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Graphene Sensor Designed for Wearable Disease Detection

Girish Kulkarni and Zhaohui Zhong

First author Girish Kulkarni, left, and Zhaohui Zhong testing the graphene sensor (Joseph Xu, University of Michigan)

7 August 2014. Engineers at University of Michigan in Ann Arbor designed a sensor from graphene that makes it possible to embed the technology into wearable devices for disease detection. The team from the labs of electrical engineering professor Zhaohui Zhong and biomedical engineering professor Sherman Fan published their results last month in the journal Nature Communications (paid subscription required).

The Michigan team is aiming at a market for wearable technologies that is expected to grow to $70 billion by 2024, according to market analysis company IDTechEx. The university filed a provision patent on the technology and the researchers are taking part in Innovation Corps, a National Science Foundation program to help academic scientists become entrepreneurs and turn their discoveries into marketable goods and services. In June, NSF extended the Innovation Corps program to National Institutes of Health to move more biomedical discoveries into the marketplace.

Zhong, Fan, and colleagues designed the sensor to detect chemical indicators of disease, exhaled or emitted through the skin. Current nano-electronic sensors for this purpose detect a change in the electric charge between the molecules being detected and the sensor. With today’s technology, say the researchers, the molecules being detected develop a strong bond with the sensor, which slows the sensor’s action and requires a higher concentration in the air or solution.

The Michigan technology takes a different approach. The researchers adapted a process known as heterodyne mixing that interacts two or more signals to generate a new frequency. In this case, the sensor detects the interaction of imbalances in polarity among the chemical molecules, called molecular dipole moments. With graphene in the sensor, the team used a material related to graphite, consisting of a single atomic layer of carbon atoms arrayed in a hexagonal mesh pattern that’s light, strong, chemically stable, and can conduct both heat and electricity.

The researchers report the sensor detects various chemical vapors in the lab that can serve as indicators of disease, such as acetone for the detection of diabetes, and nitric oxide to detect asthma. In addition, the sensor detects test substances in tenths of a second, much faster than current technology, and in concentrations measured in a few parts per billion.

The team says the technology would be part of a miniature gas chromatography system that integrates the graphene sensors in a single low-power chip, embedded in a badge-sized device worn on the body. The device could also be applied to sensing the presence of dangerous chemicals or monitoring environmental air quality.

“With our platform technology, we can measure a variety of chemicals at the same time, or modify the device to target specific chemicals,” says Zhong in a university statement. “There are limitless possibilities.”

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Efficient Sequencing Method Devised to ID Cells, Biomarkers

Brain visualization image

(Univ of California, San Francisco)

6 August 2014. Researchers at University of California in San Francisco and Fluidigm Corp. in South San Francisco developed a more efficient process for analyzing genetic material, still revealing cell types and biomarkers that previously required more in-depth analysis. The team led by Arnold Kriegstein, director of UCSF’s regeneration medicine and stem cell center, and postdoctoral researcher Alex Pollen, published its findings this week in the journal Nature Biotechnology (paid subscription required).

The UCSF/Fluidigm team employed a device made by Fluidigm, a developer of life science analytical tools, to prepare single-cell samples for sequencing messenger RNA or mRNA — the molecules in the genome transcribing DNA into proteins that give instructions to cells for performing basic life functions. Sequencing reveals the structure of the mRNA molecules that make it possible to identify the properties of cells performing these functions.

Current sequencing methods require deep analysis of samples, up to 5 million reads of individual cells, which makes the process costly, time-consuming, and needing larger specimen samples to analyze. The researchers, using Fluidigm’s single-cell prep system for mRNA analysis, were able to reduce the degree of analysis by 2 orders of magnitude, from 5 million to 50,000 reads per cell.

The team used microfluidics — lab-on-a-chip devices — to capture single cells, then analyzed mRNA transcriptions of 301 cells from 11 separate populations in the brain with the shallower sequencing methods.  The sequencing process, which required larger numbers of cells to study, revealed more diverse types including early developmental cells, such as radial glial cells that are progenitors for neurons and glia in the brain.

“In addition to exploring the consequences of low-depth analysis,” says Pollen in a Fluidigm statement, “the paper includes a pilot study in the brain that reveals some new biology about nervous system development.”  The researchers found in the analysis two types of early growth proteins, EGR1 and FOS, that serve as targets for a basic signaling pathway in human cell development, which had not been previously identified in the radial glia of mice.

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Immunotherapy Start-Up Adds $134M in Venture Funding

T-cell

T-cell (NIAID/NIH)

5  August 2014. Juno Therapeutics, a biotechnology company in Seattle developing cancer treatments that harness the human immune system, secured $134 million in its second round of venture financing. The company, a spin-off enterprise from research labs in Seattle and New York, says the new round was provided by 10 public mutual funds and health care venture funds, including its earlier major investors.

Juno is developing treatments for cancer that stimulate the body’s T-cells, white blood cells in the immune system with the ability to target invading cancer cells, without damaging healthy tissue. The company’s technology modifies T-cells with molecules called chimeric antigen receptors to better identify and attack cancer cells on their own, without invoking immune-system signals that could target non-cancerous cells.

The company’s technology also reprograms T-cells by adding a type of molecule known as human leukocyte antigens that focuses on corresponding proteins in tumors. Juno says about half of the U.S. population has the genetic composition to express these proteins if contracting cancer.

An early-stage clinical trial with 5 adult patients having relapsed B cell acute lymphoblastic leukemia shows treatments with their own reprogrammed T-cells release chimeric antigen receptors against this type of cancer, and experience rapid eradication of their tumors as well as complete remission of the disease. Two of Juno’s founding scientists, Michel Sadelain and Renier Brentjens, led this study and are listed as inventors of the technology on the patent.

Juno Therapeutics is a joint spin-off from Fred Hutchinson Cancer Research Center in Seattle, Memorial Sloan-Kettering Cancer Center in New York, and Seattle Children’s Research Institute, with founding scientists from all three institutions. Funds from the new venture round are expected to support more early and intermediate-stage clinical trials, including those testing the technology with solid tumor targets.

The company started in December 2013 and completed its first venture round in April 2014. The two rounds provide for Juno a total of $310 million in capital.

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Roche Acquiring RNA Medications Biotech Company

RNA illustration

RNA illustration (Research.gov)

5 August 2014. The pharmaceutical company Roche is acquiring Santaris Pharma, a biotechnology company developing therapies targeting ribonucleic acid or RNA that performs vital genetic functions. Roche is expected to pay as much as $450 million for Santaris, based in Hørsholm, Denmark.

Santaris designs therapies focusing on RNA, a fundamental molecular building block in the genetic system that controls chemical activities in cells. The company says its technology, called Locked Nucleic Acid, has advantages over earlier attempts to address RNA, including more potency, affinity for wider variety of targets, and smaller molecular size making it better able to interact with target cells.

Santaris’s lead candidate is miravirsen, an inhibitor of microRNA-122 controlling the expression of a gene that helps hepatitis C virus replicate and accumulate in the liver. Because miravirsen targets an enabler of the virus rather than the virus itself, it is believed to be less susceptible to resistance from mutations in the virus. The company says in lab tests miravirsen was shown to be active against all six types of hepatitis C virus.

Miravirsen is being tested in an intermediate-stage clinical trial against current drugs considered the standard of care for treating hepatitis C. The 20 patients enrolled in the trial are infected with genotype 1 of the hepatitis C virus, considered the most common, yet most difficult to treat. Current drugs, says the company, are effective in only about half of hepatitis C cases and associated with adverse side effects among some patients.

Under the acquisition, Roche is paying Santaris $250 million at signing, with another $200 million to be paid upon completion of specified milestones. Roche is expected to continue Santaris’s operations in Denmark under the name Roche Innovation Center Copenhagen.

Santaris and Roche were already collaborating on the discovery of RNA medications, in a deal announced in January. In that agreement, the companies would apply Santaris’s technology to several unspecified disease areas, in return for $10 million up front, and up to $138 million per product in subsequent milestones.

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Hat tip: FirstWord Pharma

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Consortium to Develop Common Neuroscience Data Format

Brain silhouettes (Research.gov)

(Research.gov)

4 August 2014. A coalition of research institutes and universities working in neuroscience are constructing a common format for sharing data about the brain to make emerging databases more useful to researchers. The Neurodata Without Borders project is an initiative of Allen Institute for Brain Science, California Institute of Technology, New York University School of Medicine, the Howard Hughes Medical Institute (HHMI) and the University of California in Berkeley, with funding from GE, Kavli Foundation, Allen Institute, HHMI, and International Neuroinformatics Coordinating Facility.

The field of neuroscience is growing quickly, with more researchers capturing greater volumes and more types of data. The field is also one where collaboration and data sharing are not only highly desirable, but also encouraged by undertakings such as the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) project in the U.S., and sometimes mandated by funding agencies like National Institutes of Health.

Neurodata Without Borders aims to break down the barriers and silos inhibiting the flow of neuroscience data to the broader scientific community. A team from the participating institutions will first concentrate devising a common data format for sharing cell-based neurophysiology data, including electrical and optical recordings, the kind sought most often by researchers building models of brain functions. The project has a one year timetable.

A key part of the project will tackle a common solution for data that describe the information collected about brain activity. These data about data are known as metadata and include key variables such as data collection methods and behavior of lab animals during data collection, as well as rudimentary details such as the gender and age of the animals.

Participants in the project aim to collect current data sets at Collaborative Research in Computational
Neuroscience or CRCNS, a repository at UC-Berkeley that already stores two lab animal data sets from participating research labs, with plans to add two more. The team then expects to invite proposals from data modelers and vendors for common formats to store the data.

The project also plans to write application program interfaces or APIs that make it possible for software developers to easily access the data in the common format. A Neurodata Without Borders Hackathon — an intensive, hands-on codefest to write software — is planned for 20-22 November at HHMI’s Janelia Farms in Ashburn, Virginia.

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Allied Minds, Bristol-Myers Squibb Form Life Science Venture

Drug screening samples

(Bristol-Myers Squibb)

4 August 2014. Allied Minds, a research commercialization company in Boston, and the pharmaceutical company Bristol-Myers Squibb in New York are starting a joint venture to discover new drug candidates and enterprises from promising life science research in U.S. university labs. Financial terms of the new venture, named Allied-Bristol Life Sciences LLC, were not disclosed.

Allied Minds acts as a holding company for science and technology-based start-ups in the U.S. The company forms new businesses based on research conducted in the U.S. at university and federally sponsored labs. Allied Minds then provides funding and management for the new enterprises through their initial stages. The company says it has relationships with 33 universities and 32 labs and research centers affiliated with the U.S. defense and energy departments.

Under the deal, Allied-Bristol Life Sciences will identify research discoveries at university labs with commercial potential, and form start-ups to develop those discoveries from early feasibility stages to preclinical therapy candidates. The joint venture will also provide capital for these initial stages. Once a discovery reaches drug candidate status, Bristol-Myers Squibb will have the option to acquire the enterprise, under agreed-upon terms, which were not disclosed.

In June 2013, Allied Minds reported raising $100 million for its next series of start-ups from discoveries in university and federal research labs. The company also has two subsidiaries similar to Allied-Bristol Life Sciences for the identification and development of new medical devices, and to commercialize discoveries in labs supported by U.S. government agencies. It currently supports 18 enterprises in the U.S.

Bristol-Myers Squibb says it will make available its drug discovery expertise to the university researchers. “We believe this new venture will enhance the translation of early-stage academic research,” says Carl Decicco who heads drug discovery at Bristol-Myer Squibb in a statement by the companies, “and will ultimately help advance important potential new medicines more efficiently.”

This venture is not Bristol-Myers Squibb’s first collaboration with academic research labs. In May 2012, the company established a network with 10 universities and research institutes in the U.S. and Europe to investigate opportunities in cancer immunotherapy.

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Challenge Seeks Biomarkers for Neuropathic Pain

Neuron illustration (NIH)

(National Institute on Aging, NIH)

1 August 2014. A new challenge on InnoCentive is seeking biomarkers that help predict the effectiveness of pain-killing therapies for patients with neuropathic pain. The challenge requires a detailed written proposal due on 27 September 2014, with a payout of $25,000. Free registration is required to see the challenge details.

InnoCentive in Waltham, Massachusetts conducts open-innovation, crowdsourcing competitions for corporate and organization sponsors, in this case the pharmaceutical company Astra-Zeneca. Innocentive calls this type of competition a theoretical-licensing challenge that describes a proposed implementation of an idea, but has not yet been proven as a concept.

Neuropathic pain is caused by dysfunction or disorder in peripheral nerves, those found in motor or sensory functions, that feed into the central nervous system. The label applies to various kinds of conditions and syndromes, with a range of causes — e.g., diabetes, chemotherapy for cancer, phantom limb syndrome — that makes finding clear therapy targets difficult. Those same properties of neuropathic pain make it difficult to translate results from preclinical tests with lab animals into clear behavioral targets for clinical trials.

Astra-Zeneca therefore is taking a different strategy for addressing neuropathic pain that identifies new types of biomarkers as targets for therapies. These biomarkers should make it possible to monitor the physiology and nerve functions of patients with neuropathic pain, and better predict responses of patients to pain-killing treatments.

Responses to this type of challenge require written proposals, which will be reviewed by Astra-Zeneca, and usually include detailed requirements, specifications, and descriptions. In this challenge, Astra-Zeneca is seeking a non-exclusive license to develop the winning solution. Proposals not selected retain full intellectual-property rights following the evaluation period.

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Engineered Protein Detoxes Pesticides, Chemical Weapons

Jim Kim Montclare

Jim Kim Montclare (New York University)

1 August 2014. Biochemists at New York University synthesized a protein that removes the toxic elements of chemicals found in pesticides and some chemical warfare agents. The team led by Jin Kim Montclare at NYU’s engineering school published its findings last week in the journal ChemBioChem (paid subscription required).

The process, which includes use of computational modeling software, produces a synthesized protein that removes the toxicity of organophosphates, compounds found in many commercial pesticides and sarin, a nerve agent considered a weapon of mass destruction under international law. Organophosphates limit enzymes regulating a chemical in the nervous system called acetylcholine that carries signals between nerves and muscles. Without that regulating capability, acetylcholine builds up in the nerves, resulting in paralysis of muscles, including respiratory muscles, leading to suffocation and death.

Montclare and colleagues — including Richard Bonneau, a biology and computer science professor at NYU — engineered enzymes called phosphotriesterases, which in their natural state have properties that degrade organophosphates. But also in their natural state, phosphotriesterases are unstable; they easily lose their potency and breakdown under high temperatures.

The researchers thus sought a way of improving the stability of phosphotriesterases, while maintaining their ability to act on organophosphates. “We’ve known that phosphotriesterases had the power to detoxify these nerve agents,” says Montclare in a university statement, “but they were far too fragile to be used therapeutically.”

The NYU team turned to Rosetta, software for molecular modeling of protein structures that offers algorithms for analyzing molecular interactions and designing custom molecules. The researchers used Rosetta to identify mutations in fluoridated forms of phosphotriesterases, which they knew from earlier studies improved the protein’s folding, where amino acids in proteins take the shape that specifies their functions.

The mutations revealed through Rosetta improved the stability of phosphotriesterases even further, with one variation identified as pFF-F104A shown able to work at higher temperatures, and with enough stability to continue working for many days at room temperature. The university filed a provisional patent for the process that includes the computational design of the synthesized protein.

Montclare says the engineered protein can be the basis for therapies for farm workers overexposed to pesticides or victims of nerve gas attacks. It can also be formulated into chemicals for cleaning up or decommissioning chemical weapons stores that now require heat and caustic chemicals. “These proteins could accomplish that same task enzymatically,” notes Montclare, “without the need for reactors and formation of dangerous byproducts.”

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Early Trial Shows Parkinson’s Vaccine Creates Antibodies

Alpha-synuclein illustration

Alpha-synuclein illustration (Michael J. Fox Foundation)

31 July 2014. An early-stage clinical trial testing the safety of an experimental vaccine to treat Parkinson’s disease, shows the vaccine generates antibodies that fight the build-up of proteins in the brain associated with the disorder. The vaccine is made by the biotechnology company Affiris AG, which presented the results today at a press conference in New York with the Michael J. Fox Foundation that funds the vaccine’s early clinical trials.

Affiris, in Vienna, Austria, develops vaccine therapies with a technology based on peptides called epitopes, areas on molecules to which antibodies bind. The epitopes in Affiris vaccines connect to B-cells, white blood cells programmed to generate antibodies addressing a specific target.

That target in this case is alpha-synuclein proteins, the build-up of which in the brain are a pathology associated with Parkinson’s disease, a neurodegenerative disorder. The disease is believed to result from the loss of cells in the brain that produce dopamine, a chemical that helps control movement.

The build up of alpha-synuclein proteins are believed to damage neurons, or nerve cells in the brain. Affiris is developing a vaccine with the code-name PD01A that aims to control levels of alpha-synuclein in the brain, by protecting neurons from the build-up of this protein.

The clinical trial, held in Vienna, enrolled 32 patients between the ages of 40 and 65 with Parkinson’s disease, of which 12 patients each were given four injections each month of PD01A in doses of either 15 or 75 micrograms for a year. Another eight patients receiving medications to control Parkinson’s symptoms, considered the standard of care, served as a control group.

In the first results reported from the trial, Affiris says about half of the patients receiving the vaccine developed antibodies to alpha-synuclein, which the researchers found in serum samples, as well in the patients’ cerebrospinal fluid. The trial also measured changes in motor symptoms and cognition of the patients, for which the company reported more stabilization among the vaccinated patients than those not getting the vaccine. Affiris says the vaccine was safe and well-tolerated by the patients, the main measurement objective of the trial.

The company plans a follow-up study of patients receiving PD01A, checking for any adverse effects of the vaccine after another year, as well as the vaccine’s continued ability to generate antibodies and influence Parkinson’s symptoms. An intermediate-stage clinical trial is expected to begin recruitment in September.

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Pfizer Acquires Baxter Vaccines Business

Vaccination (U.S. Army Corps of Engineers)

(U.S. Army Corps of Engineers)

31 July 2014. Baxter International in Deerfield, Illinois sold its vaccines operations to Pfizer Inc. in New York for $635 million. The deal covers two current Baxter vaccines and part of a plant in Orth, Austria where the vaccines are produced.

One of the vaccines acquired by Pfizer, FSME-IMMUN, protects against tick-borne encephalitis, a viral infection affecting the central nervous system. The disease is spread by ticks, which are often hosted on rodents. Humans, however, can act as accidental hosts. The symptoms range from headaches, malaise and vomiting to confusion, sensory disturbances, and paralysis.

FSME-IMMUN is given as an injection with an adjuvant or booster. The vaccine is available in Europe, but recommended for travelers to Europe who may be visiting regions where ticks are more numerous, such as grasslands and wooded areas, including outdoor enthusiasts, hikers, and armed forces personnel.

The second Baxter vaccine is NeisVac-C that protects against meningitis from the group C meningococcal bacteria. NeisVac-C is made from inactivated extracts of group C bacteria. It is given as an injection and available outside the U.S.

Meningitis is an inflammation of the membranes surrounding the brain and spinal cord, which can be caused by bacteria or viruses, but bacterial meningitis is considered more serious. Early symptoms of headache, fever, and a stiff neck can lead to more serious complications including hearing loss, brain damage, kidney failure, or death.

Pfizer’s current vaccines program includes developing a vaccine for group B  meningococcal bacteria, as well as Staphylococcus aureus and Clostridium difficile bacteria associated with health care associated infections.

The companies expect the deal to close by the end of the year. Before then, Baxter expects vaccine sales of about $300 million, including $50 million in one-time milestone payments from government collaborations for developing influenza vaccines.

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Hat tip: FirstWord Pharma

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