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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!