss. In addition, they displayed different strategies to protect the photosynthetic machinery, including the limited accumulation of toxic ions in leaves, increase in chlorophyll content, changes in chlorophyll fluorescence parameters, leaf anatomy and antioxidant defence mechanisms. Anatomical modifications in leaves, including an increase in palisade parenchyma and intercellular spaces and decrease in spongy parenchyma, served to facilitate CO₂ diffusion in a situation of reduced stomatal aperture. Salinity produced oxidative stress in Eugenia plants as evidenced by oxidative stress parameters values and a reduction in APX and ASC levels. Nevertheless, SOD and GSH contents increased. The post-recovery period is detected as a new stress situation, as observed through effects on plant growth and alterations in chlorophyll fluorescence and oxidative stress parameters.

     

WBSCR22/Merm1 is required for late nuclear pre-ribosomal RNA processing and mediates N7-methylation of G1639 in human 18S rRNA

Ribosomal (r)RNAs are extensively modified during ribosome synthesis and their modification is required for the fidelity and efficiency of translation. Besides numerous small nucleolar RNA-guided 2′-O methylations and pseudouridinylations, a number of individual RNA methyltransferases are involved in rRNA modification. WBSCR22/Merm1, which is affected in Williams–Beuren syndrome and has been implicated in tumorigenesis and metastasis formation, was recently shown to be involved in ribosome synthesis, but its molecular functions have remained elusive. Here we show that depletion of WBSCR22 leads to nuclear accumulation of 3′-extended 18SE pre-rRNA intermediates resulting in impaired 18S rRNA maturation. We map the 3′ ends of the 18SE pre-rRNA intermediates accumulating after depletion of WBSCR22 and in control cells using 3′-RACE and deep sequencing. Furthermore, we demonstrate that WBSCR22 is required for N⁷-methylation of G1639 in human 18S rRNA in vivo. Interestingly, the catalytic activity of WBSCR22 is not required for 18S pre-rRNA processing, suggesting that the key role of WBSCR22 in 40S subunit biogenesis is independent of its function as an RNA methyltransferase.     

The Anti-Inflammatory Activity of Curcumin Protects the Genital Mucosal Epithelial Barrier from Disruption and Blocks Replication of HIV-1 and HSV-2

Inflammation is a known mechanism that facilitates HIV acquisition and the spread of infection. In this study, we evaluated whether curcumin, a potent and safe anti-inflammatory compound, could be used to abrogate inflammatory processes that facilitate HIV-1 acquisition in the female genital tract (FGT) and contribute to HIV amplification. Primary, human genital epithelial cells (GECs) were pretreated with curcumin and exposed to HIV-1 or HIV glycoprotein 120 (gp120), both of which have been shown to disrupt epithelial tight junction proteins, including ZO-1 and occludin. Pre-treatment with curcumin prevented disruption of the mucosal barrier by maintaining ZO-1 and occludin expression and maintained trans-epithelial electric resistance across the genital epithelium. Curcumin pre-treatment also abrogated the gp120-mediated upregulation of the proinflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6, which mediate barrier disruption, as well as the chemokines IL-8, RANTES and interferon gamma-induced protein-10 (IP-10), which are capable of recruiting HIV target cells to the FGT. GECs treated with curcumin and exposed to the sexually transmitted co-infecting microbes HSV-1, HSV-2 and Neisseria gonorrhoeae were unable to elicit innate inflammatory responses that indirectly induced activation of the HIV promoter and curcumin blocked Toll-like receptor (TLR)-mediated induction of HIV replication in chronically infected T-cells. Finally, curcumin treatment resulted in significantly decreased HIV-1 and HSV-2 replication in chronically infected T-cells and primary GECs, respectively. All together, our results suggest that the use of anti-inflammatory compounds such as curcumin may offer a viable alternative for the prevention and/or control of HIV replication in the FGT.     

Lithium induces autophagy by inhibiting inositol monophosphatase

Macroautophagy is a key pathway for the clearance of aggregate-prone cytosolic proteins. Currently, the only suitable pharmacologic strategy for up-regulating autophagy in mammalian cells is to use rapamycin, which inhibits the mammalian target of rapamycin (mTOR), a negative regulator of autophagy. Here we describe a novel mTOR-independent pathway that regulates autophagy. We show that lithium induces autophagy, and thereby, enhances the clearance of autophagy substrates, like mutant huntingtin and alpha-synucleins. This effect is not mediated by glycogen synthase kinase 3beta inhibition. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate.     

The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration

BACKGROUND AND AIMS: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western World. It is now evident that both genetic and environmental factors contribute to disease susceptibility. We tested the hypotheses that (a) a common coding SNP in the LOC387715 gene is associated with advanced AMD (geographic atrophy or choroidal neovascularization), and (b) that modifiable environmental exposures alter AMD susceptibility associated with this SNP. METHODS: A case-control association analysis was performed on participants (530 advanced AMD cases and 280 controls) ascertained as part of the multi-center Age-Related Eye Disease Study. AMD status was determined by the reading center from fundus photographs using the AREDS AMD grading categorization. Environmental risk factor exposure data was collected from participants whose DNA was also genotyped for the LOC387715 gene SNP rs10490924. Multivariate logistic regression analyses were performed. RESULTS AND CONCLUSIONS: The number of risk alleles at the LOC387715 SNP was associated with advanced AMD, with odds ratios (OR) = 3.0 (95% confidence interval (CI) 2.1-4.3) for the GT heterozygous genotype and OR = 12.1 (5.6-26.5) for the homozygous TT risk genotype, after controlling for demographic and behavioral risk factors. The LOC387715 SNP was associated with both forms of advanced AMD. Current cigarette smoking and body mass index were independently related to AMD, controlling for genotype. However, there was no statistical interaction between LOC387715 genotype and smoking with regard to advanced AMD development.     

Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development

The mammalian target of rapamycin (mTOR) is a key component of a signaling pathway which integrates inputs from nutrients and growth factors to regulate cell growth. Recent studies demonstrated that mice harboring an ethylnitrosourea-induced mutation in the gene encoding mTOR die at embryonic day 12.5 (E12.5). However, others have shown that the treatment of E4.5 blastocysts with rapamycin blocks trophoblast outgrowth, suggesting that the absence of mTOR should lead to embryonic lethality at an earlier stage. To resolve this discrepancy, we set out to disrupt the mTOR gene and analyze the outcome in both heterozygous and homozygous settings. Heterozygous mTOR (mTOR(+/-)) mice do not display any overt phenotype, although mouse embryonic fibroblasts derived from these mice show a 50% reduction in mTOR protein levels and phosphorylation of S6 kinase 1 T389, a site whose phosphorylation is directly mediated by mTOR. However, S6 phosphorylation, raptor levels, cell size, and cell cycle transit times are not diminished in these cells. In contrast to the situation in mTOR(+/-) mice, embryonic development of homozygous mTOR(-/-) mice appears to be arrested at E5.5; such embryos are severely runted and display an aberrant developmental phenotype. The ability of these embryos to implant corresponds to a limited level of trophoblast outgrowth in vitro, reflecting a maternal mRNA contribution, which has been shown to persist during preimplantation development. Moreover, mTOR(-/-) embryos display a lesion in inner cell mass proliferation, consistent with the inability to establish embryonic stem cells from mTOR(-/-) embryos.