Tuesday, November 28, 2017

New cellular data recording technology utilizing CRISPR

Researchers at Columbia University Medical Center have modified bacterial immune system of human gut microbe Escherichia coli, enabling the bacteria to not only record their interactions with the environment but also time-stamp the events. They have turned bacteria into a microscopic data recorder, creating groundwork for a new class of technologies that could use bacterial cells for multiple uses like disease diagnosis to environmental monitoring.

Wang and members of his laboratory created this technology by taking advantage of CRISPR-Cas. CRISPR-Cas copies snippets of DNA from invading viruses so that subsequent generations of bacteria can repel these pathogens more effectively. As a result, the CRISPR locus of the bacterial genome accumulates a chronological record of the bacterial viruses that it and its ancestors have survived. When those same viruses try to infect again, the CRISPR-Cas system can recognize and eliminate them. CRISPR-Cas normally uses its recorded sequences to detect and cut the DNA of incoming phages.

To build their microscopic recorder, Ravi Sheth and other members of the Wang lab modified a piece of DNA called a plasmid, giving it the ability to create more copies of itself in the bacterial cell in response to an external signal. A separate recording plasmid, which drives the recorder and marks time, expresses components of the CRISPR-Cas system. In the absence of an external signal, only the recording plasmid is active, and the cell adds copies of a spacer sequence to the CRISPR locus in its genome. When an external signal is detected by the cell, the other plasmid is also activated, leading to insertion of its sequences instead. The result is a mixture of background sequences that record time and signal sequences that change depending on the cell's environment. The researchers can then examine the bacterial CRISPR locus and use computational tools to read the recording and its timing. The current paper proves the system can handle at least three simultaneous signals and record for days.

Citation: Sheth, Ravi U., Sung Sun Yim, Felix L. Wu, and Harris H. Wang. "Multiplex recording of cellular events over time on CRISPR biological tape." Science, 2017.

doi:10.1126/science.aao0958.

Funding: US Department of Defense, National Institutes of Health, Sloan Foundation.

Adapted from press release by Columbia University Medical Center.

Monday, November 20, 2017

Digital pill biosensors for monitoring opioid medication use

In a research paper published in the Anesthesia & Analgesia, Brigham and women's hospital investigators report on the results from a pilot study of 15 individuals who received a prescription to take oxycodone digital pills as needed following treatment for acute fractures.

Recently first digital pill was approved by the FDA for use with the antipsychotic drug Abilify, used to treat schizophrenia, bipolar disorder and depression. Opioids such as oxycodone are frequently prescribed on an as-needed basis for managing acute conditions, but uncertainty exists around how patients take the prescribed drug. Digital pills may offer a unique window into patterns of medication usage.

To conduct their pilot study, the investigators approached 26 individuals in the Emergency Department who had been diagnosed with an acute fracture. (Fifteen completed the study.) The team instructed participants to use oxycodone (one to two 5-mg oxycodone digital pills every six to eight hours) as needed for pain. Unused pills were returned after seven days.

The team used the eTectRx ID-Cap system. Each pill in the system consists of a unique radiofrequency emitter and a standard gelatin capsule containing an oxycodone tablet. When the capsule dissolves, the medication is released, and chloride ions energize the emitter. The patient wears a sticky patch on their abdomen, attached to a cable reader (the size of an iPod) that stores data about pill ingestion. (Since the study was conducted, advances in the technology have miniaturized the reader and added steps to validate the user of the system and provide directed feedback through a smartphone app.)

The digital pill system recorded a total of 112 ingestion events, compared to 134 ingestions based on pill count (84 percent accuracy). However, all missed ingestion events were traced back to two study participants who ingested digital pills without wearing the reader or did not interact with the reader due to severe pain. Most oxycodone doses were ingested within the first three days after discharge. On average, patients ingested only six pills, despite being given 21.

Citation: Chai, Peter R., Stephanie Carreiro, Brendan J. Innes, Brittany Chapman, Kristin L. Schreiber, Robert R. Edwards, Adam W. Carrico, and Edward W. Boyer. "Oxycodone Ingestion Patterns in Acute Fracture Pain With Digital Pills." Anesthesia & Analgesia 125, no. 6 (2017): 2105-112.
doi:10.1213/ane.0000000000002574
Funding: National Institutes of Health
Adapted from press release by Brigham And Women's Hospital.

Friday, November 17, 2017

Research shows efficacy of malarial drug Chloroquine in treating Zika infection

Zika virus remains a major global health risk. In most adults, Zika causes mild flu-like symptoms. But in pregnant women, the virus can cause serious birth defects in babies including microcephaly a neurological condition in which newborns have unusually small heads and fail to develop properly. There is no treatment or way to reverse the condition.

A new research study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC San Diego School of Medicine has found that chloroquine, a medication used to prevent and treat malaria may also be effective for Zika virus. The drug has a long history of safe use during pregnancy, and is relatively inexpensive. The research was published today in Scientific Reports.

Terskikh is co-senior author of a new study that examined the effect of chloroquine in human brain organoids and pregnant mice infected with the virus, and found the drug markedly reduced the amount of Zika virus in maternal blood and neural progenitor cells in the fetal brain. Pregnant mice received chloroquine through drinking water in dosages equivalent to acceptable levels used in humans.

Citation: Shiryaev, Sergey A., Pinar Mesci, Antonella Pinto, Isabella Fernandes, Nicholas Sheets, Sujan Shresta, Chen Farhy, Chun-Teng Huang, Alex Y. Strongin, Alysson R. Muotri, and Alexey V. Terskikh. "Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis." Scientific Reports 7, no. 1 (2017).
doi:10.1038/s41598-017-15467-6.
Funding: California Institute for Regenerative Medicine, National Institutes of Health, NARSAD Independent Investigator Grant, International Rett Syndrome Foundation.
Adapted from press release by Sanford-Burnham Prebys Medical Discovery Institute.

Thursday, November 16, 2017

Finding new uses for old medication using computer program DrugPredict

Researchers at Case Western Reserve University School of Medicine have developed a computer program called DrugPredict to discover new indications for old drugs. This program matches existing data about FDA-approved drugs to diseases, and predicts potential drug efficacy.

In a recent study published in Oncogene, the researchers successfully translated DrugPredict results into the laboratory, and showed common pain medications non-steroidal anti-inflammatory drugs, also known as NSAIDs could have applications for epithelial ovarian cancer.

DrugPredict was developed by co-first author QuanQiu Wang of ThinTek, LLC, and co-senior author Rong Xu, PhD, associate professor of biomedical informatics in the department of population and quantitative health sciences at Case Western Reserve University School of Medicine. The program works by connecting computer-generated drug profiles including mechanisms of action, clinical efficacy, and side effects with information about how a molecule may interact with human proteins in specific diseases, such as ovarian cancer.

DrugPredict searches databases of FDA-approved drugs, chemicals, and other naturally occurring compounds. It finds compounds with characteristics related to a disease-fighting mechanism. These include observable characteristics (phenotypes) and genetic factors that may influence drug efficacy. Researchers can collaborate with Xu to input a disease into DrugPredict and receive an output list of drugs or potential drugs with molecular features that correlate with strategies to fight the disease.

In the Oncogene study, DrugPredict produced a prioritized list of 6,996 chemicals with potential to treat epithelial ovarian cancer. At the top of the list were 15 drugs already FDA-approved to treat the cancer, helping to validate the DrugPredict approach. Of other FDA-approved medications on the list, NSAIDs ranked significantly higher than other drug classes. The researchers combined the DrugPredict results with anecdotal evidence about NSAIDs and cancer before confirming DrugPredict results in their laboratory experiments.

Citation: Nagaraj, A. B., Q. Q. Wang, P. Joseph, C. Zheng, Y. Chen, O. Kovalenko, S. Singh, A. Armstrong, K. Resnick, K. Zanotti, S. Waggoner, R. Xu, and A. Difeo. "Using a novel computational drug-repositioning approach (DrugPredict) to rapidly identify potent drug candidates for cancer treatment." Oncogene, 2017.

DOI: 10.1038/onc.2017.328

Funding: Gynecological Cancer Translation Research Program, Case Comprehensive Cancer Center, The Mary Kay Foundation, NIH/Eunice Kennedy Shriver National Institute Of Child Health & Human Development.

Adapted from press release by Case Western Reserve University.

Monday, June 19, 2017

Computational model uncovers progression of HIV infection in brain

University of Alberta research team successfully uncovered the progression of HIV infection in the brain using a new mathematical model. The team is utilizing this model to develop a nasal spray to administer  antiretroviral medication effectively. Their research is published in Journal of Neurovirology.

Research was done by PhD student Weston Roda and Prof. Michael Li. They used data from patients who died five to 15 years after they were infected, as well as known biological processes for the HIV virus to build the model that predicts the growth and progression of HIV in the brain, from the moment of infection onward. It is the first model of an infectious disease in the brain.

"The nature of the HIV virus allows it to travel across the blood-brain barrier in infected macrophage--or white blood cell--as early as two weeks after infection. Antiretroviral drugs, the therapy of choice for HIV, cannot enter the brain so easily," said Roda. This creates what is known as a viral reservoir, a place in the body where the virus can lay dormant and is relatively inaccessible to drugs.

Prior to this study, scientists could only study brain infection at autopsy. The new model allows scientists to backtrack, seeing the progression and development of HIV infection in the brain. Using this information, researchers can determine what level of effectiveness is needed for antiretroviral therapy in the brain to decrease active infection.

"The more we understand and can target treatment toward viral reservoirs, the closer we get to developing total suppression strategies for HIV infection," said Roda. A research team led by Chris Power, Roda's co-supervisor who is a professor in the Division of Neurology, is planning clinical trials for a nasal spray that would get the drugs into the brain faster, with critical information on dosage and improvement rate provided by Roda's model.

"Our next steps are to understand other viral reservoirs, like the gut, and develop models similar to this one, as well as understand latently infected cell populations in the brain," said Roda. "With the antiretroviral therapy, infected cells can go into a latent stage. The idea is to determine the size of the latently infected population so that clinicians can develop treatment strategies"

Citation: Roda, Weston C., Michael Y. Li, Michael S. Akinwumi, Eugene L. Asahchop, Benjamin B. Gelman, Kenneth W. Witwer, and Christopher Power. "Modeling brain lentiviral infections during antiretroviral therapy in AIDS." Journal of NeuroVirology, 2017.
doi:10.1007/s13365-017-0530-3.
Adapted from press release by University of Alberta.

Thursday, June 15, 2017

Delaying aging process by selective removal of senescent cells

A recent study, led by an international team of researchers confirms that targeted removal of senescent cells (SnCs), accumulated in many vertebrate tissues as we age, contribute significantly in delaying the onset of age-related pathologies.

Credit: Baker et al., Nature 
This breakthrough research has been led by Dr. Chaekyu Kim and Dr. Ok Hee Jeon. In the study, the research team presented a novel pharmacologic candidate that alleviates age-related degenerative joint conditions, such as osteoarthritis (OA) by selectively destroying SnCs. Their findings, published in Nature Medicine, suggest that the selective removal of old cells from joints could reduce the development of post-traumatic OA and allow new cartilage to grow and repair joints.

To test the idea that SnCs might play a causative role in OA, the research team took both younger and older mice and cut their anterior cruciate ligaments (ACL) to minic injury. They, then, administered injections of an experimental drug, named UBX0101 to selectively remove SnCs after anterior cruciate ligament transection (ACLT) surgery.

Preclinical studies in mice and human cells suggested that the removal of SnCs significantly reduced the development of post-traumatic OA and related pain and created a prochondrogenic environment for new cartilage to grow and repair joints. Indeed, the research team reported that aged mice did not exhibit signs of cartilage regeneration after treatment with UBX0101 injections,

According to the research team, the relevance of their findings to human disease was validated using chondrocytes isolated from arthritic patients. The research team notes that their findings provide new insights into therapies targeting SnCs for the treatment of trauma and age-related degenerative joint disease.

Citation: Jeon, Ok Hee, Chaekyu Kim, Remi-Martin Laberge, Marco Demaria, Sona Rathod, Alain P. Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J. Baker, Jan M Van Deursen, Judith Campisi, and Jennifer H. Elisseeff. "Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment." Nature Medicine 23, no. 6 (2017): 775-81.
doi:10.1038/nm.4324.
Adapted from press release by the Uslan National Institute of Science and Technology.

Friday, June 2, 2017

Metformin influences gut microbiome

A recent study at Sahlgrenska Academy and University of Girona indicates thatcontrol of blood glucose by metformin is achieved partly through modulation of the gut microbiota. Results of the study are published in journal Nature Medicine.

Fredrik Bäckhed's research group at Sahlgrenska Academy has previously shown that the gut microbiota is altered in patients with type 2 diabetes and after bariatric surgery. By conducting a clinical study in patients with new onset diabetes, the group could clarify how the gut microbiomeis affected by metformin.

Sequencing of the microbiome of 22 patients before and after treatment compared with a placebo treated group of patients showed that the gut microbiome was altered dramatically within two months of treatment. Through experiments in the laboratory, the researchers demonstrated that metformin increases the growth of several bacterial species that are linked to improved metabolism.

Citation: Wu, Hao, Eduardo Esteve, Valentina Tremaroli, Muhammad Tanweer Khan, Robert Caesar, Louise Mannerås-Holm, Marcus Ståhlman, Lisa M. Olsson, Matteo Serino, Mercè Planas-Fèlix, Gemma Xifra, Josep M. Mercader, David Torrents, Rémy Burcelin, Wifredo Ricart, Rosie Perkins, José Manuel Fernàndez-Real, and Fredrik Bäckhed. "Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug." Nature Medicine, 2017.
doi:10.1038/nm.4345.
Adapted from press release by  the University of Gothenburg.