Subject: Center for Cancer Systems Biology Interactome Map
From: "Systems Biology" <[email-masked]>
To: [email-masked]
Date: Wed, 28 Mar 2007 16:01:57 -0800

[1]                 

Wednesday, March 21, 2007  

*Towards a Cancer Interactome* 

*Dana-Farber Cancer Institute researcher Marc Vidal applies systems
biology approaches to identify the cast of bad and good actors in
cancer.
 *
 _By John Russell_  

What is cancer? That&rsquo;s a truly big question. Researchers and
clinicians have had varying success &ndash; from spectacular to dismal
&ndash; describing and treating cancer&rsquo;s myriad forms. Vast
resources have been spent trying to tease out pieces of the cancer
jigsaw puzzle. Sadly, producing a coherent and comprehensive picture
of cancer remains elusive or at least problematic. 

Today, researchers at the three-year-old Center for Cancer Systems
Biology[13] (CCSB), part of the Dana-Farber Cancer Institute[14]
(DFCI), affiliated with Harvard Medical School[15], are working
towards identifying the high level &ldquo;wiring diagram&rdquo; for
cancer. In this instance, that means an accurate map of all
protein-protein interactions associated with cancer.  

It&rsquo;s a daunting task. One can imagine a multitude of cancer
wiring diagrams. Even as CCSB succeeds producing these cancer circuit
descriptions, translating them into research programs and clinical
treatment is a long-term effort requiring an army of researchers.
(This article continues below)        

[16]   

Yet the challenge is part of the attraction for Marc Vidal, director
of CCSB. Trained first in engineering agronomy in Belgium, Vidal was
swept up in the molecular biology revolution. He received his PhD in
1991 from Gembloux University (Belgium) for work performed at
Northwestern University. He identified the yeast genes SIN3 and RPD3,
and demonstrated they encode global transcriptional regulators. RPD3
was later found to encode histone deacetylase. During his postdoc at
the Massachusetts General Hospital Cancer Center, he developed the
reverse two-hybrid system to genetically characterize protein-protein
interactions.  

&ldquo;In &rsquo;93, after a year and a half of my post-doc, it just
hit me one morning,&rdquo; says Vidal, &ldquo;I remember talking to my
previous advisor (Richard Gaber, Northwestern U), and saying
&rsquo;You know, all those people who want to get the next
protein-protein interaction, I want to know what&rsquo;s next. With
all the genomes coming up I wonder what the [entire] network of
interactions is going to look like.&rsquo; He said, &rsquo;I think
you&rsquo;re crazy,&rsquo; and I said, &rsquo;Well, I think it&rsquo;s
feasible.&rsquo;&rdquo; 

Turning that idea into reality has occupied much of Vidal&rsquo;s time
since. He joined DFCI in 2000 where his research still focuses on
global and local properties of interactome networks. At CCSB,
&ldquo;The first scientific project, the flagship project of the CCSB,
will be to generate a high quality human cancer interactome map that
together with other functional genomic and proteomic information, will
serve as a backbone for the drawing of a global functional wiring
diagram between both already known and yet to be discovered human
cancer gene products,&rdquo; proclaims its web site[17].  

No lack of challenges there. 

The path to such a cancer interactome leads first through an assembly
of the normal Human Interactome. Against such a gold standard, cancer
interactomes could then be compared and interpreted. Indeed, Vidal
called for a Human Interactome Project in an opinion piece in The
Scientist in March of 2006 (Time for a human interactome project?)[18]
and suggested $100 million would be needed. He also coauthored, _Towards
a proteome-scale map of the human protein-protein interaction network_,
published in Nature&rsquo;s letters section in October 2005.  

Another necessary step is compiling a high quality human ORFeome
(library of open reading frames) from which proteins can be cloned and
then have their interactions mapped. Vidal has worked extensively on
the ORFeome for C. elegans. Vidal says, &ldquo;Actually, despite what
people said, C. elegans do get cancer. It&rsquo;s sort of a simplified
form of cancer. If you give them a Ras mutation, one set of cells will
divide a few more times than they should.&rdquo; 

Vidal and CCSB colleague David Hill recently had a paper accepted at
Genomics on the human ORFeome, _hORFeome v.3.1: A resource of human
open reading frames representing over 10,000 human genes_. Vidal is
also a lead author of recently published paper on C. elegans, _Insight
into transcription factor gene duplication from Caenorhabditis elegans
Promoterome-driven expression patterns_, BMC Genomics, January 2007. 

The choice to emphasize systems biology &ndash; even to the extent of
incorporating it into the center&rsquo;s name &ndash; reflects
Vidal&rsquo;s intention to look at cancer in a broader context as well
as his belief that doing so requires a multidisciplinary approach
espoused by systems biology. For example, he has drawn heavily on
Notre Dame mathematical physicist Albert-L&aacute;szl&oacute;
Barab&aacute;si&rsquo;s research into scale-free networks[19] and
biological networks to interpret protein interaction networks.  

&ldquo;For me, the word, systems, is really well defined. You can
Google it and you might see various definitions, but there&rsquo;s a
trend. It&rsquo;s essentially an ensemble of components that interact
with each other and give rise to emerging properties, or something
like that. That applies to economy, all the way to sociology,
engineering, and biology. I go down inside cells where tens of
thousands, if not hundreds of thousands of gene products form this
complex structure we call the interactome. That&rsquo;s when you do
systems biology,&rdquo; he says. 

Clearly systems biology has been used to describe many approaches.
Some researchers, such as Bernhard Palsson[20] (UCSD), have tackled
whole organism metabolism (E. coli and yeast) and built complicated,
quantitative models than permit what-if kinds of experiments. Others
have conducted extensive modeling of individual protein-ligand
interactions and their associated pathways. 

&ldquo;My view is we all do systems biology, we just take the problem
from different angles, and hopefully at some point it will be
integratable. [There is a] difference between local and global
emerging properties. You can do beautiful systems biology with two
proteins. Say you put them together in a circuit where, you have to
two transcription factors, and they activate each other&rsquo;s
transcription, that&rsquo;s a circuit. That&rsquo;s a wonderful system
right there with properties that can be studied forever.  

&ldquo;People say, if you do that, then you need all kinds of really,
really precise measurements of how the proteins will interact with
each other. You&rsquo;ll need Kds (disassociation constants),
you&rsquo;ll need the logic of the circuit, and that&rsquo;s all very
true, and actually what comes out of that is gorgeous. It&rsquo;s the
&ldquo;local&rdquo; modeling of systems biology. 

&ldquo;Sometimes those people look at us and say, &ldquo;Oh, you guys
are not real systems biologists because you don&rsquo;t really do
mathematical modeling, you want to stay global.&rdquo; Well, we want
to stay global because we think that that&rsquo;s also an interesting
unit of study of the cell, because at the end of the day the cell is a
unit and there is a network of interacting proteins in there and the
point is that they are properties that are global that radiate back to
the biology.&rdquo; 

Vidal&rsquo;s hypothesis is that some of those global properties might
be perturbed in cancer cells. Suppose a cell has ten genes, and seven
are active. &ldquo;How they interact will be my interactome,&rdquo; he
says. Then the cell becomes cancerous. A different mix of genes is
turned on and off. &ldquo;Interactions are rewired a little bit.
That&rsquo;s my new interactome, and would correlate with the cancer
phenotype.&rdquo; 

One concrete example is CCSB work with viruses that tend to give rise
to tumorogenesis. This work focuses on identifying interaction
partners for viral proteins. &ldquo;Where do the proteins go? What do
they contact on the human interactome? Can we see anything in the
global properties of the interaction network that would relate back to
what the viral proteins touch physically,&rdquo; says Vidal. 

CCSB is also working with genes in which mutations seem to be
associated with tumorogenesis. Vidal says they just now learning how
to effectively clone, express and characterize these genes &ldquo;in
the context of the network and of all the alleles that are associated
with a phenotype such as tumorogenesis.&rdquo; 

There are lots of technical obstacles in pursing the Cancer
Interactome. It will be necessary, for example, to account for
important proteins resulting from alternative splicing or
post-translation modification. You&rsquo;ll never get them all,
concedes Vidal, but he believes it&rsquo;s possible to achieve high
coverage and to draw important conclusions. 

Likewise, the yeast two-hybrid method of identifying protein-protein
interactions can be mishandled and misused leading sometimes to
inaccurate information. Vidal agrees but emphasizes the use of careful
procedures can avoid most of those problems. &ldquo;You have to use it
with the appropriate controls.&rdquo; 

So far, Vidal seems content with CCSB&rsquo;s progress. Its publishing
performance to date is admirable. Headcount hovers around 15. CCSB has
an active seminar program with guest speakers. Funding doesn&rsquo;t
seem to be a problem. He also still believes systems biology is an
important lens through which to examine cancer. 
 
Asked when systems biology would become relevant to drug discovery,
Vidal says, &ldquo;I would take it the other way around, imagine
designing drugs and therapeutic strategies in five years time without
considering the system. Is that even conceivable? I mean seriously. So
if you asked, &ldquo;Do you think systems biology will merge with the
pharmaceutical industry?&rdquo; I don&rsquo;t know how it
wouldn&rsquo;t.&rdquo;          

*Vidal Discusses the Spirit Behind CCSB* 

&ldquo;This was part of a sort of a Dana-Farber-wide initiative called
the Strategic Planning Initiative. Dana-Farber wanted to start being
more responsive to how can we maintain, on the one hand, independence
for young researchers who come here, the assistant professors,
associate professors, while allowing the kind of interdisciplinarity
we increasingly need to solve big problems like this one [Cancer
Interactome].&rdquo; 

&ldquo;I&rsquo;ll give you a sense. So ten years ago, definitely when
I was a graduate student, I saw how my boss started &ndash; I came in
only a few months after him. It was very isolated. You got your
start-up package, your empty room, and you started buying equipment
and you needed to know about everything going on in your lab. And you
were on your own. Between 5 and 10 years later, some committee sat
down and said, &ldquo;He or she made it; they can get tenure.&rdquo;  

&ldquo;We can&rsquo;t do this any more. There&rsquo;s just no way. I
mean this solo approach takes so many different fields and an
integration of the knowledge and know-how in all those different
fields; it&rsquo;s very, very difficult. There&rsquo;s nobody who can
be at that top level in the five different fields it takes to solve a
question like that by the age of 31, by themselves, along with three
students.&rdquo;  

&ldquo;The second reason it&rsquo;s a center is to build a robust
structure, robots and informatics and that sort of thing. A new
assistant professor with three post-docs, here at Dana-Farber, could
now send one of them if they wanted to, for one, two, three months,
whatever, to use our robots, use the informatics and solve a problem
they might have in their lab. It&rsquo;s still their work.
They&rsquo;re still independent. They still have to think about it and
be creative. They don&rsquo;t have to recreate the wheel by having
their own robots and all. 

&ldquo;The third part is really [creating] an intellectual systems
biology center where we try to get as many people as possible from the
outside. We have a seminar series that&rsquo;s been going on for two
years where it&rsquo;s basically systems biology. That&rsquo;s why we
have Jason (Papin) today who trained with Bernhard [Palsson] and has
his own lab now (University of Virginia). So that brings people from
Dana-Farber, but outside Dana-Farber as well. We have what we call the
Think Tank series where post-docs and graduate students in Boston who
work on systems projects &ndash; systems biology projects can come and
give talks to each other, there&rsquo;s pizza and that sort of thing.  

&ldquo;During the next few years, the best people, I think, honestly,
if you want to hire them, you&rsquo;ll have to have something like
that, at the assistant professor level. A place that only has what we
had 10, 15 years ago -- meaning here&rsquo;s an empty space, see you
in 5 years - those kids will just not take those jobs.&rdquo;    

    

    

    

    

**   

           

** 

*Email to a Friend[21]*       

*BRIEFS*    

*Pathway Pioneer GeneGo[22] picked up two honors.* The pathway
database and analysis tool provider won Best in Show for its systems
pharmacology product, MetaDrug 2.0, at CHI&rsquo;s Molecular Medicine
Marketplace, held in San Francisco last week. MetaDrug was chosen by
conference attendee votes. MetaDrug helps to predict indications, off
target effects, and human toxicity for novel small-molecule compounds.
GeneGo was also recently awarded the 2006 Frost & Sullivan Award for
Competitive Strategy Leadership in the European bioinformatics market. 

*Compendia Bioscience*[23], a provider of cancer profiling data and
analysis tools, and *Ingenuity Systems[24]*, provider of pathway tools
and biological databases, announced the integration of their flagship
products Oncomine Professional and Ingenuity Pathways Analysis (IPA).
Users can now navigate directly from cancer gene signatures discovered
in Oncomine Professional to the curated pathway information available
from IPA, say the companies. *Separately, **SAS*[25]* and Ingenuity
announced integration* between JMP Genomics software from SAS and IPA,
enabling users to upload the results of microarray analysis directly
into IPA.  

*Ariadne Genomics[26] received two grants recently,* one for $80,000
from Montgomery County&rsquo;s Economic Development Fund to support
the company&rsquo;s growth and expansion. The county funding coincided
with Ariadne&rsquo;s relocation from the Maryland Technology
Development Center, one of three business incubators in Montgomery
County, to new offices in Rockville, MD. *Ariadne also received a
$100,000 SBIR Phase I grant from the NIH*, National Center for
Research Resources, to further develop MedScan technology. MedScan
employs natural language processing (NLP) to extract biomedical
information from scientific text into databases amenable for
computational analysis. The SBIR grant will be used to expand MedScan
into the area of toxicology, small molecule-enzyme interactions, and
human metabolism. Separately, *Ariadne announced release of Pathway
Studio 5.0*, which, among other things, has expanded functionality for
desktop users. 

*BG Medicine[27] announced FDA approval* of the first phase of a
biomarker discovery project to be conducted under a CRADA with the
FDA&rsquo;s National Center for Toxicological Research (NCTR).  As
part of FDA&rsquo;s Critical Path Initiative, the Liver Toxicity
Biomarker Study (LTBS) aims to discover biomarkers of human
hepatotoxicity in the standard pre-clinical test used by
pharmaceutical companies in the initial stages of drug development.
The first phase of the LTBS, which will last approximately nine
months, has been designed by the FDA and BG Medicine with input from
leading academic and industry scientists. *Seven participating
pharmaceutical companies - Pfizer, Johnson & Johnson Pharmaceutical
Research and Development LLC, Mitsubishi Chemical Holdings
Corporation, Orion, UCB, Sankyo Co. and Eisai* - will participate on
the Scientific Advisory Board (SAB) and provide project funding. 
Applied Biosystems will provide biomarker discovery systems based on
mass spectrometry, including service and support as well as in-kind
contributions.   

*Genedata&rsquo;s[28] lead product Phylosopher has been chosen* as the
central management and infrastructure solution for sharing and
interpreting the experimental data generated within *BaSysBio
(Bacillus Systems Biology), a European project to study* the global
regulation of gene transcription in the model bacterium Bacillus
subtilis. This bacterium has significant economic potential as a
producer of enzymes and metabolites, and is used in a wide range of
industries, from pharmaceutical and chemical manufacturers to the agro
and food sectors. Two disease-causing bacteria, Bacillus anthracis,
responsible for Anthrax, and Staphylococcus aureus, responsible for
secondary infections, are objects of research as well. The project
will adapt an array of high-throughput genomics technologies,
including transcriptomics, proteomics, metabolomics, fluxomics and
cell reporter assays.  

*Gene Network Sciences[29] and UCSD researchers* used GNS software to
create a quantitative computer model that simulates G1 cell cycle
progression and is capable of reproducing observations from in vitro
cell culture studies, and serves as a foundation for the development
of new cancer drugs targeting G1 cell cycle progression. Specifically,
the researchers used the quantitative reverse-engineering and modeling
approach reflected in the GNS software platform to predict the
presence of a previously unidentified &ldquo;modifier&rdquo; that is
postulated to cause transition of the cell cycle from the
growth-factor dependent Early G1 phase to the growth-factor
independent Late G1 phase. &ldquo;This is the first time that
quantitative evidence has pointed to the necessary existence of a key
metabolic factor controlling passage through the restriction point in
the cell cycle that commits the cell to DNA replication,&rdquo; said *Dr.
Steve Dowdy, principal UCSD investigator in the collaboration* and
Howard Hughes Medical Institute researcher. A paper on the work was
published in Molecular Systems Biology (a Nature publication), &ldquo;A
Systems Biology Dynamical Model of Mammalian G1 Cell Cycle Progression[30].&rdquo; 

*Leroy Hood will be inducted into the National Inventors Hall* of Fame
at a ceremony in Akron, Ohio, this spring. The former University of
Washington professor and founder of the Institute for Systems Biology
joins 16 other inventors in the class of 2007, bringing the total
number of inductees to 329. Others who will be inducted this year
include John Franz, inventor of the weed killer Roundup; Allen Breed,
who created the first air bag safety system for automobiles; and Paul
Baran, whose digital packet switching technology helped lay the
foundation for the Internet. 

*Pharsight[31] released* an expanded set of public-source databases
(meta-data) to accelerate model-based assessment of a drug&rsquo;s
performance against competing therapies. The databases cover clinical
indications for Type 2 diabetes, thrombosis, depression and insomnia.
Pharsight *currently offers public-source meta-databases that cover 20
disease indications.* Drug and disease models quantitatively integrate
all the available pre-clinical and clinical data on a compound, public
data in the clinical and scientific literature, and expert opinion to
inform an understanding of compound attributes and behavior. These
probabilistic mathematical models can then be used to run simulations
that predict, within an interval of uncertainty, the expected clinical
results for a wide range of treatment and patient scenarios involving
the compound and its competitors. 

*Oops. Entelos[32] discovers the downside* of being public. It
recently disclosed two of its customers will scale back programs in
which Entelos was involved, causing it to re-phase revenue forecasts.
Cost-cutting is likely, and Jill Fujisaki, VP of investor relations,
says everything is on the table and agrees the expected shortfall is
material to Entelos&rsquo; business. Details remain sketchy, but the
company will have to disclose its cost-containment plans and revenue
expectations as part of its next required financial report early in
April. Entelos (ENTL) is listed on the Alternative Investment Market
on the London Stock Exchange.

*FEATURED CONTENT*    

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_To have your white paper featured here, contact Gina Bajenaru[33] for
more information._           

*SBNL ARCHIVES*    

Entelos Strikes Deal with J&J
 [34]February 14, 2007 

Burning Questions in SB; Executives Look Ahead; Trends[35]
 January 10, 2007  

The Novartis Conjurer; Outlook 2007: SB Execs Survey; Trends[36]
 December 13, 2006  

Systems Biology DREAM(s) Big[37]
 November 13, 2006 

Pfizer SB Chief David de Graaf Looks Back and Ahead 
 [38]October 18, 2006  

SB in the Hot Seat; Regulomics Conference[39] 
September 13, 2006  

Pfizer's Progress, GNS Growth, and more[40]
 August 24, 2006  

Conversation with Genstruct's Keith Elliston[41] 
July 27, 2006  

Sunrise for Systems Biology[42] 
June 15, 2006  

*Bio-IT World SB Links* 

Pathway Pioneers[43] 

Marvelous Models of Biological Systems[44] 

Pharsight Lands CRADA to Assist FDA with Modeling Initiative[45] 

FDA Mulls Drug/Disease Model Library[46] 

Welcome MIRIAM: Researchers Propose Modeling Standard[47]           

*Contact the Editor*     

We invite your comments and feedback for this edition of _Systems
Biology_. 
 John Russell
 [48]Executive Editor                                     

[49]Published by Bio-IT World[50] Copyright &copy; 2007, a business of Cambridge
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