Tag Archives: Clinical

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.”

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.


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.


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.


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.


Consider a case where a patient has a disease with high mortality and no effective treatment available. A new experimental drug is now being tested in a clinical trial. However, this is a randomized clinical trial, which means that it will have a treatment group and a placebo group (that does not get the actual drug). Is it really ethical to include a placebo group in case of a disease with no other treatment options? Are we effectively condemning this and many other patients to death by assigning them to the placebo group – albeit randomly?

In such cases, clinical trial design presents a major ethical dilemma in the area of drug development. This and other ethical dilemmas were discussed at length at a special session “The Bioethics of Drug Development – You Make the Call!” on Monday, June 23, 2014 at #BIO2014 the 2014 BIO International Convention.

Una Ryan from Bay Area BioEconomy Initiative feels that the “old way is broken”. A previous advocate of the randomized control trial, she thinks that in the era of big data, it is possible to design open-label trials with no placebo controls and yet draw meaningful conclusions by comparing data with historical controls (control groups from previous studies and from clinical data on the disease).

Richard Moscicki, Deputy Center Director, Science Operations at the US Food and Drug ADministration (FDA) agrees that randomized control trials may not always be the best way to conduct trials but in some cases, are “the most acute tool” for us to show efficacy and obtain regulatory approval for drugs. A factor that may make open-label trials difficult is the lack of good historical control data in some cases. However, the panelists agreed there is no need for randomized control trials for drugs that have clear disease reversing effects.

Russell Medford from Salutramed Group had similar views and said that randomized control trials, though currently the gold standard, are not always required. He advocates a frank, open discussion with the FDA while designing trials.

All panelists agreed that in today’s age, there is room for innovative trial designs, such as adaptive clinical trials or open-label clinical studies. It cannot be overstated that, especially for patients with lack of treatment options, we need to identify the optimal approach for designing clinical trials and find a middle ground.

Drug Pricing and Ethics

Finally, drug pricing and access is another thorny issue in the bioethics arena. Most drugs that get approved are introduced into the market with an intimidating price tag. But the fact remains that the drug-pricing curve has a sharp rise and a sharp fall. This fall in prices comes as drugs from competitors with similar efficacy enter the market. Prices drop further as generics enter the market once companies lose their sole monopoly over drugs.

Drug Development Bioethics
Drug Pricing and Bioethics (Image Credit: www.atg.wa.gov)

The calculation of drug pricing is aimed at increasing return on investment for a company; drug companies have to consider the cost of successfully bringing a drug to the market – including the failures that never made it past the discovery or early development stages. With these calculations, the price tag on every approved drug ranges from anywhere between $1 billion to $12 billion. From a business point of view, companies need to take into account all these factors for long-term sustainability. Of course, business ethics tend to clash with healthcare ethics, necessitating the search for a middle ground. Most panelists were of the opinion that high drug prices are justified as long as they are “fair”.

There were other ethical issues to be considered too. Would it be prudent to incorporate differential pricing globally or have static pricing? What about pricing for drugs used in rare diseases that have a small market? And what about patients/patient groups unable to pay for the high costs of these drugs? These are some troubling questions that need a lot of thought and discussion among key players globally.

It was clear at this session that there is no one correct answer or solution to either of the ethical issues discussed at this BIO2014 session. These issues lie at the crossroads of business, healthcare, and public health. Stimulating a public debate and encouraging dialogue between the pharmaceutical companies, healthcare professionals, patient interest groups, and regulatory agencies would go a long way in navigating these ethical minefields.


#BIO2014 begins! The much-awaited 2014 BIO International Convention kicked off with a day of special sessions on Monday, June 23rd, 2014.

A special session on Monday afternoon titled “The Bioethics of Drug Development – You Make the Call!” featured an interactive discussion on the bioethics of a new drug on the market. This session involved a mock board meeting of a fictional company iCures. The panel moderator, Steve Usdin of BioCentury served as chairman of the board. The other panelists served as board members and included:

  • Timothy Mackey from UC San Diego
  • Rich Moscicki from the Food and Drug Administration
  • Una Ryan from Bay Area BioEconomy Initiative
  • Josh Sommer from Chordoma Foundation
  • Russell Medford from Salutramed Group, who acted as CEO of iCures
Compassionate Use in Drug Development
Bioethics Special Session in progress at BIO2014. On stage (from L to R): Tim Mackey, Rich Moscicki, Russell Medford, Una Ryan, Leighton Read, Josh Sommer, and Steve Usdin. Image Credit: BIO

Usdin started off the session by discussing the case of Joshua Hardy, an 8-year old boy from Fredericksburg, VA who had a rare cancer and was treated with bone marrow transplantation. Following his transplantation, Joshua developed a life-threatening adenovirus infection and the primary drug to fight this infection damaged his kidneys. At that stage, it was believed that an experimental drug brincidofovir (CMX001) was the only life-saving option for Josh. This drug was in clinical testing and not FDA-approved – hence unavailable in the market. Joshua’s parents hoped to get this drug under the compassionate use clause, from Chimerix, the biotech company that owns and manufactures brincidofovir.

However, the company refused, stating that it would ethically be wrong to do so for one patient and not for others who had approached them in a similar manner. What followed was a social media storm and pressure from people all over the country. Chimerix finally relented and made the drug available to Joshua, whose condition improved dramatically.

So, was it ethically right for Chimerix to initially withhold the drug for compassionate use before giving in to the pressure? Were patients justified in expecting to receive the drug for compassionate use? Where does the company draw the line?

At the BIO2014 session, the panel (board of the fictional iCures) talked about a similar but hypothetical case of a woman requesting an experimental drug based on compassionate grounds. As CEO of iCures, Russell Medford listed the main issues associated with approving an experimental drug in response to such requests:

  1. Limited supply of the drug that is primarily manufactured for the clinical trial at hand
  2. The price tag for off-the-trial drug treatment for the company
  3. More than one patient requesting drug for indications not being tested in the trial – if drug given to one, what about the other requests
  4. Can providing open access to drug for other indications affect chances of its regulatory approval for the intended clinical indication?

Medford conceded that a biotech company with a drug likely to benefit patients would like to help, but are faced with real challenges that need to be addressed as well.

Una Ray believes that regulatory issue may not be a concern, considering that the US Food and Drug Administration (FDA) already supports expanded access. However she insists that selection should be fair and medically indicated rather than “someone who has the best social media campaign”. Another factor to consider: if a patient benefits from the drug, a company may ethically “be required” to supply the drug for a long duration (or perhaps lifelong). A related practical consideration is the added costs it will entail. How does a company cover this expense? Do they go back to investors? Do they raise funds from other sources? Ray feels the best approach is to avoid another capital raise and prevent diluting these funds. She favors finding a non-diluted way to fund this added cost. Timothy Mackey suggested that patients or advocacy groups could using crowdfunding to support the costs involved for drug treatment under compassionate use.

In addition, compassionate use of a drug already in clinical testing bears the risk of affecting the ongoing clinical trial; it may not be able to recruit patients to the randomized control trial (with placebo group) that the FDA and the company have agreed to.

Russell Medford agrees and opines, “We have to somehow find a balance between compassionate use from a patient advocacy standpoint for individuals in crisis and the broader groups of patients that are patiently and sometime desperately waiting for us to finalize our clinical trial programs so that we can get the drug out.”

Leighton Read wondered if, by allowing compassionate use, we are going down a slippery slope – making sure that the drug is not toxic, but not really caring much about efficacy? This aspect needs to be focused on to prevent a drug being used indiscriminately.

Though compassionate use of a drug in clinical trials raises legitimate ethical concerns for the biotech company, for regulatory agencies and for society as a whole, the panelists at this BIO2014 session agreed unanimously on this use, after acknowledging these concerns. It remains to be seen how biotech and pharmaceutical companies, regulatory agencies, healthcare providers, patient advocacy groups, and patients can address these concerns.

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.


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.


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.


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


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.

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


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.


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.


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.


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


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.