last updated: Nov 1, 2007
Our team has studied two distinct types of diabetic diseases, with a primary focus on
the type 1 autoimmune form.
In type 1 diabetes (T1D), immune cells such as CD8+ T-cells target
and kill the insulin-secreting pancreatic beta cells. Diabetes results when
most of the beta cells have been killed. We have studied several aspects of this
For several years, we investigated the way that dead beta cells are cleared by non-
specific scavenger immune cells (macrophages), and quantified the defects in this
clearance rate that occur in diabetes-prone Non-Obese Diabetic (NOD) mice (Maree et al,
2005). We then showed (Maree et al 2006) that these defects alone can already account
for chronic inflammation in the pancreas that could set the stage for autoimmune diabetes.
This year, we revisited this research and improved our quantification of
macrophage phagocytosis (in normal and diabetic mice) using redesigned
experiments carried out in Finegood's SFU lab (Maree, Komba, Finegood, Keshet, 2007).
In separate work on Type 1 Diabetes, we have explored therapies
for prevention and treatment of autoimmune diseases. In earlier year(s),
we concentrated on peptide therapy (similar to vaccination), and showed why
this therapy is problematic (Maree, Santamaria and Edelstein-Keshet, 2006).
In a related work, Mahaffy and Keshet (2006) modeled the cyclic fluctuations
observed in levels of T cells
circulating in the blood. We showed that these oscillations could result from feedback:
killing of beta cells generates peptide that has a
differential effect on production of memory vs effector T cells, which in turn,
affect the further rate of killing of beta cells.
During the last year, Khadra and Keshet have been investigating new hypotheses
for competition between low and high avidity T-cells and therapies based on
other strategies for manipulating that competition.
In the past year, we have developed a new project that links our expertise in
Type 2 diabetes and in amyloid dynamics. Our MSc student Bailey was awarded an
internship at the Children's Hospital in Vancouver, in the group of collaborator
B. Verchere. (His internship earned an award of excellence, see Awards.) Bailey carried out in vitro experiments on the polymerization and
fibrilization of Islet Amyloid Poly-Peptide (IAPP). He used modeling and data
fitting to uncover the steps involved in the kinetics of formation of the
(toxic) oligomers that occur in the pancreas of Type 2 diabetes patients. The
significance is that understanding these kinetics can lead to strategies for
treating this symptom.
AD is one of a family of neurodegenerative diseases that
are characterized by the aggregation of a pathogenic or misfolded peptide into insoluble
aggregates. Its characteristic feature plaques and tangles were described by
Alois Alzheimer nearly a century ago. Today some half-million Canadians over 65 have
Alzheimer's disease (AD) and related dementias, and 100,000 new cases are diagnosed
every year. This burgeoning epidemic is expected to be one of the major health care
challenges in the coming years. A better understanding of AD pathogenesis should also lead to insight about other diseases involving aggregated proteins, including Type 2 diabetes.
The leading hypothesis in the field of AD research, dubbed the amyloid cascade
hypothesis, assigns the primary pathogenesis of AD to a 42-amino acid protein Amyloid
beta (A-beta). Excessive accumulation of A-beta and its resultant aggregation into senile
plaques is widely believed to be the precursor to neuronal death and cognitive
impairment. A-beta is produced from the amyloid precursor protein (APP) through two
sequential cleavages catalyzed by the enzymes beta-secretase and gamma-secretase,
respectively. Potential therapeutical strategies to combat AD target various stages of A-
beta production and aggregation. Our team members (Das, Coombs, Keshet, Bailey)
have been working with Merck scientists (Salzman, Nachbar, Bagchi) to
understand a potential drug that inhibits gamma-secretase. We have applied mathematical
modeling to determine what could account for the observed time course of the amyloid
level measured in blood after this drug is administered. A paper on our results is being submitted for publication.
We have maintained some level of expertise and work on Alzheimer's Disease ever since
our first year of operation as a team. See our interactive Alzheimer's In Silico simulation.
Periodic hematological diseases include cyclical neutropenia (CN),
periodic leukemia (PL), and cyclical thrombocytopenia (CT). These
diseases offer a glimpse into the regulation of the hematopoietic
system (i.e. system that produces blood cells). Michael Mackey and
McGill University team members are working on a physiologically accurate mathematical
model of this control system in humans, to develop eventual
strategies for treating hematological diseases. The Mackey group research
has confirmed that cyclical neutropenia is due to elevated levels of
apoptosis (programmed cell death). Further, it points to the
possibility that periodic leukemia is due to decreased levels of
apoptosis in the peripheral neutrophil line but an elevation of the
rate of apoptosis in the stem cells. Similar insights into the
origins of PL and CT have been derived from their extensive
mathematical modeling project, and have again highlighted the
importance of apoptosis as a control mechanism in normal
hematopoiesis. This is currently being extended to a study of
aplastic anemia (AA) in conjunction with the University Hospital of
Basel who have over 40 years of experience with this interesting stem
To try to understand the molecular control of apoptosis, Mackey's
team studies the operation of gene regulatory circuits (operons),
which are only partially understood qualitatively and incompletely
explored mathematically. Research on the regulation of the lactose
and tryptophan operons, as well as the lysis-lysogeny switch in phage
lambda, will help this group to develop the necessary expertise to
deal with the molecular aspects of apoptosis regulation. Mackey's
work on apoptosis regulation will link well with aspects of the T1D
diabetes projects centering on beta-cell apoptosis.
Basic Immunology and Infectious Disease Modelling:
A central theme in the adaptive immune system is the signaling between
antigen-presenting-cells (APCs) and T cells. Coombs and Dushek are working
in close collaboration with the laboratory of Valitutti (Toulouse, France)
to elucidate molecular
mechanisms of T cell stimulation by carefully screened APCs. A major part of this project
involves interpreting fluorescence recovery after photo-bleaching (FRAP) data.
This experimental technique involves fluorescently labeling a protein of interest on the
T cell surface. The labels are then removed from a small area on the cell surface.
Protein motion allows fluorescence
to return to this area. Mathematical analysis of the rate of recovery of fluorescence
is then performed, yielding the diffusion coefficient of the labeled protein. Two papers
on this topic have been completed (Dushek & Coombs, 2007, and
Dushek, Das & Coombs, submitted 2007). In a related project, Coombs, Das (PDF),
Cortes and Simpson (BSc students) have begun work on modeling single-particle
tracking data, where a single protein is labeled and followed. The goal is to
understand protein mobility on a cell surface.
The threat of emergent diseases and pandemics has made infectious diseases
caused by viruses of great current interest. Investigator Coombs and trainees
have been studying the selective pressures on viruses at multiple scales:
viruses compete for cell resources within a single infected cell, for cells to
infect within a host, and for hosts to infect within a population. To understand
how viral behaviour at the level of an individual virus translates to
population-scale dynamics of virus evolution (that can have public-health consequences),
we need to nest mathematical models drawn from each level of selection. At UBC,
investigator Coombs, (former MSc student) Ball, and (BSc student) Mehta have combined
mathematical models for chronic viral infections (such as human immunodeficiency virus
and hepatitis C virus) within a single host with simple epidemic models, to understand
how selective pressure may act on such viruses.
Stem Cell Cultures:
Stem cells have the potential to develop into heart muscle cells, bone cells, nerve cells,
skin cells, blood cells. They could be used, therefore, to repair or replace damaged tissues
in Parkinson's disease, stroke, cardiac diseases, diabetes, etc.
One of our investigators, Piret, and his
trainees (former PhD student Glover, PDF Chaudhry) have been studing the influence of the culture environment on stem cell gene expression.
Optimizing the culture conditions for embryonic stem cells is ongoing,
combining knowledge of the cells' response to process variables in conjunction with the
gene expression. The ultimate goal is to develop robust culture techniques for large-scale
expansion. Knowledge of the molecular determinants of stem-cell fate (self-renewal,
differentiation or apoptosis) as well as a greater understanding of the influence of culture
variables will significantly aid in the development of these protocols.
Dynamics of Reproductive Hormone Secretion:
Hormonal regulation of mammalian reproduction occurs at three different
levels. The gonadotropin-releasing hormone (GnRH), secreted by GnRH neurons
in the hypothalamus, is at the highest level of this hierarchical control.
GnRH plays an essential role in reproductive maturation, and in regulating
hormonal changes in menstrual and estrous cycles. GnRH is carried by local
blood circulation to the pituitary, where it triggers the release of two
intermediate hormones, the luteinizing hormone (LH) and the follicle-
stimulating hormone (FSH), from gland cells called the gonadotrophs. It has
been found that the temporal profile of the GnRH signal must be pulsatile
to be effective (i.e., sharp pulses separated by intervals of near-zero
baseline levels), with a species-specific frequency (e.g., 1 pulse per hour
Although the underlying mechanism remains obscure, it is well-known that
GnRH neurons exhibit intrinsic pulsatile secretion of GnRH. Further, as the
GnRH neurons have receptors for GnRH, it was suggested that autocrine
regulation of the neurons by the hormone was responsible for the
pulsatility. In recent work, it was proposed that high levels of GnRH
inhibit GnRH secretion though a G-protein coupled process. Based on such
new evidence, investigator Li and (PDF) Khadra have been assembling and
studying models for mechanisms of the pulsatile signal. These models
provide some predictions and crucial answers to some of the experimental
observations made in vivo and in vitro. In this work, it has been shown
recently that synchrony between different neurons through sharing a common
pool of GnRH is extremely robust. In a diversely heterogeneous population
of neurons, the pulsatile rhythm is often maintained when only a small
fraction of the neurons are active oscillators. These active oscillators
are capable of recruiting nonoscillatory neurons into a group of recruited
oscillators while forcing the non-recruitable neurons to oscillate
passively. In addition, this work predicts that the same mechanism revealed
by experiments in vitro could also operate in vivo. This is done by
elucidating some of the apparent inconsistencies obtained in vivo when
different doses of GnRH are injected into the population at different
frequencies. In other words, our models provide a plausible explanation of
the controversial effects of the negative and positive feedback loops of
GnRH on its own release observed in vivo. This work is of clinical and
fundamental value for understanding the normal reproductive system as well
as certain pathologies.
Cellular and Molecular Biology:
Several team members have been working on problems at the level of the cell.
Investigator Cytrynbaum studies dynamics of the eukaryotic cytoskeleton, including
microtubules, actin and a host of regulatory proteins and molecular motors. Cytrynbaum
explores bacterial cell division and models for the unique bacterial cytoskeletal polymers.
Our previous work on modelling the biochemistry of signalling proteins in
cell polarity gave rise to an interesting phenomenon we termed
"wave-pinning", where a travelling wave solution is initiated, slows down
and eventually stalls forming a stable stationary front. To understand the
mechanism behind wave-pinning we (Mori, Jilkine, Keshet) are considering a
simplified model of two components that has the same behaviour and can be
analyzed analytically. We determined the necessary conditions under which a
reaction diffusion system will undergo wave-pinning and in one spatial
dimension and used the method of matched asymptotic expansions to predict
the location of the pinned wave based on model parameters and initial
conditions. We are currently working on extending the model to higher