Leung Lab Blog

These days many cherish “hypothesis-driven” research and trash everything that is observational, exploratory and non-translational. And yet the hypothesis in many research is “post-research” hypothesis. The “hypothesis” itself is also often generated for the sake of having an hypothesis; the essence of the research can still be exploratory.

So when funding is getting scarce and the pressure of coming up with beautiful hypothesis is mounting, one must ask what the value of hypothesis-driven research is. Is it the only way to get important findings? Is it delivering more than other “inferior” approaches?

As I am thinking about these questions and situation all the time, I am leading a journal club in the lab on 8/1 and trying to discuss the philosophical aspects of this with my lab members. And I want to write this down and have a record before we do so. We will read a few articles:

1. Pisani E. Has the internet changed science? Prospect 2010; 177:54 [pdf]
2. Kell DB, Oliver SG. Here is the evidence, now what is the hypothesis? The complementary roles of inductive and hypothesis-driven science in the post-genomic era. Bioessays. 2004 Jan;26(1):99-105. PubMed PMID: 14696046.
3. Ioannidis JP. Why most published research findings are false. PLoS Med. 2005 Aug;2(8):e124. Epub 2005 Aug 30. PubMed PMID: 16060722; PubMed Central PMCID: PMC1182327.

and discuss a few questions, in addition to the ones I have above:

1. Are data mining or descriptive research useless?
2. What are the downsides of doing “hypothesis-driven research”?
3. Are we/funding agencies/authorities doing the society a favor by insisting scientists to have a hypothesis/justification attached to a research idea? how about research that has translational value (i.e. curing disease)? or technical value (e.g. developing a cheaper and faster way to sequence human genome?)
4. Is/Can there a balance between different scientific research approaches?

Disease

1. Shive HR, West RR, Embree LJ, Azuma M, Sood R, Liu P, Hickstein DD. brca2 in zebrafish ovarian development, spermatogenesis, and tumorigenesis. Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19350-5. Epub 2010 Oct 25. PubMed PMID: 20974951.
2. Jain S, Heutink P. From single genes to gene networks: high-throughput-high-content screening for neurological disease. Neuron. 2010 Oct 21;68(2):207-17. Review. PubMed PMID: 20955929.

Eye Disease

1. Linder B, Dill H, Hirmer A, Brocher J, Lee GP, Mathavan S, Bolz HJ, Winkler C, Laggerbauer B, Fischer U. Systemic splicing factor deficiency causes tissue-specific defects: A zebrafish model for Retinitis pigmentosa. Hum Mol Genet. 2010 Nov 3. [Epub ahead of print] PubMed PMID: 21051334.

Development

1. Lek M, Dias JM, Marklund U, Uhde CW, Kurdija S, Lei Q, Sussel L, Rubenstein JL, Matise MP, Arnold HH, Jessell TM, Ericson J. A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning. Development. 2010 Dec;137(23):4051-60. PubMed PMID: 21062862.
2. Green AA, Kennaway JR, Hanna AI, Bangham JA, Coen E. Genetic Control of Organ Shape and Tissue Polarity. PLoS Biol. 2010 Nov 9;8(11):e1000537. PubMed PMID: 21085690.
3. Cui ML, Copsey L, Green AA, Bangham JA, Coen E. Quantitative Control of Organ Shape by Combinatorial Gene Activity. PLoS Biol. 2010 Nov 9;8(11):e1000538. PubMed PMID: 21085695.

Eye Development

1. Billings NA, Emerson MM, Cepko CL. Analysis of Thyroid Response Element Activity during Retinal Development. PLoS One. 2010 Oct 29;5(10):e13739. PubMed PMID: 21060789; PubMed Central PMCID: PMC2966421.
2. Phillips MJ, Otteson DC. Differential expression of neuronal genes in Muller glia in two- and three-dimensional cultures. Invest Ophthalmol Vis Sci. 2010 Nov 4. [Epub ahead of print] PubMed PMID: 21051699.

Stem Cells

1. Hanna JH, Saha K, Jaenisch R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell. 2010 Nov 12;143(4):508-25. PubMed PMID: 21074044.
2. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. A model for neural development and treatment of rett syndrome using humaninduced pluripotent stem cells. Cell. 2010 Nov 12;143(4):527-39. PubMed PMID: 21074045.

Zebrafish

1. Newman M, Lardelli M. A hyperactive sleeping beauty transposase enhances transgenesis in zebrafish embryos. BMC Res Notes. 2010 Nov 4;3(1):282. [Epub ahead of print] PubMed PMID: 21050486.

Genomics

1. Wyart M, Botstein D, Wingreen NS. Evaluating Gene Expression Dynamics Using Pairwise RNA FISH Data. PLoS Comput Biol. 2010 Nov 4;6(11):e1000979. PubMed PMID: 21079668; PubMed Central PMCID: PMC2973809.

Systems Biology

1. Lehner B. Conflict between Noise and Plasticity in Yeast. PLoS Genet. 2010 Nov 4;6(11):e1001185. PubMed PMID: 21079670; PubMed Central PMCID: PMC2973811.
2. Li J, Yuan Z, Zhang Z. The cellular robustness by genetic redundancy in budding yeast. PLoS Genet. 2010 Nov 4;6(11):e1001187. PubMed PMID: 21079672; PubMed Central PMCID: PMC2973813.

Ethics, Society and Legal Issues

1. Johnson DG. The role of ethics in science and engineering. Trends Biotechnol. 2010 Sep 9. [Epub ahead of print] PubMed PMID: 20832883.

I suggest we read a paper recently published in Science. The title is “Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis Pigmentosa”. Retinal pigmentosa is so far found to be caused by diverse mutations in 44 genes. Patients with this diease will irreversibly lose their vision, as rod photoreceptors will die early and cone photoreceptor will be light-insensitive owing to the morphological change. But normally cone photoreceptors could persist longer. In this study, the authers genetically targeted a light activated chloride pump, which is one of the candidates for reactivating vertebrate photoreceptors, into the photorecepors of mouse models of retinitis pigmentosa by means of adneo-associated viruses, and successfully restored their light sensitivity. They also found the protein could reactivate the light-insensitive human photoreceptors in ex vivo retinas. Is this a good news for people who suffer from retinitis pigmentosa and blindness? Let’s find out together.

Link to the paper:

http://www.sciencemag.org/cgi/content/full/329/5990/413

We will all read two short articles about Cystic Fibrosis:

• Couzin-Frankel J. The promise of a cure: 20 years and counting. Science. 2009 Jun 19;324(5934):1504-7.
• Pearson H. One gene, twenty years. Nature. 2009 Jul 9;460(7252):164-9.

Each one of us will then pick one of the following topics, elaborate the discussion by reading an additional latest reference of your choice and present the major ideas in the lab meeting.  (Liyun, as a physician for years, should pick up a more research-based topic).

The format will be a 10-min presentation followed by 5-min discussion. If you are discussing a research paper, the breakdown should be as follows: 5-min for background+experimental design, 5-min for 1-2 major findings. For a review paper, the breakdown should be approximately 3 mins for each major idea. The presentation should have no more than 4 slides, preferably 3, you can also use the board. We will also bring a timer.

I suggest the following six topics:

1. Pathophysiology
2. Etiology and epidemiology
3. General therapeutic approaches excluding gene therapy
4. Functional characterization of CFTR
5. Animal models, challenges and prospects
6. Gene therapy, challenges and prospects

Please reply and this thread to select your topic, and upload both your presentation and the reference article to the appropriate lab meeting folder.  I look forward to discussing these ideas with you!