Research Interests and Goals: Dr. Allen Watkins Smith

Research Areas of Interest

My short-term research interest is in work making use of both my bioinformatics expertise, which - as seen in my dissertation titled Phylogenetics and Homology Modeling (Smith 2008) - ranges from database creation and usage to phylogenetics to network analysis to structural biology, and my experience and interest in "wet" lab work, including in a teaching and supervisory role. Areas of particular interest include:

• Genomics, such as the study of transcription levels and of genetic variation; especially of interest is genetic variation in humans. I have some experience with both these areas, via RT-qPCR for transcription levels and via the phylogenetic aspect of my dissertation work for genetic variation.
• Systems Biology, particularly feedback mechanisms, computer modeling, and the application of systems biology to disease states (Ideker & Sharan 2008). The integration of cell-level and organismal-level (e.g., endocrine) regulatory networks is a topic of interest, as is the study of environmental (e.g., dietary or toxic) and developmental effects on such systems.
• Evolutionary Biology. One possibility in this area would be continuing and expanding upon my dissertation research, potentially in combination with other work. Another possibility is tracing the genetic correlates of phenotypic changes such as of lifespan and intelligence, as seen in differences between humans and other animals. For instance, this could be via examining genetic material conserved in other species but not in humans (Ovcharenko 2008).
• Aging and diseases related to it, such as Alzheimer's, Parkinson's, and heart disease. This is a field of increasing importance, given the increasing average age of the human population (Butler et al. 2008; Farrelly 2008); it is discussed further below.
• Neuropsychology and related subjects, such as brain injuries. As with aging, this topic is discussed further below.

The exact area - or areas - of research, and thus the research goals, will depend on the available facilities and the areas of interest of fellow researchers. Of particular interest to me is work at the intersection of more than one field, such as my dissertation research, which took advantage of both my and my advisor's respective areas of prior experience.

Interdisciplinary Research

Frequently, fields of knowledge involve the areas of expertise of other fields; for this and other reasons, such interdisciplinary research, while sometimes more time-consuming, is more likely to generate novel and important results. Examples of interconnections - possible topics for interdisciplinary research - between the above areas include:

• The study of the evolution of regulatory sequences is an overlapping area between systems biology and evolutionary biology (Landry et al. 2007; Lassig 2007). Those regulatory sequences that have diverged between humans and other primates are of particular interest, as are regulatory sequences that are polymorphic in humans (Ovcharenko 2008; Polavarapuet al. 2008; Raijman, Shamir, & Tanay 2008; Schadt et al. 2008; Bird et al. 2007). Further work on models of evolution of binding sites, taking into account predicted binding affinities, may be of interest (Ward & Bussemaker 2008). One particular network of interest for aging studies is that centering on p53. The evolution of its binding sites is a possible area of exploration, as is human polymorphism in these sites (Jegga et al. 2008; Horvath et al. 2007; Tomso et al. 2005). Other network areas relevant for aging - e.g., interacting with known mutations which slow down aging - and their evolution and/or human polymorphism are of especial research interest.
• Caloric restriction is the most across-species consistent means known of retarding aging. However, its gene expression effects appear to vary between species, although with some common similarities in types of genes affected (Han & Hickey 2005). A phylogenetic study of these differences and commonalities could include, e.g., the examination of evolutionary changes in the regulatory proteins involved. Further cross-species examination of the gene expression effects of other interventions retarding aging is also needed (Barger et al. 2008a; Bargeret al. 2008b; Bartke, Bonkowski, & Masternak 2008). This area also intersects with systems biology, as noted previously.
• Regulatory networks interact with alternative splicing in proteins, which in turn is related to the phenomenon of intrinsically disordered regions - ones not visible in X-ray structures due to conformational instability (Birzele, Csaba, & Zimmer 2008; Romero et al. 2006). The evolution of such regions is of interest; preliminary evidence from my dissertation research work and elsewhere indicates that they may have somewhat different properties, such as differing amino acid distributions (Smith 2008; Penq et al. 2006; Coeytaux & Poupon 2005).
• Neuropsychology is related to the study of the evolution of human intelligence and of human polymorphisms with psychological/cognitive effects (Butcher et al. 2008; Malmberg et al. 2008; Mekel-Bobrov et al. 2007; Tan et al. 2007). This area also is related to systems biology, such as in the effects of infant diet on brain development, modulated by polymorphisms in lipid metabolism genes (Caspi et al. 2007).
• Brain injuries increase Alzheimer's disease susceptibility, with effects on this interaction from polymorphism (DeKosky et al. 2007). They are thus related to both diseases of aging and genomics.

Research Goals

In the long term, my research interests, and thus research goals, are in human gene therapy and/or human embryonic stem cell therapy using genetically modified cells, with the latter either as a route for gene therapy - by repairing the genetic problem in the stem cells prior to further culturing and implantation - or to direct differentiation to a desired endpoint. Expansions in the more distant future of human stem cell work could include the usage of genetically modified and/or cloned fetal tissues and organs. Particularly of interest for me is the treatment of aging and the diseases associated with it. Other treatment areas of interest include brain injuries and mental illness.

Bibliography

Barger, J L; Kayo, T; Pugh, T D; Prolla, T A; Weindruch, R. 2008a Jul 9. Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Experimental Gerontology Epub ahead of print. http://dx.doi.org/10.1016/j.exger.2008.06.013.

Barger, J L; Kayo, T; Vann, J M; Arias, E B; Wang, J; Hacker, T A; Wang, Y; Raederstorff, D; Morrow, J D; Leeuwenburgh, C; Allison, D B; Saupe, K W; Cartee, G D; Weindruch, R; Prolla, T A. 2008b. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. Public Library of Science ONE 3(6):2264. http://dx.doi.org/10.1371/journal.pone.0002264.

Bartke, A; Bonkowski, M; Masternak, M. 2008 Jan/Mar. How diet interacts with longevity genes. Hormones (Athens) 7(1):17-23. http://hormones.gr/preview.php?c_id=203.

Bird, C; Stranger, B; Liu, M; Thomas, D; Ingle, C; Beazley, C; Miller, W; Hurles, M; Dermitzakis, E. 2007. Fast-evolving noncoding sequences in the human genome. Genome Biology 8(6):R118. http://genomebiology.com/2007/8/6/R118.

Birzele, F; Csaba, G; Zimmer, R. 2008 Feb 2. Alternative splicing and protein structure evolution. Nucleic Acids Research 36(2):550-558. http://nar.oxfordjournals.org/cgi/content/full/36/2/550.

Butcher, L M; Davis, O S P; Craig, I W; Plomin, R. 2008 Oct 30. Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500K single nucleotide polymorphism microarrays. Genes, Brain and Behavior 7(4):435-446. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18067574.

Butler, R N; Miller, R A; Perry, D; Carnes, B A; Williams, T F; Cassel, C; Brody, J; Bernard, M A; Partridge, L; Kirkwood, T; Martin, G M; Olshansky, S J. 2008 Jul 8. New model of health promotion and disease prevention for the 21st century. British Medical Journal 337:a399. http://dx.doi.org/10.1136/bmj.a399 http://www.eurekalert.org/pub_releases/2008-07/bmj-sdt070708.php http://www.eurekalert.org/pub_releases/2008-07/uoia-ess070708.php.

Caspi, A; Williams, B; Kim-Cohen, J; Craig, I W; Milne, B J; Poulton, R; Schalkwyk, L C; Taylor, A; Werts, H; Moffitt, T E. 2007 Nov 20. Moderation of breastfeeding effects on IQ by genetic variation in fatty acid metabolism. Proceedings of the National Academy of Sciences USA 104(47):18860-18865. http://www.pnas.org/content/104/47/18860.

Coeytaux, K; Poupon, A. 2005 May 1. Prediction of unfolded segments in a protein sequence based on amino acid composition. Bioinformatics 21(9):1891-1900. http://bioinformatics.oxfordjournals.org/cgi/content/full/21/9/1891.

DeKosky, S T; Abrahamson, E E; Ciallella, J R; Paljug, W R; Wisniewski, S R; Clark, R S B; Ikonomovic, M D. 2007 Apr 1. Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Archives of Neurology 64(4):541-544. http://archneur.ama-assn.org/cgi/content/full/64/4/541.

Farrelly, C. 2008 Jul 8. Has the time come to take on time itself? British Medical Journal 337:a414. http://dx.doi.org/10.1136/bmj.a414 http://www.eurekalert.org/pub_releases/2008-07/bmj-sdt070708.php http://www.eurekalert.org/pub_releases/2008-07/uoia-ess070708.php.

Han, E-S; Hickey, M. 2005 Jun 1. Microarray evaluation of dietary restriction. Journal of Nutrition 135(6):1343-1346. http://jn.nutrition.org/cgi/content/full/135/6/1343.

Horvath, M M; Wang, X; Resnick, M A; Bell, D A. 2007 Jul 27. Divergent evolution of human p53 binding sites: Cell cycle versus apoptosis. Public Library of Science Genetics 3(7):127. http://dx.doi.org/10.1371/journal.pgen.0030127.

Ideker, T; Sharan, R. 2008 Apr 1. Protein networks in disease. Genome Research 18(4):644-652. http://genome.cshlp.org/cgi/content/full/18/4/644.

Jegga, A G; Inga, A; Menendez, D; Aronow, B J; Resnick, M A. 2008 Jan 22. Functional evolution of the p53 regulatory network through its target response elements. Proceedings of the National Academy of Sciences USA 105(3):944-949. http://www.pnas.org/content/105/3/944.

Landry, C R; Lemos, B; Rifkin, S A; Dickinson, W J; Hartl, D L. 2007 Jul 6. Genetic properties influencing the evolvability of gene expression. Science 317(5834):118-121. http://www.sciencemag.org/cgi/content/abstract/317/5834/118.

Lassig, M. 2007 Sep 27. From biophysics to evolutionary genetics: Statistical aspects of gene regulation. BioMedCentral Bioinformatics 8(S6):7. http://www.biomedcentral.com/1471-2105/8/S6/S7.

Malmberg, K; Wargelius, H-L; Lichtenstein, P; Oreland, L; Larsson, J-O. 2008 Apr 23. ADHD and Disruptive behavior scores: Associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents. BioMedCentral Psychiatry 8(1):28. http://www.biomedcentral.com/1471-244X/8/28.

Mekel-Bobrov, N; Posthuma, D; Gilbert, S L; Lind, P; Gosso, M F; Luciano, M; Harris, S E; Bates, T C; Polderman, T J C; Whalley, L J; Fox, H; Starr, J M; Evans, P D; Montgomery, G W; Fernandes, C; Heutink, P; Martin, N G; Boomsma, D I; Deary, I J; Wright, M J; de Geus, E J C; Lahn, B T. 2007 Mar 15. The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence. Human Molecular Genetics 16(6):600-608. http://hmg.oxfordjournals.org/cgi/content/full/16/6/600.

Ovcharenko, I. 2008 Aug 1. Widespread ultraconservation divergence in primates. Molecular Biology and Evolution 25(8):1668-1676. http://mbe.oxfordjournals.org/cgi/content/full/25/8/1668.

Penq, K; Radivojac, P; Vucetric, S; Dunker, A K; Obradovic, Z. 2006 Apr 17. Length-dependent prediction of protein intrinsic disorder. BioMedCentral Bioinformatics 7:208. http://www.biomedcentral.com/1471-2105/7/208.

Polavarapu, N; Marino-Ramirez, L; Landsman, D; McDonald, J; Jordan, I K. 2008 May 17. Evolutionary rates and patterns for human transcription factor binding sites derived from repetitive DNA. BioMedCentral Genomics 9(1):226. http://www.biomedcentral.com/1471-2164/9/226.

Raijman, D; Shamir, R; Tanay, A. 2008 Jan 11. Evolution and selection in yeast promoters: Analyzing the combined effect of diverse transcription factor binding sites. Public Library of Science Computational Biology 4(1):7. http://dx.doi.org/10.1371/journal.pcbi.0040007.

Romero, P R; Zaidi, S; Fang, Y Y; Uversky, V N; Radivojac, P; Oldfield, C J; Cortese, M S; Sickmeier, M; LeGall, T; Obradovic, Z; Dunker, A K. 2006 May 30. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proceedings of the National Academy of Sciences USA 103(22):8390-8395. http://www.pnas.org/cgi/content/full/103/22/8390.

Schadt, E E; Molony, C; Chudin, E; Hao, K; Yang, X; Lum, P Y; Kasarskis, A; Zhang, B; Wang, S; Suver, C; Zhu, J; Millstein, J; Sieberts, S; Lamb, J; GuhaThakurta, D; Derry, J; Storey, J D; Avila-Campillo, I; Kruger, M J; Johnson, J M; Rohl, C A; van Nas, A; Mehrabian, M; Drake, T A; Lusis, A J; Smith, R C; Guengerich, F P; Strom, S C; Schuetz, E; Rushmore, T H; Ulrich, R. 2008 May 1. Mapping the genetic architecture of gene expression in human liver. Public Library of Science Biology 6(5):107. http://dx.doi.org/10.1371/journal.pbio.0060107.

Smith, A W. 2008. Phylogenetics and Homology Modeling. Dissertation. Rutgers University and University of Medicine and Dentistry of New Jersey (New Brunswick, NJ): Joint Graduate Program in Microbiology and Molecular Genetics. http://www.drallensmith.org/research/.

Tan, H-Y; Chen, Q; Goldberg, T E; Mattay, V S; Meyer-Lindenberg, A; Weinberger, D R; Callicott, J H. 2007 Dec 5. Catechol-O-methyltransferase Val158Met modulation of prefrontal parietal striatal brain systems during arithmetic and temporal transformations in working memory. Journal of Neuroscience 27(49):13393-13401. http://www.jneurosci.org/cgi/content/full/27/49/13393.

Tomso, D J; Inga, A; Menendez, D; Pittman, G S; Campbell, M R; Storici, F; Bell, D A; Resnick, M A. 2005 May 3. Functionally distinct polymorphic sequences in the human genome that are targets for p53 transactivation. Proceedings of the National Academy of Sciences USA 102(18):6431-6436. http://www.pnas.org/content/102/18/6431.

Ward, L D; Bussemaker, H J. 2008 Jul 1. Predicting functional transcription factor binding through alignment-free and affinity-based analysis of orthologous promoter sequences. Bioinformatics 24(13):165-171. http://bioinformatics.oxfordjournals.org/cgi/content/abstract/24/13/i165.