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Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Posted in Academic Publishing, Acute Myocardial Infarction, Advanced Drug Manufacturing Technology, Alzheimer's Disease, Atherogenic Processes & Pathology, Autologous Cell Therapy, Automated Cell Processing, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone Disease and Musculoskeletal Disease, Bone marrow derived cells, Ca2+ triggered activation, Ca2+ triggered activation, Cachexia, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Endothelial cells, Epigenetics and Cardiovascular Risks, Etiology, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Phosphorylation, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, S-nitrosylation, Signaling, Skeletal muscle regeneration, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Translational Effectiveness, Translational Science, Ubiquitinylation, Water Transporters, tagged , , , , , , , , , , , , , , , , , , , , , , , , on April 28, 2014| Leave a Comment »

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Article ID #135: Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1. Published on 4/28/2014

WordCloud Image Produced by Adam Tubman

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

  • Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
  • Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
  • Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
  • Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
  • Enable the discovery of new drugs in the continuing emergence of drug resistance.
  • Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM - Part 1

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at
Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

II. Regulatory Effects of Mammalian microRNAs

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240
1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.
In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].
Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

http://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

http://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

http://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

  • In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
  • Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

http://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Synthesizing Synthetic Biology: PLOS Collections

http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

http://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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Loss of Gene Islands May Promote a Cancer Genome’s Evolution: A new Hypothesis on Oncogenesis

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Expression, Personalized and Precision Medicine & Genomic Research, Translational Research, tagged , , , , , , , , , , , , , , , on January 23, 2014| Leave a Comment »

Loss of Gene Islands May Promote a Cancer Cell’s Survival, Proliferation and Evolution: A new Hypothesis (and second paper validating model) on Oncogenesis from the Elledge Laboratory

Writer, Curator: Stephen J. Williams, Ph.D.

It is well established that a critical event in the transformation of a cell to the malignant state involves the mutation of hosts of oncogenes and tumor suppressor genes, which in turn, confer on a cell the inability to properly control its proliferation.    On a genomic scale, these mutations can result in gene amplifications, loss of heterozygosity (LOH), and epigenetic changes resulting in tumorigenesis.  The “two hit hypothesis”, proposed by Dr. Al Knudson of Fox Chase Cancer Center[1], proposes that two mutations in the same gene are required for tumorigenesis, initially proposed to explain the progression of retinoblastoma in children, indicating a recessive disease.

(Excerpts from a great article explaining the two-hit-hypothesis is given at the end of this post).

And, although many tumor genomes display haploinsufficeint tumor suppressor genes, and fit the two hit model quite nicely, recent data show that most tumors display hemizygous recurrent deletions within their genomes.  Tumors display numerous recurrent hemizygous focal deletions that seem to contain no known tumor suppressor genes. For instance a recent analysis of over three thousand tumors including breast, bladder, pancreatic, ovarian and gastric cancers averaged greater than 10 deletions/tumor and 82 regions of recurrent focal deletions,

It has been proposed these great number of hemizygous deletions may be a result of:

  • a recessive tumor suppressor gene requiring mutation or silencing of second allele
  • the mutation may recur as they are located in fragile sites (unstable genomic regions)
  • single-copy loss may provide selective advantage regardless of the other allele

Note: some definitions of hemizygosity are given below.  In general at any locus, each parental chromosome can have 3 deletion states:

  1. wild type
  2. large deletion
  3. small deletion

Hemizygous deletions only involve one allele, not both alleles which is unlike the classic tumor suppressor like TP53

To see if it is possible that only one mutated allele of a tumor suppressor gene may be a casual event for tumorigenesis, Dr. Nicole Solimini and colleagues, from Dr. Stephen Elledge’s lab at Harvard, proposed a hypothesis they termed the cancer gene island model, after analyzing the regions of these hemizygous deletions for cancer related genes[2].  Dr. Soliin and colleagues analyzed whole-genome sequence data for 526 tumors in the COSMIC database comparing to a list generated from the Cancer Gene Census for homozygous loss-of-function mutations (mutations which result in a termination codon or frame-shift mutation: {this produces a premature stop in the protein or an altered sequence leading to a nonfunctional protein}.

Results of this analysis revealed:

  1. although tumors have a wide range of deletions per tumor (most epithelial high grade like ovarian, bladder, pancreatic, and esophageal adenocarcinomas had 10-14 deletions per tumor
  2. and although tumors exhibited a wide range (2- 16 ) loss of function mutations
  3. ONLY 14 of 82 recurrent deletions contained a known tumor suppressor gene and was a low frequency event
  4. Most recurrent cancer deletions do not contain putative tumor suppressor genes.

Therefore, as the authors suggest, an alternate method to the two-hit hypothesis may account for a selective growth advantage for these types of deletions, defining these low frequency hemizygous mutations in two general classes

  1. STOP genes: suppressors of tumor growth and proliferation
  2. GO genes: growth enhancers and oncogenes

Identifying potential STOP genes

To identify the STOP and GO genes the authors performed a primary screen of an shRNA library in telomerase (hTERT) immortalized human mammary epithelial cells using increased PROLIFERATION as a screening endpoint to determine STOP genes and decreased proliferation and lethality (essential genes) to determine possible GO genes. An initial screen identified 3582 possible STOP genes.  Using further screens and higher stringency criteria which focused on:

  • Only genes which increased proliferation in independent triplicate screens
  • Validated by competition assays
  • Were enriched more than four fold in three independent shRNA screens

the authors were able to focus on and validate 878 genes to determine the molecular pathways involved in proliferation.

These genes were involved in cell cycle regulation, apoptosis, and autophagy (which will be discussed in further posts).

To further validate that these putative STOP genes are relevant in human cancer, the list of validated STOP genes found in the screen was compared to the list of loss-of-function mutations in the 526 tumors in the COSMIC database.  Surprisingly, the validated STOP gene list were significantly enriched for known and possibly NOVEL tumor suppressor genes and especially loss of function and deletion mutations but also clustered in gene deletions in cancer.  This not only validated the authors’ model system and method but suggests that hemizygous deletions in multiple STOP genes may contribute to tumorigenesis

as the function of the majority of STOP genes is to restrain tumorigenesis

A few key conclusions from this study offer strength to an alternative view of oncogenesis NAMELY:

  • Loss of multiple STOP genes per deletion optimize a cancer cell’s proliferative capacity
  • Cancer cells display an insignificant loss of GO genes, minimizing negative impacts on cellular fitness
  • Haploinsufficiency in multiple STOP genes can result in similar alteration of function similar to complete loss of both alleles of
  • Cancer evolution may result from selection of hemizygous loss of high number of STOP and low number of GO genes
  • Leads to a CANCER GENE ISLAND model where there is a clonal evolution of transformed cells due to selective pressures

A link to the supplemental data containing STOP and GO genes found in validation screens and KEGG analysis can be found at the following link:

http://www.sciencemag.org/content/337/6090/104/suppl/DC1#

A link to an interview with the authors, originally posted on Harvard’s site can be found here.

Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome; a new paper from the Elledge group in the journal Cell

http://www.cell.com/retrieve/pii/S0092867413012877

A concern of the authors was the extent to which gene silencing could have on their model in tumors.  The validation of the model was performed in cancer cell lines and compared to tumor genome sequence in publicly available databases however a followup paper by the same group shows that haploinsufficiency contributes a greater impact on the cancer genome than these studies have suggested.

In a follow-up paper by the Elledge group in the journal Cell[3], Theresa Davoli and colleagues, after analyzing 8,200 tumor-normal pairs, show there are many more cancer driver genes than once had been predicted.  In addition, the distribution and potency of STOP genes, oncogenes, and essential genes (GO) contribute to the complex picture of aneuploidy seen in many sporadic tumors.  The authors proposed that, together with these and their previous findings, that haploinsufficiency plays a crucial role in shaping the cancer genome.

Hemizygosity and Haploinsufficiency

Below are a few definitions from Wikipedia:

Zygosity is the degree of similarity of the alleles for a trait in an organism.

Most eukaryotes have two matching sets of chromosomes; that is, they are diploid. Diploid organisms have the same loci on each of their two sets of homologous chromosomes, except that the sequences at these loci may differ between the two chromosomes in a matching pair and that a few chromosomes may be mismatched as part of a chromosomal sex-determination system. If both alleles of a diploid organism are the same, the organism is homozygous at that locus. If they are different, the organism is heterozygous at that locus. If one allele is missing, it is hemizygous, and, if both alleles are missing, it is nullizygous.

Haploinsufficiency occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state. It is responsible for some but not all autosomal dominant disorders.

Al Knudsen and The “Two-Hit Hypothesis” of Cancer

Excerpt from a Scientist article by Eugene Russo about Dr. Knudson’s Two hit Hypothesis;

for full article please follow the link http://www.the-scientist.com/?articles.view/articleNo/19649/title/-Two-Hit–Hypothesis/

“

The “two-hit” hypothesis was, according to many, among the more significant milestones in that rapid evolution of biomedical science. The theory explains the relationship between the hereditary and nonhereditary, or sporadic, forms of retinoblastoma, a rare cancer affecting one in 20,000 children. Years prior to the age of gene cloning, Knudson’s 1971 paper proposed that individuals will develop cancer of the retina if they either inherit one mutated retinoblastoma (Rb) gene and incur a second mutation (possibly environmentally induced) after conception, or if they incur two mutations or hits after conception.3 If only one Rb gene functions normally, the cancer is suppressed. Knudson dubbed these preventive genes anti-oncogenes; other scientists renamed them tumor suppressors.

When first introduced, the “two-hit” hypothesis garnered more interest from geneticists than from cancer researchers. Cancer researchers thought “even if it’s right, it may not have much significance for the world of cancer,” Knudson recalls. “But I had been taught from the early days that very often we learn fundamental things from unusual cases.” Knudson’s initial motivation for the model: a desire to understand the relationship between nonhereditary forms of cancer and the much rarer hereditary forms. He also hoped to elucidate the mechanism by which common cancers, such as those of the breast, stomach, and colon, become more prevalent with age.

According to the then-accepted somatic mutation theory, the more mutations, the greater the risk of cancer. But this didn’t jibe with Knudson’s own studies on childhood cancers, which suggested that, in the case of cancers such as retinoblastoma, disease onset peaks in early childhood. Knudson set out to determine the smallest number of cancer-inducing events necessary to cause cancer and the role of these events in hereditary vs. nonhereditary cancers. Based on existing data on cancer cases and some mathematical deduction, Knudson came up with the “two-hit” hypothesis.

Not until 1986, when researchers at the Whitehead Institute for Biomedical Research in Cambridge, Mass., cloned the Rb gene, would there be solid evidence to back up Knudson’s pathogenesis paradigm.4 “Even with the cloning of the gene, it wasn’t clear how general it would be,” says Knudson. There are, it turns out, several two-hit lesions, including polyposis, neurofibromitosis, and basal cell carcinoma syndrome. Other cancers show only some correspondence with the two-hit model. In the case of Wilm’s tumor, for example, the model accounts for about 15 percent of the cancer incidence; the remaining cases seem to be more complicated.

knudsonTwoHit1600

”

His seminal paper on the two-hit hypothesis[1]

A.G. Knudson, “Mutation and cancer: statistical study of retinoblastoma,” Proceedings of the National Academy of Sciences, 68:820-3, 1971.

The two hit hypothesis proposed by A.G. Knudson.  A description with video of Dr. Knudson talk at AACR can be found at the following link (photo creditied to A.G. Knudson and Fox Chase Cancer Center at the following link:http://www.fccc.edu/research/research-awards/knudson/index.html

Sources

1.            Knudson AG, Jr.: Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 1971, 68(4):820-823.

2.            Solimini NL, Xu Q, Mermel CH, Liang AC, Schlabach MR, Luo J, Burrows AE, Anselmo AN, Bredemeyer AL, Li MZ et al: Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 2012, 337(6090):104-109.

3.            Davoli T, Xu Andrew W, Mengwasser Kristen E, Sack Laura M, Yoon John C, Park Peter J, Elledge Stephen J: Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome. Cell 2013, 155(4):948-962.

Other papers on this site on CANCER and MUTATION include:

Cancer Mutations Across the Landscape

Salivary Gland Cancer – Adenoid Cystic Carcinoma: Mutation Patterns: Exome- and Genome-Sequencing @ Memorial Sloan-Kettering Cancer Center

Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Breast Cancer and Mitochondrial Mutations

Winning Over Cancer Progression: New Oncology Drugs to Suppress Passengers Mutations vs. Driver Mutations

Hold on. Mutations in Cancer do good.

Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Read Full Post »

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Genome Biology, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, tagged , , , , , , , , , , , , , , , on September 4, 2013| Leave a Comment »

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Curator and Writer: Stephen J. Williams, Ph.D.

Article ID #77: Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn. Published on 9/4/2013

WordCloud Image Produced by Adam Tubman

In an earlier post entitled “Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing” the heterogenic nature of solid tumors was discussed.  There resulted an excellent discussion in the Oncology Pharma forum on LinkedIn so I curated the comments (below article) to foster further discussion. To summarize the original post, this was a discussion of Dr. Charles Swanton’s paper[1] in which he and colleagues had noticed that individual biopsies from primary renal tumors displayed a variety of mutations of the same and different tumor suppressor genes (TSG), thereby not only revealing the heterogeneity of individual tumors but also how tumors can evolve.  Thus it was suggested that individual cells of a primary tumor can represent individual clones, each evolving on a distinct pathway to tumorigenicity and metastasis as each clone would have accumulated different passenger mutations.  It is these passenger mutations which have been posited to be responsible for a tumor’s continued growth (as discussed in the following post Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers).  Indeed, as Dr. Swanton mentioned in the posting that it is very likely a solid tumor contains discrete clones with different driver and passenger mutations and possibly different mutated TSG but also this intra-tumor heterogeneity would have great implications for personalized chemotherapeutic strategies, not only against the primary tumor but against resistant outgrowth clones, and to the metastatic disease, as Swanton and colleagues had found that the metastatic disease displayed tremendously increased genomic instability than the underlying primary disease.

Therefore it may behoove the clinical oncologist to view solid tumors as a collection of multiple clones, each having their own mutagenic spectrum and tumorigenic phenotype.  Each of these clones may acquire further mutations which provide growth advantage over other clones in the early primary tumor.  In addition, branched evolution of a clone most likely depends more on genomic instability and epigenetic factors than on solely somatic mutation.

This is echoed in a  report in Carcinogenesis back in 2005[3] Lorena Losi, Benedicte Baisse, Hanifa Bouzourene and Jean Benhatter had shown some similar results in colorectal cancer as their abstract described:

“In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.”

Therefore if a tumor had evolved in time closer to the initial driver mutation multiple therapies may be warranted while tumors which had not yet evolved much from their driver mutation may be tackled with an agent directed against that driver, hence the branched evolution as shown in the following diagram:

branced chain evolution cancer

Cancer Sequencing

Unravels clonal evolution.

From Carlos Caldas. (2012).

Nature Biotechnology V.30

pp 405-410.[2] used with

permission.

 

 

 

 

 

 

 

An article written by Drs. Andrei Krivtsov and Scott Armstron entitled “Can One Cell Influence Cancer Heterogeneity”[4] commented on a study by Friedman-Morvinski[5] in Inder Verma’s laboratory discussed how genetic lesions can revert differentiated neorons and glial cells to an undifferentiated state [an important phenotype in development of glioblastoma multiforme].

In particular it is discussed that epigenetic state of the transformed cell may contribute to the heterogeneity of the resultant tumor.  Indeed many investigators (initially discovered and proposed by Dr. Beatrice Mintz of the Institute for Cancer Research, later to be named the Fox Chase Cancer Center) show the cellular microenvironment influences transformation and tumor development[6-8].

Briefly the Friedman-Morvinski study used intra-cerebral ventricular (ICV) injection of lentivirus to introduce oncogenes within the CNS and produced tumors of multiple cell origins including neuronal and glial cell origin (neuroblastoma and glioma).  The important takeaway was differentiated somatic cells which acquire genetic lesions can transform to form multiple tumor types.  As the authors state, “cellular differentiation and specialization are accompanied by gradual changes in epigenetic programs” and that “the cell of origin may influence the epigenetic state of the tumor”.   In essence this means that the success of therapy may depend on the cellular state (whether stem cell, progenitor cell, or differentiated specialized cell) at time of transformation.  In other words tumors arising from cells with an epigenetic state seen in stem cells would be more resistant to therapy unless given an epigenetic therapy, such as azacytididne, retinoic acid or HDAC inhibitors.

 

So as the Oncology Pharma forum on LinkedIn was such an excellent discussion I would like to post the comments for curation purposes and foster further discussion.  I would like to thank everyone’s great comments below.  I would especially like to thank Dr. Emanuel Petricoin from George Mason and Dr. David Anderson for supplying extra papers which will be the subject of a future post. I had curated each comment with inserted LIVE LINKS to make it easier to refer to a paper and/or company mentioned in the comment.

The comments seemed to center on three main themes:

  1. 1.      Clinicians pondering the benefit to mutational spectrum analysis to determine personalized therapy and develop biomarkers of early disease
  2. 2.      A shift in the clinicians paradigm of cancer development, diagnoses, and treatment from strictly histologic evaluation to a genetic and altered cellular pathway view
  3. 3.      Use of proteomics, microarray and epigenetics as an alternative to mutational analysis to determine aberrant cellular networks in various stages of tumor development

 

Victor Levenson • Thanks for posting this! To be honest, I am puzzled by the insistence on sequencing as a tool for tumor analysis – we know that expression patterns rather than mutations in a limited number of genes determine tumor physiology (or, even more, physiology of any tissue). Since the AACR-2012 we know that different tumors have similar or even identical mutations, so >functional< rather than >structural< differences are important. Frankly, I’d be much more excited learning about expression pattern heterogeneity in tumors.Granted that is much more challenging than NGS sequencing, but the value of the data would be incomparable, especially in its application to biomarker development.

Stephen J. Williams, Ph.D. • Dear Dr. Levenson, thanks for your comments. I agree with you and in no way am insisting on the releiance of sequencing mutations in cancer as the sole means for determining therapy. It is extremely true that tumors will show tremendous heterogeneity of mRNA expression. There are a number of studies (one which I will post on pharmaceuticalintelligence.com) that individual tumor cells will have differing expression patterns based on the levels of regional hypoxia within the tumor as well as other microenvironmental factors. I do have two posts on pharmaceuticalintelligence.com on this matter, curating various programs around the world which are using microarray expression analysis of tumors to determine personalized strategies. I believe the reliance on mutational analysis is based on the drugs that have been developed (such as Gleevec and crizotinib) which are based on mutant forms of BCR-Abl and ALK, respectively. However (as per two posts I did based on Mike Martin on our site “Mathematical Models of Driver and Passenger mutations) where he discusses how certain driver mutations will get the senescent cell over the hump to get to fully transformed and contribute to a certain level of growth while subsequent passengers are responsible for the sustained survival and expansion of the tumor.

Victor Levenson • Dr. Williams, thanks for the comments. Driving a senescent cell into proliferative stage is a tremendous change, which >may< begin with a mutation, but involves dramatic restructuring of transcription patterns that will drive the process. Hypoxia will definitely contribute to variations in the patterns, although will probably not be the main driver of the process. As to whether a mutation or a change in transcription pattern initiate the process, I am not sure we will ever be able to determine <grin>.

Vanisree Staniforth • Thanks for posting! Certainly a thought provoking article with regard to the future of personalized cancer therapies.

 

Dr. Raj Batra • If we follow Dr Levenson’s proposed conceptual approach (which we also published in 2009 and 2010), we are MUCH more likely to significantly impact tumor morbidity and mortality.

Stephen J. Williams, Ph.D. • Thanks Vanisiree and Dr. Batra for your comments. Hopefully we will see, from the future cancer statistics, how personlized therapy have improved outcomes for the solid tumors, like the hematologic cancers. 26 days ago

Emanuel Petricoin • The issue about intra and inter tumor heterogeneity is very important however since it is unknown which mutations are true drivers, an explanation of the results found in these studies simply could be the variances are all in the inconsequential mutations and the commonality is the driver mutations. Moreover, at the end of the day, its not the mRNA expression that we really care about but the functional protein signaling -phosphoprotein driven signaling architecture, that we care about since these are the drug targets directly.

Mohammad Azhar Aziz,PhD • This article addresses the potential complexity of dealing with cancer which is apparently increasing proportionally with the amount of data generated. Intratumor heterogeneity will remain there and even multiple biopsies that are randomly chosen will offer no conclusive solution.Mutations,expression profiles and functional protein signaling (as discussed above) alone can not provide any breakthrough. It will be a composite picture of all these and many other components (e.g. microenvironment, alternative splicing, epigenetics,non-coding RNAs etc.) that will hold the promises in the future. We have made phenomenal advances in understanding each of these aspects separately but definitely lack the tools to integrate all these. Developing tools to integrate all these data may provide some breakthrough in understanding and thus treating cancer.

Emanuel Petricoin • I agree Mohammad in a systems biology approach however the current compendium of drugs largely are kinase inhibitors or enzymatic inhibitors. Since most studies have shown little correlation between gene mutation and protein levels and phosphoprotein levels, for example, it is no wonder why the recent spate of failed trials (e.g. stratification by PIK3CA mutation or PTEN mutation for AKT-mTOR inhibitors) should come as any shock. We will be publishing work using protein pathway activation mapping coupled to laser dissection of a number of intra and inter tumoral analysis that indicates that the signaling architecture appears much more stable.

Stephen J. Williams, Ph.D. • Thank you Dr. Pettricoin for your comments. I eagerly await the publication of your results concerning proteomic evaluation of multiple biopsies of a tumor. I am very interested that you found limited intratuoral heterogeneity of signaling pathways given the diversity of intratumoral microenvironmental stresses (changes in regional hypoxia, blood flow, and populations of cancer stem cells). I agree with you and Mohammed that proteomic profiling will be imperative in determining personalized approaches for targeted therapy. Dr. Swanton had informed me that they had used IHC to determine if mTOR signaling had correlated with the mutational spectrum they had seen. In addition he had mentioned that there was enhanced genomic instability in the metastatic disease relative to the primary tumor and it would be very interesting to see how signaling pathways change in cohorts of matched metastatic and primary tumors. A few years ago we were looking at genes which were completely lost upon transformation of ovarian epithelial cells and worked up one of those genes (CRBP1) in cohorts of human ovarian cancer samples, using expression analysis in conjunction with laser capture microdissection and backed up by IHC analysis, and found that the expression pattern of CRBP1 was uniform in a tumor, either there was a complete loss in all cells in a tumor of CRBP1 or all the cells expressed the protein. Therefore I am curious if intratumor heterogeneity is dependent on the cell lineage and evolution of the transformed cell into a full tumor or a function of a discrete population of stem cells with varied genomic instability. Your results might suggest a more clonal evolution rather than a branched evolution which was found in this paper.
It is interesting that you mention the tough trials with the PTEN/PI3K/AKT axis of inhibitors. In high grade serous ovarian cancer we were never able to find any PI3K, PTEN, nor AKT mutations yet PI3K activity is usually overactive. If feel both your and Mohammed’s assessment that a systems biology approach instead of just relying on DNA mutational analysis will be more important in the future. In addition, there is nice work from Dr. Jefferey Peterson at Fox Chase and the development of a database of kinase inhibitors and activity effects on the kinome, showing the vast amount of crosstalk between once thought linear enzyme systems. If TKI’s will be the brunt of pharma’s development I feel they need to quickly develop as many TKI’s as they can now before we get to a clinical problem (resistance and lack of available therapeutics).

Emanuel Petricoin • Thanks Steven- yes, we are working with Charlie Swanton and Marco on the renal sets- our other studies are from breast and colon cancers. I think one of the things we do that really no one else is doing, unfortunately, is to laser capture microdissect the tumor cells from these specimens so that we have a more pure and accurate view of the signaling architecture. One confounder from the proteomic stand-point is the fact that pre-analytical variables such as post-excision delay times where the tissue is a hypoxic wound and signaling changes fluctuating as the tissue reacts to the ex-vivo condition can really effect things. When we look at tissue sets where the tissue is biopsied and immediately frozen we really dont see big differences in the signaling – the within tumor architecture is much more similar then between. We use the reverse phase array technology we invented to provide quantitative analysis on hundreds of phosphoproteins at once – so a nice view of the functional protein activation network. Your results of CRBP1 in ovarian tumors and the IHC data are very interesting. We will see how this all plays out. Of course once other confounder with the mutational data is that we really dont know what are the drivers and what are the passengers…
Yes I know Jeff Peterson’s work- its fantastic. In the end the hope I think- and in my personal opinion- will be rationally combined therapeutics based on the signaling architecture of each individual patient.

Incidentally, we just published a paper that you may be interested in from a “systems biology” standpoint-

SYSTEMS ANALYSIS OF THE NCI-60 CANCER CELL LINES BY ALIGNMENT OF PROTEIN PATHWAY ACTIVATION MODULES WITH “-OMIC” DATA FIELDS AND THERAPEUTIC RESPONSE SIGNATURES.

Federici G, Gao X, Slawek J, Arodz T, Shitaye A, Wulfkuhle JD, De Maria R, Liotta LA, Petricoin EF 3rd. Mol Cancer Res. 2013 May

also- we published a paper that speaks directly to your point where we compared the signaling network activation of patient-matched primary colorectal cancers and synchronous liver mets. indeed there is huge systemic differences in the liver metastasis compared to the primary. there is no doubt in my mind that we will need to biopsy the metastasis to know how to treat. Looking at the primary tumor as a guide for therapy is a fools errand. here is the paper reference:

Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations.

Silvestri A, Calvert V, Belluco C, Lipsky M, De Maria R, Deng J, Colombatti A, De Marchi F, Nitti D, Mammano E, Liotta L, Petricoin E, Pierobon M.

Clin Exp Metastasis. 2013 Mar;30(3):309-16. doi: 10.1007/s10585-012-9538-5. Epub 2012 Sep 29.

Center for Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd., Manassas, VA, 20110, USA.

Abstract

The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC.

Adrian Anghel • I think both patterns (protein phosphorylation and mRNA) should be important in this complicated equation of heterogeneity. Let’s not forget the so-called functional miRNA-mRNA regulatory modules (FMRMs). Also I think we have different patterns of this heterogeneity for different evolutive stages of the tumour.

 

Alvin L. Beers, Jr., M.D. • This is a great study, but bad news for attempting to tailor treatment based on molecular markers. Dr. Swanton’s comment: “herterogeneity is likely to complicate matters” is an understatement. Intratumoral heterogeneity, branched, instead of linear, evolution of mutational events portends a nightmare in trying to predict location and volume of biopsies. I am reminded of a series of articles in Nature 491 (22 November 2012) “Physical Scientists take on Cancer”. There is a great comment by Jennie Dusheck: “Cancer researchers now recognize that taming wild cancer cells – populations of cells that evolve, cooperate, and roam freely through the body-demand a wider-angle view than molecular biology has been able to offer. Cross-disciplinary collaborations can approach cancer a greater spatial and temporal scales, using mathematical methods more typical of engineering, physics, ecology and evolutionary biology. The sense of failure so evident five years ago is giving way to the excitement of a productive intellectual partnership.” I’m not certain how well the “productive partnership” is going, but this Swanton study confirms the limitations of molecular biology.

Stephen J. Williams, Ph.D. • Thanks Dr. Beers for adding in your comment and adding in Jennie’s comment. Certainly it is something to be aware of if a cancer center’s strategy is to rely solely on gene arrays to genotype tumors. I think Dr. Pettricoin’s work on using proteomics might give some resolution to the matter however, in communicating with Dr. Swanton, I did not get the feeling of an “all hope is lost” but just that, in the case of solid tumors like renal, that careful monitoring of tumors after treatment may be warranted and, more interestingly, from a scientific standpoint, is the genetic complexity surrounding the origin of the disease, and not simple mutational spectrum of a single clone.

Burke Lillian • This is clinically a very important issue. Right now, sequencing or massive approaches such as pan-phosphorylation studies are helpful because, although we know many of the drivers, these studies are actually identifying new genes or new pathways that are activated. After a few (or several years), we truly will know which genes are typically activated and there will be panels to look for these.

Emanuel Petricoin • yes, I agree. In fact, the company that I co-founded, Theranostics Health, Inc– is launching a CLIA based protein pathway activation mapping test at ASCO that measures actionable drug targets (e.g. phospho HER2, EGFR, HER3, AKT, ERK, JAK, STAT, p70S6) and total HER2, EGFR, HER3 and PTEN. So these tests are coming even now.

 

Alvin L. Beers, Jr., M.D. • I do not think that “all hope is lost” nor did I have the impression that Dr. Swanton feels that way with regards to molecular profiling of cancer. I certainly applaud further research into the molecular aspects of cancer biology. But I do not believe that this will be sufficient. Integrating physicial sciences into cancer biology makes perfect sense toward better understanding of this complex disease.

Eleni Papadopoulos-Bergquist • I have enjoyed reading these comments and different ideas regarding genetic testing and profiling. As a nurse and researcher at heart, this is information that will make a huge impact on drug protocols, therefore allowing the best and most specific treatment to each individual rather than having a standard treatment protocol. Even with the scientific complexity of specifying genotypes of particular cancers, there is still the question of each individuals body responding to treatment. I’d love to have some dialogue regarding immune response.

Bradford Graves • I too have enjoyed reading this discussion. I am not a clinician but as a drug discovery researcher I have been struck by some parallels to the concept of virus fitness in virology – particularly as applied to HIV. Drug discovery cannot wait for the final answers to the many important questions being addressed in the discussion initiated by Dr. Williams. The best we can do is to pursue a broad range of therapeutics that will give the clinicians the armament they will need to either cure a given cancer or to at least turn it into a chronic as opposed to an acute disease. There has been a measure of success in the HIV field and it seems like it will be achievable for cancer. Obviously, to the extent that the labels of driver and passenger mutations can be correctly applied will help to prioritize the targets we address.

David W. Anderson • I would suggest that you look at the following publications:

Horn and Pao, (2009) JCO 26: 4232-4234.

Bunn and Doebele (2011) JCO:29:1-3

Boguski et al. (2009) Customized care 2020: how medical sequencing and network biology will enable personalized medicine. F1000 Bio Report 1:7.

Jones, S et al. (2010). Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biology. 11:R82. Marco Marra’s group in Toronto.

Also look at how companies and organizations like Foundation Medicine, Caris, Clarient, and CollabRx who are using genomics and sequencing on a large scale to address cancer from a personalized/individual approach.

Cancer is/will be a chronic disease requiring individualized/combinatorial therapies in many cases.

Alvin L. Beers, Jr., M.D. • David. These are excellent articles by Paul Bunn and Mark Boguski regarding integrating molecular markers into diagnostic evaluation, and I’ve seen other papers of similiar elk, and likely there will be more to come. Particularly in NSC lung cancer, the SOC is to use these markers up front. Diagnosis based on histology alone can no longer be recommended. The challenge for the future is how to integrate other aspects of cell biology with these markers. It remains daunting that not only do we see heterogeneity in molecular within tumors at a particularly point in time, but that there is often an evolution of markers over time, ie, a “plasticity” of markers, whether treatment is given or not. We know that targeted agents, TKI’s, enzyme inhibitors are not curative, but do give an improvement in PFS. A great deal of this resistance has to do with this “moving target” aspect of cancer cell biology..

 

References:

1.         Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine 2012, 366(10):883-892.

2.         Caldas C: Cancer sequencing unravels clonal evolution. Nature biotechnology 2012, 30(5):408-410.

3.         Losi L, Baisse B, Bouzourene H, Benhattar J: Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 2005, 26(5):916-922.

4.         Krivtsov AV, Armstrong SA: Cancer. Can one cell influence cancer heterogeneity? Science 2012, 338(6110):1035-1036.

5.         Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM: Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 2012, 338(6110):1080-1084.

6.         Mintz B, Cronmiller C: Normal blood cells of anemic genotype in teratocarcinoma-derived mosaic mice. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(12):6247-6251.

7.         Watanabe T, Dewey MJ, Mintz B: Teratocarcinoma cells as vehicles for introducing specific mutant mitochondrial genes into mice. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(10):5113-5117.

8.         Mintz B, Cronmiller C, Custer RP: Somatic cell origin of teratocarcinomas. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(6):2834-2838.

 

 

Other articles on this site on “PERSONALIZED MEDICINE” and “CANCER” and “OMICS” include:

Personalized medicine-based diagnostic test for NSCLC

Personalized medicine and Colon cancer

Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center

Systems Diagnostics – Real Personalized Medicine: David de Graaf, PhD, CEO, Selventa Inc.

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Personalized Medicine: Clinical Aspiration of Microarrays

Understanding the Role of Personalized Medicine

Directions for Genomics in Personalized Medicine

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Proteomics and Biomarker Discovery

 

 Also please see our upcoming e-book “Genomics Orientations for Individualized Medicine” in our Medical E-book Series at http://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-one-genomics-orientations-for-personalized-medicine/

 

 

 

 

 

 

 

 

 

 

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5th Annual Consumer Genetics Conference (CGC), September 25-27, 2013 Seaport Hotel, Boston, MA

Posted in Genome Biology, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , on June 27, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

The Consumer Genetics Conference (CGC) is a one-of-a-kind event that draws together a dynamic community of scientists, clinicians, technology innovators, and patients to discuss the burning issues around the analysis and delivery of genomics results directly to patients and consumers. Over three days, attendees will hear about disruptive diagnostic technologies, cognitive barriers to patients (and medical professionals), ethical/regulatory/privacy issues, the thorny issue of reimbursement, and the challenges of building relationships to realize the potential of personal genomics and individualized medicine. CGC provides an opportunity for all stakeholders to come together at one venue, share viewpoints and engage in an honest dialogue, and together learn how to move the elephant of change. Program topics will include:
  • Whole Genome Debates
  • Translational Genomics
  • Clinical & Third-Generation Sequencing
  • Personal Genome Analysis & Interpretation
  • Empowering Patients: Companies & Technologies
  • Molecular Diagnostics & Point-of-Care
  • Investment & Funding Opportunities
  • Reimbursement Models
  • Five-Year Plan for Consumer Genomics
  • Data Analysis & Management
  • Ethics, Privacy & Regulation
  • Digital Health Tracking Apps

SPEAKERS

2013 Distinguished Faculty

Bonnie Ancone, Vice President, Molecular Diagnostics, XIFIN, Inc.
Bonnie Ancone has 25 years experience in the medical industry of which 15 years have been directly related to medical billing and collections. Prior to coming to XIFIN, Ms. Ancone worked in Anatomic Pathology Reference laboratory settings for 10 years. She held multiple positions including Billing Supervisor, Billing Manager and Director of Billing & Collections. She was also a partner in a medical billing company. Ms. Ancone’s prior experience includes 10 years in outpatient substance abuse clinics as a nurse and Assistant Director. In this capacity, she interacted with regulatory bodies such as DEA, FDA and multiple state behavioral health agencies dealing with licensing, auditing and regulations. She participated in the development of state methadone regulations and the state methadone coalition for Arizona and Nevada. She started her career on the operations side of banking.

Nazneen Aziz, Ph.D., Director, Molecular Medicine, Transformation Program Office, College of American Pathologists
Nazneen Aziz is the Director of Molecular Medicine at the College of American Pathologists. In this role, Dr. Aziz is guiding strategies and leading projects related to genomic medicine at CAP. Currently, she leads a committee that focuses on critical issues surrounding next generation sequencing. She is a member of the Association for Molecular Pathology Workgroup for Whole Genome Analysis and the Center for Disease Control Nex-StoCT-II Workgroup on next generation sequencing bioinformatics and the Interpretation of Sequence Variant Work Group at the College of American College of Medical Genetics. In her prior positions, Dr. Aziz was Vice President of Research and Development at Interleukin Genetics, Vice President of External Research at Point Therapeutics and Director of Translational Research at Novartis Institute of Biomedical Research. In her industry career, she has focused on personalized medicine, biomarkers, genetic tests, and development of drugs in cancer and diabetes. Prior to joining the biotechnology industry Dr. Aziz was an Assistant Professor at Harvard Medical School and Children’s Hospital in Boston where she discovered and characterized the function of novel genes involved in recessive polycystic kidney disease. Nazneen received her Ph.D. in molecular genetics and Masters Degree in biochemistry at the Massachusetts Institute of Technology and her Bachelor’s Degree from Wellesley College.

Pam Baker, Senior Director, Market Access, CardioDx
Ms. Pam Baker is Senior Director of Market Access & Policy with Cardio Dx. She is a life sciences professional with 17 years of experience in pharma, biotech and diagnostics in a series of commercial roles across marketing, new product commercialization, reimbursement, pipeline and sales management. She started her healthcare career 17 years ago, beginning with Johnson & Johnson (Janssen, Ortho and Mc Neil), followed by Genentech. Ms Baker started out in sales, then moved into sales training, sales leadership and to multiple marketing roles, from product launch, to in-line marketing. She then moved into the reimbursement arena, leading the Program Strategy & Management team for Genentech Access Solutions, and has recently joined a molecular diagnostics company in Palo Alto, CA called CardioDx. Ms Baker received a Bachelor of Arts, Political Science and Asian Studies from Northwestern University and a Master, International Management from Thunderbird School of Global Management. She is a mom of 5 year old twin girls.

Shawn C. Baker, Ph.D., CSO, BlueSEQ
Dr. Shawn C. Baker is the Chief Science Officer and co-founder of BlueSEQ, an independent guide for researchers outsourcing their DNA sequencing. Having received his Ph.D. at the University of California – Davis, he started his career as a Research Scientist at Illumina when it was a 15-person startup. After spending several years at the bench developing gene expression array products, he transitioned to Product Marketing where he led a team in charge of Illumina’s Expression and Regulation sequencing portfolio. Dr. Baker started working with BlueSEQ in 2011, helping to establish an online marketplace for life science researchers to gain access to the best sequencing technology for their projects. In addition, BlueSEQ has created the Knowledge Bank, a neutral source of information on the various sequencing technologies, platforms and applications.

Cinnamon S. Bloss, Ph.D., Director, Social Sciences & Bioethics, Assistant Professor, Scripps Translational Science Institute

Dr. Bloss is an Assistant Professor, as well as Director of Social Sciences and Bioethics at the Scripps Translational Science Institute. Her research is funded by the National Institutes of Health and is focused on investigating individuals’ behavioral and psychological responses to disclosure of personal genomic information. She is the lead researcher on STSI’s Scripps Genomic Health Initiative, and her work on this project was recently published in the New England Journal of Medicine and has been highlighted at a number of national and international scientific meetings. She has also presented invited testimony on consumer genomics before the Food and Drug Administration Advisory Panel. Dr. Bloss’ other research interests include developing ways of combining genomics with traditional disease risk factors to make predictions about disease development, progression and response to treatment, as well as designing effective health interventions that leverage genomic information. She also conducts genetic association studies and has several collaborations to investigate the genetic underpinnings of neurological, behavioral, and other health-related phenotypes. Dr. Bloss received her B.A. in Psychology from Smith College, her Ph.D. in Clinical Psychology from the University of California, San Diego, and completed a predoctoral internship in clinical neuropsychology at the University of Florida. Dr. Bloss completed a post-doctoral fellowship in statistical genetics and genomic medicine at The Scripps Research Institute. At STSI, Dr. Bloss directs the Summer Undergraduate Research Internship and is an instructor in the TSRI Graduate Program. She is also a California-licensed clinical psychologist and has worked with adults and children with a wide range of neurological and psychiatric conditions.
John Boyce, President and CEO, GnuBIO
John Boyce is President, CEO and Co-Founder of GnuBIO. Prior to starting GnuBIO, John co-founded Delphi Bio, LLC, a strategic consulting company that serves startup and fortune 500 companies within the life sciences market. Using his proven ability to drive companies to commercial success, John served as the Business Development head for a number of clients, including Affomix. Over a two year period, John developed the business plan for Affomix, oversaw all commercial activities, as well as initiated and drove the sale of the company to a multi-billion dollar sequencing corporation in July 2010. Prior to Delphi and Affomix, John served as Head of Business Development for Helicos BioSciences (HLCS), where he was responsible for identifying new market opportunities. Prior to Helicos, John was the Senior Director of Commercial Development for Parallele Biosciences, Inc. where he played an integral role of building the company leading to an acquisition of the company by Affymetrix (AFFY). He was the Senior Director of Business Development for Genomics Collaborative where he was responsible for putting in place and building the Sales, Marketing, and Business Development infrastructure. John executed several key deals and played a key role in the acquisition by SeraCare Life Sciences, Inc. Prior to Genomics Collaborative, John led the successful expansion of Sequenom’s MassARRAY system as Director, United States Sales at Sequenom Inc. (SQNM), from 2000 to 2003.

Catherine Brownstein, Ph.D., Project Manager, The Gene Partnership, Boston Children’s Hospital; Instructor, Pediatrics, Harvard Medical School
Catherine Brownstein, PhD, MPH is the Project Manager for The Gene Partnership at Boston Children’s Hospital and an Instructor in Pediatrics at Harvard Medical School. For the last two years, Catherine has worked to establish and develop new sequencing and pharmacogenomics programs at the hospital. Before coming to BCH and HMS, Catherine was a toxicologist at the Massachusetts Department of Public Health, and spent four years in the world of Health 2.0, creating online patient communities for individuals with chronic and terminal diseases. Catherine’s interests and expertise lie with the intersection of genotype and phenotype, and the integration of patient-reported outcomes with genomics and medicine.

Kenneth Chahine, Ph.D., J.D., Senior Vice President and General Manager, DNA, ancestry.com
Ken Chahine has served as Senior Vice President and General Manager for Ancestry DNA, LLC since 2011. Prior to joining us he held several positions, including as Chief Executive Officer of Avigen, a biotechnology company, in the Department of Human Genetics at the University of Utah, and at Parke-Davis Pharmaceuticals (currently Pfizer). Mr. Chahine also teaches a course focused on new venture development, intellectual property, and licensing at the University of Utah’s College of Law. He earned a Ph.D. in Biochemistry from the University of Michigan, a J.D. from the University of Utah College of Law, and a B.A. in Chemistry from Florida State University.

Mick Correll, COO, Genospace
Mick Correll is the Co-Founder and Chief Operating Officer of GenoSpace, a Cambridge, Massachusetts-based company that is pioneering a bold and innovative software platform for advancing 21st-century genomic medicine. Prior to launching GenoSpace, Mick was the Associate Director of the Center for Cancer Computational Biology (CCCB) at the Dana-Farber Cancer Institute, overseeing the Center’s next-generation sequencing facility, bioinformatics consulting service and software development efforts.Mick started his career as a Bioinformatician at Lion Bioscience Research Inc, where he was the principle architect of a globally distributed gene annotation and analysis platform, and subsequently served asHead of Professional Services for Lion Bioscience Inc in North America, and Director of Healthcare Product Management at InforSense LLC.

Steven Dickman, President & Owner, CBT Advisors
Steven Dickman is President & Owner of CBT Advisors, a boutique life sciences consulting firm in Cambridge, Massachusetts. CBT Advisors works with over 20 clients a year on product positioning and corporate strategy; communications and fund-raising materials; and market analysis based on research and expert interviews. Clients include public and private biotech companies and life science venture funds. Before founding CBT Advisors in 2003, Mr. Dickman spent four years in venture capital with TVM Capital. There, Mr. Dickman’s deals included Sirna Therapeutics, sold to Merck in 2006 for $1.1 billion. Earlier, he was a Knight Science Journalism Fellow at MIT, a freelance contributor to The Economist, Discover, Science, GEO and Die Zeit and the founding bureau chief for Nature in Munich, Germany. Fluent in German, Mr. Dickman received his biochemistry degree cum laude from Princeton University.
Lynn Doucette-Stamm, Ph.D., Vice President, Development and Clinical Operations, Interleukin Genetics, Inc.
Lynn Doucette-Stamm has served as Vice President of Development and Clinical Operations at Interleukin Genetics since 2011. Prior to joining Interleukin she has worked in numerous capacities in Life Sciences for greater than 25 years. Key positions she has held prior to Interleukin include Vice President of Business Development at Beckman Coulter Genomics and Agencourt Bioscience, and Vice President and General Manager of the GenomeVisionTM Services Business Unit at Genome Therapeutics. She earned a Ph.D. in Cell Biology and Genetics from Cornell University Graduate School of Medical Sciences and a B.S. in Biology from McMaster University.
Yaniv Erlich, Ph.D., Principal Investigator and Whitehead Fellow, Whitehead Institute for Biomedical Research 
Dr. Yaniv Erlich is Andria and Paul Heafy Family Fellow and Principal Investigator at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology. He received a bachelor’s degree from Tel-Aviv University at Israel and his PhD from the Watson School of Biological Sciences at Cold Spring Harbor Laboratory. Dr. Erlich’s research interests are computational human genetics. He has extensive experience in developing new algorithms for high throughputs sequencing and to detect disease genes. In two of his studies, he identified the genetic basis of devastating genetic disorders. His lab works on a wide range of topics including developing compressed sensing approach to identify rare genetic variations, devising new algorithms for personal genomics, and using Web 2.0 information for genetic studies. Dr. Erlich is the recipient of the Harold M. Weintraub award, the IEEE/ACM-CS HPC award, Goldberg-Lindsay Fellowship, Wolf foundation scholarship for Excellence in exact science, and Emmanuel Ax scholarship, and he was selected as one of 2010 Tomorrow’s PIs team of Genome Technology.

Kyle Fetter, Associate Vice President, Molecular Diagnostics, XIFIN, Inc.
Kyle Fetter has overseen the commercialization, billing, and reimbursement processes for more than 10 molecular diagnostic companies releasing new high complexity laboratory testing services into the healthcare market. He currently manages billing processes for more than 10 companies at various stages of commercialization and third party payer contracting. In addition to overseeing a large molecular diagnostic billing department, Mr. Fetter consults with molecular diagnostic companies on projecting cash flow for non-covered services, implementing successful appeals strategies, and the relationship between sales and reimbursement for new medical technology. He came to the healthcare industry with a background in private equity and technology commercialization. Mr. Fetter has a B.A. in History and Journalism from the University of Southern California and an M.B.A from the University of Utah.
Birgit Funke, Ph.D., FACMG, Assistant Molecular Pathologist and Director of Clinical Research and Development, Laboratory for Molecular Medicine, Massachusetts General Hospital; Assistant Professor in Pathology, Harvard Medical School
Birgit Funke, Ph.D., FACMG is an Associate Laboratory Director of the Laboratory for Molecular Medicine (LMM) at PCPGM and is an Instructor in Pathology at Harvard Medical School. She currently oversees genetic testing and test development in the area of cardiovascular disease at the LMM. She has authored and co-authored many publications focusing on a wide array of topics, most recently incentive learning and memory in mice. Currently, Dr. Funke focuses on genetic testing with emphasis on genetically heterogeneous cardiovascular diseases, with the goal of defining the genetic basis for these disorders and developing comprehensive tests using new emerging molecular technologies. In addition, she is interested in developing genetic tests for common, complex disorders, working to understand the genetic variants that have been linked with psychotic and affective disorders.

Amanda Gammon, MS, CGC, Licensed Genetic Counselor, Huntsman Cancer Institute, University of Utah 
Amanda Gammon is a board-certified genetic counselor with a master’s degree in genetic counseling from University of Colorado at Denver Health Sciences Center. She received her bachelor’s degree from the University of Colorado at Boulder in molecular, cellular, and developmental biology and English literature. While completing her education, Amanda worked at Rocky Mountain Cancer Centers. She began working at Huntsman Cancer Institute in July 2007. She provides genetic counseling to patients in the Family Cancer Assessment Clinic and the research-oriented High Risk Breast Cancer Clinic. She also provides counseling for two National Institutes of Health-funded studies. For one study, she discusses familial colorectal cancer risk with individuals by telephone in rural Utah and Idaho to assess effectiveness of telephone intervention versus written risk information in encouraging individuals to pursue colonoscopy. In the other, she provides hereditary breast and ovarian cancer counseling to women in rural Utah both by phone and in-person to assess equivalency. Her main research interests include hereditary breast cancer and provision of genetic counseling through alternative modes for individuals with limited access to genetic counseling centers.

Manuel L. Gonzalez-Garay, Ph.D., Assistant Professor, The University of Texas Health Science Center at Houston
Dr. Gonzalez-Garay obtained his B.S. from the University of Nuevo Leon, Mexico in 1988. He wrote a bachelor’s research dissertation “Papillomavirus and cervical cancer in Mexican population” under the supervision of Dr. Barrera-Saldana and Dr. Gariglio. After a pre-doctoral fellowship at University of Texas, he joined the doctoral program in 1990. In 1996, Dr. Gonzalez-Garay completed his Ph.D. at the University of Texas, writing a dissertation about the regulation of the stoichiometry of tubulin. After a two-year Post-Doctoral Fellowship in the lab of Dr. Fernando Cabral, he joined Lexicon Genetics as a Bioinformatician. He was subsequently promoted to manager of Bioinformatics Group. During his stay at Lexicon Genetics, Dr. Gonzalez-Garay developed a large number of proprietary software and databases to support the gene knockout and drug discovery pipelines. During 2002, Dr. Gonzalez-Garay moved to Baylor College of Medicine, Human Genome Sequencing Center (HGSC) where he working as a Senior Scientific Programmer and team leader. During his stay at the HGSC he developed “Genboree discovery system” and participated as a bioinformatician in a large number of sequencing projects including the sequencing of the Human chromosome 3 and 12, the complete genomes of Rat and Sea Urchin. Dr. Gonzalez-Garay was instrumental in the development of pipelines for the re-sequencing of candidate genes at HGSC. From 2007 to 2009 he actively participated in the Tumor Sequencing Project (TSP) and the cancer genome atlas (TCGA) project. In January, 2010, The IMM recruited Dr. Gonzalez-Garay as Research Assistant Professor for The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases. Dr. Gonzalez-Garay is currently developing the pipelines to analyze whole genome and exome sequences and he is currently participating in three main projects: The identification of the causal mutations for tuberous sclerosis, cardiomyopathy and schizophrenia.

Robert Green, M.D., M.P.H., Associate Professor of Medicine, Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School 
Robert C. Green, MD, MPH is a medical geneticist and a clinical researcher who directs the G2P research program (genomes2people.org) in translational genomics and health outcomes in the Division of Genetics at Brigham and Women’s Hospital and Harvard Medical School. Dr. Green is principal investigator of the NIH-funded REVEAL Study, in which a cross-disciplinary team has conducted 4 separate multi-center randomized clinical trials collectively enrolling 1100 individuals to disclose a genetic risk factor for Alzheimer’s disease in order to explore emerging themes in translational genomics. Dr. Green also co-directs the NIH-funded PGen Study, the first prospective study of direct-to-consumer genetic testing services and leads the MedSeq Project, the first NIH-funded research study to explore the use of whole genome sequencing in preventive medicine. Dr. Green is currently Associate Director for Research of the Partners Center for Personalized Genetic Medicine, a Board Member of the Council for Responsible Genetics and a member of the Informed Cohort Oversight Boards for both the Children’s Hospital Boston Gene Partnership Program and the Coriell Personalized Medicine Collaborative. He co-chairs the ACMG working group that is currently developing recommendations for management of incidental findings in clinical sequencing.

Steve Gullans, Managing Director, Excel Venture Management
Dr. Gullans is an experienced investor, entrepreneur and scientist. At Excel, he focuses on life science technology companies with a particular interest in disruptive platforms that can impact multiple industries. Steve is currently a Director at Tetraphase Pharmaceuticals, PathoGenetix, nanoMR, Cleveland HeartLab, and Catch.com. He was previously a board member of Activate Networks as well as BioTrove which was acquired by Life Technologies (LIFE) in 2009 and Biocius Life Sciences which was acquired by Agilent Technologies (A) in 2011. Prior to Excel, Steve co-founded RxGen, Inc., a pharma services company where he served as CEO from 2004-2008. In 2002, Steve stepped in as a senior executive at U.S. Genomics to direct operations, recruit a new CEO, and assist with fundraising. In the 1990s, he co-developed the technology that launched CellAct Pharma GmbH, a drug development company. Steve’s experience with venture investing began in the late 1980s when he became an active advisor to small biotechs and venture investors, including being a Senior Advisor to CB Health Ventures for 10 years. Dr. Gullans is an expert in advanced life science technologies and was a faculty member at Harvard Medical School and Brigham and Women’s Hospital for nearly 20 years. He has published more than 130 scientific papersin many leading journals, lectured internationally, and co-invented numerous patents. He recently co-authored with Juan Enriquez an eBook entitled, Homo evolutis: A Short Tour of Our New Species, and a comment in Nature entitled, “Genetically Enhanced Olympics Are Coming,” which describe a world where humans increasingly shape their environment, themselves, and other species. Steve received his B.S. at Union College, Ph.D. at Duke University, and postdoctoral training at the Yale School of Medicine. He is a Fellow of the AAAS and the AHA.

Tina Hambuch, Senior Scientist, Illumina, Inc.
Tina Hambuch earned her Bachelor’s degree from UC Riverside and her doctorate from UC Berkeley, focusing on genetic analyses of genes that control the immune system. She continued her studies of genetic variation as a post-doctoral fellow at the Centers for Disease Control and an assistant professor at the Ludwig Maximillians University in Munich. After her academic career, Tina used her understanding of genetics and genetic variation to help identify and design diagnostic sequencing tests for clinical application at Ambry Genetics. Tina joined Illumina in 2008 where she combined her experience in genetics, genomics, and clinical diagnostics to contribute to the development of the CLIA-certified, CAP-accredited Illumina Clinical Services Laboratory (ICSL). In 2010, she launched a California-certified Clinical Genetic Molecular Biologist Scientist training program in which she serves as the Education Coordinator and Director. Tina is currently active in the development and validation of genetic testing, as well as clinical tools for doctor support and education. Tina is a member of the American College of Medical Genetics and the American Society of Human Genetics.

Michael Hawley, Chief Design Officer, Mad*Pow

As leader of the Mad*Pow Experience Design team, Michael leverages expertise in usability and user experience to help clients achieve their goals through design. Michael holds his MS in Human Factors in Information Design from Bentley College McCallum Graduate School of Business, and BA in Cellular and Molecular Biology from the University of Michigan. He is an active member of the professional design community, serving as an officer in the User Experience Professional’s Association and contributing ideas as a speaker and author, exploring trends within the UX discipline as a published columnist in publications such as UXMatters, iMedia, TMCNet and CPWire.
Caleb J Kennedy, Ph.D., Lead Scientist, Good Start Genetics, Inc.
Caleb currently leads an amazing group of scientist-engineers developing high-performance analytical tools for next-generation advances in genetic testing and research. He holds a Ph.D. in genetics from Harvard University, as well as M.S. and B.S. degrees in molecular and cellular biology from Texas A&M University. Caleb has two beautiful boys, one with Down syndrome.
Ayub Khattak, CEO, ruubix
Ayub Khattak, CEO or ruubix inc., uses his background in biochemistry, programming and electronics in the development of the ruubix digital diagnostic platform. He has his degree in Mathematics from UCLA and developed a NSF funded project in the genetic engineering of RNAi systems before founding ruubix.

Wendy Kohlmann, MS, CGC, Licensed Genetic Counselor, Huntsman Cancer Institute, University of Utah 
Wendy Kohlmann is a board-certified genetic counselor with a master’s degree in genetic counseling from the University of Cincinnati and a bachelor’s degree in zoology from the University of Wisconsin. She has worked as a genetic counselor at the University of Texas-M.D. Anderson Cancer Center in Houston and the University of Michigan Comprehensive Cancer Center in Ann Arbor. She began working at Huntsman Cancer Institute as a research associate in 2006. Wendy Kohlmann’s research interests include the inherited basis of melanoma and pancreatic cancer, psychosocial and behavioral outcomes of genetic counseling, and issues for children and adolescents with hereditary cancer syndromes.

Antoinette F. Konski, J.D., Partner, Foley & Lardner LLP
Antoinette F. Konski is a partner with Foley & Lardner LLP where her practice focuses on intellectual property. She works with life science clients, creating and optimizing value in intellectual property portfolios encompassing technologies that include personalized medicine, regenerative and stem cell biology, antibodies, immunology, gene therapy, nanotechnology, diagnostics, small molecules and drug delivery. She represents public and private companies and universities. Ms. Konski currently serves as the firm’s Silicon Valley IP office chairperson and co-chair of the Life Sciences Industry Team.

Gary J. Kurtzman, MD, Managing Director, Healthcare, Safeguard
Gary has 25+ years of experience in operations and investments, leveraging his medical expertise to enable businesses to enhance their products and grow their services, as well as to discover new partnering potential in developing entrepreneurial companies. Gary joined Safeguard in 2006, where he is responsible for identifying, deploying capital in and supporting emerging healthcare companies in molecular and point-of-care diagnostics, medical devices and healthcare IT. He targets companies with solutions that address the high cost of medical care, and safer and more effective treatments. Gary is a board member of Safeguard partner companies Alverix, Crescendo Bioscience, Good Start Genetics, Medivo, and PixelOptics. Gary has realized value for companies through a series of successful IPOs, M&A and turnaround transactions—most recently Shire’s acquisition of Safeguard’s partner company Advanced BioHealing for $750 million, in cash, representing a 13x cash-on-cash return for Safeguard; and Eli Lilly’s acquisition of Safeguard’s partner company Avid Radiopharmaceuticals for $300 million, up front, with an additional $500 million payout dependent upon the achievement of future regulatory and commercial milestones, representing an initial 3x cash-on-cash return for Safeguard with the potential to realize up to 8x. Gary joined Safeguard from BioAdvance, a state initiative committed to funding early-stage life sciences companies, where he served as Managing Director and Chief Operating Officer. Previously, he was Chief Executive Officer at Pluvita Corporation, a company developing biological and bioinformatic solutions for drug and diagnostic development. Gary also previously served as Chief Operating Officer at Genovo, Inc., a gene therapy start-up company. He was also employed as head of research & development by Avigen, Inc., an early-stage gene therapy company located in San Francisco. Gary began his career with Gilead Sciences, Inc.—at the time, a pre-IPO biotechnology company—as virology group leader. A board-certified internist from Barnes Hospital in St. Louis, MO, with a hematology sub-specialty, Gary has authored more than 40 research articles, book chapters and reviews, and is credited as inventor on twelve issued United States patents. Presently, Gary serves on various academic and biomedical committees and boards along with the editorial board of Biotechnology Healthcare. Presently, Gary is a lecturer in the Health Care Systems Department at the Wharton School at the University of Pennsylvania where he teaches entrepreneurship in life sciences.

Gholson Lyon, M.D., Ph.D., Assistant Professor of Human Genetics, Cold Spring Harbor Laboratory; Research Scientist, Utah Foundation for Biomedical Research
Gholson Lyon is an assistant professor in human genetics at Cold Spring Harbor Laboratory and a research scientist at the Utah Foundation for Biomedical Research. He is also a board-certified child, adolescent and adult psychiatrist. He earned an M.Phil. in Genetics at the University of Cambridge, England, then received a Ph.D. and M.D. through the combined Cornell/Sloan-Kettering/Rockefeller University training program. He started his independent research career in 2009, after finishing clinical residencies in child, adolescent and adult psychiatry. In addition to his research on the genetics of neuropsychiatric illnesses, Dr. Lyon is focusing on the genetic basis of rare Mendelian diseases.

Daniel MacArthur, Ph.D., Assistant Professor, Massachusetts General Hospital; Co-founder, Genomes Unzipped 
Daniel MacArthur is a group leader at the Analytic and Translational Genetics Unit at Massachusetts General Hospital, an assistant professor at Harvard Medical School, and a research affiliate at the Broad Institute of Harvard and MIT. His research focuses on understanding the functional impact of genetic variation using genome sequencing data. His writing on personal genomics is archived at Wired Science, and his research is described on his lab page at http://www.macarthurlab.org/.

Ellen T. Matloff, M.S., Research Scientist, Department of Genetics and Director, Cancer Genetic Counseling, Yale Cancer Center
Ellen T. Matloff, M.S., C.G.C., received her Bachelor’s degree in Biology from Union College, her Master’s degree in Genetic Counseling from Northwestern University, and her board certification from the American Board of Genetic Counseling. She specializes in hereditary breast and ovarian cancer syndrome (BRCA1, BRCA2), hereditary colon cancer syndromes (HNPCC, FAP), and rare cancer syndromes. Her interests include patient and provider issues in genetic counseling, sexuality and cancer patients, and the impact of patents on clinical practice.

Martin Mendiola, M.D., MPH, Director, Clinical Program Development, Happtique
Martin Mendiola is responsible for clinical needs assessments of mHealth technology for the purposes of enhancing the provision of care and patient engagement and satisfaction. He is involved in the clinical implementation of Happtique’s solutions within client health systems while serving as a liaison to its healthcare providers. He has also created the medical, health, and wellness library intellectual property offered to Happtique’s members. Prior to joining Happtique, Martin worked in the direct delivery of care within several hospital systems and through international humanitarian relief efforts, and has conducted extensive clinical research. He earned his MD from the Ponce School of Medicine and MPH in Health Policy from Columbia University Mailman School of Public Health.

Peter S. Miller, COO, Genomic Healthcare Strategies
Peter Miller is Chief Operating Officer of Genomic Healthcare Strategies, a company focused on the changes in healthcare resulting from advances in molecular medicine. Peter spent his career building companies which have operated in expanding markets driven by new technology. He has a track record of spotting trends and successful implementation. He did his undergraduate work at MIT. While working on his MBA at MIT’s Sloan School, he was a founding member of Abt Associates Inc, and over a period of 17 years worked as COO and Board member as the company grew from 3 people to 800. Peter has been a key advisor to firms facing a variety of transitional events (external or internal), entering new markets, and facing choices around mergers/acquisitions/going public. He has helped build successful companies in software and professional services, three of which were sold to public companies. He has served on a number of boards of innovative technology companies, helping build their success, both organizationally and in their markets. He has a long term interest in health care. He established the original health care research group at Abt Associates. He has helped teach a course at Harvard School of Public Health, working with Dr. John Bryant, later Dean of Columbia’s School of Public Health. He has worked on physician education with the American Association of Medical Colleges and has been a board member of several health care services firms. He has extensive experience with entrepreneurial companies, having successfully worked with firms raising money seven times, both as an employee and as a business plan quarterback. He is involved in M&A activities on both the buy and sell sides. In addition he has been a licensed (NASD) broker/dealer. Peter is a frequent invited speaker on the changing healthcare landscape, writing and speaking on Personalized Medicine for many years as a thought leader. He has been invited to speak at the Molecular Medicine Tri-Conference, LabCompete, the University of California at Santa Barbara’s Technology Management Program, among others. Peter is co-author with Keith Batchelder of GHS of an invited Nature Biotechnology commentary: “A Change in the Market – Investing in Diagnostics.” He is active with his alma mater, having been Board Chairman of the Global MIT Enterprise Forum, a past board member of the MIT Alumni Association, and currently helps fledgling startups as Co-Director of the MIT Venture Mentoring Service.

Georgia Mitsi, MSc, Ph.D., MBA, Founder and CEO, Apptomics LLC 
Georgia Mitsi MSc, PhD, MBA is the Founder and CEO of Apptomics LLC ,a health technology firm specializing in the design and validation of quality medical mobile applications for selected conditions with high unmet need focusing primarily in CNS. Georgia received her PhD in Health Sciences and MSc in Applied Medical Sciences from University of Patras, Greece and her MBA from University of Miami. She has extensive experience in Pharmaceutical Industry and Healthcare Consulting where she has been involved in positions of increased responsibility in areas such as Clinical Research, Health Outcomes and Health Economics. She often played an instrumental role in uncovering and fostering new business opportunities and developing a strategic roadmap for product’s value proposition. Georgia also worked at the Health Services Research Center (HSRC), a joint venture between Humana and University of Miami and among other responsibilities she led the scientific effort for Games for Health initiative. She has completed successfully many research projects of high complexity and has collaborated with pharmaceutical companies as well as academic institutions. She has co-authored several scientific publications and presented in conferences such as ISPOR and DIA. Georgia is also a published novelist in her native language, Greek.

David Mittelman, Ph.D., Associate Professor, Virginia Bioinformatics Institute, Virginia Tech Department of Biological Sciences, and VTC School of Medicine
Dr. Mittelman is an Associate Professor at the Virginia Bioinformatics Institute, the Virginia Tech Department of Biological Sciences, and the VTC School of Medicine. David Mittelman holds a PhD in Molecular Biophysics through the Department of Biochemistry at Baylor College of Medicine (BCM). Dr. Mittelman completed his postdoctoral training in the Department of Molecular and Human Genetics at BCM. In 2009, Dr. Mittelman was awarded the Ruth L. Kirschstein National Research Service Award, and began an independent research program in population-scale genomics at BCM’s Human Genome Sequencing Center (HGSC). Currently, Dr. Mittelman leads the Genetics and Genomic Medicine Laboratory at Virginia Tech, combining experimental and computational approaches to characterizing personal genomes.

Anne Morriss, Founder and CEO, Genepeeks
Anne is the founder and CEO of Genepeeks, a genetic information company that helps families to protect their future children. She has helped to launch and grow multiple technology companies, and is the best-selling co-author of Uncommon Service: How to Win By Putting Customers at the Core of Your Business (Harvard Business Review Press). Anne received her B.A in American Studies from Brown University and an M.B.A from Harvard Business School.

Julia Oh, Chief Science Officer, 1eq

Heidi L. Rehm, Ph.D., FACMG, Chief Laboratory Director, Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine (PCPGM); Assistant Professor of Pathology, Harvard Medical School
Heidi Rehm, Ph.D. was recruited in 2001 to build the Laboratory for Molecular Medicine at PCPGM and serves as its Laboratory Director. She is a board-certified clinical molecular geneticist and Assistant Professor of Pathology at Harvard Medical School with appointments at BWH, MGH and Children’s Hospital Boston. Her undergraduate degree is from Middlebury College, her graduate degree in Genetics is from Harvard University and her postdoctoral and fellowship training was at HMS. Heidi has served as the Director of the ABMG Clinical Molecular Genetics Training Program at HMS since 2006. In addition to running the LMM and the molecular training program, she also conducts research in hearing loss, Usher syndrome, cardiomyopathy and the use of IT in enabling personalized medicine.
Jessica Richman, CEO and Co-Founder, uBiome

Gabe Rudy, Vice President, Product Development, Golden Helix and Author “A Hitchhikers Guide to Next Generation Sequencing”
Gabe Rudy has been GHI’s Vice President of Product Development and team member since 2002. Gabe thrives in the dynamic and fast-changing field of bioinformatics and genetic analysis. Leading a killer team of Computer Scientists and Statisticians in building powerful products and providing world-class support, Gabe puts his passion into enabling Golden Helix’s customers to accelerate their research. When not reading or blogging, Gabe enjoys the outdoor Montana lifestyle. But most importantly, Gabe truly loves spending time with his sons and wife.

Meredith Salisbury, Senior Consultant, Bioscribe
Prior to becoming a consultant for Bioscribe, Meredith was CEO and Editor-in-Chief of GenomeWeb, the leading news and information service for scientists in the systems biology field. During her 11 years with the company, Meredith honed her knowledge of the genomics market, with a particular focus on next-gen DNA sequencing. She is the co-founder of the Consumer Genetics Conference held annually in Boston. Before joining GenomeWeb, Meredith had an extended internship in the busy newsroom at Newsweek in New York City. Meredith brings her industry knowledge and connections to oversee editorial strategy for Bioscribe clients. Meredith enjoys hot-air ballooning and is based in the NYC metropolitan area.

Anish Sebastian, Co-Founder and CEO, 1eq

Juhan Sonin, Creative Director, Involution Studios, MIT
Juhan Sonin is an emeritus of some of the finest software organizations in the world: Apple, the National Center for Supercomputing Applications (NCSA) and the Massachusetts Institute of Technology (MIT). He has been a creative director for almost two decades with his work being featured in the New York Times, Newsweek, BBC International, Billboard Magazine and National Public Radio (NPR). He is also a lecturer on design and rapid prototyping at the Massachusetts Institute of Technology (MIT).

Vasisht Tadigotla, Ph.D., Senior Bioinformatics Scientist, Courtagen Life Sciences, Inc.
Vasisht is currently working as a Senior Bioinformatics Scientist at Courtagen Life Sciences. Previously, he has worked as a Staff Scientist at Life Technologies helping develop the SOLiD and Ion Torrent sequencing technologies and at the Department of Physics at Boston University. Vasisht earned a Ph.D. in Biophysics and Computational Biology from Rutgers University and a B.Tech. in Biochemical Engineering from Indian Institute of Technology, New Delhi.

Spencer Wells, Ph.D., Explorer-in-Residence and Director, The Genographic Project, National Geographic Society
Spencer Wells is a leading population geneticist and director of the Genographic Project from National Geographic and IBM. His fascination with the past has led the scientist, author, and documentary filmmaker to the farthest reaches of the globe in search of human populations who hold the history of humankind in their DNA. By studying humankind’s family tree he hopes to close the gaps in our knowledge of human migration. A National Geographic explorer-in-residence, Wells is spearheading the Genographic Project, calling it “a dream come true.” His hope is that the project, which builds on Wells’s earlier work (featured in his book and television program, The Journey of Man) and is being conducted in collaboration with other scientists around the world, will capture an invaluable genetic snapshot of humanity before modern-day influences erase it forever. Wells’s own journey of discovery began as a child whose zeal for history and biology led him to the University of Texas, where he enrolled at age 16, majored in biology, and graduated Phi Beta Kappa three years later. He then pursued his Ph.D. at Harvard University under the tutelage of distinguished evolutionary geneticist Richard Lewontin. Beginning in 1994, Wells conducted postdoctoral training at Stanford University’s School of Medicine with famed geneticist Luca Cavalli-Sforza, considered the “father of anthropological genetics.” It was there that Wells became committed to studying genetic diversity in indigenous populations and unraveling age-old mysteries about early human migration. Wells’s field studies began in earnest in 1996 with his survey of Central Asia. In 1998 Wells and his colleagues expanded their study to include some 25,000 miles of Asia and the former Soviet republics. His landmark research findings led to advances in the understanding of the male Y chromosome and its ability to trace ancestral human migration. Wells then returned to academia where, at Oxford University, he served as director of the Population Genetics Research Group of the Wellcome Trust Centre for Human Genetics at Oxford. Following a stint as head of research for a Massachusetts-based biotechnology company, Wells made the decision in 2001 to focus on communicating scientific discovery through books and documentary films. From that was born The Journey of Man: A Genetic Odyssey, an award-winning book and documentary that aired on PBS in the U.S. and National Geographic Channel internationally. Written and presented by Wells, the film chronicled his globe-circling, DNA-gathering expeditions in 2001-02 and laid the groundwork for the Genographic Project. Since the Genographic Project began, Wells’s work has taken him to over three dozen countries, including Chad, Tajikistan, Morocco, Papua New Guinea, and French Polynesia, and he recently published his second book, Deep Ancestry: Inside the Genographic Project. He lives with his wife, a documentary filmmaker, in Washington, D.C.
Eric P. Williams, Ph.D., Senior Bioinformatics Scientist, National Marrow Donor Program
Dr. Eric Williams is Senior Bioinformatics Scientist at the National Marrow Donor Program (NMDP) which is entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry. Eric has 9 years of experience working in research related to aspects of biology, histocompatibility and population genetics associated with finding matching donors for patients needing stem cell therapies. His interests include the utilization of genetic information to further medicine, infer ancestry, and aid in family history research. He has led development of systems utilized by worldwide transplant centers to access population HLA frequency and ancestry information critical to the process of finding matching, unrelated donors for patients. Other activities have included utilizing Geographic Information Systems to map global frequencies of HLA haplotypes and a US market area capacity analysis resulting in increased funding to develop facilities at medical institutions supporting stem cell therapy programs. Prior to his work with the NMDP, Eric has 18 years experience supporting marker assisted plant breeding programs at Pioneer Hi-Bred, Mycogen Seeds and Syngenta Seeds. Dr. Williams received a Ph.D. in Plant Breeding and Genetics and a MS in Plant Physiology from the University of Nebraska-Lincoln and a BA in Agronomy from Brigham Young University.
Rina Wolf, Vice President, Commercialization Strategies, XIFIN, Inc.
Rina Wolf is a nationally recognized expert in the field of laboratory commercialization and reimbursement, with over 20 years of experience in the diagnostic laboratory industry, specializing in Molecular Diagnostic Laboratories. She lectures extensively on these topics and has consulted for major laboratories and laboratory associations throughout the U.S.. She is a former President and board member of the California Clinical Laboratory Association and is an active participant with the ACLA (American Clinical Laboratory Association) and the Personalized Medicine Coalition. Ms. Wolf also advises and presents to investor audiences, recent speaking engagements include Piper Jaffray, Cowen Group and Bloomberg’s G2 Intelligence Lab Investment Forum. Most recently Ms. Wolf held the position of Vice President of Reimbursement and Regulatory Affairs at Axial Biotech, Inc. where she was responsible for creating and implementing their successful reimbursement strategies. Prior to joining Axial Biotech, Inc., Ms. Wolf held executive positions in the area of commercialization and reimbursement at RedPath Integrated Pathology, Inc., Genomic Health, Inc., and Esoterix (now LabCorp). Ms. Wolf has a Bachelor of Arts degree from UCLA and a Masters of HealthCare Administration.

http://www.consumergeneticsconference.com/cgc_content.aspx?id=116061
 

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Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, tagged , , , on May 29, 2013| 2 Comments »

Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Reporter: Aviva Lev-Ari, PhD, RN

Article 10.7. Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Mayo Launches OncoSpire with Cancer Genetics; Opens Exome Service for Rare Diseases, Advanced Cancer

May 29, 2013
 

The Mayo Clinic is continuing its push into clinical sequencing with several new initiatives. Recently, it announced that it has teamed up with Cancer Genetics to form a commercial entity dedicated to developing products to better diagnose cancer, guide treatment, and predict outcomes. Additionally, the center has now opened a whole-exome sequencing service for patients with unknown diseases or advanced cancer, Gianrico Farrugia, who heads Mayo’s Center for Individualized Medicine, told Clinical Sequencing News.

It has also launched a clinical trial involving next-gen sequencing of patients with castration-resistant prostate cancer, called Prostate Cancer Medically Optimized Genome-Enhanced Therapy, or PROMOTE. The goal is to use sequencing technologies to identify treatment options for prostate cancer patients.

In addition, in April, it launched its first next-generation sequencing panel for hereditary colorectal cancer, and it has around 26 additional panels in the pipeline, Farrugia said.

OncoSpire Genomics

The Mayo/Cancer Genetics entity, dubbed OncoSpire Genomics, will be based in Rochester, Minn. It will focus on cancer biomarker discovery, around which tests can be developed to diagnose cancer, guide treatment, predict drug response and resistance, and predict outcomes.

“We felt that this was an opportunity for us to create a new company that would allow Mayo’s expertise to be partnered with outside resources to accelerate the process of bringing new biomarkers out for our patients,” Farrugia said.

The venture will leverage Mayo Clinic’s clinical expertise and next-generation sequencing resources with Cancer Genetics’ “commercial acumen” and operating capital, Panna Sharma, Cancer Genetics’ CEO, told CSN.

Initially, OncoSpire will focus on hematological and urogenital cancers. A board composed of both Mayo and Cancer Genetics employees will choose the projects, which will be carried out by Mayo staff, Farrugia said. The Mayo has one of the “best clinically annotated biobanks,” he said, and “the ability to use that is key.”

The initial board of governors consists of six members, three Mayo Clinic appointees and three Cancer Genetics appointees. Farrugia is on the board along with Scott Beck, administrator of the Mayo’s Center for Individualized Medicine, and Kathy Bates, director of business development for Mayo’s Medical Laboratories. The three representatives from Cancer Genetics are Sharma, Founder and Chairman of the Board Raju Chaganti, and John Pappajohn, a member of the firm’s board of directors.

Sequencing will initially be done at Mayo, but Farrugia said that the team has not yet decided if that will be its long-term plan.

Sharma added that more details about the products and commercial timeline would be provided at an analyst day conference that will be held in Rochester in the next month or two.

WES Service

Separately, the Mayo has launched a whole-exome sequencing service for patients with unknown diseases and advanced cancer.

For this service, Mayo has been contracting sequencing to Baylor College of Medicine and Foundation Medicine, but plans to do more in-house sequencing by the end of year when its pipeline is CLIA certified. The center is working with Silicon Valley Biosystems to develop that clinical sequencing pipeline (CSN 1/23/2013).

The exome service has been available since September, said Farrugia, but Mayo has only recently begun advertising for it. Around 30 to 35 patients have gone through the pipeline thus far.

The diagnostic rate is about 40 percent for the cancer patients and slightly higher for the diagnostic odyssey patients, said Farrugia, but those “numbers are too small to attach too much significance to them,” he said.

The Mayo Clinic works with patients’ insurance companies to obtain reimbursement for the services, which often will include targeted sequencing as well as whole-exome sequencing, and the average out-of-pocket expense ranges between $7,000 and $11,000, depending on the patient’s condition and what the service entails, said Farrugia.

For instance, the service for cancer patients can include obtaining a new tissue sample, sequencing both normal and tumor samples, and sometimes doing both targeted sequencing for a quicker turnaround and exome sequencing, Farrugia said.

As such, the total price charged for the cancer service can be much higher than what is charged for patients with a rare disease, sometimes approaching $30,000, Farrugia said, although prices vary.

Because of all these variables, Farrugia said there isn’t a list price for the service. “We’re really tailoring it to the patient and what we think they can best benefit from,” he said.

Turnaround time is still too long, he said, about one to two months, which he said will be reduced when the center’s clinical sequencing pipeline becomes CLIA certified and more can be done in-house.

Additionally, every patient that receives clinical sequencing also has the option of participating in research, said Farrugia. If the patient consents to research sequencing, that is done at the Mayo Clinic, while the clinical sequencing is outsourced. However, he said that is a temporary model until Mayo’s clinical exome pipeline is CLIA certified and has New York state approval.

The center also offers patients a choice in terms of which incidental findings to receive from the sequencing. Typically, patients with advanced cancer just want to hear about anything that’s actionable, while the conversation with patients and families with diagnostic odysseys is longer and more complicated, he said.

Like other labs offering clinical sequencing, Mayo has decided to diverge from recommendations recently published by the American College of Medical Genetics and Genomics, which say that providers should always return pathogenic variants from a list of 57 genes related to 24 disorders (CSN 5/8/2013).

The recommendations, which were released in March, have sparked a debate in the field as to how best to deal with incidental findings, and a number of groups have written publications both in support of and disagreeing with the recommendations (CSN 5/22/2013).

Farrugia said that Mayo has also written a formal response to ACMG, which he said would be published in an upcoming journal, detailing where it agrees and where it disagrees with the recommendations.

    Monica Heger tracks trends in next-generation sequencing for research and clinical applications for GenomeWeb’s In Sequenceand Clinical Sequencing News. E-mail Monica Heger or follow her GenomeWeb Twitter accounts at @InSequence and@ClinSeqNews.

Related Stories

http://www.genomeweb.com/sequencing/mayo-launches-oncospire-cancer-genetics-opens-exome-service-rare-diseases-advanc?hq_e=el&hq_m=1586418&hq_l=8&hq_v=e1df6f3681

 

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Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Posted in Biological Networks, Gene Regulation and Evolution, Cancer Prevention: Research & Programs, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Nutrigenomics, Personalized and Precision Medicine & Genomic Research, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , on May 18, 2013| 1 Comment »

Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Author: Larry H Bernstein, MD, FCAP

In this article I will address the following article by Dr. SJ Williams.

Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies

 

In the November 23, 2012 issue of Science, Jocelyn Kaiser reports (Genetic Influences On Disease  Remain Hidden in News and  Analysis) on the difficulties that many genomic studies are encountering correlating genetic variants to high risk of type 2 diabetes and heart disease. American Society of  Human Genetics annual 2012 meeting, results of DNA sequencing studies reporting on genetic variants and links to high risk type 2 diabetes and heart disease, part of an international effort to determine the genetic events contributing to complex, common diseases like diabetes.
The key point is that these disease links are challenged by the identification of genetic determinants that do not follow Mendelian Genetics.  There are many disease associated gene variants, and they have not been deleted as a result of natural selection.  In the case of diabetes (type 2), the genetic risk is a low as 26%.

Gene-wide-association studies (GAWS) have identified single nucleotide polymorphisms (SNPs) with associations for common diseases, most of these individually carry only only 20-40% of risk. This is not sufficient for prediction
and use in personalized  treatment.

What is the implication of this.  Researchers have gone to exome-sequencing and  to whole genome sequencing for answers. SNPs can be easily done  by microarray, and in a clinic setting. GWAS is difficult and has inherent complexity, and it has had high cost of use. But the cost of the technology has been dropping precipitously. Technology is being redesigned for more rapid diagnosis and use in clinical research and personalized medicine.  It appears that this is not  yet a game changer.

My own thinking is that the answer doesn’t  fully lie in the genome sequencing, but that it must turn on the very large weight of importance in the regulatory function in the genome, that which was once “considered” dark matter.  In the regulatory function you have a variety of interactions and adaptive changes to the proximate environment, and this is a key to the nascent study of metabolomics.

Three projects highlighted are:
1.  National Heart, Lung and Blood Institute Exome Sequencing Project (ESP)[2]: heart, lung, blood

  • A majority of variants linked to any disease are rare
  • Groups of variants in the same gene confirmed a link between
    APOC3 and risk for early-onset heart attack

2.  T2D-GENES Consortium
3.  GoT2D

  • SNP and PAX4 gene association for type 2 diabetes in East Asians
  • No new rare variants above 1.5% frequency for diabetes

http://www.phgfoundation.org/news/5164/

The unsupported conclusion from this has been

  1. the common disease-common variant hypothesis, which predicts that common disease-causing genetic variants exist in all human populations, but   (common unexplained complexity?) each individual variant will necessarily only have a small effect on disease susceptibility (i.e. a low associated relative risk).
  1. the common disease, many rare variants hypothesis, which postulates that disease is caused by multiple strong-effect variants, (an alternative complexity situation?) Dickson et al. (2010)  PLoS Biol 2010 8(1):e1000294

The reality is that it has been difficult to associate any variant with prediction of risk, but an alternative approach appears to be intron sequencing and missing information on gene-gene interactions.

Jocelyn Kaiser’s Science article notes this in a brief interview with Harry Dietz of Johns Hopkins University where he suspects that “much of the missing heritability lies in gene-gene interactions”.

Oliver Harismendy and Kelly Frazer and colleagues’ recent publication in Genome Biology  http://genomebiology.com/content/11/11/R118 support this notion.  The authors used targeted resequencing
of two endocannabinoid metabolic enzyme genes (fatty-acid-amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal weight and 142 extremely obese patients.

Related articles

English: The human genome, categorized by func...

English: The human genome, categorized by function of each gene product, given both as number of genes and as percentage of all genes. (Photo credit: Wikipedia)

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Finding the Genetic Links in Common Disease: Caveats of Whole Genome Sequencing Studies

Posted in Alzheimer's Disease, Biological Networks, Gene Regulation and Evolution, Cardiovascular Pharmacogenomics, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Etiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged , , , , , , , , , , , , , , , , , , , , , on May 15, 2013| 5 Comments »

Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies

Writer and Reporter: Stephen J. Williams, Ph.D.

Article 2.7 Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies

In the November 23, 2012 issue of Science, Jocelyn Kaiser reports (Genetic Influences On Disease Remain Hidden in News and Analysis)[1] on the difficulties that many genomic studies are encountering correlating genetic variants to high risk of type 2 diabetes and heart disease.  At the recent American Society of Human Genetics annual 2012 meeting, results of several DNA sequencing studies reported difficulties in finding genetic variants and links to high risk type 2 diabetes and heart disease.  These studies were a part of an international effort to determine the multiple genetic events contributing to complex, common diseases like diabetes.  Unlike Mendelian inherited diseases (like ataxia telangiectasia) which are characterized by defects mainly in one gene, finding genetic links to more complex diseases may pose a problem as outlined in the article:

  • Variants may be so rare that massive number of patient’s genome would need to be analyzed
  • For most diseases, individual SNPs (single nucleotide polymorphisms) raise risk modestly
  • Hard to find isolated families (hemophilia) or isolated populations (Ashkenazi Jew)
  • Disease-influencing genes have not been weeded out by natural selection after human population explosion (~5000 years ago) resulted in numerous gene variants
  • What percentage variants account for disease heritability (studies have shown this is as low as 26% for diabetes with the remaining risk determined by environment)

Although many genome-wide-associations studies have found SNPs that have causality to increasing risk diseases such as cancer, diabetes, and heart disease, most individual SNPs for common diseases raise risk by about only 20-40% and would be useless for predicting an individual’s chance they will develop disease and be a candidate for a personalized therapy approach.  Therefore, for common diseases, investigators are relying on direct exome sequencing and whole-genome sequencing to detect these medium-rare risk variants, rather than relying on genome-wide association studies (which are usually fine for detecting the higher frequency variants associated with common diseases).

Three of the many projects (one for heart risk and two for diabetes risk) are highlighted in the article:

1.  National Heart, Lung and Blood Institute Exome Sequencing Project (ESP)[2]: heart, lung, blood

  • Sequenced 6,700 exomes of European or African descent
  • Majority of variants linked to disease too rare (as low as one variant)
  • Groups of variants in the same gene confirmed link between APOC3 and higher risk for early-onset heart attack
  • No other significant gene variants linked with heart disease

2.  T2D-GENES Consortium: diabetes

Sequenced 5,300 exomes of type 2 diabetes patients and controls from five ancestry groups
SNP in PAX4 gene associated with disease in East Asians
No low-frequency variant with large effect though

3.  GoT2D: diabetes

  • After sequencing 2700 patient’s exomes and whole genome no new rare variants above 1.5% frequency with a strong effect on diabetes risk

A nice article by Dr. Sowmiya Moorthie entitled Involvement of rare variants in common disease can be found at the PGH Foundation site http://www.phgfoundation.org/news/5164/ further discusses this conundrum,  and is summarized below:

“Although GWAs have identified many SNPs associated with common disease, they have as yet had little success in identifying the causative genetic variants. Those that have been identified have only a weak effect on disease risk, and therefore only explain a small proportion of the heritable, genetic component of susceptibility to that disease. This has led to the common disease-common variant hypothesis, which predicts that common disease-causing genetic variants exist in all human populations, but each individual variant will necessarily only have a small effect on disease susceptibility (i.e. a low associated relative risk).

An alternative hypothesis is the common disease, many rare variants hypothesis, which postulates that disease is caused by multiple strong-effect variants, each of which is only found in a few individuals. Dickson et al. in a paper in PLoS Biology postulate that these rare variants can be indirectly associated with common variants; they call these synthetic associations and demonstrate how further investigation could help explain findings from GWA studies [Dickson et al. (2010) PLoS Biol. 8(1):e1000294][3].  In simulation experiments, 30% of synthetic associations were caused by the presence of rare causative variants and furthermore, the strength of the association with common variants also increased if the number of rare causative variants increased. “

one_of_many rare variants

Figure from Dr. Moorthie’s article showing the problem of “finding one in many”.

(please   click to enlarge)

Indeed, other examples of such issues concerning gene variant association studies occur with other common diseases such as neurologic diseases and obesity, where it has been difficult to clearly and definitively associate any variant with prediction of risk.

For example, Nuytemans et. al.[4] used exome sequencing to find variants in the vascular protein sorting 3J (VPS35) and eukaryotic transcription initiation factor 4  gamma1 (EIF4G1) genes, tow genes causally linked to Parkinson’s Disease (PD).  Although they identified novel VPS35 variants none of these variants could be correlated to higher risk of PD.   One EIF4G1 variant seemed to be a strong Parkinson’s Disease risk factor however there was “no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development”.

These negative results may have relevance as companies such as 23andme (www.23andme.com) claim to be able to test for Parkinson’s predisposition.  To see a description of the LLRK2 mutational analysis which they use to determine risk for the disease please see the following link: https://www.23andme.com/health/Parkinsons-Disease/. This company and other like it have been subjects of posts on this site (Personalized Medicine: Clinical Aspiration of Microarrays)

However there seems to be more luck with strategies focused on analyzing intronic sequence rather than exome sequence. Jocelyn Kaiser’s Science article notes this in a brief interview with Harry Dietz of Johns Hopkins University where he suspects that “much of the missing heritability lies in gene-gene interactions”.  Oliver Harismendy and Kelly Frazer and colleagues’ recent publication in Genome Biology  http://genomebiology.com/content/11/11/R118 support this notion[5].  The authors used targeted resequencing of two endocannabinoid metabolic enzyme genes (fatty-acid-amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal weight and 142 extremely obese patients.

These patients were enrolled in the CRESCENDO trial and patients analyzed were of European descent. However, instead of just exome sequencing, the group resequenced exome AND intronic sequence, especially focusing on promoter regions.   They identified 1,448 single nucleotide variants but using a statistical filter (called RareCover which is referred to as a collapsing method) they found 4 variants in the promoters and intronic areas of the FAAH and MGLL genes which correlated to body mass index.  It should be noted that anandamide, a substrate for FAAH, is elevated in obese patients. The authors did note some issues though mentioning that “some other loci, more weakly or inconsistently associated in the original GWASs, were not replicated in our samples, which is not too surprising given the sample size of our cohort is inadequate to replicate modest associations”.

PLEASE WATCH VIDEO on the National Heart, Lung and Blood Institute Exome Sequencing Project

https://www.youtube.com/watch?v=-Qr5ahk1HEI

REFERENCES

http://www.phgfoundation.org/news/5164/  PHG Foundation

1.            Kaiser J: Human genetics. Genetic influences on disease remain hidden. Science 2012, 338(6110):1016-1017.

2.            Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G et al: Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 2012, 337(6090):64-69.

3.            Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS biology 2010, 8(1):e1000294.

4.            Nuytemans K, Bademci G, Inchausti V, Dressen A, Kinnamon DD, Mehta A, Wang L, Zuchner S, Beecham GW, Martin ER et al: Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 2013, 80(11):982-989.

5.            Harismendy O, Bansal V, Bhatia G, Nakano M, Scott M, Wang X, Dib C, Turlotte E, Sipe JC, Murray SS et al: Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level. Genome biology 2010, 11(11):R118.

Other posts on this site related to Genomics include:

Cancer Biology and Genomics for Disease Diagnosis

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Genomics-based cure for diabetes on-the-way

Personalized Medicine: Clinical Aspiration of Microarrays

Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Genetics of Disease: More Complex is How to Creating New Drugs

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Centers of Excellence in Genomic Sciences (CEGS): NHGRI to Fund New CEGS on the Brain: Mental Disorders and the Nervous System

Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed

Mitochondrial Metabolism and Cardiac Function

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Quantum Biology And Computational Medicine

Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

Centers of Excellence in Genomic Sciences (CEGS): NHGRI to Fund New CEGS on the Brain: Mental Disorders and the Nervous System

LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

Consumer Market for Personal DNA Sequencing: Part 4

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Whole-Genome Sequencing Data will be Stored in Coriell’s Spin off For-Profit Entity

 

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Personalized Medicine: Clinical Aspiration of Microarrays

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, HealthCare IT, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, tagged , , , , , , , , , , , , , , , , , , , on March 13, 2013| 7 Comments »

Personalized Medicine: Clinical Aspiration of Microarrays

Reporter, Writer: Stephen J. Williams, Ph.D.

 In this month’s Science, Mike May (at http://www.sciencemag.org/site/products/lst_20130215.xhtml) describes some of the challenges and successes in introducing microarray analysis to the clinical setting.  Traditionally used for investigational research, microarray is now being developed, customized and used for biomarker analysis, prognostic and predictive value, in a disease-specific manner.

Challenges in data interpretation

      In an interview with Seth Crosby, director of the Genome Technology Access Center at Washington University School of Medicine in St. Louis, “the biggest challenge” in moving microarray to the clinical setting is data interpretation.  The current technology makes it possible to evaluate expression of thousands of genes from a patient’s sample however as Crosby describes is assigning clinical relevance to the data.  For example Crosby explains that Washington University had validated a panel of 45 oncology genes by next generation sequencing and are using these genes to develop diagnostic tests to screen patient tumors for the purpose of determining a personalized therapeutic strategy. Seth Crosby noted it took “hundreds of Ph.D. and M.D. hours” to sift through the hundreds of papers to determine which genes were relevant to a specific cancer type. However, he notes, that once we better understand which changes in the patient’s genome are related to a specific disease we will be able to narrow down the list and be able to produce both economical and more disease-relevant microarrays.

Is this aberration pathogenic or not?

     Microarrays are becoming an invaluable tool in cytogenetics, as eluded by Andy Last, executive vice president of the genetic analysis business unit at Affymetrix.  Certain diseases like Down syndrome have well characterized chromosomal alterations like additions or deletions of parts or entire chromosomes.  According to Affymetrix, the most common use of microarrays is for determining copy number variation.  However according to James Clough, vice president of clinical and genomic services at Oxford Gene Technology, given the hundreds of syndromes associated with chromosomal rearrangements, the challenge will be to determine if a small chromosomal aberration has pathologic significance, given that microarray affords much higher diagnostic yield and speed of analysis than traditional microscopic techniques.  To address this challenge, Oxford Gene Technologies, PerkinElmer, Affymetrix, and Agilent all have custom designed microarrays to evaluate disease specific copy number and SNP (single nucleotide polymorphism) microarrays.  For example PerkinElmer designed OncoChip™ to evaluate copy number variation in more than 1.800 cancer genes.  Agilent makes microarrays that evaluates both copy number variation such as its CGH (comparative genomic hybridization) plus SNP microarrays.  Patricia Barco, product manager for cytogenetics at Agilent, notes these arrays can be used in prenatal and postnatal research and cancer, and “can be customized from more than 28 million probes in our library”.

Custom Tools and Software to Handle the Onslaught of Big Data

     There is a need for FDA approved diagnostic tools based on microarrays. Pathwork Diagnostic’s has one such tool (the Pathwork Tissue of Origin test), which uses 2,000 transcript markers and a proprietary computational algorithm to determine from expression analysis, the tissue of origin of a patient’s tumor.  Pathwork also provides a fast, custom turn-around analytical service for pathologists who encounter difficult to interpret samples.  Illumina provides the Infinium HumanCore BeadChip family of microarrays, which can determine genetic variations for purposes of biological tissue banking.  This system uses a set of over 300,000 SNP probes plus 240,000 exome-based markers.

     Tools have also been developed to validate microarray results.  A common validation strategy is the use of quantitative real-time PCR to verify the expression changes seen on the microarray.  Life Technologies developed the TaqMan OpenArray Real Time PCR plates, which have 3,072 wells and can be custom-formatted using their library of eight million validated TaqMan assays.

Making Sense of the Big Data: Bridging the Knowledge Gap using Bioinformatics

          The use of microarray has spurned industries devoted to developing the bioinformatics software to analyze the massive amounts of data and provide clinical significance.  For example companies such as Expression Analysis use their bioinformatics software to provide pathway analysis for microarray data in order to translate the data into the biology.  Using such strategies can also validate the design of microarrays for various diseases.

Foundation Medicine, Inc., a molecular information company, provides cancer genomics test solutions. It offers FoundationOne, an informative genomic profile to identify a patient’s individual molecular alterations and match them with relevant targeted therapies and clinical trials. The company’s product enables physicians to recommend treatment options for patients based on the molecular subtype of their cancer.

The Canadian Bioinformatics Workshops series recently offered a course on using bioinformatic approaches to analyze clinical data generated from microarray approaches (http://bioinformatics.ca/workshops/2012/bioinformatics-cancer-genomics-bicg).   The course objectives are described below:

Course Objectives

Cancer research has rapidly embraced high throughput technologies into its research, using various microarray, tissue array, and next generation sequencing platforms. The result has been a rapid increase in cancer data output and data types. Now more than ever, having the bioinformatic skills and knowledge of available bioinformatic resources specific to cancer is critical. The CBW will host a 5-day workshop covering the key bioinformatics concepts and tools required to analyze cancer genomic data sets. Participants will gain experience in genomic data visualization tools which will be applied throughout the development of the skills required to analyze cancer -omic data for gene expression, genome rearrangement, somatic mutations and copy number variation. The workshop will conclude with analyzing and conducting pathway analysis on the resultant cancer gene list and integration of clinical data.

Successful Examples of Clinical Ventures Integrating Bioinformatics in Cancer Treatment Decision –Making

The University of Pavia, Italy developed a fully integrated oncology bioinformatics workflow as described on their website and at the ESMO 2012 Congress meeting:

http://abstracts.webges.com/viewing/view.php?congress=esmo2012&congress_id=370&publication_id=2530

ESMO

ONCO-I2B2 PROJECT: A BIOINFORMATICS TOOL INTEGRATING –OMICS AND CLINICAL DATA TO SUPPORT TRANSLATIONAL RESEARCH

Abstract:

2530

Congress:

ESMO 2012

Type:

Abstract

Topic:

Translational research

Authors:

A. Zambelli, D. Segagni, V. Tibollo, A. Dagliati, A. Malovini, V. Fotia, S. Manera, R. Bellazzi; Pavia/IT
  • Body

The ONCO-i2b2 project, supported by the University of Pavia and the Fondazione Salvatore Maugeri (FSM), aims at supporting translational research in oncology and exploits the software solutions implemented by the Informatics for Integrating Biology and the Bedside (i2b2) research centre, an initiative funded by the NIH Roadmap National Centres for Biomedical Computing. The ONCO-i2b2 software is designed to integrate the i2b2 infrastructure with the FSM hospital information system and the Bruno Boerci Biobank, in order to provide well-characterized cancer specimens along with an accurate patients clinical data-base. The i2b2 infrastructure provides a web-based access to all the electronic medical records of cancer patients, and allow researchers analyzing the vast amount of biological and clinical information, relying on a user-friendly interface. Data coming from multiple sources are integrated and jointly queried.

In 2011 at AIOM Meeting we reported the preliminary experience of the ONCO-i2b2 project, now we’re able to present the up and running platform and the extended data set. Currently, more than 4400 specimens are stored and more than 600 of breast cancer patients give the consent for the use of specimens in the context of clinical research, in addition, more than 5000 histological reports are stored in order to integrate clinical data.

Within the ONCO-i2b2 project is possible to query and merge data regarding:

• Anonymous patient personal data;

• Diagnosis and therapy ICD9-CM subset from the hospital information system;

• Histological data (tumour SNOMED and TNM codes) and receptor profile testing (Her2, Ki67) from anatomic pathology database;

• Specimen molecular characteristics (DNA, RNA, blood, plasma and cancer tissues) from the Bruno Boerci Biobank management system.

The research infrastructure will be completed by the development of new set of components designed to enhance the ability of an i2b2 hive to utilize data generated by NGS technology, providing a mechanism to apply custom genomic annotations. The translational tool created at FSM is a concrete example regarding how the integration of different information from heterogeneous sources could bring scientific research closer to understand the nature of disease itself and to create novel diagnostics through handy interfaces.

Disclosure

All authors have declared no conflicts of interest.

NCI has under-taken a similar effort under the Recovery Act (the full text of the latest report is taken from their website http://www.cancer.gov/aboutnci/recovery/recoveryfunding/investmentreports/bioinformatics:

Cancer Bioinformatics: Recovery Act Investment Report

November 2009

Public Health Burden of Cancer

Cancer is the second leading cause of death in the United States after heart disease. In 2009, it is estimated that nearly 1.5 million new cases of invasive cancer will be diagnosed in this country and more than 560,000 people will die of the disease.

To learn more, visit:

Cancer Bioinformatics Program Overview

Over the past five years, NCI’s Center for Biomedical Informatics and Information Technology (CBIIT) has led the effort to develop and deploy the cancer Biomedical Informatics Grid® (caBIG) in partnership with the broader cancer community.  The caBIG network is designed to enable the integration and exchange of data among researchers in the laboratory and the clinic, simplify collaboration, and realize the potential of information-based (personalized) medicine in improving patient outcomes. caBIG has connected major components of the cancer community, including NCI-designated Cancer Centers, participating institutions of the NCI Community Cancer Centers Program (NCCCP), and numerous large-scale scientific endeavors, as well as basic, translational, and clinical researchers at public and private institutions across the United States and around the world.  Beyond cancer research, caBIG capabilities—infrastructure, standards, and tools—provide a prototype for linking other disease communities and catalyzing a new 21st-century biomedical ecosystem that unifies research and care. ARRA funding will allow NCI to accelerate the ongoing development of the Cancer Knowledge Cloud and Oncology Electronic Health Records (EHRs) initiatives, thereby providing for continued job creation in the areas of biomedical informatics development and application as well as healthcare delivery.

The caBIG Cancer Knowledge Cloud: Extending the Research Infrastructure

The Cancer Knowledge Cloud is a virtual biomedical capability that utilizes caBIG tools, infrastructure, and security frameworks to integrate distributed individual and organizational data, software applications, and computational capacity throughout the broad cancer research and treatment community. The Cancer Knowledge Cloud connects, integrates, and facilitates sharing of the diverse primary data generated through basic and clinical research and care delivery to enable personalized medicine. The cloud includes information generated through large-scale research projects such as The Cancer Genome Atlas (TCGA), the cancer Human Biobank (caHUB) tissue acquisition network, the NCI Functional Biology Consortium, the NCI Patient Characterization Center, and the NCI Preclinical Development Pipeline, academic and industry counterparts to these projects, and clinical observations (from entities such as the NCCCP) captured in oncology-extended Electronic Health Records.  Through the use of the caBIG Data Sharing and Security Framework, the Cloud will support appropriate sharing of information, supporting in silico hypothesis generation and testing, and enabling a learning healthcare system.

A caBIG-Based Rapid-Learning Healthcare System: Incorporating Oncology-Extended Electronic Healthcare Records (EHRs)

The 21st-century Cancer Knowledge Cloud will connect individuals, organizations, institutions, and their associated information within an information technology-enabled cycle of discovery, development, and clinical care—the paradigm of a rapid-learning healthcare system. This will transform these disconnected sectors into a system that is personalized, preventive, pre-emptive, and patient-participatory.  To be realized, this model requires the adoption of standards-based EHRs. Presently, however, no certified oncology-based EHR exists, and fewer than 3 percent of oncologists with outpatient-based practices utilize EHRs. caBIG has recently established a collaboration with the American Society of Clinical Oncology (ASCO) to develop an oncology-specific EHR (caEHR) specification based on open standards already in use in the oncology community that will utilize caBIG standards for interoperability. NCI will implement an open-source version of this specification to validate the specification and to provide a free alternative to sites that choose not to purchase a commercial system. The launch customer for the caEHR will be NCCCP participating sites. NCI will work with appropriate entities to provide a mechanism for certifying that caEHR implementations are consistent with the NCI/ASCO specification.

Bards Cancer Institute has another clinical bioinformatics program to support their clinical efforts:

Clinical Bioinformatics Program in Oncology at Barts Cancer Institute at Barts and the London School of Medicine

http://www.bci.qmul.ac.uk/cancer-bioinformatics

BCI HomeCancer Bioinformatics

Bards

Why we focus on Cancer Bioinformatics

Bioinformatics is a new interdisciplinary area involving biological, statistical and computational sciences. Bioinformatics will enable cancer researchers not only to manage, analyze, mine and understand the currently accumulated, valuable, high-throughput data, but also to integrate these in their current research programs. The need for bioinformatics will become ever more important as new technologies increase the already exponential rate at which cancer data are generated.

What we do

  • We work alongside clinical and basic scientists to support the cancer projects within BCI.  This is an ideal partnership between scientific experts, who know the research questions that will be relevant from a cancer biologist or clinician’s perspective, and bioinformatics experts, who know how to develop the proposed methods to provide answers.
  • We also conduct independent bioinformatics research, focusing on the development of computational and integrative methods, algorithms, databases and tools to tackle the analysis of the high volumes of cancer data.
  • We also are actively involved in the development of bioinformatics educational courses at BCI. Our courses offer a unique opportunity for biologists to gain a basic understanding in the use of bioinformatics methods to access and harness large complicated high-throughput data and uncover meaningful information that could be used to understand molecular mechanisms and develop novel targeted therapeutics/diagnostic tools.

Developing Criteria for Genomic Profiling in Lung Cancer:

A Report from U.S. Cancer Centers

In a report by Pao et. al., a group of clinicians organized a meeting to standardize some protocols for the integration of microarray and genomic data from lung cancer patients into the clinical setting.[1]  There has been ample evidence that adenocarcinomas could be classified into “clinically relevant molecular subsets” based on distinct genomic changes.  For example EGFR (epidermal growth factor receptor) exon 19 deletions and exon 21 point mutations predict sensitivity to tyrosine kinase inhibitors (TKIs) like gefitinib, whereas exon 20 insertions predict primary resistance[2].

However, as the authors note, “mutational profiling has not been widely accepted or adopted into practice in thoracic oncology”.  

     Therefore, a multi-institutional workshop was held in 2009 among participants from Massachusetts General Hospital (MGH) Cancer Center, Memorial Sloan-Kettering Cancer Center (MSKCC), the Dana-Farber/Bingham & Women’s Cancer Center (DF/BWCC), the M.D. Anderson Cancer Center (VICC), and the Vanderbilt-Ingram Cancer Center (VICC) to discuss their institutes molecular profiling programs with emphasis on:

·         Organization/workflow

·         Mutation detection technologies

·         Clinical protocols and reporting

·         Patient consent

In addition to the aforementioned challenges, the panel discussed further issues for developing improved science-driven criteria for determining targeted therapies including:

1)      Including pathologists into criteria development as pathology departments are usually the main repositories for specimens

2)      Developing integrated informatics systems

3)      Standardizing new target validation methodology across cancer centers

 References

1.            Pao W, Kris MG, Iafrate AJ, Ladanyi M, Janne PA, Wistuba, II, Miake-Lye R, Herbst RS, Carbone DP, Johnson BE et al: Integration of molecular profiling into the lung cancer clinic. Clinical cancer research : an official journal of the American Association for Cancer Research 2009, 15(17):5317-5322.

2.            Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, Shih JY, Yang PC: Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clinical cancer research : an official journal of the American Association for Cancer Research 2008, 14(15):4877-4882.

Other posts on this website on Cancer and Genomics include:

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DNA Sequencing Technology

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Genome Biology, Genomic Testing: Methodology for Diagnosis, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , , on March 3, 2013| 1 Comment »

DNA Sequencing Technology

Reporter: Larry H Bernstein, MD, FCAP

Focus on DNA Sequencing Technology
Nature Biotechnology  feb 2013; 31: 2.

 Editorial
Knocking on the clinic door  Nature Biotechnology 2012; 1009  http://dx.doi.org/10.1038/nbt.2428
The New York Genome Center – pp1021 – 1022  http://dx.doi.org/10.1038/nbt.2429
Direct-to-consumer genomics reinvents itself – pp1027 – 1029
Malorye Allison  By putting its foot in the door at the FDA, can 23andMe reinvigorate direct-to-consumer genomics?

Genomic DNA is fragmented into random pieces a...

Genomic DNA is fragmented into random pieces and cloned as a bacterial library. DNA from individual bacterial clones is sequenced and the sequence is assembled by using overlapping DNA regions.(click to expand) (Photo credit: Wikipedia)

Science Fellows

Science Fellows (Photo credit: AlphachimpStudio)

English: Created by Abizar Lakdawalla.

English: Created by Abizar Lakdawalla. (Photo credit: Wikipedia)

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Genomics in Medicine – Tomorrow’s Promise

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Health Law & Patient Safety, International Global Work in Pharmaceutical, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , on March 3, 2013| 3 Comments »

Genomics in Medicine – Tomorrow’s Promise

Reporter: Larry H Bernstein, MD, FCAP

Genomics in Medicine: Today’s Issues, Tomorrow’s Promise

KM Beima-Sofie, EH Dorfman, JM Kocarnik, MY Laurino
Feb 13, 2013 Medscape Genomic Medicine

What do you think about these issues before reading this piece?

The Broader Implications of Genetic Sciences
The 62nd annual meeting of the American Society of Human Genetics (ASHG), which was held in San Francisco, California, in November 2012, featured a diverse array of research in basic, clinical, and population science contributed by human geneticists across the globe.
Genetic Sequencing Moves Beyond the Laboratory
Several presentations at the meeting focused on the lessons learned from the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project. The goal of the project was to
  • develop and validate a cost-effective and high-throughput sequencing technology
  • capable of analyzing the DNA sequence in the exome, which
  • consists of all protein-coding regions in the human genome.
At previous ASHG meetings, presentations and discussions largely focused on
  • the development of sequencing technology and on applications of this technology for research.
Now that sequencing is an increasing reality, this year’s conference featured presentations on
  • what to do with the resulting information, in both research and clinical settings.
Issues discussed include the challenges of
  • interpreting sequence data,
  • determining which results should be returned to various parties, and
  • the potential impacts of different testing techniques.
Results from the NHLBI Exome Sequencing Project and other projects are fueling the discussion on
legal issues surrounding gene patenting, a hotly debated topic that is currently under consideration by the US Supreme Court. During a plenary session on gene discovery and patent law,
Of particular focus was the lawsuit brought by the American Civil Liberties Union against Myriad Genetics,
  • contesting the company’s patent of the BRCA1 and BRCA2 genes for hereditary breast and ovarian cancer.
At present, Myriad has exclusive rights to offer clinical genetic testing for these genes; one of the main arguments of the lawsuit is
  • that gene patents hinder the pursuit of confirmatory tests and limit the testing options available to women.

DNAPrint Genomics

DNAPrint Genomics (Photo credit: Wikipedia)

English: Exome sequencing workflow: Part 2. Ta...

English: Exome sequencing workflow: Part 2. Target exons are enriched, eluted and then amplified by ligation-mediated PCR. Amplified target DNA is then ready for high-throughput sequencing. (Photo credit: Wikipedia)

Cost per Megabase of DNA Sequence (Why biologi...

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