Mass Spec: Shedding Light on Cancer Biomarkers with Century-Old Technology

October 5, 2016 | Posted by Christina Cordova in Research, Stories, Uncategorized |

Imagine telling the inventor of the radio that the technology he discovered was now found in almost every kitchen in America, and that you used it to make your popcorn last night. He’d probably be surprised, and maybe you are, too.  Sound far-fetched? Many aspects of modern life rely on technology that was first identified by 19th century physicists and then adapted to new applications. This not only includes microwave ovens from the example above, but state-of-the-art lab equipment which is poised to change the way researchers treat cancer. It might be hard to imagine cutting-edge discoveries in proteomics or precision medicine are the result of technology first conceived over a hundred years ago, but that’s what a new application called proteomic mass spectrometry imaging is doing for cancer diagnostic tests.

Many life scientists utilize research tools built on principles first explored and defined by physics, and mass spectrometry is a particularly impactful example. The technology we now use to measure mass-to-charge ratios of ions for the purpose of molecular analysis was first developed by J.J. Thomson on an instrument called a parabolic spectrograph in 1913. The spectrograph generated ions in gas discharge tubes, then passed the ions through parallel electric and magnetic fields. Subjecting the ions to these fields forced them to move in certain parabolic trajectories which would then be recorded on a photographic plate, as seen in the rather beautiful image below.

Discovery_of_neon_isotopesIt was Thomson’s research at the end of the 19th century that lead to the discovery of the electron, work that eventually won him the Nobel Prize in physics in 1906. To hear a 77 year-old Thomson talk about that research (and how very small electrons are at around the 2:50 mark), watch this video filmed in 1934.

Besides the name change (there aren’t any spectrographs in labs these days), mass spectrometry has come a long way technologically. Advances by subsequent researchers made the technology more precise and the resulting output more accurate. In 1920 the first modern mass spectrometer was developed by Arthur Dempster, of uranium isotope fame, and by the 1970s scientists had begun experimenting with joining liquid chromatography techniques to the process. In 1989 the first LC-MS instrument was launched, securing it as a ubiquitous technique now in its third decade of use. The staying power of this technology is due to its versatility; it is able to directly analyze any biological molecule receptive to ionization. Scientists can use LC-MS to better understand the molecular structure of everything from wastewater to skin cream. The data collected during analysis can inform evaluation of product effectiveness, environmental toxins, or the function of a protein. For this reason it provides valuable research applications in environmental analysis, consumer products, agriculture, and in this case, precision medicine.

Now a bona fide buzzword, the concept of precision medicine was catapulted into the social vernacular in 2015 when President Obama announced the Precision Medicine Initiative in his State of the Union Address. In practice, precision medicine isn’t entirely new; physicians and researchers have long understood the importance of individualized factors in treating or diagnosing patients. The concept of blood type matching and bone marrow donation registries are both examples of precision medicine we have accepted as standard treatments. Advances in biotechnology are ushering in a new emphasis on specialized medicine and carry with it the hope of more effective diagnostics and treatments for ailments like cardiovascular disease and cancer. Much of this promise rests on discoveries being made in the field of proteomics, particularly about the role of proteins in healthy cells versus diseased cells. The form, function, and interaction of these proteins can indicate the presence of disease, identify molecular therapeutic targets, and help define molecular disease taxonomies for future research. Finding a measurable indicator for any of these biological states is called a biomarker, making it the focus of many proteomics and cancer researchers.

It turns out, a very familiar technology is proving to be the best tool for unlocking the largely unknown world of proteins. LC-MS breaks down the complicated protein structures from their three dimensional form, and then into even smaller units called peptides. The quantitative analysis of these peptides makes it possible for scientists to identify protein expression profiles associated with certain cancers. Clinically viable biomarker panels could greatly increase early detection and definitive disease identification in patients, both of which are known to improve patient survival rate. This specificity in diagnosis allows patients and physicians to be better informed when making treatment decisions by understanding the disease on a molecular level. Biomarkers can improve standard differential diagnosis descriptions, which up to now have largely included physical symptoms that manifest at later stages of disease development, like metastasis. Some diseases like malignant melanoma present in very cryptic ways, making them difficult to diagnose, even for highly trained dermatopathologists. Inconclusive biopsy results or histological features that are also found in non-cancerous moles complicate diagnosis and can lead to costly mistakes in the course of treatment for such a common and potentially deadly disease. According to the American Cancer Society over 10,000 people will die this year from the disease, making it the most lethal of all skin cancers. A collaborative research project between Yale scientists and Protea Biosciences is seeking to change that with a new diagnostic technology. In April of this year they announced exclusive licensing for a method which uses unique protein expression profiles to discern the presence of cancer. The results of the first clinical study were presented in 2015, showing 99 percent accuracy in identifying malignant melanoma and benign melanocytic nevi.

Achievements like this highlight the benefit of partnerships between academia and industry, which are becoming more common in many sectors of biotechnology. If precision medicine is to become a reality, it will have to tackle complex disease models that have historically confounded individual pharmaceutical companies or research labs. Open innovation between researchers on both sides advances scientific discovery and expedites successful clinical implementation of potentially life-saving drugs. As scientists work on more complicated human health issues, they will need to find collaborators who are best suited to solve the research objective at hand, while accessing novel technologies best suited for the job.

Just as the concept of precision medicine has expanded with scientific discoveries in biotechnology, the technique of mass spectrometry has evolved to address new research questions with advances in bioinformatics and lab technology. Deciphering the human proteome is still a ways off, but innovative techniques and research partnerships will surely have a role to play in unlocking the power of proteomics for human health. As LC-MS capabilities continue to improve, new disease diagnostics and treatments will be added to the arsenal of options available to physicians. The next time you hear about an advancement in precision medicine (or pop a bag of popcorn), thank a physicist.

Looking for a cutting-edge collaborator like Protea to help with your research project? Visit our marketplace to find the right provider for your mass spec analysis, or any of the thousands of experiment types we offer.

The Importance of Replication Studies

July 28, 2016 | Posted by Team in Company, Reproducibility, Research, Science Exchange News, Uncategorized |

My TEDMED talk about scientific reproducibility was released today, so I wanted to take the opportunity to provide some additional thoughts about the importance of replication studies.

Every year, billions of dollars are spent funding biomedical research, resulting in more than one million new publications presenting promising new results. This research is the foundation upon which new therapies will be developed to enhance health, lengthen life, and reduce the burdens of illness and disability.

In order to build upon this foundational research, these results must be reproducible. Simply put, this means that when an experiment is repeated, similar results are observed. Over the last five years, multiple groups have raised concerns over the reproducibility of biomedical studies, with some estimates indicating only ~20% of published results may be reproducible (Scott et al. 2008, Gordon et al. 2007, Prinz et al. 2011, Steward et al. 2012, Begley and Ellis 2012). The National Institutes of Health (NIH), the largest public funder of biomedical research, has stated, “There remains a troubling frequency of published reports that claim a significant result, but fail to be reproducible. As a funding agency, the NIH is deeply concerned about this problem”.

Despite the growing concern over lack of reproducibility, funding for replication studies, the only way to determine reproducibility, is still absent. With no funding systematically allocated to such studies, scientists almost never conduct replication studies. It would be interesting to obtain the exact numbers, but it appears that last year the NIH allocated $0 to funding replication studies, out of a $30B+ budget. In the absence of replication studies, scientists end up wasting precious time and resources trying to build on a vast, unreliable body of knowledge.

It is easy to see why funders might shy away from funding replication studies. Funders want to demonstrate their “impact,” and it is tempting for them to solely focus on funding novel exploratory findings that can more easily be published in high profile journals. This is a mistake. Funders should instead focus on how to truly achieve their stated goals of enhancing health, lengthening life, and reducing the burdens of illness and disability. Although allocating a portion of funding towards replication studies would divert funds from new discoveries, it would enable scientists to efficiently determine which discoveries were robust and reproducible and which were not. This would allow more rapid advancements by allowing scientists to build upon the most promising findings and avoid wasting their time and funding pursuing non-robust results.

Some researchers find the idea of replicating previous studies unnecessary or even offensive. However, it is the responsibility of the scientific community, including funders, to work as quickly and cost effectively as possible to make progress. Introducing replication studies as part of the process provides an effective way to enable this.

If you would like to see funding specifically allocated for replication studies, please register your support. We will share this information with funders in the hope that it will encourage them to establish funding programs specifically for replication studies to improve the speed and efficiency of progress in biomedical research.

by Elizabeth Iorns, Ph.D.

CEO and Co-Founder

Science Exchange

About Science Exchange

 

Science Exchange is the world’s leading marketplace for outsourced research. The Science Exchange network of 3000+ scientific service providers has run the experiments for the major replication studies that have been conducted to date including the largest biomedical replication study undertaken (Reproducibility Project: Cancer Biology). Additional details are available here: https://www.scienceexchange.com/applications/reproducibility

 

References

  1. https://www.nih.gov/about-nih/what-we-do/budget#note
  2. http://www.ncbi.nlm.nih.gov/pubmed
  3. https://www.nih.gov/about-nih/what-we-do/mission-goals
  4. Scott et al. Amyotroph Lateral Scler. 9, 4-15 (2008)
  5. Gordon et al. Lancet Neurol. 6, 1045–1053 (2007)
  6. Prinz et al. Nat Rev Drug Discov. 10, 712 (2011)
  7. Stuart et al. Experimental Neurology 233, 597–605 (2012)
  8. Begley and Ellis. Nature. 483, 531-3 (2012)
  9. http://www.nature.com/news/policy-nih-plans-to-enhance-reproducibility-1.14586
  10. http://www.nature.com/news/reproducibility-the-risks-of-the-replication-drive-1.14184

 

 

Science Exchange Acquires OnDeckBiotech to Expand Scientific Services Marketplace in Biotech Industry

June 7, 2016 | Posted by Team in Company, Science Exchange News, Uncategorized |

Science Exchange, the world’s leading marketplace for scientific research, announced today that it has acquired OnDeckBiotech, an international community and marketplace that connects biopharmaceutical companies with contract service providers. The acquisition brings together two of the major platforms for outsourced scientific services, and strengthens Science Exchange’s market-leading position by significantly increasing its global network of contract research organizations, core facilities, and other scientific service suppliers.

“Over $40B a year is spent on outsourced scientific research by the top 50 pharmaceutical companies alone, and much of this spend is highly fragmented across thousands of individual scientific service suppliers. Platforms for outsourced scientific services, like Science Exchange and OnDeckBiotech, solve the challenges associated with this fragmentation by providing scientists with efficient access to a diverse network of qualified suppliers under a single relationship,” said Dr. Elizabeth Iorns, Co-founder & CEO of Science Exchange. In praising the fit of the two companies, Iorns added, “OnDeckBiotech has developed a number of strategic relationships with industry groups and research foundations which complement the direct channels Science Exchange has developed with biopharmaceutical, government, and academic researchers.” OnDeckBiotech’s relationships, which include MassBio through the MassBio Gateway, the Biotechnology Innovation Organization (BIO) through BIO BizLink, and the Alzheimer’s Drug Discovery Foundation (ADDF) through ADDF ACCESS, will continue to be supported by Science Exchange as part of its strategy to become the ubiquitous platform for scientific outsourcing across all disease areas and stages of research and development.

As part of the acquisition, Science Exchange will take over OnDeckBiotech’s office in Cambridge, MA, giving Science Exchange a physical presence in two of the world’s largest and fastest growing biotech research clusters. “Science Exchange already works with 8 of the 10 largest pharmaceutical companies, many of which have invested heavily in these two clusters.  Now with offices in Palo Alto and Cambridge, in addition to Account Managers operating remotely in San Diego, New York, and other core markets, our team is uniquely positioned to help researchers inside these organizations access the world’s leading scientific service providers and most innovative scientific technologies,” said Iorns.

OnDeckBiotech’s Founder & CEO, Cliff Culver, will join Science Exchange as VP, Strategy and General Manager, Boston as part of the acquisition. “Cliff has been a visionary in the outsourced scientific services space, and we’re incredibly excited for him to join our team and continue our joint mission of enabling better, faster, and more efficient scientific collaboration,” said Dan Knox, Co-founder & COO of Science Exchange. Culver added, “We can’t wait to get started working with Science Exchange. The industry consistently reports that time and effort spent identifying and managing outsourced contracts hurts research productivity. Our companies have each demonstrated the value we can create by addressing these challenges, and our combined platforms and networks are uniquely positioned to continue to lead the market.”

Iorns concluded, “The total transactional volume of experiments conducted through the Science Exchange platform grew over 500% in 2015, and the OnDeckBiotech acquisition will further accelerate our already remarkable growth in 2016.”

About Science Exchange

Since its founding in 2011, Science Exchange has become the world’s leading marketplace for scientific research. Through Science Exchange, researchers can securely access a network of 1,000s of screened and verified contract research organizations (CROs), academic labs, and government facilities that are available to conduct scientific experiments. Science Exchange has been used by researchers from over 2,500 different companies and organizations, including many large pharmaceutical companies and government research facilities like the NIH, the FDA, and NASA. The company’s mission is to enable breakthrough scientific discoveries by providing researchers with easy access to the world’s best service providers. To date, the company has raised over $30 million from Maverick Capital Ventures, Union Square Ventures, Index Ventures, OATV, the YC Continuity Fund, and others.

Science Exchange Announces $25 Million in New Funding Led by Maverick Capital Ventures

March 23, 2016 | Posted by Team in Company, Science Exchange News, Uncategorized |

Science Exchange, the leading marketplace for scientific research, announced today that it has raised $25 million in new funding. The latest funding round was led by Maverick Capital Ventures and also included participation from Union Square Ventures, Index Ventures, YC Continuity Fund, Sam Altman, and others.

Since its founding in 2011, Science Exchange has become the world’s leading marketplace for scientific research services. The company provides secure access to a network of 1000s of screened and verified contract research organizations (CROs), academic labs, and government facilities that are available to conduct experiments on the behalf of scientists. The Science Exchange platform has been used by scientists from over 2,500 different companies and organizations. The company has experienced significant growth in the last 12 months, including seeing the total transactional volume of experiments conducted through the Science Exchange platform grow over 500% in 2015.

“Over $40B a year is spent on outsourced scientific research by the top 50 pharmaceutical companies alone. Much of this spend is highly fragmented across thousands of individual scientific service suppliers, and this fragmentation represents a challenge to both individual scientists and sourcing procurement departments,” said Dr. Elizabeth Iorns, Founder & CEO of Science Exchange. “The Science Exchange platform solves this challenge: we provide scientists with efficient access to a diverse network of qualified suppliers under a single relationship, and at the same time we provide sourcing departments with more information and control over their outsourcing spend.”

8 of the top 10 pharmaceutical companies now use Science Exchange, viewing it as a way to efficiently access innovative external resources. Science Exchange also helps tackle one of the most significant challenges facing the highly-trained researchers at these companies: time and resources spent identifying and managing outsourcing contracts. James Lillie, VP In Vitro Biology at Genzyme (a Sanofi company), was recently quoted as saying, “We now look at the Science Exchange as the best way of finding new outsourcing opportunities with collaborators and CROs. We’re shifting more of our efforts for new outsourcing contracts there.”

As part of the Series B, Maverick Capital Ventures Managing Partner David Singer (former Founder/CEO of Affymetrix, GeneSoft Pharmaceuticals, and Corcept Therapeutics) will join the company’s board. “We spent a lot of time evaluating the growing market for outsourced scientific services. We concluded first, that there is an expanding market need for a marketplace to aggregate the thousands of suppliers, and second, that Science Exchange is poised to become the ubiquitous platform for scientific outsourcing,” said Singer.

Andy Weissman, Partner at Union Square Ventures, who has been on the company’s board since 2013, agrees. “With over 500% growth in marketplace transaction volume in 2015 and some companies already spending over $1M each month on the platform, Science Exchange is the clear market leader,” said Weissman.

Science Exchange is headquartered in Palo Alto, CA, and has clients, including many large pharmaceutical companies, around the globe. The company has now raised over $30 million and plans to use the new funding to expand its team in all areas including product, engineering, sales, marketing, and customer success. The full list of investors in the latest round is Maverick Capital Ventures, Union Square Ventures, Index Ventures, OATV, YC Continuity Fund, Windham Venture Partners, Collaborative Fund, Fenwick & West, Jose Suarez (CEO of TEDMED), Sam Altman, Steve Case, Kal Vepuri, Jenny Haeg, Alexander Levy, Paul Buchheit, and Silicon Valley Bank.

 

 

 

The UCLA Microarray Core just received new HiSeq 3000 and HiSeq 4000 instruments

September 28, 2015 | Posted by Keith Osiewicz in Uncategorized |

The UCLA Clinical Microarray Core/JCCC Genomics Shared Resource (CMC/GSR), directed by Dr. Xinmin Li, just received new Illumina HiSeq 3000 and HiSeq 4000 instruments. These instruments greatly expand the lab’s ability to sequence nucleic acids and perform many next generation sequencing applications including whole genome and whole exome sequencing. Here is a table from the Illumina website describing the capabilities of these new instruments.

illumina-3-4-use

View all of the the UCLA Microarray Core’s services.

 

The Reproducibility Project: Cancer Biology – Experiments have begun

July 10, 2015 | Posted by Keith Osiewicz in Uncategorized |

The RPCB is a first of its kind attempt to directly replicate a subset of high-impact, pre-clinical cancer biology papers. Importantly, the methodology, quality control steps and replication data will be open and accessible on the Open Science Framework.

We are very excited to report that 13 Registered Reports have been accepted in eLife, and experiments from 12 of those studies are underway. These include:

  • Registered Report: BET bromodomain inhibition as a therapeutic strategy to target c-Myc
  • Registered Report: Interactions between cancer stem cells and their niche govern metastatic colonization
  • Registered Report: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs
  • Registered Report: Discovery of preclinical validation of drug indications using compendia of public gene expression data
  • Registered Report: Intestinal inflammation targets cancer-inducing activity of the microbiota
  • Registered Report: Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells
  • Registered Report: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors
  • Registered Report: Transcriptional amplification in tumor cells with elevated c-Myc
  • Registered Report: Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
  • Registered Report: Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
  • Registered Report: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
  • Registered Report: Melanoma genome sequencing reveals frequent PREX2 mutations

Before each replicating lab begins experimental work, critical reagents (often kindly shared by authors of the original studies) are quality checked. For example, all of the cell lines are authenticated and mycoplasma tested, plasmid sequences are sequenced, and rodents are pathogen tested. These quality check steps will be included on the Open Science Framework along with the data for the replication experiments themselves.

 

Tracking Our Progress

Keep track here as we continue to move projects forward. Our current status as of July 2015 is described below:

Reproducibility project progress

Phase:

  1. Replication experiments identified for each original paper
  2. Protocols drafted
  3. Protocols transferred to Registered Report format
  4. Review and feedback from original authors (requests for necessary reagents)
  5. Expert provider identified
  6. Registered Report peer reviewed at eLife
  7. Experimental work
  8. Experiment work is finished
  9. Replication experiments analyzed and evaluated
  10. Replication Study published in eLife

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