Kelvin H. Lee

"Translation, Secretion, Proteomics, Nanobiotechnology:
With the right tools, one can identify the genetic basis for many different phenotypes or disease states. Our research laboratory is focused on the development of next generation tools for protein expression profiling and the use of existing tools applied to specific problems in biomolecular engineering and medicine.

Tools:
We are at the leading edge in the use of mass spectrometry to profile and quantify changes in protein and peptide expression. Although we are not analytical chemists, we work closely with instrument vendors on the development of new labeling chemistry and new software for data analysis and interpretation. Additionally, we have been working to develop next generation technology for the analysis of mixtures of proteins. Using the tools and techniques developed in the semiconductor industry, we are working on microfluidic platforms for protein separations. We are also working on chemistries to permit the sensing of specific protein-protein interactions using giantmagnetoresistive materials such as might be needed for the development of diagnostic assays for the presence or absence of a disease. Although most of our efforts focus on protein and peptide based analyses, we are also applying next generation whole genome shotgun sequencing to better understand the genetic basis for hypersecretion in industrially-relevant cell types.

Applications:
Our effort has recently focused on two main problems: 1) the diagnosis and treatment of Alzheimer's disease and 2) improving the productivity of bacterial and mammalian cells.

Our Alzheimer's efforts have led to the first validated premortem test for the diagnosis of Alzheimer's disease. Using a "proteomics" approach to study changes in protein expression in cerebrospinal fluid, we identified a panel of biomarkers useful for the diagnosis of the disease in living individuals, a previously unmet challenge because a definitive diagnosis must await postmortem confirmation. In close collaboration with clinical collaborators, we have extended this approach to the assessment of a passive immunization strategy for the treatment of Alzheimer's disease which has resulted in the first human treatment to show clinical improvement in human subjects in a Phase I clinical trial.

In terms of protein secretion, our goal has been to improve the ability of cells to "manufacture" protein-based therapeutics. We discovered that altering the synthesis rate of the product in the cell in a specific way, without changing the amino acid sequence, can lead to a nearly 10-fold improvement in productivity. We are continuing this work in bacteria and extending it to define how certain genes can lead to two different expression proteins in a process called programmed ribosomal frameshifting. We also work actively in studying enhanced productivity in mammalian cells."