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Research :

Laura Landweber

Below is a snapshot of our research. Click here for a CV or a research summary .
Research in my laboratory combines multiple approaches - from comparative bioinformatic sequence analysis to functional experiments - to study early molecular evolution, the origin of the genetic code and genetic systems, and how cells and DNA solve biological problems, such as the creation and assembly of genes.

     The current explosion of activity in molecular biology has permitted us to study the process of evolution at its most fundamental level. DNA sequence analysis, for example, has provided us with insight into the mechanisms of selection and evolution at the level of the gene. The discovery of catalytic RNA, furthermore, has led to advances in the study of the origin of life, and suggests that there are other "molecular fossils," or primitive biological mechanisms, still present in modern species. Protists, in particular, have surprised molecular biologists with a bewildering diversity of gene organization, from the impressive scrambled genes in ciliates to bizarre forms of RNA processing, including splicing and RNA editing, and an abundance of nonstandard genetic codes. Therefore they seem to be the natural place to study primitive or aberrant genetic systems.

      Gene unscrambling appears to be a recent invention in a lineage known as stichotrichous ciliates. A major focus of our laboratory recently has been to understand how these genes become reordered from so many dispersed parts with every round of conjugation (inset), and also how these genes became scrambled over evolutionary time. Both processes of editing and unscrambling manage to assemble patchwork genes from their constituent pieces, but at different levels (RNA or DNA) and via very different routes. In gene unscrambling, disordered DNA fragments become linked together in the correct order and orientation by the presence of short direct repeats, termed pointers, at their ends. The process of matching up these DNA sequence words like AATAAGC, uniquely present at the end of piece 3 and the beginning of piece 4, for example, permits the assembly of protein-coding genes from 48 or more scrambled bits (Landweber et al. PNAS 2000). This pathway resembles an intrinsically computational route.


     Functional evolution experiments use the powerful new technology of in vitro genetics to select RNA molecules with desired properties from large pools (10^15) of random sequences. The steps involve an iterative procedure of selection (usually on an affinity column or by a functional assay) and PCR amplification of the rare sequences. We have used this approach to test the emergence of catalytic function from random RNA sequences (Landweber and Pokrovskaya PNAS 1999) and also to develop robust quantitative tests for the role of RNA-amino acid interactions in the origin of the Genetic Code (see Knight and Landweber 1998, 2000). Perhaps surprisingly, this same in vitro selection procedure also allowed us to construct a molecular computer out of RNA that can find solutions to small mathematical search problems (Faulhammer et al. PNAS 2000). The ability to isolate new ribozymes from random sequences (e.g. Landweber and Pokrovskaya PNAS 1999) has fueled a new excitement about the possibility of discovering early pathways of RNA evolution (e.g., Freeland et al. 1999). Ultimately, this will make the world of possible primordial enzymes accessible even when the molecules are no longer present in modern species.