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Large-Scale Process Devised for Lab-Made Liver Tissue

Liver illustration

(Mikael Häggström, Wikimedia Commons)

5 December 2017. Researchers in Japan and the U.S. created techniques for producing liver tissue in large quantities in the lab for transplant or drug testing. The team from Cincinnati Children’s Hospital Medical Center in Ohio and Yokohama City University in Japan describes its process in today’s issue of the journal Cell Reports.

The team led by Hideki Taniguchi and Takanori Takebe are seeking ways of producing liver cells and tissue from stem cells in larger quantities than current processes. Taniguchi studies regenerative medicine at Yokohama City University, while Takebe is on the faculty at both Yokohama City University and Cincinnati Children’s Hospital. The researchers focus particularly on producing organoids, three-dimensional clusters of cells from stem cells that can form into organs.

In earlier studies, Takebe transformed induced pluripotent stem cells — often called adult stem cells, since they are not derived from embryonic tissue — into organoids, or buds, for pancreas, kidney, and liver tissue, which showed therapeutic potential in lab mice. The problem for the researchers, is scaling up that process and making it reliable enough for day-to-day clinical or lab applications.

For their solution, the Yohohama-Cincinnati team devised plates with tiny dimple-like wells to grow liver buds, which required a number of versions to optimize the plate’s construction for transforming stem cells. The plate is coated with a film containing the growth cultures needed to transform the stem cells, and stem cells seeded into the wells.

The researchers seeded the plates with 3 types of precursor cells derived from stem cells. Hepatic endoderm cells resemble early embryonic liver cells, but are derived in this case from induced pluripotent stem cells. Endothelial cells like those in blood vessels are derived from human umbilical cord cells. And mesenchymal stem cells are derived from bone marrow that transform into connective tissue like bone and cartilage.

The team reports its process produces more than 20,000 liver buds in each batch that self-assemble and grow in the plates, and are harvested with an ordinary lab pipette. A preliminary quality analysis shows the liver buds are similar to organoids produced earlier is smaller lab quantities. The researchers then assessed the liver buds’ genetic properties and protein production, and found the new organoids are more like adult liver tissue than two-dimensional organoids generated with earlier methods.

The researchers refined their processes to produce organoids solely from induced pluripotent stem cells, with these adult stem cells generating the 3 types of precursor cells needed to produce liver buds. The team tested the liver buds in lab mice induced with liver failure, and found the organoids can restore liver functions in the mice, including production of the protein albumin and metabolites of the inflammation drug diclofenac given to the test mice.

The authors conclude their techniques can be the basis of a production-scale process for functioning liver buds that meets current manufacturing standards for clinical-grade biological products. “The ability to do this,” says Takebe in a Cincinnati Children’s statement, “will eventually allow us to help many people with final-stage liver disease. We want to save the lives of children who need liver transplants by overcoming the shortage of donor livers available for this.”

Healios Inc., a company in Tokyo developing regenerative medicine treatments from adult stem cells, licenses the technology from Yokohoma City University. Both Takebe and Taniguchi are scientific board members of the company.

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Programmable Nanoscale Drug Capsules Designed

Jessica Rouge

Jessica Rouge talks with Ph.D. student Josh Santiana (Sean Flynn, UConn Photo)

5 December 2017. A lab at University of Connecticut is developing nanoscale capsules that release drug cargoes only when encountering specific enzymes, even inside cells. The team led UConn chemistry professor Jessica Rouge describes its technology and results of lab tests in the 30 November issue of the journal Bioconjugate Chemistry (paid subscription required).

Rouge and colleagues are seeking more accurate delivery of drugs to specific targets, down to genetic material such as DNA or RNA inside cells. Not only can more accurate targeting of drugs deliver higher doses of compounds that kill cancer cells, but also spare healthy cells and tissue, thus reducing adverse side effects, like those experienced by cancer patients receiving chemotherapy.

The UConn researchers are developing a technology they call a nucleic acid nanoscale capsule — 1 nanometer equals 1 billionth of a meter — that uses cross-linking, a chemical method for bonding to proteins and other biological molecules. In this case, the team combines peptides with nucleic acids from DNA or RNA, which would release the drugs only in the presence of a specific enzyme. When the nano-capsule encounters that enzyme, it causes the capsule to degrade and release its contents.

The team tested the nano-capsules in lab and cell cultures with two different enzymes: cathepsin B found inside cells and associated with some cancers and inflammation, and matrix metallopeptidase 9 or MMP9 involved in the breakdown of extracellular matrices outside cells. The researchers found their nano-capsules would degrade when in the presence of these target enzymes, but remain intact in other environments. The team also found the nano-capsules could be made to remain intact in enzyme solutions with pH levels below certain thresholds, then degrade when exceeding that pH level.

“There’s no one-size-fits-all delivery system,” says Rouge in a university statement. “The beauty of this system is that it is programmable, modular, and has the ability to rapidly integrate diverse peptide sequences. It can be tailored to combat new disease challenges as they emerge.”

UConn says Rouge’s team in Storrs is working with other university labs to design drug-delivery mechanisms that treat various diseases, including inherited disorders requiring genetic therapies. One of those collaborators is Steven Szczepanek, who studies disease pathology and vaccines, and with whom Rouge is investigating a method for delivering drugs that silence genes producing proteins associated with inflammation in asthma.

The researchers plan to test their process soon in mice induced with asthma. The university says a patent is pending on the technology, and industry partners are being solicited to take the process to market.

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Engineered Cells Identify Rare Epilepsy Drug Candidates

Genetic testing illustration

(National Institute of General Medical Sciences, NIH)

4 December 2017. A process using high-speed screening of drug candidates with genetically engineered cells identified potential drugs to treat a rare form of childhood epilepsy. A team from the start-up company Pairnomix LLC in Plymouth, Minnesota and the KCNQ2 Cure Alliance are presenting their findings at the annual meeting of the American Epilepsy Society now underway in Washington, D.C.

Pairnomix, which began in January 2016, offers personalized genetic testing to find treatments for rare disorders. The company says it creates a lab model of genomic mutations responsible for rare diseases by genetically engineering healthy DNA to simulate the mutation, then inserting the mutated DNA into cells. There the cells are tested for functions similar to cells with the rare disease. The cells with mutated DNA are used to screen some 1,300 approved drugs for activity against the rare disease, highlighting and confirming the top candidates.

When Pairnormix got underway, it began a joint project with the KCNQ2 Cure Alliance in Denver to find potential treatments for KCNQ2 epileptic encephalopathy, or KCNQ2E, a rare form of epilepsy. The disorder results from a mutation in the KCNQ2 gene responsible for proteins that make potassium channels for sending and receiving signals from cells. These proteins and channels are particularly important in nerve cells, where they regulate electrical signals in the brain, keeping the nerve cells from becoming overactive or excitable.

KCNQ2E is believed to affect some 500 individuals worldwide, mainly infants that exhibit seizures in their first weeks of life. KCNQ2 Cure Alliance says the seizures often resolve themselves as children get older, but they can leave children with mild to severe impaired development, including symptoms similar to autism. The low numbers of reported cases, says Pairnormix, may be due to the relatively recent discovery of the disorder as well as the need for genetic testing to detect it.

In the conference paper, the team led by David Goldstein — geneticist and neurology professor at Columbia University, and scientific board member at Pairnormix — added mutated KCNQ2 genes to standard lab cell lines to generate signaling patterns similar to those found in KCNQ2E. These cells with mutated genes and comparable cells with normal genes were then used to screen a library of 1,280 known off-patent drugs, as well as known epilepsy drugs and compounds that act against the signaling channels affected by the mutations.

The screening identified 60 drugs that act against signals from the mutated cells. Among the more active drugs found through this process is paroxetine, an anti-depressant also prescribed for bipolar disorder and other neurological conditions. The team says many of the drugs highlighted through the screening were not previously associated with signaling patterns like those found in KCNQ2E. The researchers conclude that the screening process with genetically-modified cells can be useful in identifying treatments for rare disorders among currently available drugs developed for other, even unrelated, conditions.

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FDA Approves Precision Solid Tumor Cancer Diagnostics

DNA puzzle

(Arek Socha, Pixabay)

4 December 2017. The Food and Drug Administration approved genomic tests for solid tumor cancers that identify the most promising available therapies matched to the tumor’s genetic mutations. At the same time, a separate U.S. agency proposed that the cost of the tests, developed by Foundation Medicine in Cambridge, Massachusetts, should be covered for patients enrolled in Medicare.

The cancer tests, known as FoundationOne CDx, is a companion diagnostic that performs high-throughput genomic sequencing of DNA samples from cancer patients reporting on 324 genes most associated with tumor growth to help determine the most promising available treatments. FDA’s approval applies to patients with certain types of non-small cell lung cancer, melanoma, colorectal cancer, ovarian cancer, or breast cancer where the results are matched to 15 treatment options approved for those conditions, including 12 first-line therapies, according to the company.

Foundation Medicine says FoundationOne CDx also evaluates indicators, such as microsatellite instability and tumor mutational burden that help determine benefits of immunotherapies and other specialized cancer treatments. Microsatellite instability is a defect in the repeating sequences of DNA preventing the repair of errors when DNA is copied in cells, and is associated with development of some solid tumors. Tumor mutational burden is a quantitative measure of the total number of mutations per coding error in a tumor genome. Tumors with a higher level of mutational burden are considered more likely to express immune-system targets specific to those tumors, making them better candidates for immunotherapies.

The company says based on its projections, 1 in 3 patients with the 5 types of solid tumors approved for FoundationOne CDx tests, can be matched to an FDA-approved treatment. Foundation Medicine says where treatments are not yet approved by FDA, the tests can identify clinical trials evaluating experimental therapies that match the patients’ tumor genomic profiles.

In a parallel action, Centers for Medicare and Medicaid Services, or CMS, in the U.S. Department of Health and Human Services, proposed that FoundationOne CDx and similar high-throughput genomic tests are eligible for reimbursement for patients with advanced cases of the 5 types of solid tumor cancers, who have not been previously tested. Final approval of Medicare coverage for these tests is expected in the first quarter of 2018, following a public comment period. The agencies say this is only the second diagnostic test to receive simultaneous FDA and CMS review and approval.

“This FDA approval,” says Andrea Ferris, CEO of LUNGevity Foundation in a company statement, “means that, in one test, patients can access therapies where companion diagnostics have been established for their cancer while getting a broad tumor profile that can identify the therapies and clinical trials they could most benefit from. Along with the preliminary national coverage determination, this has the potential to democratize next-generation sequencing, lowering the barriers for patients treated in the community to access these biomarker-driven treatments.”

Foundation Medicine was founded in 2010 by genomics researchers at Dana-Farber Cancer Institute in Boston, Harvard Medical School, and Broad Institute, a medical research center affiliated with Harvard and MIT. As reported by Science & Enterprise in January 2015, drug maker Roche acquired a majority stake in Foundation Medicine, in a deal valued at more than $1 billion.

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Drug Price Report Calls for Govt Negotiation, More Generics

Norman Augustine

Norman Augustine, chair of the National Academies’ drug affordability committee, at National Press Club, 30 November 2017 (A. Kotok)

1 December 2017. A panel convened by the National Academies calls for the federal government to use its buying power to negotiate better drug prices for consumers. That recommendation was part of 8 sets of actions in a report, which also generated two dissenting statements, including from industry representatives on the committee. The report was released yesterday at a news conference in Washington, D.C.

The committee of the National Academies of Science, Engineering, and Medicine sought solutions to the problem of rapidly rising prices for prescription drugs, which is a major driver of overall health care costs, now estimated at 18 percent of the U.S. gross domestic product. The panel chaired by Norman Augustine, former chairman of the National Academy of Engineering and CEO of Lockheed Martin Corp., recognized the complex factors making up the issue of drug affordability, including role played by insurance and the need for continued innovation by drug companies.

Nonetheless the rapid and continuing rise in the cost of drugs, says the 189-page report, is not sustainable and becoming out of reach for consumers, which threatens public health, social equity, and economic development. In remarks during the press conference and in a preface to the report, Augustine noted that the “burden of high-priced drugs often falls disproportionately on the most vulnerable elements of the population.” He cited a Kaiser Family Foundation report that shows in 2015 about 1 in 5 Americans did not fill a prescription because of its price, while other individuals rationed the drugs they had.

The panel’s report calls for Congress to authorize consolidation of drug purchasing in the U.S. Department of Health and Human Services, or HHS, for the department to negotiate directly with drug companies as a single entity, using its combined purchasing power to lower prices on prescription drugs. In addition, HHS should refine its methods for determining the value of drugs, and use those value-based approaches in negotiations and establishment of formularies that list the drugs covered for specified diseases and conditions.

The committee highlights generics and biosimilars as a key factor in promoting more choices and competition in the marketplace, calling for new laws and more regulatory oversight to encourage more availability of these alternatives to branded drugs. The recommendations urge the Justice Department and Federal Trade Commission to put a halt to “pay for delay” practices, where makers of branded drugs pay generics producers to slow the introduction of their competing products, as well as more scrutiny of mergers and acquisitions that may limit the availability of generics or biosimilars. In addition, the panel endorsed establishing reciprocal arrangements with regulatory authorities in other developed regions to encourage more generics and biosimilars, as well as reduce barriers to entry of generics and biosimilars from overseas.

Other recommendations from the panel focus on consumer-related matters. One set of proposals calls for an end to tax deductions to drug companies for direct-to-consumer advertising of prescription drugs, and encourages instead codes of conduct to foster more awareness of disease prevention and management. The committee also recommends ending patient coupon programs unless no competing drugs are on the market.

A separate set of proposals is designed to change health insurance practices to reduce the cost of prescription drugs for patients covered by Medicare. These recommendations call for rewriting cost-sharing formulas — to include, for example, costs and clinical effectiveness of specific drugs — and placing a cap on annual out-of-pocket costs paid by Medicare Part D (drug benefit) enrollees.

Other recommendations cover financial transparency, including costs and rebates, in the pharmaceutical supply chain, reforming insurance rules to reward prescribing practices emphasizing value to consumers, and restricting financial incentives for developing orphan drugs to the program’s original intent, development of new therapeutics for rare diseases. In comments at the news conference, panel members noted that the trend toward precision medicine could make it possible to call drugs prescribed to address particular genetic variations “orphan drugs,” even if they were originally developed to treat much larger populations.

Consensus, but not unanimous

In response to a question from Science & Enterprise, panel member Michelle Mello, a law professor at Stanford University, said that many drug companies are taking steps to bring down their research and production costs, particularly the high costs of clinical trials. She added however, that producing new medicines is inherently risky, with 9 out of 10 new drugs in development not surviving to the market. She also pointed out that early work on new products is often undertaken by smaller companies, focusing on one new drug at a time, with these small enterprises highly dependent on private venture capital.

While the committee’s recommendations represent a consensus of its members, the findings were not unanimous. Two members of the panel, both from industry — Michael Rosenblatt, former chief medical officer at Merck, and Henri Termeer, former CEO of Genzyme Corp, — offered a dissenting option. Rosenblatt and Termeer say many the report’s recommendations would have unintended consequences damaging both to the health of patients and the industry.

Their alternative recommendations include more financial transparency throughout the supply chain, particularly for pharmacy benefit managers, third-party administrators of prescription drug plans for insurance providers, and to level the playing field for drug prices among developed countries, where patients in the U.S. are asked to pay higher prices. However, Rosenblatt and Termeer, came out against the panel’s proposals for government-wide negotiations and importation of drugs from overseas.

Seven other members of the panel also offered a minority opinion. While they endorsed the panel’s overall recommendations, they believe the proposals were not aggressive enough and called for more systemic changes to create a more comprehensive, patient-centric system. Their recommendations call for steps to ensure greater transparency, better value assessments, and exploration of direct government funding and purchasing of drugs, where needed to correct distortions in investment and deployment.

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Four Signs You’re Not Ready To Start A Business (Yet)

– Contributed content –

1 December 2017. Self employment is becoming more common. With the job market rather depressed, thousands of people are turning to their own skills and going into business for themselves.

The boom in self-employment may have made you wonder if you can join the ranks, and start a business for yourself. There’s no denying that the idea is tempting. You wouldn’t have to worry about a boss; all the profit you generate would benefit you rather than the company; and you’re able to arrange your working hours as you see fit.

As attractive as this self-employment may be, it isn’t the easy choice. There is a lot to learn and a lot to prepare yourself for. Understanding whether or not you’re truly prepared for the task of running your own business is difficult; you have never done this before, so you don’t realistically know what to expect.

Rather than being in the dark about your readiness for the entrepreneurial life, let’s examine a few signs that suggest you’re not quite ready to join the ranks of the self-employed just yet.

1 – You Don’t Have A Three-Year Plan

Idea-Plan-Action

(Teneric.co.uk)

Launching a business is all well and good; it’s even possible to say it’s relatively easy to do these days. However, the big stumbling block for many businesses is… what comes after the launch?

To answer this question, you need to ensure you have a comprehensive three-year plan in place. You have to be able to look into the future when you’re considering your business aspirations. The launch is important, but you also have to look beyond that. While you can’t predict the future exactly, you can try to make sound, reasonable estimates about where you expect your business to be and what you expect the growth trajectory to look like.

Before you action any plans you have for your business, you have to have some idea of what your goals are for the next three years, as well as sound strategies of how you are going to achieve them.

2 – You Don’t Understand The Terminology

Business terminology is confusing. It’s full of acronyms, titles you have never heard before, and legislation that you didn’t know exists. If you want to survive in the business world, then you have to be willing to learn all of the necessary background information that will allow you to grow your business.

Take the time to learn exactly what makes a limited company shareholder different from a sole trader; the different regulations around business and corporation tax, and memorize the list of the most common business acronyms. Until you can use these terms instantly — without having to scramble in your memory to recall what they mean — it’s wise to keep your business plans on ice. You will need this vocabulary to progress your business and project professionalism in all of your dealings, so this is one step you just can’t afford to skip.

3 – You Have Not Researched Your Competitors

Before you launch a business, you have to have some idea of your potential competitors. If you neglect this, you could find yourself launching a business that effectively already exists and have no USP of its own.

You should research local and national competitors, so you can put together a strategy that can improve on and better the offerings already available to customers.

4 – You Have Not Separated Your Finances

Finance, calculator

(stevepb, Pixabay)

Money matters in business, and the control of where money is going from and to even more so. Your business and your personal finances need to be completely separate entities. You need separate accounts, separate books, separate everything.

If you intermingle your personal finances with business finances, then you make life far more difficult and outright confusing. Start with a fresh slate of business accounts. This will mean that you can always see how the business is doing in and of itself, rather than taking into account all of your personal financial matters.

Furthermore, if you are self-funding your startup costs, ensure you have procedures in place to document the funds as you would any other outside investment.

Remember: all of the above can be achieved. You may not be ready to start a business right now, as you’re sitting reading this, but that doesn’t mean you can’t be. With a little more research and dedication, you can catch up the skills you need and be ready to move into self-employment in a relatively short amount of time.

While it can be time-consuming to have to put so much effort into preparing yourself to launch a business, it’s worth reminding yourself that the process will be worth it when you reach your end goal. Good luck with your business endeavors in the future.

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FDA Clears Smart Watch EKG Device

Apple Watch with Kardia Band

Apple Watch with Kardia Band and app (AliveCor Inc.)

30 November 2017. The Food and Drug Administration approved an electrocardiogram, or EKG device, designed to work with Apple smart watches, according to AliveCor, developer of the device. The company, based in Mountain View, California, says it’s the first medical device for smart watches approved by FDA for marketing in the U.S.

The EKG device, known as KardiaBand, is built into the Apple Watch wrist band and connects to the watch itself to measure heart rhythms and detect atrial fibrillation, or AFib. Atrial fibrillation is a common problem affecting some 33.5 million people worldwide in 2010, including at least 2.7 million people in the U.S., according to CDC. AFib is an irregular heartbeat that can lead to stroke or heart failure, where heart muscle contractions in the upper chambers beat irregularly instead of in a regular rhythm.  Those irregular rhythms can cause blood to pool and lead to blood clots, including clots that move to the brain and cause a stroke.

AliveCor says the KardiaBand can record an EKG in 30 seconds and display the results on the Apple Watch face. The watch band contains a sensor where the person places a thumb for 30 seconds to detect and transmit heart rhythms to an app on the watch. The app has an algorithm that evaluates recorded heart rhythms and reports either a normal or irregular heartbeat, or asks the session be repeated.

The KardiaBand now has a feature called SmartRhythm that uses artificial intelligence to assess heart rate and physical activity measured on the Apple Watch’s built-in sensors. If the data from those sensors are not in sync, the wearer is advised to take an EKG. The company says a version of SmartRhythm is also built into the smartphone version, called Kardia Mobile.

As reported by Science & Enterprise in August 2017, a clinical trial in the U.K. showed more participants using the Kardia Mobile device detected atrial fibrillation than in the comparison group receiving routine care. Among the Kardia users, 19 new AFib cases were found in the 12 month test period, compared to 5 cases in the comparison group. All new AFib cases were confirmed by cardiologists and began treatment with anticoagulants.

The KardiaBand costs $199.00 and requires an annual subscription to AliveCor’s cloud-based analysis, storage, and alert service for $99.00 per year. The service includes sending of EKG reports by e-mail and a monthly printed report of EKG readings.

“KardiaBand paired with SmartRhythm technology will be life-changing for people who are serious about heart health,” says AliveCor CEO Vic Gundotra in a company statement. “These capabilities will allow people to easily and discreetly check their heart rhythms when they may be abnormal, capturing essential information to help doctors identify the issue and inform a clear path of care to help manage AFib, a leading cause of stroke, and other serious conditions.”

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RNA Injections Shown to Rebuild Damaged Heart Muscle

Cardiomyocytes in a mouse heart

Cardiomyocytes, in green, grown in a mouse heart after gel injection (University of Pennsylvania)

30 November 2017. Engineers and medical researchers developed a technique to deliver genetic material into damaged heart muscle that in lab mice regrows heart cells. A team from the engineering and medical schools at University of Pennsylvania in Philadelphia published its findings in the 27 November issue of the journal Nature Biomedical Engineering (paid subscription required).

Researchers led by cardiovascular researcher Edward Morrisey and biomedical engineering professor Jason Burdick are seeking better treatments for damage to heart muscle caused by heart attacks. A heart attack occurs when oxygen and nutrients supplied to heart muscles in coronary arteries are reduced or cut off, such as from blood clots that form around the build-up of plaques in the arteries. When starved for oxygen and nutrients, heart muscles become damaged or die, causing a life-threatening condition. American Heart Association says a heart attack occurs about every 40 seconds in the U.S.

Heart muscles are not able to regenerate, which limits recovery from heart attacks and increases the mortality of people who suffer a heart attack. Possible solutions include regenerating heart tissue in the lab from stem cells into healthy heart muscle cells called cardiomyocytes, or fixing the damaged heart tissue with a surgically implanted patch containing cardiomyocytes. Morrisey, Burdick, and colleagues instead sought a more direct treatment that regenerates heart muscle cells from inside the heart.

The UPenn team looked into ways of delivering micro RNA into the damaged heart muscles to restart cell production. Micro RNAs or miRNAs, are genetic molecules that serve as regulators of the genome. They start out small, but evolve into more complex molecules that interact with another type of RNA — messenger RNA — to control the expression of genes responding to various proteins.

The researchers identified a specific type of miRNA, known as miR-302 that regulates cardiomyocyte growth and development in prenatal and infant heart muscle. But miRNAs are unstable and break down quickly, which requires a method for delivering a high-enough dose into damaged heart muscles to be effective. Micro RNAs in high doses also pose a risk of instigating tumors, since they promote cell proliferation.

In lab cultures, the miR-302 concentrations encouraged cardiomyocyte regeneration for a week, but a method was still needed to deliver the miRNAs into damaged heart muscles. For this task, the team used a hydrogel, a water-based polymer with hyaluronic acid, a natural substance fund in the eyes and other fluids in the body. As reported in Science & Enterprise, Burdick’s lab showed in 2014 hydrogels could deliver enzymes directly into the heart as a possible preventive treatment for heart attacks.

“The most important traits of this gel are that it’s shear-thinning and self-healing,” says Burdick in a university statement. “Shear-thinning means it has bonds that can be broken under mechanical stress, making it more fluid and allowing it to flow through a syringe or catheter.  Self-healing means that when that stress is removed, the gel’s bonds re-form, allowing it to stay in place within the heart muscle.”

Tests in lab mice induced with heart damage showed that a single injection of the hydrogel with miRNAs results in cardiomyocyte proliferation for 2 weeks. Mice receiving the injections also show better heart performance on a number of indicators, including ejection fraction, the percentage of blood that’s pumped out of a filled ventricle with each heart beat.

The authors conclude that the delivery of miRNAs with a biocompatible hydrogel is a promising treatment candidate for regenerating heart tissue, and the team plans to test the process further, including in pigs with hearts similar to humans. The university also filed provisional patents for the technology.

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Updated 30 November 2017, to fix usage error in third paragraph.

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Protein Made by Synthetic Bacteria with Expanded DNA

Cells express green fluorescent protein

Cells express green fluorescent protein encoded from artificial DNA (Bill Kiosses, Scripps Research Institute)

29 November 2017. An academic-industry lab team produced a synthetic protein from an engineered bacteria, with DNA modified to expand its number of chemical coding components. Researchers from Synthorx Inc. and Scripps Research Institute, both in La Jolla, California published their findings in today’s issue of the journal Nature (paid subscription required).

Synthorx is a 3 year-old company spun-off from the Scripps synthetic biology lab of Floyd Romesberg that studies protein chemistry. Romesberg is Synthorx’s scientific founder and continues on the company’s board.

Among the lab’s discoveries is a process for adding 2 more base-pairs, nucleic acid components configured into an organism’s genetic code, to DNA. Natural DNA has 4 base pairs, combinations of adenine (A), thymine (T), cytosine (C), and guanine (G). Amino acids are made from sequences of 3 of these components, which form the building blocks of proteins in organisms with instructions for cells.

Romesberg and colleagues found a way of adding 2 more base pairs, labeled X and Y, to DNA. With these extra base pairs, new kinds of proteins can be produced with “unnatural” chemistries for therapeutics that offer additional properties beyond the capability of proteins with a natural chemistry. The added base pairs make it possible to encode for up to 152 new amino acids for proteins with unique chemical characteristics that can be configured into therapies or other applications.

In the Nature paper, the Synthorx-Scripps team reports developing a new strain of E. coli bacteria, a microbe popularly associated with food poisoning, but in its benign forms is often used as a model organism in labs. The engineered E. coli was created with a plasmid, a circular DNA molecule found in bacteria, containing the X and Y base pairs. With this extra pair of components, the bacterial cell’s ribosome, or protein synthesis molecule, successfully decoded the DNA into new kinds of proteins.

The researchers tested the new E. coli strain’s ability to produce a new type of designed protein. The product in this case is a synthetic form of green fluorescent protein, a compound found naturally in jellyfish that illuminates by absorbing ultraviolet light. In labs, green fluorescent proteins are a workhorse compound often used to track the status of biological processes.

Scripps graduate student and first author Yorke Zhang says in an institute statement, “We were able to achieve purities of desired amino acid incorporation above 98 percent, which demonstrates how seamlessly our synthetic bases can be integrated into the natural processes for encoding and decoding genetic information.”

The new type of green fluorescent protein from the engineered E. coli served solely as a proof of concept, was not given any additional functions, and required the researchers to add the X and Y base pairs to the DNA. As a result, say the researchers, the engineered E. coli cannot exist outside the lab.

Laura Shawver, CEO of Synthorx, adds in a company statement, “Now that we have a semi-synthetic organism that can encode and translate expanded genetic information, we have an efficient system for the design and scale-up of novel protein therapeutics that impart improved pharmacological properties of biologics making them more efficacious, safer, and more convenient for patients.”

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Marine Animal Venom Studied for Pain Drugs

Textile cone snail

Textile cone snail (Richard Ling, Wikimedia Commons)

29 November 2017. A medical research team is investigating the chemistry in venom from snail-like marine animals to discover natural alternative drugs for pain. The four-year project at University of Utah in Salt Lake City is funded by a $10 million grant from the U.S. Department of Defense.

Researchers led by biologist Baldomero Olivera are seeking new compounds from nature that address chronic pain, for which opioid drugs are often the only option available today. Opioids work by reducing the intensity of pain signals to the brain, particularly regions of the brain controlling emotion, which reduces effects of the pain stimulus. But by binding to receptors in the brain affecting emotions, opioids can also drive up dopamine levels, creating an addiction. A report from the National Academies in July 2017 says as of 2015, some 2 million Americans age 12 and over are addicted to prescription opioid drugs.

The Utah team is looking into the venom created by snails and similar marine organisms as a source for new compounds that address chronic pain. Olivera’s lab studies the venom produced by conus or cone snails, a predatory species of mollusk, and so far identified more than 100,000 chemically active peptides in their venom. Many of these peptides, short chains of amino acids similar to proteins, target pathways and receptors in the nervous system to numb or stun their prey. The lab’s work already led to a powerful chronic pain drug, ziconotide, marketed as Prialt by Jazz Pharmaceuticals.

In February 2017, a team led by Olivera and Utah psychiatry professor J. Michael McIntosh published a study of venom from the conus regius snail found in the Caribbean as an alternative to opioids. In tests with lab rodents, the researchers found a compound in the venom used a pathway different from opioids to block pain receptors. One notable finding from the study was pain relief from the compound continued for 72 hours, well after it cleared the bodies of test animals.

“Pain is not a disease,” says Utah biology research professor Russell Teichert in a university statement. ““It is an important sensory response. Our intent is not to block pain, but to block abnormal neuropathic pain, especially if it becomes chronic.” Teichert joins Olivera and McIntosh on the research team.

In the new project, the Utah team is evaluating venom from a number of marine mollusk species, not just cone snails, for sources of natural alternative pain drugs. The researchers are first identifying new targets for pain drugs, followed by compilation and screening of compounds from these marine organisms for candidates that prevent or relieve chronic pain. The team will then advance the best prospects through preclinical testing and eventually clinical trials.

The following video tells more about the project.

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