Cambridge University. UK: The first comprehensive computer model to simulate the development of blood cells could help in the development of new treatments for leukaemia and lymphoma, say researchers at the University of Cambridge and Microsoft Research.
The
human body produces over 2.5 million new blood cells during every
second of our adult lives, but how this process is controlled remains
poorly understood. Around 30,000 new patients each year are diagnosed
with cancers of the blood each year in the UK alone. These cancers,
which include leukaemia, lymphoma and myeloma, occur when the production
of new blood cells gets out of balance, for example if the body
produces an overabundance of white blood cells.
Biomedical scientists from the Wellcome Trust-MRC Cambridge Stem Cell
Institute and the Cambridge Institute for Medical Research collaborated
for the past 2 years with computational biologists at Microsoft Research
and Cambridge University’s Department of Biochemistry. This
interdisciplinary team of researchers have developed a computer model to
help gain a better understanding of the control mechanisms that keep
blood production normal. The details are published today in the journal
Nature Biotechnology.
“With this new computer model, we can carry out simulated experiments
in seconds that would take many weeks to perform in the laboratory,
dramatically speeding up research into blood development and the genetic
mutations that cause leukaemia,” says Professor Bertie Gottgens whose
research team is based at the University’s Cambridge Institute for
Medical Research.
Dr Jasmin Fisher from Microsoft Research and the Department of
Biochemistry at the University of Cambridge says: “This is yet another
endorsement of how computer programs empower us to gain better
understanding of remarkably complicated processes. What is
ground-breaking about the current work is that we show how we can
automate the process of building such programs based on raw experimental
data. It provides us with a blueprint to develop computer models
relevant to other human diseases including common cancers such as breast
and colon cancer.”
To construct the computer model, PhD student Vicki Moignard from the
Stem Cell Institute measured the activity of 48 genes in over 3,900
blood progenitor cells that give rise to all other types of blood cell:
red and white blood cells, and platelets. These genes include TAL1 and
RUNX1, both of which are essential for the development of blood stem
cells, and hence to human life.
Computational biology PhD student Steven Woodhouse then used the
resulting dataset to construct the computer model of blood cell
development, using computational approaches originally developed at
Microsoft Research for synthesis of computer code. Importantly,
subsequent laboratory experiments validated the accuracy of this new
computer model.
One way the computer model can be used is to simulate the activity of
key genes implicated in blood cancers. For example, around one in five
of all children who develop leukaemia has a faulty version of the gene
RUNX1, as does a similar proportion of adults with acute myeloid
leukaemia, one of the most deadly forms of leukaemia in adults. The
computer model shows how RUNX1 interacts with other genes to control
blood cell development: the gene produces a protein also known as Runx1,
which in healthy patients activates a particular network of key genes;
in patients with leukaemia, an altered form of the protein is thought to
suppress this same network. If the researchers change the ‘rules’ in
the network model, they can simulate the formation of abnormal leukaemia
cells. By tweaking the leukaemia model until the behaviour of the
network reverts back to normal, the researchers believe they can
identify promising pathways to target with drugs.
Professor Gottgens adds: “Because the computer simulations are very
fast, we can quickly screen through lots of possibilities to pick the
most promising ones as pathways for drug development. The cost of
developing a new drug is enormous, and much of this cost comes from new
candidate drugs failing late in the drug development process. Our model
could significantly reduce the risk of failure, with the potential to
make drug discovery faster and cheaper.”
The research was supported by the Medical Research Council, the
Biotechnology and Biological Sciences Research Council, Leukaemia and
Lymphoma Research, the Leukemia and Lymphoma Society, Microsoft Research
and the Wellcome Trust.
Dr Matt Kaiser, Head of Research at UK blood cancer charity Leukaemia
& Lymphoma Research, which has funded Professor Gottgens’ team for
over a decade, said: “For some leukaemias, the majority of patients
still ultimately die from their disease. Even for blood cancers for
which the long-term survival chances are fairly good, such as childhood
leukaemia, the treatment can be really gruelling. By harnessing the
power of cutting-edge computer technology, this research will
dramatically speed up the search for more effective and kinder
treatments that target these cancers at their roots.”
Reference
Moignard, V et al. Decoding the regulatory network of early blood development from single-cell gene expression measurements. Nature Biotech; 9 Feb 2015.
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