Biology is undergoing a revolution and is becoming a more analytical science with the advent of omics, high content screening, next generation sequencing, and other methods. These methods lead to the more in-depth understanding of systems biology and the discovery of new biomarkers. This greater understanding can be used to fill-in our knowledge about pathways, to the point of building mathematical models of the multiple processes involved in any response to stimuli. All of this taken together should increase the odds of success by having better information to base decisions on.
The other area in biology that has great opportunities is in the use of biologics as drug entities. These drug entities range in complexity from antibodies, vaccines, siRNA, etc. The value to the marketplace is in the hundreds of billions of dollars and intellectual property (IP) protection is essential. Some of the largest patent infringement cases ever awarded are around biologics.
In the process of building-out of these analytical biology systems, and the biologics as drug entities, there are many biological innovations and inventions. For example, new stem cell lines, antibody generation as a tool or as a drug entity, plasmids, algae strains, etc. There is also a lot more inventory, reagents and data to track today than ever before. The best way to track data across multiple sources is the use of a consistent and meaningful key. The way this is handled in the chemical space is to use a registration system to uniquely identify an entity and give the entity a unique integer that represents the entity in every data system. Until recently, the biologist might track a bar code for a cell line or antibody in their notebook, and a possible location for this entity in a lab-based, simple inventory system. However, this type of system only tells the same researcher where the cell line is, not uniquely what it is. In order for the entire company to benefit from the inventory, and protect their IP, there is the need for describing the biological entity uniquely. This is a rather new concept for biologist which needs to be carefully considered moving forward to better protect IP, manage expensive reagents, implement safety systems and most importantly, to ensure the query and aggregation of data. All of this has been implemented in chemistry and shown to be of great value, now it is biology’s turn.
Does your organization have a Biological Registration system? How could such a system add value to your organization?
The 2009 Molecular Medicine Tri-Conference blasted off like a rocket with John Crowley’s keynote, “When Drug Research is Personal.” His family’s struggle is the inspiration for the motion picture Extraordinary Measures. It was a profoundly moving experience to witness this father’s story of his family’s search for a cure for Pompe disease. This journey eventually led to the founding of Novazyme Pharmaceuticals. This is the kind of story that encourages us at both the human and scientific level.
I had a really tough time choosing which talks to attend but mostly settled on Molecular Diagnostics, Personalized Diagnostics, Cancer Profiling and Pathways, and Informatics Systems. It was painful to miss the RNA Interfere, Cancer Biologics, and Translational Medicine sessions. Many talks totally rocked. Here are some of my favorites, in no particular order. These talks come to mind because the material was fascinating, the delivery was exceptional, and they were all in areas for which I have a passionate scientific interest.
Single Molecule Real Time Biology: New technologies Enabling a More Complete Characterization of Disease Biology, Eric Schadt, Ph.D., Chief Scientific Officer, Pacific Biosciences
The Onco-SNP and Cancer Risk: microRNA Binding Site Polymorphisms as Biomarkers, Joanne B. Weidhaas, Ph.D., Assistant Professor, Therapeutic Radiology, Yale University
Expression Based Patient Stratification for Cancer Prognostics, Peter J. van der Spek, Ph.D., Department of Bioinformatics, Erasmus MC - Medical Faculty
Consumers and Their Genomes, Brian Naughton, Ph.D., Founding Scientist, 23andMe
Systematic Discovery of Cancer Gene Fusions using Paired End Transcriptome Sequencing, Chandan Kumar, Ph.D., Michigan Center for Translational Pathology, University of Michigan
Enterprise Scientific Workflow Environment Drives Innovation, Daniel J. Chin, Ph.D., Senior Principal Research Scientist, Roche Palo Alto
This year I presented a poster on biomarkers ala Pipeline Pilot™, attended talks, and caught up with professional colleagues. The Outrageous Character awards affectionately (and respectfully) go to Eric Schadt and Peter van der Spek. The Thank You award goes to Daniel for his kind words about our work together. The Exquisite Explanation awards go Joanne and Chandan. They did an amazing job of bridging any gaps in the audience’s varied background by presenting technical concepts in essential simplicity—truly beautiful. Brian gets the award for my Favorite DTC Genetics Company. I have spent many hours studying my own SNPs data (and that of my family members) thanks to 23andme. I have derived much pleasure from connecting with relatives, all over the world, that I found through the 23andme site. I am very grateful that I was able to get this type of genetic information AND the raw data, too.
As a product manager, I help map out where we move next to support omics-based research within our Pipeline Pilot™ collections. An area of great research interest is the role of microRNA (miRNA) in understanding disease pathways, diagnosis of diseases, and possible treatments. miRNA and small interfering RNA (siRNA) are gene products that collectively comprise a group of small nucleotides called RNA interference (RNAi). These gene products bind to other cellular RNA products that up or down regulate gene activity which, in turn, impact the proteins that our bodies manufacture. Proteins carry out the functions of life. A specific miRNA, although only 20 or so nucleotides long, can impact the hundreds of genes and hence their protein products.
Our knowledge about these miRNAs is growing rapidly. The number of miRNAs was less than 500 in May 2007; 9,539 in May 2009; and 10, 883 in Sep 2009. The rate at which miRBase is growing at and the rate at which miRNA publications are proliferating, demonstrates the exponential growth in interest.
We do know that miRNAs impact the immune system and cellular growth/development. miRNAs appear to mostly turn down gene activity and are being studied for their role in cancer, cardiac, and mental illnesses. [As an aside, I would say that the link to mental illness is sensible given the connections being proposed between infections and onset of schizophrenia or PANDAS with tics, to name a few.]
This week’s Science (Science 27 November 2009: 1284-1287) magazine contained a product summary for various technologies that are currently used for commercial miRNA microarrays: microfluidics, electronics, and Tailored DNA. This product summary conveniently lists several major players along with their websites, which you may find interesting.
Our omics R&D team creates component “readers” for various technology platforms to facilitate ease of analysis. I would be very interested in knowing which technology you feel is the most reliable now, and which you see as most promising 3 years from now. It appears that each technology has its own strength and weaknesses and the utility is also strongly based on the use case. I welcome your comments.
I started the Thanksgiving Week thankful that it was a short week. It needed to be short to recover from the action packed agenda at the 2009 Chemical and Biological Science and Technology Conference in Dallas the week prior. The conference was a huge success on many different levels. Although, the conference has been ongoing for the last few years, this was a first time combination of physical science and medicinal disciplines and to the credit of the conference organizers, it was well done! There were over 1400 people in attendance with over 600 poster presentations and countless oral presentations; however, even with the number of people and logistical challenges that existed, this was one of the best events I have attended (and I have attended a few).
I enjoyed the conference from the perspective that I was able to connect with former colleagues and make new friends (accomplices). However, the most important aspect for me was hearing about some of the great work that is going into making our country safer. The science and technology is cutting edge and driving innovation in so many different disciplines.
As mentioned in a previous post we were honored to present two posters;
Dr. Nick Reynolds presented a poster on “Applications of nanoscale simulations methods for understanding the structure and mechanisms of chemical sensors”.
Both posters were well received and very applicable to the technology challenges that we face; Dr Reynolds and Ms. Miller Latimer directed and managed the traffic expertly (and there were a lot of people at the presentation).
Over the past few conferences that I have been to, data management and integration is becoming an increasing concern to all the Federal Agencies as more and more data intensive programs come into existence. From new drug and vaccine discovery to biometrics, the data produced for use and reuse is overwhelming legacy systems and there is increasing focus on how to address this challenge.
Addressing this challenge and back to Ms. Miller Latimer’s discussion on Data Pipelining;
She demonstrated “data pipelining”, using Pipeline Pilot™, in a biomarker case study for ALI (Acute Lung Injury). As part of this analysis, Pipeline Pilot was used to analyze and integrate mass spec proteomics data with gene expression data and sequences using data pipelining. Additionally, this study also showed how to automatically mine the literature analysis results for differentially expressed genes/proteins and then publish enterprise-wide interactive solutions via web portals.
To underscore the interest in this integrative and flexible capability, Ms. Miller Latimer’s work was recognized as the best poster overall (over 600 poster were presented). I was proud to be there as she received the award from Colonel Michael O’Keefe, Deputy Director, Chemical/Biological Technologies, Defense Threat Reduction Agency. Accelrys is proud of Ms. Miller Latimer’s contribution. Well Done!!
Two Accelrys posters have been selected to be presented during this conference:
Dr. Nick Reynolds will be presenting a poster on “Applications of nanoscale simulations methods for understanding the structure and mechanisms of chemical sensors." The poster presentation will be on Wednesday, November 18 and will be part of the “Novel Material Science Approaches for CB Defense”
Nancy Latimer will be presenting a poster on “Using Data Pipelining to Analyze Biological Threats: A Biomarker Case Study." The poster presentation will be on Wednesday, November 18 and will be part of the “Integrative Informatics, Systems, and Synthetic Biology Approaches for CB Defense”.
As is the research and development for new drug and vaccines continues to be important to the general health of our country, we need to be mindful that there is always the possibility of emergent threats that will require rapid response. September 11, 2001 was a painful reminder of this and since, there has been significant progress made in capability to counter these threats.
Accelrys is proud of its contribution to enabling innovative discovery and will continue to work closely with both commercial and federal agencies to ensure that the Unites States continues to be on leading edge.
I am trying to concentrate on creating a “Biomarkers” poster for the Chemical and Biological Defense Science and Technology Conference that I am attending next month in Dallas. However, I have a hard time resisting my email. Just now, I received GenomeWeb Daily News that contained a blurb about: Amway to Sell Interleukin Genetics Health Tests, October 29, 2009.
I thought, "Is this really the Amway that my neighbor tried to get me to sell 30 years ago by telling me how great their laundry powder was?" Yes, it is. Can anyone have any doubt that the genomic era has arrived?
“The Weight Management Genetic Test is used in a program to determine if an individual is likely to lose weight more from low-calorie or balanced diets, or from increased exercise based on genotype.
The Heart Health Genetic Test uses variations in the IL1 gene in order to determine predisposition for inflammation, which has been implicated as a risk factor for heart disease, the company said.
The Nutritional Needs Genetic Test uses variations in genes related to B-vitamin metabolism and potential cell damage due to oxidative stress, and the Bone Health Genetic Test, which is expected to be available by the end of 2009, identifies susceptibilities to spine fractures and low bone mineral density associated with osteoporosis."
This is not necessarily a new phenomenon and there are lots of folks that feel they need to protect the public from spending money on these DTC tests. I find it interesting, however, that no one feels compelled to press the government or FDA to legislate the height of my red-spike high heels or how much my husband should be allowed to pay for them. We know these shoes wreck havoc on my back and knees, yet my husband will happily pay hundreds of dollars if he can only get me to wear them! And what about all those promises about the face cream that will make me look 10 years younger.
I am all for DTC genetic tests. I am still waiting on a few specific SNPs to be incorporated in the report before I send my spit to 23andme. Amway’s tests are very simple and, to me, are a new twist to DTC genetic testing. It is not necessarily about medicine but choices that I as a consumer should be allowed to make. I want to know how much will these tests cost? I don’t gamble but I am certainly into recreational genetic tests. Call me weird, call me Harriet, just make sure you call me eXXcited! Bring on the soap, baby. I’m ready.
Scott Markel’s article, “Drowning Research Scientists, Meet Life Preserver,” found in the Sep 16, 2009 version of Drug Discovery & Development makes an impressive case for using pipelining technology in bioinformatics research community and in the broader biomarker and translational research communities. As he points out, there will never be a one-size fits all research approach for these scientific communities. The sheer volume of data sources and open source and third party integration opportunities just continue to grow and Pipeline Pilot, a leader in data pipelining, is uniquely capable of handling this challenge.
I loved his conclusion: Rather than relying on standard templates, users should be able to configure what they want to see and how it is presented. This degree of flexibility leaves room for the innovation so vital to these initiatives, while still providing a framework for faster decision-making and ultimately faster results.
Scott is a Vice-President and member of the Board of Directors of the International Society for Computational Biology. Scott is also the head of ACCL’s talented biosciences R&D team and developer/architect extraordinaire. I get paid to work with him. Lucky me.
Chatting with Christopher Lipinski at Drug Discovery & Development Week
Some ten years ago, I first “met” the Lipinski rules in a software project. That was my last direct “hands-on” encounter with chemistry. At Accelrys I am the senior product manager for the Biosciences and Analytics Collections for Pipeline Pilot. Think genomics, proteomics, sequencing, and ontologies and not chemistry! This week I was at the DDDW show in Boston – don’t think “booth babe”.
The conference was not as busy this year as it had been in the past and it was the afternoon of the last day. A distinguished gentleman walked up to our booth wearing a name tag of “Christopher A. Lipinski,” happy to see a fellow booth dweller. Half in jest I asked if he might be the man with 5 rules. Turns out he was and, boy, I was in for an intellectual treat. That Lipinski filter came to life in a new way over the next hour or so. I was spell bound by Dr. Lipinski’s breadth of knowledge, passion for science, and his out of the box thinking. What I didn’t anticipate were his insights into the importance of chemistry for the biomarker and translational research space.
He was saying some really awesome things so I started writing them down. It was hard to focus on note taking because Dr. Lipinski is an excellent speaker and very animated. Below are a few items that I am willing to share in no particular order:
Translational research must have good chemistry married to good biology.
Your company (Accelrys) combines chemistry and biology in one software application. If biologists are using your software to look at high throughput screening (assay) data that has associated chemical structures, they could better filter out results for poor compounds.
When faced with people problems (like chemistry—biology conflicts) versus technical problems—the people problems are always much more difficult to solve.
The people side is the most important.
NIH is making good strides in the dialog between chemists and biologists.
As soon as the biologist has an assay for a small molecule they should probe/stress test the assay with compounds known historically to cause assay problems.
In software for the (bench) biologist – it needs to be dead easy. Too many peer-reviewed publications have great biology but rotten chemistry.
Biologically active compounds are tightly clustered in chemical space. It is always best to look for new activity in areas of chemical space where you previously found activity.
It takes 10 years to “mature” a medicinal chemist. He then becomes an expert in pattern recognition even if he can’t articulate why certain structures look better than others
Many previously proprietary databases are now in the public domain (See PMID: 17897036). These provide a great starting point for the discovery of drugs for rare diseases.
Dr Lipinski’s long and prestigious career in medicinal chemistry, assay development, computational chemistry, and now in consulting, lecturing, and as an expert witness does not look anything like retirement. That is good news for me.
Dr. Lipinski is shown here with his rapt audience.
Note: Lipinski’s total number of rules actually equals 4. His rules are known as the “Rule of Five” because each of them incorporates the number 5 in some way. For all you literalists out there, “5 Rules” should be interpreted in this way.
At the World Biomarker Congress in Philadelphia this past week, I had a chance to catch up with a colleague, now a senior executive at a European-based global pharma company. Our conversation inevitably turned to Personalized Medicine, a shared interest of ours.
He updated me on some pre-release data that will be shown at Sunday’s meeting of the American Society of Clinical Oncologists (ASCO), concerning Iressa, Astra Zeneca’s lung cancer medication. Previously thought to be a commercial and scientific failure, Iressa is now at the vanguard of therapies “rescued by targeting.”
Targeted therapies are drugs that are shown to have a particular effectiveness in a subset of the overall population. “Targetting” in this context refers to the identification of a genetic difference which corresponds to better clinical outcomes for a particular group of patients. In the case of Iressa, the data that will be presented tomorrow shows that cancer progression is halted for over nine months in patients with the mutation, compared with 6 months for patients receiving chemotherapy (median values).
About one in ten cancer patients has this mutation. Overall, lung cancer kills 1.3 million people per year.
But what if a patient doesn’t have the mutation? Then Chemotherapy is the better treatment option, which can hold back the cancer progression for five months, compared to only 1 month for Iressa (again, median values).
If these results are confirmed, Iressa will join the growing list of personalized medicine success stories in Oncology, which began with world’s first targeted therapy, Genentech’s Herceptin, in 1998. Since Herceptin, we’ve seen other highly publicized therapies with genetic targeting, such as Erbitux.
But why so much genetic targeting in cancer, and not (yet) in other indications? Is it the serious nature of the disease or the quality of the data (high compliance in large populations) or something else? The Iressa story gives us a clue.
Astra Zeneca didn’t give up on it, and pursued semi-anecdotal findings of efficacy in some patients, even though it was not effective in the larger clinical trial population. Because of the large potential revenues resulting from effective cancer treatments, it becomes economic for companies to invest in risky clinical trials for treatments that might only be effective in 10% of the population.
As my colleague summed it up during lunch at a café on Rittenhouse Square in Philadelphia, “It’s about the money, of course. Cancer kills, and so cancer treatments cost.”
Oncology is clearly the vanguard for targeted therapies. But as scientists and marketing executives become more familiar and comfortable with a development process that results in a fragmented market, the techniques will inevitably be replicated in treatments that can only demand lower prices because they treat less serious diseases.
And that will make us all winners, no matter what mutations we have.
The abstracts for the semi-annual meeting of the American Society of Clinical Oncologists (ASCO) go up on their website this Thursday, May 14 at 6PM EST. This is a scientific conference that consistently reverberates on Wall Street, because so much of pharmaceutical sales is driven by cancer indications. Many of the largest mergers over the last six months had oncology as the subtext, such as Roche & Genentech and Eli Lilly & ImClone.
At a recent ASCO conference in January, 2009, “personalized medicine” went from a theoretical concept from science to a genuine business reality. At that conference, ASCO recommended a genetic test for a mutation in a crucial gene on human chromosome 12, called "KRAS," that regulates cell division via signal transduction. If a colorectal cancer patient had the mutation, entire groups of therapies, called "anti-EFGRs," were no longer recommended. This is not a rare mutation, as an estimated 40% of patients have the mutation.
The result? Profound, immediate changes in market share potential for pharma companies offering the anti-EFGR monoclonal antibody therapies cetuximab and panitumumab.
In terms of pharmaceutical revenue, this is a very big deal. Each therapy carries a price tag that reflects the critical nature of the cancer indication, generally over $2000 per month. There are 150,000 new cases diagnosed in the US every year (resulting in 50,000 deaths). So just a simple calculation of the market shows that about $1.5 billion annual new business disappeared for makers of anti-EGFRs (40% of patients x $2,000 per month per patient x 12 months x 150,000 new patients per year), which of course excludes revenues from the estimated 400,000 current colorectal cancer patients.
And in terms of fighting this nasty scourge, the ASCO announcement was a very big deal. It personalized the treatment for 60,000 new patients annually (40% x 150,000) who would have otherwise placed their hopes for survival on a therapy that simply wouldn't work for them.
The trade name for Cetuximab is Erbitux(FDA approval 2004), which is marketed in the US by ImClone & BMS, and in the rest of the world by Merck. Panitumumab is marketed by Amgen globally as Vectibix (FDA approval 2006).
Based on the stock market dip over the last 18 months (called the "Global Financial Crisis"), it is hard to discern definitively what effect the ASCO recommendation had on the stock prices of the companies involved.
But the bigger change will likely be observed internally at these companies, as they continue to commit resources to biomarker discovery and qualification. Biomarker activities around KRAS might have identified the lack of efficacy in the mutant form, which corresponds to not being effective in 40% of patients.
When it comes to post-hoc personalized medicine for blockbuster drugs, the pharma industry clearly doesn’t like surprises. Biomarker activities and translating those activities into clinical trials push those surprises into the research phase, where they belong.