Natalie H. Kuldell, Ph.D.
Instructor of Biological Engineering
Phone: (617) 324-0085
Fax: (617) 258-8676
Administrative Assistant: Rita DeMeo
Courses: 20.109 Laboratory Fundamentals in Biological Engineering
20.20 Introduction to Biological Engineering Design
I want my students to have a lasting and meaningful educational experience that will enable them to formulate and articulate ideas and to apply information. One way to achieve this goal is to engage students in an authentic curriculum. I try to connect disciplinary content to real world problems and events, to ongoing research efforts, and to future issues as best we can anticipate them. Students engaged in such authentic curricula genuinely care about the outcome of their efforts. Undoubtedly, the current crop of 18-22 year olds will, soon enough, be responsible for understanding and reacting to the good and bad things that present themselves, including engineered biological systems. It's my hope that their current coursework will be a helpful foundation for thoughtful and informed responses.
In addition to challenging my students with meaningful curricula around biological engineering, I try to motivate their learning through positive and responsive connections to them as individuals. Students all have strengths and vulnerabilities. By responding directly to their perspectives, I require that my students master the course content, think and rethink their ideas, and communicate with clarity and persuasiveness. Assessment tools become teaching tools that not only measure understanding but also further it, and my hope is that no student in my class feels lost, disenfranchised or defeated.
The laboratory subjects in Biological Engineering are cornerstones of the new undergraduate major. Each term I have redesigned one of these subjects, 20.109, to integrate ongoing research interests of my own and of my teaching colleagues. The experimental content is roughly divided into four areas, listed below along with descriptors and links to the investigations themselves. All use biochemical and molecular techniques to study questions from a quantitative engineering perspective.
Genome Engineering, including synthetic biology modules with Drew Endy for teaching genome design and systems engineering as well as a genetic recombination module with Bevin Engelward.
Protein Engineering, including characterization and isolation of trypsin inhibitors and introduction of unnatural amino acids into b-galactosidase.
Expression Engineering, including analysis of chromatin remodeling in yeast and RNA interference in mammalian cell culture as well as a module with Alan Jasanoff focused on biophysical signal measurements.
Biomaterials Engineering, including yeast surface display of gold-binding peptides and building a bacteriophage-based electrochromic device, both with Angela Belcher.
Science cannot just be for scientists. To engage all stakeholders, I'm involved in outreach efforts that accurately describe the scientific enterprise. Some of these efforts are intended to teach scientific content to undergraduates who are outside of traditional science majors. Others are lessons to be implemented by teachers (both K-12 and college level) who want to accurately depict what science is and how it works. Additionally, I've linked MIT into bridge building efforts that pair practicing scientists with a wider network of interested parties (http://www.copusproject.org/). Finally, I'm developing a web-based educational program to teach synthetic biology (BioBuilder.org).
Gene expression is affected by many factors including the arrangement of genes within the genome, the condensation of DNA into chromatin, and the protein machinery that can enhance or diminish the rate of transcription. My overall research goal is to understand gene expression in eukaryotic cells, examining factors that affect both nuclear and mitochondrial gene expression. Ultimately, a detailed understanding of gene expression may support the predictable design of novel gene expression systems.
I have approached this goal by building artificial gene expression systems in the genetically amenable yeast, Saccharomyces cerevisiae. This organism is ideal for genetic analysis as well as for molecular manipulations. Additionally, the conservation this yeast shows to more complex organisms makes it an attractive experimental model. For example, several human diseases arise from mis-expression of genes in both the nucleus and the mitochondria and so analysis of mutant gene expression patterns in S. cerevisiae is likely to give insight into physiologies associated with more complex eukaryotes. Ongoing projects combine molecular, genetic and synthetic techniques to understand eukaryotic gene expression and to build new expression systems.
Research Goal 1: Mitochondrial manipulation and redesign
The yeast mitochondria present an insulated compartment within the cell that might be useful for carrying out processes that the nuclear genome can't encode or support. The mitochondrial genome can be genetically manipulated and my aim is to design a mitochondrial genome that is easy to work with and that can be predictably programmed. To this end, I have built two artificial gene expression systems for yeast mitochondria. One is an in vivo reporter construct based on the cell's requirement for heme. The second is a gene regulation system that modulates mitochondrial gene expression using guide RNAs with short hairpins and a nuclear RNase redirected to the mitochondria.
Research Goal 2: Chromatin remodeling
Large protein complexes regulate eukaryotic gene expression by modifying the nucleosomes that package DNA into chromatin. One such chromatin-modifying complex, SAGA, is functionally conserved in other eukaryotic cells. Given the notable but limited sequence conservation of its subunits, its modular nature and its critical role in gene expression, SAGA is an attractive engineering platform. My aim is to develop a generic SAGA complex that can function in a wide variety of cell types, from yeast to flies to human. As a first step to such a useful complex, I have swapped nonessential subunits of the S. cerevisiae complex with their homologs from S. pombe, an evolutionarily distant yeast species. Phenotypes associated with the subunit deletions and replacements are being explored as they may give insight into the natural function of the SAGA complex and help define the constraints for its modification.
Research Goal 3: Transcription elongation
Transcription is traditionally described in three phases, namely initiation, elongation and termination. All three are subject to regulation by proteins that bind the DNA, affecting the rate of each phase. There is evidence from experiments performed in vitro that transcription elongation is enhanced in the presence of transcription factor IIF (TFIIF). This role for TFIIF is distinct from its well-characterized and critical role in transcription initiation. My aim is to characterize the molecular interactions that underlie the action of TFIIF in elongation, and to distinguish these interactions from those that control transcription initiation.
Much of this work is being done in collaboration with Dr. Fred Winston's lab in the Department of Genetics at Harvard Medical School.
Dixon, J., and N. Kuldell, "BioBuilding: Using Banana-Scented Bacteria to Teach Synthetic Biology" in Christopher Voigt, editor: Methods in Enzymology, Vol. 497, Burlington: Academic Press, 2011, pp. 255-271. [ISBN: 978-0-12-385075-1]
Mitchell, R., J.D. Yehudit, and N. Kuldell, "Experiential Engineering Through iGEM -- An Undergraduate Summer Competition in Synthetic Biology" Journal of Science Education and Technology. (2011) Vol. 20(2): 156. [DOI:10.1007/s10956-010-9242-7]
Kuldell, N. and N. Lerner "Genome Refactoring" (2009) Morgan & Claypool Publishers. [ISBN-10: 1598299476]
Carpi, A., A. Egger, N. Kuldell. "Scientific Writing II: Peer Review," Visionlearning (2009) Vol. POS-2 (2)
Kuldell, N. "Authentic Teaching through Synthetic Biology" Journal of Biological Engineering. (2007) 1:8 [DOI:10.1186/1754-1611-1-8]
Kuldell, N. "Genetics II: Mendel, Morgan and the molecular basis of inheritance" VisionLearning. 2007 http//www.visionlearning.com/library
Kuldell, N. "How Golden is Silence? Teaching Undergraduates the Power and Limits of RNA interference" CBE Life Sci Educ. 2006 Fall;5(3):247-54.
Kuldell, N . "Genetics I: Mendel's Laws of Inheritance" VisionLearning. 2006 http//www.visionlearning.com/library
Kuldell, N. "Genetics I: Mendel's Laws of Inheritance," Visionlearning Vol. BIO-2 (7), 2005. http://www.visionlearning.com/library/module_viewer.php?mid=129
Iuchi, S and N Kuldell, editors. "Zinc Finger Proteins: from Atomic Contact to Cellular Function." ISBN: 0-306-48231-2. Landes BioScience/Eurekah.com. 2005
Kuldell, N. "The Multiple Cellular Functions of TFIIIA" Chapter 26 in "Zinc Finger Proteins: from Atomic Contact to Cellular Function." Landes Bioscience/Eurekah.com. 2005
Kuldell, N. "Scientific Writing: Peer Review and Scientific Journals," VisionlearningVol. SCI (2), 2004. http://www.visionlearning.com/library/module_viewer.php?mid=123
Kuldell, N. The control of gene expression by the cI protein: a single experiment to teach concepts in genetics, molecular biology and transcription regulation.Bioscene (2003) 29(4): 23-31.
Kuldell, N. Read Like a Scientist to Write Like a Scientist. Journal of College Science Teaching (2003) 33(2): 32-35.
Kuldell, N. and S. Buratowski. Genetic Analysis of the Large Subunit of Yeast Transcription Factor IIE Reveals Two Regions with Distinct Functions. Molecular and Cellular Biology (1997) 17(9): 5288-5298.
Kuldell, N. and A. Hochschild. Amino acid substitutions in -35 recognition motif of s-70that result in defects in phage l repressor-stimulated transcription. Journal of Bacteriology (1994) 176: 2991-2998.
Whipple, F., N. Kuldell, L. Cheatham, and A. Hochschild. Specificity determinants for the interaction of l repressor and P22 repressor dimers. Genes and Development (1994) 8: 1212-1223.