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Oxford University--Denis Noble and colleagues
Tuesday a.m.
Attending from Oxford: Denis Noble, Ming Lei, Peter Kohl, Penny Noble
Attending from Systems Biology Panel: Cindy Stokes, Doug Lauffenburger, Hassan Ali
Cardiac program:
Dr. Noble has been studying cardiac biology through experimental and modeling work
for about 40 years. His program aims to connect levels of biology, from molecule to cell
to tissue to organ. Over time he’s collaborated with numerous researchers, notably Rai
Winslow, Peter Hunter, and Andrew McCullough. Early work with Winslow was to
create a multicellular cardiac tissue model with each cell being calculated separately and
including cell-to-cell connections. This is very computationally intensive and impractical
for a large piece of tissue or the whole heart. Current models use finite element
calculations, where each grid point represents a piece of tissue that has homogeneous cell
properties attributed to it. Hunter’s group has provided important anatomical information
from imaging work. With this model they can simulate waves of excitation in the heart,
specifically the dog heart. They find that the cell level models and fiber structures impact
results. They use data from their own lab and from many other places to develop and test
the model.
What’s made the extensive multi-level model of the heart possible is that relevant
experimental work (electrophysiology in particular) has been ongoing for 40 years,
providing a vast body of data and knowledge, the major regulators of the cell and tissue
function (ion channels generally) are quite accessible to measurement, and the cell
properties that contribute to whole organ function are relatively few and don’t depend on
vast intracellular signaling networks.
The model doesn’t deal with progression of disease in the heart dynamically. Rather, the
user can impose differences in parameters (e.g., different wall thickness) to look at
snapshots in time if they want to explore some disease in which progressive changes
might occur. Dr. Noble referred us to Natalia Trayanova at Tulane and her work on
defribillation for some chronic work.
Peter Kohl described his research on mechanical effects on the heart. In one project, he
used modeling and experimental work to understand how a particular medical procedure
works, specifically, thumping the chest strongly for restarting a stopped heart or slowing
down one that is beating too fast. He showed a simulation of 250x250 neurons as a 2D
slice through the ventricular wall. He found that mechanical stimulation (through stretch
receptors) in a certain area at certain time of heartbeat can result in arrhythmia, while
other times/areas of stimulation wouldn’t. This reproduces what is seen experimentally.
However, they found that the mechanisms by which the arrhythmias arose were quite
different than was expected, so they’ve gained some insight into underlying biology.
They’ve not yet verified experimentally the latter findings. In the lab tour, Dr. Kohl
illustrated how they’re measuring the mechanical effects on the heart beat. In a related
clinical study, they measured how physicians in US and Britain did the chest thump
(speed, force) and found specific differences that were related to greater success in US to
save patients. He’s now following up to influence training in the procedure to improve
it’s effectiveness.
Ming Lei also gave us a tour of his lab and described research on several posters. He’s
doing gene expression of the mouse heart and looking for ion channels that are
differentially expressed in different parts of the heart, especially the AV node. After gene
expression, they then work to understand how expression differences could relate to the
function of the AV node compared to other areas. One issue discussed was that mRNA
levels don’t relate well to protein expression, and so it’s difficult to know how directly
relevant the mRNA measurements are to functional studies.
Dr. Noble noted that while they’ve been quite successful in linking several levels of
biology from ion channels to organ within models and learning from those, they have not
yet progressed much in his lab to linking to more detailed molecular levels, notably, the
electrophysiology to metabolic and genetic pathways. On this he noted we should see
Akinori Noma’s group at Kyoto University (Prof of Physiology), who heads a consortium
of 5 Universities, with an investment of 7 billion yen, on biological simulation.
They have used and/or discussed using their models with pharmaceutical companies for
drug development, notably Novartis and GSK. An abstract by Helmlinger at
http://www.bc2.ch/2004/abstracts_list.html#Helmlinger (Basel computational
conference) describes a project with Novartis. For certain chemical compounds,
Novartis knew some functions and their whole cell effect but did not have a full
functional characterization, so the group used a model to infer the other effects the
compounds were likely having rather than going and doing all the experiments it would
have taken to narrow it down.
The project direction for the next five years is to work on arrhythmia at the whole organ
level. They have significant work now at the cellular level. In addition, the group will
continue to further develop and make available enabling software/technology (COR,
GRID, ML…).
Dr. Noble noted that there is a large cardiac research effort at Oxford beyond his
laboratory. Others he noted include Richard Ron Jones, who studies proton transport,
which is important in ischemia, both experimentally and through modeling; and Karen
Clark, who has a large NMR team working on ischemia. He noted that Peter Hunter is
taking a visiting professorship at Oxford at Oxford and will be in residence for 2-4
months per year.
This group has a well established program of both experimental and modeling work.
They noted that doing their own experimental work to test their models was critical to
their success using models since they gained significant insight from the interplay
between experimental and modeling work.
Lung research:
Dr. Noble only briefly described their work on the lung. For this program, Hunter in
New Zealand is again contributing anatomical work, and there is experimental and
modeling work also with collaborators in Bordeaux.
Systems Biology:
The group discussed a number of ideas about systems biology. Dr. Noble posited that
systems biology is “the” post genome science, noting, however, that proponents need to
be careful about how the field is sold. The necessity and promise must be described, but
the difficulty must not be overlooked. Dr. Noble’s view is that a fully bottom up
approach – whereby we get “all” the data and only then try to model a system – is not
appropriate (see summary in Nature’s Encyclopedia of Life Sciences). His rationale
includes that the function of proteins is not specified in the DNA but rather emerges at
multiple levels of organization, the combinatorics of including every protein and
interactions is simply too large to do computing on even if we wait for that data, and
there are feedbacks across biological levels, so knowing only information from the
genome will not be sufficient anyway (see also Nature Rev Molec Cell Biol 3, 460-463).
This view of “not needing all the data first” isn’t the generally held view by funding
agencies or researchers in UK, he reported, although funding agencies are funding more
and more modeling/quantitative work now.
Dr. Noble’s approach is to start somewhere in the middle of the biological hierarchy and
work both ways out to physiology and down to genes. He noted that for any system, we
won’t know a priori exactly what level to start at. A key aim is to find what level (gene
network, cell, tissue…) is required to assign a function, e.g., some functions can be
described by a network of a few genes, some only at the cell (e.g., an action potential),
some only by a groups of cells (e.g., some traveling waves in a tissue).
Software resources:
Dr. Noble’s lab is investing significant effort to create software that could improve model
integration and communication by modelers. He notes that a major problem is that many
models are not published accurately, and even if accurate, it is significant effort for
another researcher to translate the equations into software to use such a model or
integrate it with another model. He is involved in several efforts to address such
problems, including development of CellML and an associated model repository (see
www.cellml.org), and the development of COR, a model development and simulation
package. A description of COR can be found in International Journal of Bifurcation and
Chaos, 13(12): 3579-3590(2003). A first version should be available to others late in
2004.
Funding/Resources:
Dr. Noble noted that funding is increasing in systems biology in the UK, with more
interest in quantitative and modeling work starting with EPSRC and now also the
BBSRC. The UK government is involved in development of GRID computing for the
UK via EPSRC and DTI initiatives. He noted that the GRID computing initiative has
pulled the CS people in and should result in availability of more powerful computing for
projects such as his.
Education:
Oxford has significant interdisciplinary programs related to biology. There is very good
integration of mathematics, computer science, engineering, physiology, and clinical
sciences. Some of Noble’s models are used in the medical school to teach med and
physiology students. They’ve found the students accomplish more with the models than
when they’ve tried to get everyone to do a patch clamp in the lab.