September Spotlight

“Smaller Is Better” Chemical Bioproduction

Ramon Gonzalez, professor of chemical and biomolecular engineering at Rice University and director of its Advanced Biomanufacturing Initiative (iBIO), believes that “waste” methane represents an opportunity for biomanufacturing that should not be missed. Instead of getting burned off, methane could and should generate profits. With advancements in biomanufacturing, wild-type or genetically modified bacteria can turn carbon-rich methane into valuable chemicals — producing them at smaller scales in more environmentally friendly processes than those of classical chemical manufacturing.

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Gonzalez specializes in genetically engineering bacteria for biotechnology. In a January 2017 Science paper, he and his Rice colleagues — research scientist James Clomburg and graduate student Anna Crumbley — show that advances in metabolic engineering, genomics, and industrial process design have brought industrial biomanufacturing closer than ever to widespread adoption. But they argue that it could and should go much further.

“Biotech in general has four branches of applications: medical, agricultural, environmental, and industrial (the one in which we primarily work),” said Gonzalez. “The industrial side aims at generating molecules produced from many feedstocks, including oil and natural gas. What has not been explored much in this space is what biology brings to the table, regardless of whether you use starting materials that are renewable.”

Renewable feedstocks include corn and lignocellulosic biomass used to produce ethanol and other molecules. Nonrenewables include oil and gas used to produce thousands of chemicals required by industry, typically at immense facilities that offer economies of scale. Gonzalez said that small-scale biomanufacturing tends to be associated with renewable sources, but his team doesn’t see that as the only use of the growing technology.

“You don’t need to go big,” he said. “That’s not necessarily what biology is good at.”

The team found that waste methane burned off in 2014 alone could have been transformed with biomanufacturing to meet all industrial needs that year for seven important organic chemicals: methanol, ethylene, propylene, butadiene, xylene, benzene, and toluene. Potential feedstock could come from flared methane, waste-treatment facilities, and agricultural facilities around the country. Combined, they could produce most chemicals used by industry.

Those feedstocks are not easily accessible to megafacilities that require efficiently delivered large quantities of raw materials (mostly fossil-based). By contrast, biomanufacturing facilities operate at smaller scales requiring quantities of feedstocks that match the output of typical methane-generating sites. A distribution of small factories would place them closer to feedstocks and where chemicals are needed. As an example, Gonzalez noted that small, strategically placed bioconversion facilities have increased the nation’s ethanol output tenfold over the past two decades.

The researchers pointed out that environmental, geopolitical, and economic factors already are pushing manufacturers to look at smaller, better distributed manufacturing facilities. The science of programming bacteria such as fast-growing Escherichia coli to make chemicals using genome-editing techniques such as CRISPR/Cas-9 is rapidly catching up to demand.

“Do you need to produce millions of tons of chemicals?” he asked. “Well, if you have hundreds or thousands of small plants, of course you’re going to make an impact. You can leverage an ‘economies of unit number’ model, which can be defined as a shift from a small number of high-capacity units or facilities to a large number of units or facilities operating at a smaller scale. The good news is that, as we demonstrate in this paper, industrial biomanufacturing can both support and benefit from economies of unit number.”

Gonzalez said that developing nations might benefit greatly from decentralized biomanufacturing, and then he looked even farther afield. “The atmosphere of Mars is 95% carbon dioxide. To plant a flag there, you really have to start with that and solar energy, whether you like it or not,” he said. “And you can do it with something like I’m describing here. You don’t need to bring a chemical plant to Mars. You could bring microbes in a vial that replicate and grow and produce what you need from the abundant carbon already there.”

Reference: doi:10.1126/science.aag0804.

Cambridge Stem Cell Breakthrough

In March 2017, Cell Guidance Systems based in Cambridge, UK, licensed a technology for simulating major events in mouse embryo development without using eggs or sperm. The company develops technologies for cell-based research and regenerative medicine. Magdalena Zernicka-Goetz and her colleagues studied trophoblast and embryonic stem cells (ESCs), two of the earliest cell types to develop from the fertilized eggs. They found that growing such cells together creates embryonic structures that strongly resemble mouse embryos in the days after they implant themselves into a mouse’s uterine wall. Developing a specific culture medium was a key to this success.

With all genetic identity of derived tissues from an ESC, embryos produced would be clones of it. How far they can develop remains to be seen, but they could transform both embryology and stem-cell science. Potential applications include improved generation of transgenic animals for research and novel ways to make tissues and organs for research.

The company’s CEO Michael Jones says, “This is arguably the most significant breakthrough in stem-cell science for a decade, and these discoveries provide key insights into mammalian development. The potential benefits for basic research and the development of new medical therapies [are] very exciting.”

Massachusetts Life Sciences Center Launches Ramp-Up Program

The Massachusetts Life Sciences Center (MLSC), an investment agency that supports life-science innovation, has launched a program to provide state-grant funding to leverage federal small business innovation and technology transfer grants for early stage companies. Through the Massachusetts Ramp-Up Program (MassRamp), companies that get federal grants can compete for supplemental funding. MassRamp’s goal is to bridge funding gaps associated with long research and development (R&D) cycles and the high cost of translating research into commercially viable products.

“The strength, breadth, and variety of early stage life-science companies is a critical element of the Massachusetts life sciences ecosystem,” said Travis McCready (MLSC’s president and chief executive officer). “Our young, dynamic companies are a wellspring of innovation that represent future IPOs and serve as a magnet for larger companies seeking strategic partnerships and acquisitions. The MLSC designed MassRamp to help sustain companies with early validation of technologies through what can be a tumultuous stage of R&D.”

Awardees will receive grants of ≤US$300,000 to help cover the costs of direct labor, clinical trials, consultants and contractors, materials, supplies, and equipment. MassRamp is designed to provide additional resources to complement approved federal projects or expand the scope of federal grant based on the approved technology. Proposals must focus on human health with an identified commercial product or service.

Will Adams (president and CEO of Riparian Pharmaceuticals) calls it “a unique resource sure to promote a vibrant pipeline. Such programs ensure that the region is an obvious choice for new biotech companies.” Find more information online at www.masslifesciences.com.

Influenza Bested By Frog Peptides

Frogs’ skin secretions contain a number of peptides that defend the sensitive amphibians against bacterial infection. Researchers from Emory Vaccine Center (Atlanta, GA) and the Rajiv Gandhi Center for Biotechnology (Poojappura, India) discovered that the Indian frog Hydrophylax bahuvistara (pictured above) secretes antiviral peptides as well. As published in the April 2017 issue of Immunity, the researchers found that one such peptide can kill H1 strains of influenza.

Given the nature of viruses and their ability to mutate and develop resistance to antiviral drugs, finding new antivirals is an ongoing need. Antiviral treatment will be the first line of defense in the event of a flu pandemic because vaccines cannot be produced quickly enough to protect the public immediately.

The authors found several peptides able to kill viruses; however, most of them also were toxic to mammalian cells. The team collected frog secretions by administering mild electrical stimulation. One peptide specifically targeted the conserved stalk region of H1 hemagglutinin, making it virucidal for human influenza A H1 viruses (including drug-resistant strains) but was not toxic to mammalian cells. With an electron microscope, the peptide could be seen physically destroying influenza virions. The authors named this peptide urumin, after a whip-like sword called an urumi that was used in southern India centuries ago. The team administered urumin intranasally to unvaccinated mice before exposing them to lethal doses of flu virus. Urumin proved to be specific for H1 strains of flu and protected the mice from those strains.

Next, the researchers are working to stabilize antiviral peptides such as urumin because enzymes in human bodies can break down peptides. The team also is exploring other viruses that frog-derived peptides might be active against (e.g., dengue and Zika). Because frogs are not susceptible to human flu viruses, urumin must have evolved to fight off some other pathogen.

Reference: doi:10.1016/j.immuni.2017.03.018

“Silent Genes” Could Provide New Drugs

If you could turn on so-called “silent genes” in the human genome, what interesting proteins might be expressed? In a new study, chemical and biomolecular engineering professor Huimin Zhao and other researchers at the University of Illinois — along with collaborators at the Agency for Science, Technology, and Research in Singapore — have done just that. Using CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 gene-editing technology, they turned on unexpressed (“silent”) gene clusters in five Streptomyces species. Molecules already produced by that common class of bacteria have been used as antibiotics, anticancer agents, and other drugs. This study was published online in April in Nature Chemical Biology.

Zhao said, “The vast majority of biosynthetic gene clusters are not expressed under laboratory conditions, or they are expressed at very low levels. That’s why we call them silent. There are a lot of new drugs and new knowledge waiting to be discovered from these silent gene clusters.”

The researchers identified specific silent biosynthetic gene clusters by using computational tools. Then they used CRISPR–Cas9 technology to insert a strong promoter sequence in front of each gene they wanted to activate. That triggered production of unique metabolites coded for by the different gene clusters.

Previous CRISPR-related research has used the same technology for biomedical applications such as treating genetic diseases. Zhao’s laboratory is using it for drug discovery and was the first to adapt it to turn on or off specific genes in Streptomyces. The team hopes to discover new compounds with interesting bioactivities and did activate silent biosynthetic gene clusters. These researchers demonstrated the process by isolating and determining the structure of each molecule produced. In one case, they produced a novel pentangular type II polyketide from a silent gene cluster in Streptomyces viridochromogenes.

Zhao said that new compounds could lead to new classes of drugs that might fight cancer or counter microbial drug resistance. “Antimicrobial resistance is a global challenge,” he said. “We want to find new modes of action and new properties so that we can uncover new ways to attack cancer or pathogens. We want to identify new chemical scaffolds leading to new drugs, rather than modifying existing types of drugs.”

Reference: doi:10.1038/nchembio.2341

UK Clinical Trial Patients Dropping Out: Can Local General Practitioners (GPs) Help?

In May, CenterWatch reported that over half (58%) of clinical study volunteers decline consent for a trial, nearly a third (32%) fail screening, and nearly a fifth (18%) drop out after enrolment. But a new model for running trials through patients’ local GPs could reduce those numbers.

Developed by UK clinical trial company Interface Clinical Research, the new model is based on working with large GP practices across the United Kingdom to run phase 3 and 4 clinical trials using existing practice facilities and recruiting local patients from each practice’s own database. Patients are recruited after a sophisticated database screen that identifies the most suitable participants. The company finds that fewer patients decline their consent for trials being run through their local providers and familiar staff. Dropout rates following trial enrollment are lower when patients do not have to travel long distances to dedicated trial sites. Interface Clinical Services has run hundreds of patient clinics in GP practices over the past decade.

Fixed costs of dedicated research centers present a barrier to offering competitive services. Such facilities have limited access to patient databases and suffer from high dropout rates. But the individual GP model always has been inefficient: On average, GPs in the United Kingdom typically recruit just five patients per trial and can lose patients because of heavy workloads leading to appointment delays or cancellations for study participants. That could lead to dropouts as well.

To counteract those effects, Interface networked more than 40 GP practices and larger healthcare organizations in the United Kingdom. A hub-and-spoke model connects adjacent practices interested in becoming involved. The company is conducting large-scale feasibility studies for a number of major contract research organizations (CROs) based on its combined GP databases comprising millions of UK patients.

Free Online Networking for Bioengineers

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The American Society of Mechanical Engineers (ASME) hosts a website to connect biomedical engineers with the latest research and foster collaboration, knowledge sharing, and information exchange. The Alliance of Advanced Biomedical Engineering (aabme.org) amalgamates technical articles, reports, and events on topics ranging from cell therapy and thermal medicine to medical devices and 3D printing. Registered users can join the alliance to connect with like-minded professionals seeking networking opportunities in this growing interdisciplinary field.

ASME’s chief operating officer Jeff Patterson says, “Collaboration in this arena is required to advance the field. ASME is championing efforts to make that a reality.”