Tag Archives: Research

This article was originally published on Assay Depot blog.

In the world of drug discovery, pharmaceutical companies face a very sobering statistic – more than 90% of the drugs that reach clinical testing will fail. This high failure rate is not only a major financial concern for the pharma industry, but it also negatively affects the millions of patients that are sick and desperately waiting for new medicines. Reducing the clinical failure rate is a critical step in creating a more successful and sustainable pharmaceutical industry.

Researchers in pharma/biotech and academia faced a similar challenge during the late 1980s and early 1990s with AIDS/HIV. At that time, the scientific community was able to rapidly and successfully develop several anti-HIV drugs thanks, in no small part, to the use of pre-competitive research collaborations. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA), writes, “precompetitive research is a subset of translational research that focuses on improving the tools and techniques needed for successful translation, and not on development of a specific product.” In a precompetitive collaboration, a variety of different organizations (that typically would compete with each other) work together or share information. For AIDS/HIV research, partners that worked together precompetitively included pharmaceutical and biotech companies, academic research centers and government research institutes.

Pharmaceutical companies have historically done all of their drug discovery research in house. But in the last 10 years, it has become increasingly clear that the pharmaceutical industry must change its research model if it is to remain viable. Challenges facing the industry include:

  1. Increasing cost of research coupled with abysmal rates of clinical success
  2. Expiration of patent protection leading to loss of exclusivity (the so-called patent cliff)
  3. Competition from biosimilars and generics

Precompetitive Collaboration – A Strategy for Success

To address these challenges, some pharmaceutical companies are, for the first time, engaging in precompetitive partnerships with other pharma competitors, with government organizations and with academic research centers. For example, the large pharma company GlaxoSmithKline recently formed a precompetitive collaboration with the Wellcome Trust Sanger Institute and the European Bioinformatics Institute to establish the Center for Therapeutic Target Validation (CTTV). The three organizations will pool resources to discover new potential drug targets that all of the partners will be able to access.

Precompetitive Collaboration
Precompetitive Collaboration is rapidly becoming a necessity in drug development (Image Credit: NIH.gov)

Similarly, the US National Institutes of Health (NIH) launched a precollaborative effort called the Accelerating Medicines Partnership (AMP) to identify efficacy and safety issues for compound collections that serve as the starting points for many new drug discovery projects. By working precompetitively to identify compound liabilities early in the research process, it is hoped that everyone will benefit from reduced clinical failure rate.

Additional precompetitive partnership examples include the Innovative Medicines Initiative (IMI) in Europe, the Critical Path Institute (CPI) in the US, the Structural Genomics Consortium (SGC) and Oxford University’s Target Discovery Institute (TDI). These partnerships are specifically geared toward translational research that will lead ultimately to the commercialization of new medicines.

Pharmaceutical companies and other large research organizations are beginning to work together precompetitively in other ways as well. Pfizer, AstraZeneca, the US National Cancer Institute and a host of other biotech, pharma and academic organizations have worked together with Assay Depot to create preclinical research marketplaces that share precompetitive information. Each Assay Depot client has its own private research marketplace but the underlying supplier and service databases are shared precompetitively. In 2015, some of the pharma companies will begin sharing supplier ratings as well.

Precompetitive research partnerships can, at times, be difficult to manage owing to the size and bureaucratic nature of large research partners. At times there are also legal challenges involving intellectual property rights that are often difficult to overcome. Nevertheless, the pooling of resources early in the drug discovery process, before a drug candidate has been selected for the clinic, should have an outsized effect on pharma productivity, leading to both increased innovation and reduced costs.

That said, it is important to understand that the time to act and establish precompetitive collaboration is now; as Janet Woodcock says in her article, “(T)he success of the drug development enterprise over the next decade may be at stake.”

This week witnessed a horrifying plane crash in Ukraine. Another Malaysian Airlines flight went down – this time shot down by a missile. Almost 300 lives were lost in this crash. Among the people killed on this flight was a group of AIDS researchers, traveling to the International AIDS Conference to be held in Australia. The entire AIDS research is in a state of shock. “These were men and women who had dedicated their own lives to saving the lives of others, and they were taken from us in a senseless act of violence,” said President Barack Obama at a White House news conference.

Here’s a roundup of other articles and news on genomics, medicine, business and policy from this week.

sciberomics roundup genomics
Sciberomics Weekly Roundup (Image Credit: www.dhs.gov)

Science and Medicine

Malaria and resistance to drugs

Resistance is an emerging problem for drugs used to treat malaria. Newer, more effective approaches are necessary to counter this scourge. Now, researchers from Australia report in a recent study published in Nature about a protein designated PTEX that can form a novel drug target against malaria.

Gene Therapy and the heart

A study published this week demonstrates that ordinary cardiac muscle cells can be converted into specialized cells that beat steadily. These cells were converted by using a gene therapy procedure. If successful, this procedure may replace implanted electronic pacemakers for cardiac patients with rhythm abnormalities.

We choose our friends wisely!

It has always been a mystery as to how we “choose” friends. Now genetics or genomics may have the answer. Or at least, an answer. A recent study using genome-wide association studies (GWAS) shows that we pick friends who have more DNA in common with us than those we do not. Friends are as similar genetically as fourth cousins (~1% genes similar).

Gut microbiome and disease

Our gut is home to hundreds of thousands of microbes that are increasingly being recognized as being important in maintaining our health. However, the question still remains whether sequencing the gut microbiome is of any value in predicting the health. This article discusses how we can detect changes in our health by looking at our microbiome.

Clinical Studies

New Alzheimer’s Trial

In partnership with Banner Alzheimer’s Institute from Phoenix, AZ, Novartis will conduct a clinical study to test experimental drugs for patients with Alzheimer’s who are genetically predisposed to the disease but without symptoms. The two test drugs will target the amyloid protein that accumulates in the brains of Alzheimer’s disease patients. This study will be funded in part by the National Institutes of Health, through a $33.2 million grant.

Regulatory

Approval for CombiMatrix test

The molecular diagnostics company, CombiMatrix Corporation recently developed a chromosomal microarray analysis (CMA) test that can identify development disorders in children with developmental delays, birth defects, physical deformities or autism or autism spectrum disorder. This test was conditionally approved by the New York Department of Health for patient samples.

Business

Translation of Genomics - Illumina buys Myraqa

The sequencing giant Illumina recently acquired Myraqa, a consulting firm that specializes in companion diagnostics. Experts believe that this deal will strengthen Illumina’s capabilities to take genomics into the clinic. Myraqa is expected to provide Illumina with expertise in regulatory, quality, clinical, biostatistics and development, focusing on regulatory strategy and application support.

What a week! I spent most of it at the 2014 BIO International Convention and truly enjoyed the feeding frenzy. Sessions covering biopharmaceutical companies, business partnering, new therapies, science, the business of science, talks, panel discussions, high-profile keynotes by Richard Branson and Hillary Clinton, exhibitor sessions, receptions, and watching World Cup football (soccer) matches – there was so much to listen to, so much to learn, so much to think about.

Sciberomics Science Biotech BIO2014
Former Secretary of State Hillary Rodham Clinton at the Keynote Luncheon, BIO2014 with Jim Greenwood, President and CEO of BIO (Image by author)

Towards the end of BIO2014, the Scientific American WorldView session featured a thought-provoking discussion on the biotech and life sciences development on the global stage. David Brancaccio, host of Marketplace Morning Report moderated this session. It was here that the latest issue of Scientific American worldVIEW was released.

Biotech San Diego BIO2014
David Brancaccio, host of Marketplace Morning Report at the BIO2014 Scientific American worldVIEW super-session (Image by author)

In addition, at Sciberomics, I have posted articles that I wrote while covering sessions at #BIO2014.

Sciberomics

Bioethics of Compassionate Use of Drugs

Drug Development – A Bioethical Minefield

Future of Cancer Therapeutics

Are Public-Private Partnerships The Way Forward?

Here’s a roundup of other articles and news on science, medicine, and policy from this week.

Science and Medicine

California governor Jerry Brown signed into law a state budget allocating $2 million for California Blueprint for Research to Advance Innovations in Neuroscience (Cal-BRAIN) project. This project will be run in coordination with the national Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative.

We are so “connected” to our cellphones today that phones now carry the microbiomes of their owners. Read more in the original study on microbiome and cellphone.

In a recent study published in the journal Nature, researchers have developed a vaccine against brain cancer and tested it in mice. This vaccine targets a specific mutation of isocitrate dehydrogenase 1 – IDH1, found in a subgroup of patient with the brain tumor, glioma. Studies in mice show that this vaccine can prevent tumor progression.

A new study shows that an implant into the brain of a paralyzed person helped him move his hand with the power of thought.

UK has revived an old competition and the people voted on what area of science this competition should cover. Antibiotic resistance was the people’s choice. Known as Longitude Prize, this initiative involves a prize of £10 million ($17 million).

A recent NPR news article talks about CRISPR, a new technology that allows editing the genome.

Business

The pharmaceutical giant Roche and startup Stratos Genomics will now collaborate to develop a method for single molecule sequencing of DNA fragments using protein nanopores.

That is all for this week. Now, it is time to ruminate on everything that went on this week. And I'm looking forward to a quiet weekend, watching football matches from the round of 16.

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The tide is turning. Finally!

It has been four decades since the initiation of President Nixon’s “War on Cancer”, but never have the signs for victory looked so encouraging. This is an exciting phase in cancer research, so much so that some in the field are even using the “c” word. Cure!

So what is happening in the world of cancer therapeutics? And where are we headed? This was the topic of the Super Session: “A New Paradigm in Oncology Treatment” on Tuesday, June 24, 2014 at the 2014 BIO International Convention.

The thought-provoking discussion in this session reviewed current approaches and obstacles in oncology treatment, and discussed the way forward. Moderated by Susan Schaeffer of BioCentury, the panelists included:

  1. Ronald DePinho, MD Anderson Cancer Center
  2. Peter Lebowitz, Janssen Pharmaceutical Companies of J & J
  3. Bahija Jallal, AstraZeneca and MedImmune
  4. Robert Hugin, Celgene Corporation
  5. Jeff Allen, Friends of Cancer Research
Big Data, Cancer Therapeutics
Panelists at the Super Session "A New Paradigm for Oncology Treatment" (from L to R): Susan Schaeffer, Ronald A. DePinho, Peter Lebowitz, Bahija Jallal, Robert Hugin, Jeff Allen (Image Credit: BIO via Flickr)

Advances in Cancer Biology and Medicine

Developments in the omics fields have enabled scientists to molecularly characterize different cancers. Since each person’s cancer is different, the ability to profile a cancer is proving to be a valuable tool in the clinician’s armamentarium. In addition, we are witnessing the rapid development of newer targeted drugs. In the year 2012, the US Food and Drug Administration approved 39 targeted drugs for cancer (18 in the year 2013). Owing to these factors, oncologists can now develop personalized medicine approaches to treat cancer patients.

During the panel discussion, Peter Lebowitz agreed that better understanding of the disease biology has driven this progress; however, he hopes that technological advances would help us, especially to understand the tumor microenvironment, since that is crucial for cancer growth and maintenance.

Cancer Immunotherapy

With the advent of successful immunotherapy, the possibilities for cancer therapeutics have expanded even further. The success of immunotherapy over the past few years is just becoming obvious; it has succeeded in prolonging disease-free survival in patients with aggressive malignancies, such as non-small cell lung cancer and melanoma. Previously, clinicians rarely saw such durable responses with targeted therapies.

“Immunotherapy is definitely transforming the way we look at cancers,” said Bahija Jallal.

Ronald DePinho is excited by the success of immunotherapy and believes that it is the best approach for solid tumors, which are highly heterogeneous. However, he feels that we cannot entirely overlook targeted therapy. According to both DePinho and Robert Hugin, the ideal approach would be to use combinations in ways that produce synergies.

Regarding the use of immunotherapy, Lebowitz had a word of caution. “Often our dogma gets us in trouble” he quipped.

Lebowitz insisted that we should study and understand how each therapy acts, before using combinations in the clinic. This would prevent counter-productive effects of either therapy on cancer, when administered together.

Novel Approaches to Clinical Oncology

With better disease understanding, clinicians are matching targeted therapies to cancers. It is clear now that the one mutation-one drug paradigm for treating cancers is a gross over-simplification and does not work in the clinic. Successful cancer treatment requires the use of a panel of biomarkers to identify effective therapy. Generating these biomarker panels is possible due to newer technologies in the fields of genomics and proteomics. Further, in order to identify effective therapeutic options, innovative algorithms are required that account for the complexity of cancer and make predictions.

Apart from therapies, the field of clinical cancer medicine is shifting towards innovative clinical trials, such as the recent Lung-MAP trial – the first precision medicine trial from the National Clinical Trials Network. This is a multi-drug, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer that will be conducted under a public-private collaboration. Such emerging public-private collaborations may hold the key to future success in developing disease-targeted therapies.

The world of cancer research, academia and industry, represents an ecosystem. The key to success in this ecosystem is collaboration – integrating research data and clinical data, and sharing it freely between academia and industry. This synergistic collaboration will benefit both clinicians and researchers – to draw conclusions, to facilitate clinical decision-making, and to drive research.

Happy Solstice Day!

As we wind up this week, I am already looking forward to the exciting event next week, right here in San Diego – 2014 BIO International Convention, the “world’s largest biotechnology gathering”. I will be blogging from BIO2014, though it has been hard to decide which sessions to write about because there are so many good ones to choose from. Stay tuned!

Here’s a roundup of articles and news on science, medicine, and policy from this week.

Sciberomics

This week I blogged about high diversity of cells in glioblastoma – a brain cancer with extremely poor prognosis. RNA sequencing (RNA-seq) or transcriptomics of single cells from patient tumors was able to identify a highly heterogeneous population of cells in a tumor. This has implications for glioblastoma diagnosis and therapy. You can read more on my blog RNA-seq reveals glioblastoma heterogeneity.

Science Research Clinical Medicine
Weekly science roundup (Image credit: ASBMB.org)

Science and Medicine

The human immunodeficiency virus, aka HIV is notoriously difficult to eliminate from the body with drug therapy. This is at least in part because this virus can hide in the body. One way around it is to try and make the virus “announce” where it is. For this, in a recent study published in Science, scientists tried increasing the variation in the gene expression of the virus. In other words, they increased its “noise”, which in turn reactivated the latent, hidden HIV. This form of the virus is more sensitive to drugs.

The first precision medicine trial from the National Clinical Trials Network, Lung-MAP was launched. This trial will be conducted under a public-private collaboration. This trial is a multi-drug, biomarker-driven clinical trial for patients with advanced squamous cell lung cancer.

Takeda Pharmaceutical has voluntarily decided to end the development program for its investigational compound, orteronel (TAK-700). This is a nonsteroidal, selective inhibitor of 17,20-lyase that was being tested for prostate cancer. Orteronel was unable to extend overall survival in patients in phase III clinical trials.

Increasing advances in the microbiome research have revealed that the composition of microbiota in the gut can play an important role in the development of metabolic disorders. A recent study now shows that the diabetic drug, metformin can modulate the gut microbiome and in turn lead to better control of blood sugar.

Regulatory

The FDA is taking social media seriously as well. And it is about time. As a testament to this fact, the FDA has now proposed specific rules for listing risks on social media platforms.

Qiagen received FDA approval for CMV RGQ MDx Kit for human cytomegalovirus (CMV) – an assay that can allow rapid quantification of CMV DNA in patient samples, an important test for transplant patients.

Policy

The European Medicines Agency (EMA) has announced that it is relaxing data-sharing rules to enable clinical trials data to undergo public scrutiny.

Business

The life sciences company Sequenom Laboratories is now collaborating with Quest Diagnostics. As part of this collaboration, Quest is set to offer national access to Sequenom’s MaterniT21 PLUS test. This test analyzes chromosomal material in cell-free fetal DNA of pregnant women and can help diagnose fetal chromosomal abnormalities.

It is the age of mergers and acquisitions. Now an academic institute is getting in on the game. University of Southern California is in discussions to possible acquire or merge with the Scripps Research Institute.

So let's call it a week. See you back next week with lots of exciting news from BIO2014.

Diversity defines cancer.

Thanks to technological advances, we know that each person’s cancer is different. Just like a snowflake, no two are alike. This diversity between different individuals is termed intertumoral heterogeneity. Its corollary is that we need personalized therapy or individualized medicine, in order for cancer treatment to be effective.

Another layer of complexity is intratumoral heterogeneity, which means all cells in a single tumor are not necessarily the same (molecularly). Different groups of cells in a tumor (also called clones) likely have diverse molecular features. This is true in case of most cancers. Of these, glioblastoma is considered to be one of the most heterogeneous cancers.

An aggressive brain cancer, glioblastoma is very difficult to treat and recurs in most cases even after treatment. Out of every 100 patients with glioblastoma, 50 die in less than 15 months of diagnosis and very few live more than 5 years. An important reason for this dismal prognosis is the high degree of intratumoral heterogeneity. Individual cells within this tumor are different from each other, both genetically and functionally. Hence these cells respond to treatment differentially, making this tumor difficult to eradicate completely and more prone for recurrence.

Numerous previous studies have looked at genomic profiles of glioblastoma by analyzing chunks of tumors, each containing hundreds of thousands of tumor cells. One such landmark study, conducted by Verhaak and colleagues as part of The Cancer Genome Atlas (TCGA), used genomic analysis and found different tumors to have distinct genomic characteristics [1]. Based on these genomic profiles, they classified glioblastoma into 4 subtypes:

  1. Classical
  2. Mesenchymal
  3. Proneural
  4. Neural

These different subtypes of glioblastoma can each have variable degree of intratumoral heterogeneity. However, the diverse cellularity has never been systematically quantified. A recent study published in Science on June 12, 2014 does just that. Researchers from Broad Institute and Harvard use next-generation sequencing of individual cells in the tumor [2] and show that glioblastoma cells are far more heterogeneous than “previously thought”.

RNA-seq analysis of Glioblastoma

These researchers took 430 individual glioblastoma tumor cells isolated freshly from five different patients, and analyzed each cell by RNA sequencing (RNA-seq), an approach that involves profiling the transcriptome of the cell. The transcriptome includes all RNA in the cell – total RNA, messenger or mRNA, and other RNAs such as microRNA. Transcriptome sequencing or RNA-seq is a highly sensitive technique to detect genomic abnormalities commonly associated with cancer, such as gene fusion events or mutations. Change in expression of genes (either over-expression or decreased expressed) is an anomaly frequently seen in cancer; RNA-seq identifies gene expression levels in cancer cells as well.

RNA-seq glioblastoma
Single-cell RNA-seq reveals glioblastoma heterogeneity and may help design new, more effective therapies (Image Credit: cancer.gov)

In the Science study, RNA-seq analysis of glioblastoma cells revealed a high degree of cell-to-cell variability. Cells had different expression profiles of tyrosine kinase receptors, which are important targets for therapy. A direct clinical implication of this is that any single targeted therapeutic agent, no matter how effective will not kill all tumor cells. This provides a strong rationale for the use of combinations therapy for this and possibly other cancers.

This study also used RNA-seq to determine what state individual cells are in. Each tumor comprised cells in different states:

  • Some were differentiated, mature and hence sensitive to therapeutic agents,
  • Some were stem cell-like (glioma stem cells), had the potential for self-renewal and were resistant to most treatments, and
  • Some were in different intermediate states and showed variable responses to treatments

Considering this level of diversity, no single drug can completely kill all cells. Also, there are subtypes of cells that can reform the tumor after therapy. Hence, almost all glioblastoma tumors eventually recur even following the most aggressive therapies.

Researchers also determined which TCGA subtype (listed above) the individual tumor cells belong to. Surprisingly, every glioblastoma tumor was a heterogeneous mixture of cells from these different subtypes, pointing to the true diversity in tumor cells that we would miss when analyzing data from whole tumor chunks.

Clinical Implications

Important from a clinical standpoint, this study showed that increased heterogeneity in tumors is associated with poor prognosis (decreased patient survival). Heterogeneity thus has direct translational relevance and need to be considered for therapy. Bradley Bernstein from the Broad Institute, one of the senior authors on this study said in the press release, “Understanding the cellular landscape can provide a blueprint for identifying new therapies that target each of the various sub­populations of cancer cells, and ultimately for tailoring such therapies to individual patient tumors.”

This study is probably the first to quantify the extreme heterogeneity of glioblastoma. It reveals glioblastoma to be a formidable disease to manage clinically. While it underscores the challenge in successfully treating a cancer like glioblastoma, knowing this diversity helps us understand its basic biology. An ideal approach would be to leverage data on intratumoral heterogeneity to design new and effective therapeutic strategies against this deadly disease.

References

  1. Verhaak, R.G., et al., Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 2010. 17(1): p. 98-110. doi: 10.1016/j.ccr.2009.12.020
  2. Patel, A.P., et al., Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science, 2014. DOI: 10.1126/science.1254257

 

Here’s a roundup of articles and news on science, medicine, and policy from this week.

Sciberomics

This week, I blogged about the use of next-generation sequencing for diagnosing infections – based on a case study published in last week’s issue of The New England Journal of Medicine.

Around the Globe

Neuroscience World Cup
Neuroscience research allowed paraplegic to kick the football at the opening ceremony.

On 12th June 2014, the world witnessed the kickoff of the FIFA World Cup, 2014 in São Paulo, Brazil. And the biggest celebrity at this grand opening ceremony was neuroscience research! A 29-year old paraplegic (= paralyzed below the waist) wearing a min-controlled robotic suit kicked off the ball that marked the beginning of the World Cup. This suit was designed by a neuroscientist Miguel Nicolelis. Read more on this on the NIH Director’s blog.

Science and Medicine

Why did I have that extra cookie? Or why did I not get up earlier this morning? Regrets…we all know what they are. Now, in an elegant study, neuroscientists show that rats show regret after making “wrong” choices. Read this news article in National Geographic news and the original paper in Nature Neuroscience.

Scientists have developed a new molecule that can glow either red or blue, depending on the drug levels in a patient’s blood. This molecule finds application for patients taking different drugs for diseases and it can be used to prevent overdosing. The glow from this molecule can be seen using a digital camera and can give “instant results”.

Are we an inherently violent species? Is our violence so deeply ingrained that evolution actually “takes this into account” while shaping us? Now a study published in Biological Reviews suggests that the human face (particularly the male) evolved to reduce the effect of injuries from direct punches to the face.

Science Research Clinical Medicine Roundup
Weekly science roundup (Image Credit: ASBMB.org)

Scientists from Imperial College London have produced genetic modified mosquitoes such that it will eventually lead to a “crash” in the mosquito population and help eradicate malaria. The Guardian has a detailed report: "GM mosquitoes a ‘quantum leap’ towards tackling malaria." The original study can be found here.

In a potentially game-changing study for the field of HIV medicine, by modifying the genome of inducible pluripotent stem cells (iPSCs), scientists have succeeded in producing white blood cells that are resistant to the human immunodeficiency virus.

A study conducted at the Broad Institute and Massachusetts General Hospital, and published in this week’s issue of Science used single-cell RNA sequencing of glioblastoma tumor cells. This study demonstrates the high degree of intratumoral heterogeneity and complexity in glioblastoma that can have implications for treatment.

Regulatory

The U.S. Food and Drug Administration approved Biogen Idec Inc.'s long-lasting hemophilia A drug, Eloctate. This drug is likely to be available in the US starting July.

FDA Approved Panitumumab Plus FOLFOX for Wild-Type KRAS Metastatic Colorectal Cancer.

Policy

Researchers should take heart – NIH funding for research is set to improve. A Senate Subcommittee approved a 2% increase in the NIH budget for research.

Business

WaferGen Biosystems, Inc. a biotech company working in the genomic analysis space recently filed for $40 million public offering.

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Stop the presses! We have a new addition to the list of diseases that benefit from next-generation sequencing – infections.

In a case study published last week in The New England Journal of Medicine, routine medical and laboratory testing failed to identify the cause of encephalitis in a 14-year old patient [1], leaving him in a medically induced coma, with few treatment options and little hope. Encephalitis is brain inflammation, and can lead to severe neurologic abnormalities and death. Identifying the exact cause is critical for therapy but may be challenging. In this case, routine testing failed to provide a definitive diagnosis. Even a brain biopsy was inconclusive. As a last resort, doctors used a novel approach to figure out what was wrong with the patient. They analyzed his cerebrospinal fluid (CSF) using next-generation sequencing.

Next-generation sequencing infections
Sequencing for infectious diseases (Image Credit: Thomas Anthony Zampetti, Flickr)

Basically, researchers studied the CSF for evidence of microorganisms, in the form of DNA sequences. They used an unbiased approach to next-generation sequencing. I asked Charles Chiu, MD, PhD, Assistant Professor and Director of UCSF-Abbott Viral Diagnostics and Discovery Center, who is senior author on the study, about this approach.

“The term alludes to the fact that we are not targeting any specific pathogen or type of pathogen,” explained Chiu. It means that the researchers used sequencing and analysis to search for all known pathogens, including rare organisms.

Within 48 hours of receiving the CSF sample, next-generation sequencing and bioinformatics analysis revealed an obscure cause of encephalitis in this teenager – leptospirosis, an infection caused by the bacterium leptospira. Inability to accurately diagnose and treat this condition can be fatal. The good news: once diagnosed, leptospirosis is easily treatable with regular, old-fashioned penicillin. This antibiotic was administered in high doses, and the patient recovered completely.

Leptospirosis, Next-Generation Sequencing
Brain MRI of patient with encephalitis: Panels A, B, and C - images before treatment show signs of inflammation (arrows); Panel D - 7 days after penicillin treatment, shows inflammation resolved. From The New England Journal of Medicine, Wilson MR et al., Actionable Diagnosis of Neuroleptospirosis by Next-Generation Sequencing. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Next-generation sequencing identified the cause of infection in 2 days – something that months of traditional testing had not achieved. It saved the life of this teenager.

Clinical Translation of Next-Generation Sequencing

Next-generation sequencing is increasingly used in oncology for tumor profiling; in addition, it is a valuable tool for the diagnoses of various rare diseases and genetic disorders. The big question is: can successful diagnosis of an infection lead to the routine use of sequencing for other difficult-to-diagnose infections?

Charles Chiu believes so.

“I view this technology as being used as a broad-spectrum, second-line diagnostic assay after initial screening tests are negative and physicians have to resort to costly additional tests for rare and uncommon infections”, said Chiu.

However, this technology is far from clinic-ready. We need to come up with means to reliably identify disease-producing organisms, with high sensitivity and specificity, and differentiate them from the normal microbiome in relevant areas of the body. For example, the human gut contains 300-500 different species of bacteria [2]. So, one can appreciate the challenge of identifying an infection-causing microorganism from among the gut microbiome, by sequencing. Moreover, using next-generation sequencing routinely in the clinic for infectious diseases would require comprehensive testing and technology validation in order to obtain regulatory approval.

Clinically diagnosing infections (especially in cases of emergency) requires rapid sequencing and reliable analysis to deliver actionable results to the clinician. And all this needs to happen at affordable costs. Elaine Mardis, PhD, Professor of Medicine and Co-Director of The Genome Institute at Washington University, St. Louis, who was not part of The New England Journal of Medicine study agrees, “Probably the biggest hurdle is making it faster, cheaper and better than current assays.”

The Future

Once in routine clinical use, next-generation sequencing can prove critical for diagnosing cases of encephalitis and meningitis, like the one reported here. In addition, it will be beneficial for many zoonotic and infectious diseases that are difficult to diagnose using routine testing. Sequencing-driven diagnoses may be valuable, especially in critically ill patients with severe infections, including sepsis. In such cases, sequencing may not only identify the responsible microorganisms, but may also provide clues on drug resistance.

The successful use of next-generation sequencing by Chiu and colleagues provides us a rare window into a world where this technology can drive treatment decisions by diagnosing infections. As Elaine Mardis reflects, “(This study) beautifully illustrates how an unbiased look and smart bioinformatic analysis can provide answers that are life-saving.”

References Cited

  1. Wilson, M.R., et al., Actionable Diagnosis of Neuroleptospirosis by Next-Generation Sequencing. N Engl J Med, 2014. DOI: 10.1056/NEJMoa1401268
  2. Guarner, F. and J.R. Malagelada, Gut flora in health and disease. Lancet, 2003. 361(9356): p. 512-9. DOI: 10.1016/S0140-6736(03)12489-0

 

Starting with today's edition, Sciberomics will present a weekly roundup of science research from around the globe.

ASCO Annual Meeting

This past week was super-busy – science-wise, with the NIH grant deadline, many significant papers being published, and the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, IL. The fun of having to work on an NIH grant notwithstanding, my experience at ASCO makes me say that it was indeed an awesome meeting. Scientists and clinicians presented some very exciting research. To list all the important studies presented at ASCO would make this post a #longread. But here I am listing only a few of the many important clinical research studies that featured at this meeting:

Adjuvant Ipilimumab Significantly Improves Recurrence-Free Survival in Patients With High-Risk Stage III Melanoma

PD-1–Targeting Antibody Pembrolizumab Produces Long-Term Responses in Patients With Metastatic Melanoma

Cediranib Plus Olaparib Significantly Increases Progression-Free Survival in Women With Recurrent Ovarian Cancer

Chemotherapy Plus Either Bevacizumab or Cetuximab Results in Similar Survival Benefits in Metastatic Colorectal Cancer

Research News

There were several other notable developments in the research world of biology and medicine this week.

Science Research Clinical Medicine
Weekly science roundup (Image credit: ASBMB.org)

Increasing analyses of microbes from different locations in the human body has helped us understand the importance of the human microbiome. Now a study published in this week’s Nature (June 4, 2014) shows how early childhood malnutrition affects the maturation of gut microbes. Moreover, even after correcting this early malnutrition with diet, gut microbes do not sufficiently recover from the early insult and may require additional intervention.

A study published in Science (June 6, 2014) presents an innovative computational model that predicts when embryonic stem cells will self-renew or differentiate in culture. This model identifies, with high accuracy, a small number of transcription factors that can drive the stem cells either to pluripotency or to differentiation.

A new development in stem cell biology may signal a major advance for regenerative medicine. Scientists at Harvard show that by using Laser, they can stimulate human dental stem cells to differentiate and produce tissue regeneration. This research has implications for regenerative medicine for a variety of clinical applications.

The world of 3-D printing is witnessing exciting advances. Now to add to this excitement, scientists in Boston have been able to create synthetic blood vessels using 3-D printing. All the possible applications that this development can result in, makes it very noteworthy.

If you are planning for that late-night movie or an all-night work session, think again. It is very important to get a good night’s sleep or you risk developing Alzheimer's disease. The findings of a recent randomized clinical trial published in JAMA Neurology show that sleep deprivation increases levels of the protein beta-amyloid, which in turn increases the risk of Alzheimer’s.

With the increasing use of computers, tablets and smartphones, handwriting is becoming a lost art. But now scientists and psychologists have research that shows how handwriting is important for brain development in kids and for increased understanding. “New evidence suggests that the links between handwriting and broader educational development run deep.”

Science Business News

Genomics being the new kid on the block, sequencing technology takes center stage today. Seeking to further expand its reach in molecular diagnostics to sequencing, Swiss pharmaceutical giant Roche acquired Genia Technologies Inc. DNA sequencing firm.

In the research world of today, collaborations, mergers, and acquisitions have become the key to success and survival. As a testament to this, we are witnessing a number of collaborations among different groups.

  1. Sysmex Inostics is collaborating with Merck to develop and commercialize a biomarker test (RAS kit) for patients with metastatic colorectal cancer.
  2. NanoString and Celgene are collaborating to develop a companion diagnostic to support the clinical validation of the drug lenalidomide (REVLIMID) used for the treatment of diffuse large B-cell lymphoma (DLBCL).
  3. AstraZeneca’s MedImmune is developing a novel immune therapy for patients with non-small cell lung cancer (anti-PD-L1 therapy - MEDI4736). Now Roche’s Ventana has established collaboration with MedImmune to develop a companion diagnostic for this drug MEDI4736 that is currently in clinical studies.

Revolution! It drives radical transformation.

The omics revolution over the past decade has been a tour de force leading to unprecedented advances in biomedical sciences. Omics is a generic term for all fields of biomedicine with the suffix –omics. For instance, genomics indicates study of genome, epigenomics indicates study of epigenetic modifications, and so on for other fields such as proteomics, transcriptomics, microbiomics, metabolomics, etc. (each of these words deserves a separate blog post and will get one in due course). Advances in these areas have arguably been the most disruptive innovations of our time.

Breakthroughs in Biomedical Sciences

Technological innovations in the nineties spurred rapid development of the omics field, leading to a never-before-seen “intersection of biology and technology” (“Steve Jobs” by Walter Isaacson, 2011). The international Human Genome Project was a key landmark or rather, a precursor of this revolution. What started out as an extremely expensive venture has now made genome sequencing affordable enough for routine clinical application (almost!). The cost of sequencing has dropped precipitously, from $3 billion in the late nineties to approximately $1000 for a single genome today. This rate of advancement in sequencing technologies has truly defied Moore’s law.

Newer technologies and their application to biomedical research meant more and more data generated everyday. Making sense out of these data required additional technologies, which in turn, drove systematic evolution of a specialized field – computational or quantitative biology. This discipline uses techniques in physics, mathematics, computer sciences and related branches to decipher riddles in biology. Today, closely related interdisciplinary branches such as bioinformatics, systems biology, and network pharmacology have emerged. These varied branches are driving progress by analyzing and interpreting the tremendous amounts of data generated in the omics world.

Projects in academia and in industry are becoming increasingly collaborative in nature. Successfully translating these research findings into the clinic is critical to providing more effective treatment options for many diseases. These developments are poised to make personalized medicine or individualized medicine a reality.

Science, Medicine, Sequencing, Biology, Cancer
Sciberomics - Snapshots of Science and Life (Image by author)

Sciberomics and Science Outreach

In light of the interdisciplinary research and its application to humans, science communication assumes a vital role. Not only does it inform curious minds, but it also serves as an antidote to ignorance and misinformation. It spreads public awareness about science and facilitates dialog between peers. Science outreach is critical to driving public opinion, which can, directly and indirectly influence policy and funding. Add to that the availability of innumerable platforms for communication, and one would have to agree that there has been no better time for science writing.

All this has prompted me to join the world of active blogging. I am really excited to launch my new blog, and to use this platform to communicate science. How did I decide on a name for the blog? Well, I have to confess I am guilty of neologizing. I wanted the name to reflect the fact that this blog will communicate science, in cyberspace. Though I intend to cover all areas of science, I realize that I may end up being partial to the omics field. Taking all these factors into consideration, the newly minted word Sciberomics seems like a good fit as a name.

At Sciberomics, I will discuss recent developments in biology and medicine, focusing on how they affect human life. Blog posts will include studies that are hot off the press, areas that are mired in controversies and topics that are hotly debated. Active discussion and feedback from readers, in the form of comments are welcome and will provide flavor to the blog. The aim of Sciberomics is outreach to peers and non-scientific audience alike.

So, here goes Sciberomics – Snapshots of Science and Life. Welcome!