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Repair Patch Devised for Heart Attacks

Heart and major blood vessels

(NIH.gov)

18 Apr. 2019. Researchers in the U.S. and China designed a hydrogel patch that in lab animals reduces the damage to heart muscle occurring after a heart attack. A team from Brown University in Providence, Rhode Island, Fudan University in Shanghai, and Soochow University in Suzhou, China describe the the patch and its development in the 15 April issue of the journal Nature Biomedical Engineering (paid subscription required).

A heart attack occurs when blood flow in one or more of the coronary arteries is blocked, reducing the amount of oxygen needed by heart muscles to function. Blockages often occur when cholesterol plaques building up in an artery break off and form a clot. Heart muscle tissue, in this circumstance, becomes damaged, with the amount of damage depending on the size of the area affected by the blockage. Scar tissue forms in the damaged area, and while the heart continues to pump blood, it becomes weakened as a result. National Institute on Aging says more than 1 million people in the U.S. suffer a heart attack each year, with about half of those dying.

Researchers led by engineering professor Huajian Gao at Brown, cardiology professor Ning Sun at Fudan University, and Lei Yang, a recent Brown Ph.D graduate who now studies biomaterials at Soochow University and Hebei University of Technology, are seeking solutions for fixing the damaged muscle tissue that occurs in a heart attack. “Part of the reason that it’s hard for the heart to recover after a heart attack,” says Gao in a Brown University statement, “is that it has to keep pumping. The idea here is to provide mechanical support for damaged tissue, which hopefully gives it a chance to heal.”

While mechanical patches to fix heart attack damage were tried before, little research up to now determined the optimal properties of the patch, such as thickness and stiffness, which in previous attempts varied widely. “If the material is too hard or stiff, then you could confine the movement of the heart so that it can’t expand to the volume it needs to,” notes Gao. “But if the material is too soft, then it won’t provide enough support. So we needed some mechanical principles to guide us.”

The team gained those principles from computer models of a beating heart created in Gao’s lab. The models highlight heart functions of a normal, healthy heart, then the damage when a heart attack occurs in heart muscle tissue, revealing the changes in structure that weaken the tissue. The models also provided specifications for designing a patch with adequate support in the damaged areas, while not confining the rest of the heart.

Those specifications enabled Yang’s biomaterials lab to design a patch made from a hydrogel, a water-based biocompatible polymer. The hydrogel is viscoelastic, which means it exhibits both liquid and solid properties. As a result, the patch retains its fluid properties while under stress, but solidifies when needed to provide support to the heart.

The Fudan University team led by Sun tested the patch on lab rats induced with heart attacks. The tests show the patch provides the needed mechanical support for damaged hearts, while reducing the stress on remaining heart tissue cells. The patched hearts also show less cell death in the damaged regions and less accumulation of scar tissue.

In addition, say the researchers, the patch is non-toxic, easy to produce, and low in cost, with the materials costing about 1 cent per patch. More tests with animals are planned, but the eventual goal is to advance the patch to human clinical trials.

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Patent Awarded for Engineered T-Cell Cancer Therapy

Human T-cell

Scanning electron micrograph of a healthy human T-cell (NIH.gov)

17 Apr. 2019. An experimental treatment using a person’s modified T-cells from the immune system to attack solid tumor cancers received a U.S. patent. The Patent and Trademark Office awarded patent number 10,259,855 to inventors at the Wistar Institute in Philadelphia, which licensed the rights exclusively to Anixa Biosciences Inc. in San Jose, California.

Anixa is developing treatments initially for ovarian cancer with the licensed Wistar technology. That technology is based on T-cells, white blood cells in the immune system altered to express chimeric antigen receptors, being adopted as treatments for some blood-related cancers, such as leukemia. For these blood-related cancers, the engineered T-cells seek out and bind to a protein called CD19 found on the surface of B cells — another type of white blood cell — associated with several blood-related cancers.

Solid-tumor cancers, however, require other targets. In the Wistar-Anixa approach, described in the patent, the chimeric antigen receptor T-cells, or CAR T-cells, are modified to target proteins found on ovarian tumors. While expressed on ovarian tumor cells, these proteins, known as follicle-stimulating hormone receptors, are rarely found on healthy cells. Thus treatments seeking out these proteins are likely to cause fewer adverse effects than many current chemotherapies.

The patent covers the entire process of extracting T-cells from the patient, modifying the T-cells to add chimeric antigen receptors, expanding the volume of modified T-cells in the lab, priming the patient’s immune system with chemotherapy, and returning the modified T-cells to the patient. The patent also covers solid tumors other than those found in the ovaries, including prostate, breast, colon, pancreas, urinary bladder, kidney, lung, liver, stomach, and testis. Anixa says follicle-stimulating hormone receptors may be expressed on the surface of ovarian cells, but they’re also found on blood vessels that feed other solid tumors. In addition, the patent text covers primary tumors and those that spread to other parts of the body.

In January 2017, a team from Wistar Institute led by Jose Conejo-Garcia, one of the inventors on the patent, published a study testing modified T-cells that target follicle-stimulating hormone receptors in lab cultures and mice grafted with several types of human ovarian cancer. The researchers found the engineered T-cells attacked only the tumor cells across all of the ovarian cancer types in the mice, and not the surrounding healthy tissue.

In the study, mice receiving the altered T-cells showed measurable therapeutic effects, including clearance of the tumors in some cases. Moreover, the modified T-cells persisted in the mice, providing immunity against a later introduction of ovarian tumor cells. And the researchers reported longer survival times among the T-cell recipient mice, without noticeable toxicity.

Science & Enterprise reported in November 2017 on Anixa — then known as ITUS Corp. — licensing the technology from Wistar. In that same month, the company began a collaboration with Conejo-Garcia, who moved to Moffitt Cancer Center in Tampa, Florida, to advance the technology through preclinical stages.

“This technology,” says Amit Kumar, Anixa’s president and CEO in a company statement, “takes advantage of specific hormone–hormone receptor biology to address malignancies and may hold promise to be the one of the first successful CAR-T therapies against solid tumors.  While our initial focus is the treatment of ovarian cancer, the technology covered by the patent is broad and may also be effective in treating other solid tumors by exploiting an anti-angiogenesis mechanism of action.”

Anixa expects to file an investigational new drug application to FDA, in effect requesting permission to begin clinical trials, by the end of the year.

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Crispr Used to Create Circuit-Like Genes

Half-adder circuit

Basic half-adder circuit. (Inductiveload, Wikimedia Commons)

17 Apr. 2019. A biotechnology team uses genome-editing to create synthetic genes acting like electronic circuits that can be arrayed in cells like computer components. Researchers from the lab of bioengineering professor Martin Fussenegger at ETH Zurich located in Basel, Switzerland, describe their techniques in the 9 April issue of Proceedings of the National Academy of Sciences.

Fussenegger and colleagues aim to build on earlier attempts at biological programming with proteins to control gene expression in a way that emulates the control and reliability of integrated circuits. Using proteins, however, makes possible only the most simple of circuits, processing one a single input at a time. The ETH Zurich team seeks a more flexible, modular, and scalable process enabling more complex and sophisticated biological circuits.

That process turns out to be the genome editing technique Crispr — short for clustered, regularly interspaced short palindromic repeats. Crispr makes it possible to edit genomes of organisms by harnessing bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. The actual editing of genomes with Crispr in most cases today uses an enzyme known as Crispr-associated protein 9 or Cas9, guided with RNA molecules to specific genes needing repair or modification.

In this study, the researchers use Crispr-Cas9 to edit genes so they perform in predictable ways, in this case coding for and expressing a specific protein. This predictable property makes it possible to connect these edited genes into circuit-like assemblies that perform Boolean logic computations. To prove the concept, the team connected the genes into a circuit that acts like a half-adder electronic component. A half-adder performs computations adding 2 single-digit binary numbers into a 2-digit output. Putting 2 half-adder components together performs full addition operations.

To further prove the concept, the ETH Zurich researchers assembled these edited genes configured to run like a central processing unit with dual cores, or 2 independent processing components. Gene circuits in the Crispr-CPU, as they call it, were taken from 2 different bacteria and assembled inside cells, including adult bone marrow stem cells. Tests of the gene circuits and Crispr-CPU, say the researchers, show they work efficiently and can be readily assembled into more complex circuit designs.

The team believes these gene circuits can be configured into programmable components that detect specific biomarkers. When assembled into half-adders, for example, the circuits can be programmed to detect 2 different biomarkers, then output both a detection alert protein and a therapeutic protein. The circuits could also be programmed to operate for specific periods of time, with longer-term circuits tracking the presence of disease-producing proteins after treatments.

The researchers’ next step is to construct multi-core processors resembling modern processing chips from these gene circuits. Fussenegger believes these biological circuits can become more efficient than electronic components. “Imagine a microtissue with billions of cells,” says  Fussenegger in an ETH Zurich statement, “each equipped with its own dual-core processor. Such ‘computational organs’ could theoretically attain computing power that far outstrips that of a digital supercomputer, and using just a fraction of the energy.”

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Engineered Moth to Control Soybean Pest

Soybean looper caterpillar

Soybean looper caterpillar (Russ Ottens, University of Georgia, Wikimedia Commons)

16 Apr. 2019. A company providing genetically engineered insects to control threats to health and agriculture is designing a modified moth that now destroys soybeans and other crops. Oxitec Ltd. in Oxford, U.K., is creating an engineered variety of soybean looper, a pest ravaging various crops in the southern United States and elsewhere in the Americas, for an undisclosed client.

The soybean looper is a moth, which as a larva or caterpillar, consumes large quantities of foliage, particularly soybeans, but also cotton, sweet potatoes, peanuts, lettuce, herbs, tomato, and tobacco. In addition, female soybean loopers lay as many as 700 eggs in their lifetimes, allowing just a few of the species to grow very quickly in numbers. Soybean loopers have developed a resistance to many older pesticides, making them a problem to control. Moreover, they reside under the leaf canopy, or on the underside of leaves, which makes the insects difficult to target visually, even with newer pesticides.

Oxitec, a subsidiary of the synthetic biology company Intrexon, develops insect varieties genetically engineered to limit their reproduction and quickly reduce their numbers. The company’s technology genetically engineers the insect males that mate with females of the species to produce offspring with a gene causing them to die before they reach adulthood. Thus the engineered offspring are prevented from mating, which collapses their communities. Oxitec-engineered species also have a gene with a fluorescent marker, making them visible with a special light and trackable by authorities, if needed.

“Growers are facing compounding challenges including rising pest populations, growing resistance in pests, and a demand for more efficiencies in production,” says Kelly Matzen, who heads Oxitec’s research and development, in a company statement. “We anticipate that our self-limiting soybean looper will provide growers with a new, effective management option that will help to protect their yields by reducing losses ensuring traditional and new crop protection methods remain effective.”

As reported by Science & Enterprise in September 2017, Oxitec developed a genetically-altered variety of diamondback moth, another destructive agricultural pest with caterpillars that eat brassica or crucifer vegetable crops including popular items such as broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, and kale. At the time, Oxitec began field tests of its self-limiting varieties, partnering with an entomology lab at Cornell University. Oxitec says data from the field trials are now being analyzed.

The company also develops genetically-engineered insect varieties to meet public health threats. In June 2018, Science & Enterprise reported on a new Oxitec project with the Bill and Melinda Gates Foundation to create a variety of mosquito to help stop the spread of malaria. The foundation invests heavily in discovery of new drugs that prevent and treat malaria, but also supports other vector-control strategies, such as controlling mosquito populations.

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Human Heart 3-D Printed from Patient Cells

3-D printed heart

3-D printed, small-scale human heart engineered from the patient’s own materials and cells. (Advanced Science, Tel Aviv University)

16 Apr. 2019. A biomedical engineering team printed a three-dimensional scale model of a human heart, including blood vessels, from cells donated by a living person. Researchers at Tel Aviv University in Israel describe their process in yesterday’s issue of the journal Advanced Science.

The Tel Aviv team from the regenerative medicine lab led by biomedical engineering professor Tal Dvir is seeking longer term treatment options for patients with heart disease. The problem of heart disease is growing as populations in many parts of the world are aging. Heart failure, where the heart cannot pump enough blood to meet the body’s needs, for example, is a condition affecting some 5.7 million people in the U.S., according to Centers for Disease Control and Prevention. For people with end-stage heart failure, a transplant is the only available option, but donated hearts with a close genetic match are often not available.

Printing of cardiac tissue from stem cells is a longer-term alternative to transplants under study, which up to now, is successful in producing pieces of heart muscle tissue. Dvir and colleagues, including doctoral candidate Nadav Noor who led the project, aim to extend that process to a complete heart, including blood vessels, not just pieces of heart muscle. They started with donated cells taken from an individual’s omentum, the tissue surrounding organs in the abdomen that wraps around the intestines.

Those donated cells were then cultured and reprogrammed into pluripotent stem cells, for transformation into precursor cells of heart muscle tissue and blood vessels. The framework for those cells, known as the extracellular matrix, was then extracted and formulated into a hydrogel, a form of water-based polymer. The team produced separate hydrogels for heart muscle tissue and blood vessels, mixing the hydrogel with the extracellular matrix with precursor heart muscle and blood vessel cells, to make bioinks for a 3-D printer.

The researchers used computer models to design the 3-D printed heart, particularly the blood vessel structure. The team first printed pieces of heart muscle tissue under lab conditions, which revealed cells similar to those in living hearts. They then 3-D printed a smaller-scale model of a human heart, about the size of a rabbit’s heart, but with a blood vessel architecture similar to a human heart. The same technology can be used, say the researchers, to print a human-size organ.

A key advantage of this technique is its ability to produce an organ that matches the biological characteristics of the donor. “The biocompatibility of engineered materials is crucial to eliminating the risk of implant rejection, which jeopardizes the success of such treatments,” says Dvir in a university statement. “Here, we can report a simple approach to 3-D printed thick, vascularized and perfusable cardiac tissues that completely match the immunological, cellular, biochemical, and anatomical properties of the patient.”

The team points out that their 3-D printed heart is not yet a working model, the next stage in the project. “We need to develop the printed heart further,” notes Dvir. “The cells need to form a pumping ability. They can currently contract, but we need them to work together.”

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Start-Up Analyzes Images to Determine Medical Condition

Stewart Wang

Stewart Wang (University of Michigan)

15 Apr. 2019. A new company provides a service that determines a person’s condition for disease treatments based on indicators derived from an analysis of huge medical-image databases. Applied Morphomics Inc. in Ann Arbor is a 2 year-old spin-off enterprise founded by surgery professor Stewart Wang at University of Michigan medical school, also in Ann Arbor.

Wang, who specializes in treatments for burns and other injuries, also studies morphomics, the analysis of biomarkers or molecular indicators of a person’s physical condition. Rather than identifying those biomarkers from specimen samples such as blood or urine, Wang and colleagues in the Morphomics Analysis Group find digital biomarkers in medical images, such as computed tomography or CT scans, compared to large-scale databases of similar images collected over the years. Specimen samples generally have a short shelf life and are discarded after tests are performed, while medical images can be stored almost indefinitely, and added to the database for later analysis.

“This is the ultimate selfie,” says Wang in a university statement. “A patient’s body is their biological medical record and contains a tremendous amount of information that clinicians to date have not been able to comprehend.”

Wang and colleagues write algorithms that analyze CT images looking for visual evidence of digital biomarkers. Their analysis so far covers CT scans from more than 100,000 individuals over a 20-year period. From that collection, the researchers calculate baselines for different ages, genders, and fitness levels. And from those baselines, the techniques make it possible to identify digital biomarkers related to specific diseases or conditions. For example, muscle mass identified in CT scans is a good indicator of an individual’s overall health, and can help predict recovery from major surgery or trauma, compared to similar age and gender groups at large.

In the past year, Wang’s lab published a study showing factors identified through CT scans, such as bone density and body fat, can predict successful lung transplant procedures, as well as highlight factors influencing the length of hospital stays and survival times.  Another study published last year uses morphomics for computing an index to screen for malnutrition in adults, comparing people independently diagnosed with malnutrition to healthy kidney donors, and indicating nutrition levels among the kidney donors. The lab makes available a reference set of CT scans from 6,000 trauma patients at University of Michigan called Reference Analytic Morphomic Population, or RAMP, as well as a library of morphomics measures for body mass, spine, and other bones.

Wang’s company Applied Morphomics refines the algorithms to provide guidance to individual patients based on digital biomarkers in the person’s CT scans compared to baselines for the population at large. Applied Morphomics has an exclusive license from the university to commercialize the lab’s technology, which it offers as a tool for precision medicine decision-making.

“The deep analysis of the variety and often less apparent nuances of our physical structure that have been developed by the morphomics project,” notes Wang, “is a phenomenally deep and sophisticated benchmarking reference. The variety of applications for this collection of personalized structural human roadmaps is staggering in its potential applications.”

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Univ-Business Consortium Developing Advanced Satellites

Australia from space

(NASA.gov)

15 April 2019. An international consortium, led by University of South Australia, plans to create a new generation of space satellites with greater sensing and communications capabilities. The Cooperative Research Centre for Smart Satellite Technologies and Analytics, or SmartSatCRC, is funded by AU$245 million ($US 175.8 million) in public funding, private grants, and in-kind contributions from participating companies and institutions, with the Australian government announcing the SmartSatCRC designation today.

SmartSatCRC is expected to develop onboard and analytics technologies that provide better connectivity with satellites and improved sensing of land and ocean conditions. Those technologies, says the center, will offer faster and more reliable communications, as well as better integration with ground-based networks, including emerging Internet of Things devices. The center also anticipates developing advanced systems to help make satellites more responsive, agile, resilient, and more adaptable to different payloads. In addition, SmartSatCRC expects to create better data analytics for satellites, and better design and testing facilities for those systems.

The smart satellite center resides at University of South Australia in Adelaide, led by Andy Koronios, the university’s dean of industry and enterprise, and former professor of information technology. Joining the university in administering the center is Nova Systems, a technology services company also in Adelaide. Taking part in SmartSatCRC as well are more than 90 other companies, universities, and government science agencies in Australia, as well as corporate partners and agencies from Europe and the U.S., such as Airbus, BAE Systems, Northrup Grumman, NASA, and the European Space Agency.

SmartSatCRC aims to make Australia a leading player in the global space systems industry, by developing a new generation of payload technologies rather than launch vehicles. “Australia has had a strong pedigree and a long history in space with excellent scientific capabilities in instrumentation and communications technologies,” says Koronios in a university statement, “but until now, the research has not been brought together to build a new industry for Australia, and to capitalize on the exponential growth of the global space economy.”

“Globally space technologies and industries are worth more than $500 billion,” adds Koronios, “but that success has been underpinned by serious global investment in research.”

The center is also expected to make Australia less dependent on satellite services from other countries, such as the U.S. and China. Koronios notes that “we cannot rely exclusively on the goodwill of other nations or our deep pockets to meet our communications and connectivity needs or to monitor our nation and our resources.” And he adds, “For example, through their advanced remote sensing capabilities with satellites passing over Australia every day, other nations have the ability to predict our crop yields before we can.”

The announcement today designating SmartSatCRC was made by Karen Andrews, the country’s Minister of Industry, Science and Technology, which includes a commitment of $55 million from the Australian government. The center is Australia’s largest investment in space technology, with the goal of growing into a $12 billion industry, and creating some 20,000 jobs by 2030.

Koronios tells more about SmartSatCRC in this video.

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New on Medium – Guide to Demystify A.I.

Artificial intelligence graphic

(Gerd Altmann, Pixabay)

15 Apr. 2019. We report a lot about artificial intelligence here on Science & Enterprise, so I decided to share reporting tips on A.I. with fellow journalists to help make the algorithms in our lives more understandable to lay readers. We posted the story last night on the publishing site Medium.

The story recommends reporters ask A.I. systems developers the kinds of questions they would ask other subjects: What does your product do? How does it do what it claims? And how do you know if it’s any good? Our story refines those 3 broad questions into 7 more specific queries about machine learning algorithms, and provides a recent example from the pages of Science & Enterprise to illustrate their use.

As we say in the story, it’s better to light a candle than curse the algorithm. Check it out.

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Infographic – Venture Deals Cool Off in Q1 2019

Chart, venture funding by quarter

Click on image for full-size view. (CB Insights)

14 Apr. 2019. Venture capital investments worldwide declined in the first quarter of 2019, compared to the near record-setting pace of the last 3 months of 2018. But the data in this weekend’s infographic, from the quarterly CB Insights and PwC Moneytree Report, also show some gains in venture investing compared to the first quarter of 2018.

The report shows global venture investors made 3,327 deals in the first quarter of 2019 with a total of $52.2 billion dollars. Those numbers are down compared to the last quarter of 2018, when venture companies placed $67 billion in start-up enterprises in more than 3,500 deals. However, when compared to the first quarter of 2018, to account for seasonal factors, total venture funding in the first quarter of 2019 was still somewhat higher — $52.2 billion in Q1 2019, compared to $49.4 billion in Q1 2018 — while the 3,327 deals executed so far in 2019 declined from about 3,600 the same time in 2018.

Investments in companies developing systems using artificial intelligence, a topic covered frequently on Science & Enterprise, fell 22 percent to $2 billion in the first quarter of 2019, compared to the fourth quarter of 2018.

Venture financing in the U.S. during the first quarter of 2019 reflects the worldwide numbers, with 4 percent fewer deals and 36 percent less dollar volume, at $25 billion, compared to the fourth quarter of 2018. Seed-stage deals in the U.S., with funding for the newest start-ups, fell to 24 percent of all deals in the first quarter of 2019, continuing a decline begun in the third quarter of 2018, when 36 percent of all venture transactions went to seed-stage companies.

The New York City metropolitan area recorded $4.5 billion in venture financing in the first quarter of 2019, more than doubling the dollar amount in the fourth quarter of 2018, while investments in Silicon Valley companies declined 19 percent to $4.3 billion.

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Lung Model Developed to Test E-Cigarettes, Hookah

Juul e-cigarette

Juul e-cigarette device (Mylesclark96, Wikimedia Commons)

12 April 2019. A three-dimensional model of a human lung is being developed to test health effects of new trends in smoking, such as electronic cigarettes and hookahs. The model lung is a project of the University of Colorado medical school in Denver, funded by a $3.4 million grant from Food and Drug Administration.

Electronic cigarettes, or e-cigarettes, are battery-powered nicotine delivery devices, that heat a liquid containing nicotine, moisturizing and flavoring agents, as well as preservatives and artificial coloring. Makers of e-cigarettes often market the devices as safer alternatives to tobacco-burning cigarettes and sometimes as a technique to help tobacco smokers quit conventional cigarettes. Hookahs are water pipes, used for centuries in the Middle East, but becoming popular in cafes in the West, including the U.S. Hookahs are smoked through a water bowl and flexible tube, often with flavored tobacco, much like e-cigarettes.

Data from a Centers for Disease Control and Prevention survey in reported in November 2018 show large increases in electronic cigarette use in high school and middle school children in just the past year. The results show the number of e-cigarette users in high school rose 78 percent to more than 3 million, or about 21 percent of all high school students, since the last survey in 2017. Even among middle school students, e-cigarette smoking jumped by 48 percent in the past year to 570,000 or about 5 percent of all middle school students. At the same time, tobacco use of any kind among high-school students rose in the past year by 38 percent to 4 million, and among middle-schoolers, tobacco use increased by 29 percent to 840,000.

As reported by Science & Enterprise last month, Scott Gottlieb, the recently-departed commissioner of the FDA, described the sharp rise in youth e-cigarette use “an epidemic,” adding that, “All the gains made against youth tobacco use over the years will be reversed by these products.” Gottlieb added that some evidence shows e-cigarettes can help current smokers quit their conventional cigarettes, but that’s far outweighed by the marked increases in teen use of e-cigarettes and upticks in combustible tobacco.

The 3-D lung project is led by Kambez Benam, a biomedical engineering professor at Colorado, whose lab is developing tissue engineered models of lungs to better understand effects of smoking and other pathologies. In this project, Benam and colleagues are creating an engineered airways, the passage through which air reaches the lungs and respiratory tract, with living cells that line the airways. The airway tissue cells will be seeded on an extracellurlar matrix, the framework or scaffold for the airways, as well as stromal, or connective tissue cells surrounding the lung.

The model lung is expected to provide realistic effects of e-cigarette and hookah smoking on lung tissue and cells, as well as related impacts on on genes, proteins, and functions of organs and the immune system. Researchers in the past used animals for these kinds of tests, but results from animal tests are not always transferable to humans.

“Providing the next generation of a human lung model to compare the toxicity of emerging products,” says Benam in a university statement, “particularly hookah and e-cigarettes, will help identify dangerous and carcinogenic formulations. This study has an unprecedented potential to advance the available tool kits for FDA to better protect and promote public health concerns around tobacco products.”

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