The goal of my current research effort is to understand how cancers
originate by testing hypotheses of carcinogenesis with age-specific
incidence data. This involves the analysis of large
datasets provided by the National Cancer Institute's Surveilland
Epidemiology and End Results program. This work is being conducted
in collaboration with Luis Soto-Ortiz, a PhD student in Biomedical
Engineering.
Here is a short talk I gave on this research
topic:
Highlights of
Past Research Areas
Microfluidics. In the mid 1990's, I was one
of the first people to put cells and liquids into microfabricated
channels. This work led to many journal papers and patents.
Perhaps the most significant were this
paper published in Biophysical Journal describing the fluid
dynamics and physics of fluid flow in microchannels. A close second in
significance is this 1996
research proposal followed by a 1998 paper in Physical
Review Letters, which described a method of mixing of liquids
much faster than previously available. Slow mixing was a key
roadblock to understanding how proteins fold into specific
conformations, and thus this paper has become influential in the
field. This microfluidics work was started as part of my PhD thesis at
Princeton University, but expanded significantly at the Department of
Bioengineering of the University of Washignton. Many of these
patents were licensed to a company I co-founded,
Micronics, to apply the technology to medical diagnostics (blood
testing). Micronics is now a division of Sony.
DNA microarrays and gene expression. In the
late 1990's and early 2000's I was interested in the measurement and
analysis of large scale gene expression data. My primary
contribution in measurement of gene expression was in the
characterization of DNA arrays, work published in Nucleic
Acids Research and
PNAS. To better understand large scale gene expression
data, I wrote software to analyse data that was becoming available as
part of large scale cDNA sequencing studies. The most
significant outcome of this research effort was
this paper published in Genome Research, in work led by Garrett
Thompson, who was a postdoc at the time. This paper identified a group
of genes activated in cancers. The function of this group of
genes was unknown at the time, but has since been associated
with the autophagic response.
p62/PDEF/Zibra/SQSTM1. The study published
in Genome Research led directly to a thorough biochemical
investigation of several of these genes by Garrett Thompson working
with Joe Harris. The most significant was this
2003 study published in Oncogene, which showed that a protein
known as p62 was overexpressed in human breast cancer tissue.
This was one of the first studies to link p62 with any disease, and
presaged a tidal wave of studies linking p62 and the autophagic
response to cancer.
Surface plasmon resonance and transcriptional regulation.
To better understand how transcription within a cell is controlled, we
sought a method to measure the amounts of protein bound to different
regions of a gene’s promoter and correlate this with mRNA measurements
from this gene. With enough data, this approach should allow one
reverse engineer the transcriptional control system. Limin Lin (as
part of her PhD thesis) demonstrated the feasability of this approach.
Grace Mao (as part of her PhD thesis) performed such a reverse
engineering of the RNR1 transcriptional control system. We found
that the transcriptional control in this gene could be summarized by a
simple set of Boolean logic. This work was published in Analytical
Chemistry, BBRC
and
PLoSOne
Single
Molecule Enzymology. Alan Lee (as part of his PhD thesis)
and I were interested in studying the diversity of enzyme activity by
observing individual enzymes. Alan developed an assay to measure
the activity of single molecules of chymotrypsin, which we published
in the Biophysical
Journal. This work was followed up by Angela Chen who, for her
PhD thesis, made significant improvements to the assay by using
microfabricated wells. Her work was published in Biotechnology
Progress.