Tag Archives: US National Institutes of Health

The Canadian science scene and the 2017 Canadian federal budget

There’s not much happening in the 2017-18 budget in terms of new spending according to Paul Wells’ March 22, 2017 article for TheStar.com,

This is the 22nd or 23rd federal budget I’ve covered. And I’ve never seen the like of the one Bill Morneau introduced on Wednesday [March 22, 2017].

Not even in the last days of the Harper Conservatives did a budget provide for so little new spending — $1.3 billion in the current budget year, total, in all fields of government. That’s a little less than half of one per cent of all federal program spending for this year.

But times are tight. The future is a place where we can dream. So the dollars flow more freely in later years. In 2021-22, the budget’s fifth planning year, new spending peaks at $8.2 billion. Which will be about 2.4 per cent of all program spending.

He’s not alone in this 2017 federal budget analysis; CBC (Canadian Broadcasting Corporation) pundits, Chantal Hébert, Andrew Coyne, and Jennifer Ditchburn said much the same during their ‘At Issue’ segment of the March 22, 2017 broadcast of The National (news).

Before I focus on the science and technology budget, here are some general highlights from the CBC’s March 22, 2017 article on the 2017-18 budget announcement (Note: Links have been removed,

Here are highlights from the 2017 federal budget:

  • Deficit: $28.5 billion, up from $25.4 billion projected in the fall.
  • Trend: Deficits gradually decline over next five years — but still at $18.8 billion in 2021-22.
  • Housing: $11.2 billion over 11 years, already budgeted, will go to a national housing strategy.
  • Child care: $7 billion over 10 years, already budgeted, for new spaces, starting 2018-19.
  • Indigenous: $3.4 billion in new money over five years for infrastructure, health and education.
  • Defence: $8.4 billion in capital spending for equipment pushed forward to 2035.
  • Care givers: New care-giving benefit up to 15 weeks, starting next year.
  • Skills: New agency to research and measure skills development, starting 2018-19.
  • Innovation: $950 million over five years to support business-led “superclusters.”
  • Startups: $400 million over three years for a new venture capital catalyst initiative.
  • AI: $125 million to launch a pan-Canadian Artificial Intelligence Strategy.
  • Coding kids: $50 million over two years for initiatives to teach children to code.
  • Families: Option to extend parental leave up to 18 months.
  • Uber tax: GST to be collected on ride-sharing services.
  • Sin taxes: One cent more on a bottle of wine, five cents on 24 case of beer.
  • Bye-bye: No more Canada Savings Bonds.
  • Transit credit killed: 15 per cent non-refundable public transit tax credit phased out this year.

You can find the entire 2017-18 budget here.

Science and the 2017-18 budget

For anyone interested in the science news, you’ll find most of that in the 2017 budget’s Chapter 1 — Skills, Innovation and Middle Class jobs. As well, Wayne Kondro has written up a précis in his March 22, 2017 article for Science (magazine),

Finance officials, who speak on condition of anonymity during the budget lock-up, indicated the budgets of the granting councils, the main source of operational grants for university researchers, will be “static” until the government can assess recommendations that emerge from an expert panel formed in 2015 and headed by former University of Toronto President David Naylor to review basic science in Canada [highlighted in my June 15, 2016 posting ; $2M has been allocated for the advisor and associated secretariat]. Until then, the officials said, funding for the Natural Sciences and Engineering Research Council of Canada (NSERC) will remain at roughly $848 million, whereas that for the Canadian Institutes of Health Research (CIHR) will remain at $773 million, and for the Social Sciences and Humanities Research Council [SSHRC] at $547 million.

NSERC, though, will receive $8.1 million over 5 years to administer a PromoScience Program that introduces youth, particularly unrepresented groups like Aboriginal people and women, to science, technology, engineering, and mathematics through measures like “space camps and conservation projects.” CIHR, meanwhile, could receive modest amounts from separate plans to identify climate change health risks and to reduce drug and substance abuse, the officials added.

… Canada’s Innovation and Skills Plan, would funnel $600 million over 5 years allocated in 2016, and $112.5 million slated for public transit and green infrastructure, to create Silicon Valley–like “super clusters,” which the budget defined as “dense areas of business activity that contain large and small companies, post-secondary institutions and specialized talent and infrastructure.” …

… The Canadian Institute for Advanced Research will receive $93.7 million [emphasis mine] to “launch a Pan-Canadian Artificial Intelligence Strategy … (to) position Canada as a world-leading destination for companies seeking to invest in artificial intelligence and innovation.”

… Among more specific measures are vows to: Use $87.7 million in previous allocations to the Canada Research Chairs program to create 25 “Canada 150 Research Chairs” honoring the nation’s 150th year of existence, provide $1.5 million per year to support the operations of the office of the as-yet-unappointed national science adviser [see my Dec. 7, 2016 post for information about the job posting, which is now closed]; provide $165.7 million [emphasis mine] over 5 years for the nonprofit organization Mitacs to create roughly 6300 more co-op positions for university students and grads, and provide $60.7 million over five years for new Canadian Space Agency projects, particularly for Canadian participation in the National Aeronautics and Space Administration’s next Mars Orbiter Mission.

Kondros was either reading an earlier version of the budget or made an error regarding Mitacs (from the budget in the “A New, Ambitious Approach to Work-Integrated Learning” subsection),

Mitacs has set an ambitious goal of providing 10,000 work-integrated learning placements for Canadian post-secondary students and graduates each year—up from the current level of around 3,750 placements. Budget 2017 proposes to provide $221 million [emphasis mine] over five years, starting in 2017–18, to achieve this goal and provide relevant work experience to Canadian students.

As well, the budget item for the Pan-Canadian Artificial Intelligence Strategy is $125M.

Moving from Kondros’ précis, the budget (in the “Positioning National Research Council Canada Within the Innovation and Skills Plan” subsection) announces support for these specific areas of science,

Stem Cell Research

The Stem Cell Network, established in 2001, is a national not-for-profit organization that helps translate stem cell research into clinical applications, commercial products and public policy. Its research holds great promise, offering the potential for new therapies and medical treatments for respiratory and heart diseases, cancer, diabetes, spinal cord injury, multiple sclerosis, Crohn’s disease, auto-immune disorders and Parkinson’s disease. To support this important work, Budget 2017 proposes to provide the Stem Cell Network with renewed funding of $6 million in 2018–19.

Space Exploration

Canada has a long and proud history as a space-faring nation. As our international partners prepare to chart new missions, Budget 2017 proposes investments that will underscore Canada’s commitment to innovation and leadership in space. Budget 2017 proposes to provide $80.9 million on a cash basis over five years, starting in 2017–18, for new projects through the Canadian Space Agency that will demonstrate and utilize Canadian innovations in space, including in the field of quantum technology as well as for Mars surface observation. The latter project will enable Canada to join the National Aeronautics and Space Administration’s (NASA’s) next Mars Orbiter Mission.

Quantum Information

The development of new quantum technologies has the potential to transform markets, create new industries and produce leading-edge jobs. The Institute for Quantum Computing is a world-leading Canadian research facility that furthers our understanding of these innovative technologies. Budget 2017 proposes to provide the Institute with renewed funding of $10 million over two years, starting in 2017–18.

Social Innovation

Through community-college partnerships, the Community and College Social Innovation Fund fosters positive social outcomes, such as the integration of vulnerable populations into Canadian communities. Following the success of this pilot program, Budget 2017 proposes to invest $10 million over two years, starting in 2017–18, to continue this work.

International Research Collaborations

The Canadian Institute for Advanced Research (CIFAR) connects Canadian researchers with collaborative research networks led by eminent Canadian and international researchers on topics that touch all humanity. Past collaborations facilitated by CIFAR are credited with fostering Canada’s leadership in artificial intelligence and deep learning. Budget 2017 proposes to provide renewed and enhanced funding of $35 million over five years, starting in 2017–18.

Earlier this week, I highlighted Canada’s strength in the field of regenerative medicine, specifically stem cells in a March 21, 2017 posting. The $6M in the current budget doesn’t look like increased funding but rather a one-year extension. I’m sure they’re happy to receive it  but I imagine it’s a little hard to plan major research projects when you’re not sure how long your funding will last.

As for Canadian leadership in artificial intelligence, that was news to me. Here’s more from the budget,

Canada a Pioneer in Deep Learning in Machines and Brains

CIFAR’s Learning in Machines & Brains program has shaken up the field of artificial intelligence by pioneering a technique called “deep learning,” a computer technique inspired by the human brain and neural networks, which is now routinely used by the likes of Google and Facebook. The program brings together computer scientists, biologists, neuroscientists, psychologists and others, and the result is rich collaborations that have propelled artificial intelligence research forward. The program is co-directed by one of Canada’s foremost experts in artificial intelligence, the Université de Montréal’s Yoshua Bengio, and for his many contributions to the program, the University of Toronto’s Geoffrey Hinton, another Canadian leader in this field, was awarded the title of Distinguished Fellow by CIFAR in 2014.

Meanwhile, from chapter 1 of the budget in the subsection titled “Preparing for the Digital Economy,” there is this provision for children,

Providing educational opportunities for digital skills development to Canadian girls and boys—from kindergarten to grade 12—will give them the head start they need to find and keep good, well-paying, in-demand jobs. To help provide coding and digital skills education to more young Canadians, the Government intends to launch a competitive process through which digital skills training organizations can apply for funding. Budget 2017 proposes to provide $50 million over two years, starting in 2017–18, to support these teaching initiatives.

I wonder if BC Premier Christy Clark is heaving a sigh of relief. At the 2016 #BCTECH Summit, she announced that students in BC would learn to code at school and in newly enhanced coding camp programmes (see my Jan. 19, 2016 posting). Interestingly, there was no mention of additional funding to support her initiative. I guess this money from the federal government comes at a good time as we will have a provincial election later this spring where she can announce the initiative again and, this time, mention there’s money for it.

Attracting brains from afar

Ivan Semeniuk in his March 23, 2017 article (for the Globe and Mail) reads between the lines to analyze the budget’s possible impact on Canadian science,

But a between-the-lines reading of the budget document suggests the government also has another audience in mind: uneasy scientists from the United States and Britain.

The federal government showed its hand at the 2017 #BCTECH Summit. From a March 16, 2017 article by Meera Bains for the CBC news online,

At the B.C. tech summit, Navdeep Bains, Canada’s minister of innovation, said the government will act quickly to fast track work permits to attract highly skilled talent from other countries.

“We’re taking the processing time, which takes months, and reducing it to two weeks for immigration processing for individuals [who] need to come here to help companies grow and scale up,” Bains said.

“So this is a big deal. It’s a game changer.”

That change will happen through the Global Talent Stream, a new program under the federal government’s temporary foreign worker program.  It’s scheduled to begin on June 12, 2017.

U.S. companies are taking notice and a Canadian firm, True North, is offering to help them set up shop.

“What we suggest is that they think about moving their operations, or at least a chunk of their operations, to Vancouver, set up a Canadian subsidiary,” said the company’s founder, Michael Tippett.

“And that subsidiary would be able to house and accommodate those employees.”

Industry experts says while the future is unclear for the tech sector in the U.S., it’s clear high tech in B.C. is gearing up to take advantage.

US business attempts to take advantage of Canada’s relative stability and openness to immigration would seem to be the motive for at least one cross border initiative, the Cascadia Urban Analytics Cooperative. From my Feb. 28, 2017 posting,

There was some big news about the smallest version of the Cascadia region on Thursday, Feb. 23, 2017 when the University of British Columbia (UBC) , the University of Washington (state; UW), and Microsoft announced the launch of the Cascadia Urban Analytics Cooperative. From the joint Feb. 23, 2017 news release (read on the UBC website or read on the UW website),

In an expansion of regional cooperation, the University of British Columbia and the University of Washington today announced the establishment of the Cascadia Urban Analytics Cooperative to use data to help cities and communities address challenges from traffic to homelessness. The largest industry-funded research partnership between UBC and the UW, the collaborative will bring faculty, students and community stakeholders together to solve problems, and is made possible thanks to a $1-million gift from Microsoft.

Today’s announcement follows last September’s [2016] Emerging Cascadia Innovation Corridor Conference in Vancouver, B.C. The forum brought together regional leaders for the first time to identify concrete opportunities for partnerships in education, transportation, university research, human capital and other areas.

A Boston Consulting Group study unveiled at the conference showed the region between Seattle and Vancouver has “high potential to cultivate an innovation corridor” that competes on an international scale, but only if regional leaders work together. The study says that could be possible through sustained collaboration aided by an educated and skilled workforce, a vibrant network of research universities and a dynamic policy environment.

It gets better, it seems Microsoft has been positioning itself for a while if Matt Day’s analysis is correct (from my Feb. 28, 2017 posting),

Matt Day in a Feb. 23, 2017 article for the The Seattle Times provides additional perspective (Note: Links have been removed),

Microsoft’s effort to nudge Seattle and Vancouver, B.C., a bit closer together got an endorsement Thursday [Feb. 23, 2017] from the leading university in each city.

The partnership has its roots in a September [2016] conference in Vancouver organized by Microsoft’s public affairs and lobbying unit [emphasis mine.] That gathering was aimed at tying business, government and educational institutions in Microsoft’s home region in the Seattle area closer to its Canadian neighbor.

Microsoft last year [2016] opened an expanded office in downtown Vancouver with space for 750 employees, an outpost partly designed to draw to the Northwest more engineers than the company can get through the U.S. guest worker system [emphasis mine].

This was all prior to President Trump’s legislative moves in the US, which have at least one Canadian observer a little more gleeful than I’m comfortable with. From a March 21, 2017 article by Susan Lum  for CBC News online,

U.S. President Donald Trump’s efforts to limit travel into his country while simultaneously cutting money from science-based programs provides an opportunity for Canada’s science sector, says a leading Canadian researcher.

“This is Canada’s moment. I think it’s a time we should be bold,” said Alan Bernstein, president of CIFAR [which on March 22, 2017 was awarded $125M to launch the Pan Canada Artificial Intelligence Strategy in the Canadian federal budget announcement], a global research network that funds hundreds of scientists in 16 countries.

Bernstein believes there are many reasons why Canada has become increasingly attractive to scientists around the world, including the political climate in the United States and the Trump administration’s travel bans.

Thankfully, Bernstein calms down a bit,

“It used to be if you were a bright young person anywhere in the world, you would want to go to Harvard or Berkeley or Stanford, or what have you. Now I think you should give pause to that,” he said. “We have pretty good universities here [emphasis mine]. We speak English. We’re a welcoming society for immigrants.”​

Bernstein cautions that Canada should not be seen to be poaching scientists from the United States — but there is an opportunity.

“It’s as if we’ve been in a choir of an opera in the back of the stage and all of a sudden the stars all left the stage. And the audience is expecting us to sing an aria. So we should sing,” Bernstein said.

Bernstein said the federal government, with this week’s so-called innovation budget, can help Canada hit the right notes.

“Innovation is built on fundamental science, so I’m looking to see if the government is willing to support, in a big way, fundamental science in the country.”

Pretty good universities, eh? Thank you, Dr. Bernstein, for keeping some of the boosterism in check. Let’s leave the chest thumping to President Trump and his cronies.

Ivan Semeniuk’s March 23, 2017 article (for the Globe and Mail) provides more details about the situation in the US and in Britain,

Last week, Donald Trump’s first budget request made clear the U.S. President would significantly reduce or entirely eliminate research funding in areas such as climate science and renewable energy if permitted by Congress. Even the National Institutes of Health, which spearheads medical research in the United States and is historically supported across party lines, was unexpectedly targeted for a $6-billion (U.S.) cut that the White House said could be achieved through “efficiencies.”

In Britain, a recent survey found that 42 per cent of academics were considering leaving the country over worries about a less welcoming environment and the loss of research money that a split with the European Union is expected to bring.

In contrast, Canada’s upbeat language about science in the budget makes a not-so-subtle pitch for diversity and talent from abroad, including $117.6-million to establish 25 research chairs with the aim of attracting “top-tier international scholars.”

For good measure, the budget also includes funding for science promotion and $2-million annually for Canada’s yet-to-be-hired Chief Science Advisor, whose duties will include ensuring that government researchers can speak freely about their work.

“What we’ve been hearing over the last few months is that Canada is seen as a beacon, for its openness and for its commitment to science,” said Ms. Duncan [Kirsty Duncan, Minister of Science], who did not refer directly to either the United States or Britain in her comments.

Providing a less optimistic note, Erica Alini in her March 22, 2017 online article for Global News mentions a perennial problem, the Canadian brain drain,

The budget includes a slew of proposed reforms and boosted funding for existing training programs, as well as new skills-development resources for unemployed and underemployed Canadians not covered under current EI-funded programs.

There are initiatives to help women and indigenous people get degrees or training in science, technology, engineering and mathematics (the so-called STEM subjects) and even to teach kids as young as kindergarten-age to code.

But there was no mention of how to make sure Canadians with the right skills remain in Canada, TD’s DePratto {Toronto Dominion Bank} Economics; TD is currently experiencing a scandal {March 13, 2017 Huffington Post news item}] told Global News.

Canada ranks in the middle of the pack compared to other advanced economies when it comes to its share of its graduates in STEM fields, but the U.S. doesn’t shine either, said DePratto [Brian DePratto, senior economist at TD .

The key difference between Canada and the U.S. is the ability to retain domestic talent and attract brains from all over the world, he noted.

To be blunt, there may be some opportunities for Canadian science but it does well to remember (a) US businesses have no particular loyalty to Canada and (b) all it takes is an election to change any perceived advantages to disadvantages.

Digital policy and intellectual property issues

Dubbed by some as the ‘innovation’ budget (official title:  Building a Strong Middle Class), there is an attempt to address a longstanding innovation issue (from a March 22, 2017 posting by Michael Geist on his eponymous blog (Note: Links have been removed),

The release of today’s [march 22, 2017] federal budget is expected to include a significant emphasis on innovation, with the government revealing how it plans to spend (or re-allocate) hundreds of millions of dollars that is intended to support innovation. Canada’s dismal innovation record needs attention, but spending our way to a more innovative economy is unlikely to yield the desired results. While Navdeep Bains, the Innovation, Science and Economic Development Minister, has talked for months about the importance of innovation, Toronto Star columnist Paul Wells today delivers a cutting but accurate assessment of those efforts:

“This government is the first with a minister for innovation! He’s Navdeep Bains. He frequently posts photos of his meetings on Twitter, with the hashtag “#innovation.” That’s how you know there is innovation going on. A year and a half after he became the minister for #innovation, it’s not clear what Bains’s plans are. It’s pretty clear that within the government he has less than complete control over #innovation. There’s an advisory council on economic growth, chaired by the McKinsey guru Dominic Barton, which periodically reports to the government urging more #innovation.

There’s a science advisory panel, chaired by former University of Toronto president David Naylor, that delivered a report to Science Minister Kirsty Duncan more than three months ago. That report has vanished. One presumes that’s because it offered some advice. Whatever Bains proposes, it will have company.”

Wells is right. Bains has been very visible with plenty of meetings and public photo shoots but no obvious innovation policy direction. This represents a missed opportunity since Bains has plenty of policy tools at his disposal that could advance Canada’s innovation framework without focusing on government spending.

For example, Canada’s communications system – wireless and broadband Internet access – falls directly within his portfolio and is crucial for both business and consumers. Yet Bains has been largely missing in action on the file. He gave approval for the Bell – MTS merger that virtually everyone concedes will increase prices in the province and make the communications market less competitive. There are potential policy measures that could bring new competitors into the market (MVNOs [mobile virtual network operators] and municipal broadband) and that could make it easier for consumers to switch providers (ban on unlocking devices). Some of this falls to the CRTC, but government direction and emphasis would make a difference.

Even more troubling has been his near total invisibility on issues relating to new fees or taxes on Internet access and digital services. Canadian Heritage Minister Mélanie Joly has taken control of the issue with the possibility that Canadians could face increased costs for their Internet access or digital services through mandatory fees to contribute to Canadian content.  Leaving aside the policy objections to such an approach (reducing affordable access and the fact that foreign sources now contribute more toward Canadian English language TV production than Canadian broadcasters and distributors), Internet access and e-commerce are supposed to be Bains’ issue and they have a direct connection to the innovation file. How is it possible for the Innovation, Science and Economic Development Minister to have remained silent for months on the issue?

Bains has been largely missing on trade related innovation issues as well. My Globe and Mail column today focuses on a digital-era NAFTA, pointing to likely U.S. demands on data localization, data transfers, e-commerce rules, and net neutrality.  These are all issues that fall under Bains’ portfolio and will impact investment in Canadian networks and digital services. There are innovation opportunities for Canada here, but Bains has been content to leave the policy issues to others, who will be willing to sacrifice potential gains in those areas.

Intellectual property policy is yet another area that falls directly under Bains’ mandate with an obvious link to innovation, but he has done little on the file. Canada won a huge NAFTA victory late last week involving the Canadian patent system, which was challenged by pharmaceutical giant Eli Lilly. Why has Bains not promoted the decision as an affirmation of how Canada’s intellectual property rules?

On the copyright front, the government is scheduled to conduct a review of the Copyright Act later this year, but it is not clear whether Bains will take the lead or again cede responsibility to Joly. The Copyright Act is statutorily under the Industry Minister and reform offers the chance to kickstart innovation. …

For anyone who’s not familiar with this area, innovation is often code for commercialization of science and technology research efforts. These days, digital service and access policies and intellectual property policies are all key to research and innovation efforts.

The country that’s most often (except in mainstream Canadian news media) held up as an example of leadership in innovation is Estonia. The Economist profiled the country in a July 31, 2013 article and a July 7, 2016 article on apolitical.co provides and update.

Conclusions

Science monies for the tri-council science funding agencies (NSERC, SSHRC, and CIHR) are more or less flat but there were a number of line items in the federal budget which qualify as science funding. The $221M over five years for Mitacs, the $125M for the Pan-Canadian Artificial Intelligence Strategy, additional funding for the Canada research chairs, and some of the digital funding could also be included as part of the overall haul. This is in line with the former government’s (Stephen Harper’s Conservatives) penchant for keeping the tri-council’s budgets under control while spreading largesse elsewhere (notably the Perimeter Institute, TRIUMF [Canada’s National Laboratory for Particle and Nuclear Physics], and, in the 2015 budget, $243.5-million towards the Thirty Metre Telescope (TMT) — a massive astronomical observatory to be constructed on the summit of Mauna Kea, Hawaii, a $1.5-billion project). This has lead to some hard feelings in the past with regard to ‘big science’ projects getting what some have felt is an undeserved boost in finances while the ‘small fish’ are left scrabbling for the ever-diminishing (due to budget cuts in years past and inflation) pittances available from the tri-council agencies.

Mitacs, which started life as a federally funded Network Centre for Excellence focused on mathematics, has since shifted focus to become an innovation ‘champion’. You can find Mitacs here and you can find the organization’s March 2016 budget submission to the House of Commons Standing Committee on Finance here. At the time, they did not request a specific amount of money; they just asked for more.

The amount Mitacs expects to receive this year is over $40M which represents more than double what they received from the federal government and almost of 1/2 of their total income in the 2015-16 fiscal year according to their 2015-16 annual report (see p. 327 for the Mitacs Statement of Operations to March 31, 2016). In fact, the federal government forked over $39,900,189. in the 2015-16 fiscal year to be their largest supporter while Mitacs’ total income (receipts) was $81,993,390.

It’s a strange thing but too much money, etc. can be as bad as too little. I wish the folks Mitacs nothing but good luck with their windfall.

I don’t see anything in the budget that encourages innovation and investment from the industrial sector in Canada.

Finallyl, innovation is a cultural issue as much as it is a financial issue and having worked with a number of developers and start-up companies, the most popular business model is to develop a successful business that will be acquired by a large enterprise thereby allowing the entrepreneurs to retire before the age of 30 (or 40 at the latest). I don’t see anything from the government acknowledging the problem let alone any attempts to tackle it.

All in all, it was a decent budget with nothing in it to seriously offend anyone.

Nanoelectronic thread (NET) brain probes for long-term neural recording

A rendering of the ultra-flexible probe in neural tissue gives viewers a sense of the device’s tiny size and footprint in the brain. Image credit: Science Advances.

As long time readers have likely noted, I’m not a big a fan of this rush to ‘colonize’ the brain but it continues apace as a Feb. 15, 2017 news item on Nanowerk announces a new type of brain probe,

Engineering researchers at The University of Texas at Austin have designed ultra-flexible, nanoelectronic thread (NET) brain probes that can achieve more reliable long-term neural recording than existing probes and don’t elicit scar formation when implanted.

A Feb. 15, 2017 University of Texas at Austin news release, which originated the news item, provides more information about the new probes (Note: A link has been removed),

A team led by Chong Xie, an assistant professor in the Department of Biomedical Engineering in the Cockrell School of Engineering, and Lan Luan, a research scientist in the Cockrell School and the College of Natural Sciences, have developed new probes that have mechanical compliances approaching that of the brain tissue and are more than 1,000 times more flexible than other neural probes. This ultra-flexibility leads to an improved ability to reliably record and track the electrical activity of individual neurons for long periods of time. There is a growing interest in developing long-term tracking of individual neurons for neural interface applications, such as extracting neural-control signals for amputees to control high-performance prostheses. It also opens up new possibilities to follow the progression of neurovascular and neurodegenerative diseases such as stroke, Parkinson’s and Alzheimer’s diseases.

One of the problems with conventional probes is their size and mechanical stiffness; their larger dimensions and stiffer structures often cause damage around the tissue they encompass. Additionally, while it is possible for the conventional electrodes to record brain activity for months, they often provide unreliable and degrading recordings. It is also challenging for conventional electrodes to electrophysiologically track individual neurons for more than a few days.

In contrast, the UT Austin team’s electrodes are flexible enough that they comply with the microscale movements of tissue and still stay in place. The probe’s size also drastically reduces the tissue displacement, so the brain interface is more stable, and the readings are more reliable for longer periods of time. To the researchers’ knowledge, the UT Austin probe — which is as small as 10 microns at a thickness below 1 micron, and has a cross-section that is only a fraction of that of a neuron or blood capillary — is the smallest among all neural probes.

“What we did in our research is prove that we can suppress tissue reaction while maintaining a stable recording,” Xie said. “In our case, because the electrodes are very, very flexible, we don’t see any sign of brain damage — neurons stayed alive even in contact with the NET probes, glial cells remained inactive and the vasculature didn’t become leaky.”

In experiments in mouse models, the researchers found that the probe’s flexibility and size prevented the agitation of glial cells, which is the normal biological reaction to a foreign body and leads to scarring and neuronal loss.

“The most surprising part of our work is that the living brain tissue, the biological system, really doesn’t mind having an artificial device around for months,” Luan said.

The researchers also used advanced imaging techniques in collaboration with biomedical engineering professor Andrew Dunn and neuroscientists Raymond Chitwood and Jenni Siegel from the Institute for Neuroscience at UT Austin to confirm that the NET enabled neural interface did not degrade in the mouse model for over four months of experiments. The researchers plan to continue testing their probes in animal models and hope to eventually engage in clinical testing. The research received funding from the UT BRAIN seed grant program, the Department of Defense and National Institutes of Health.

Here’s a link to and citation for the paper,

Ultraflexible nanoelectronic probes form reliable, glial scar–free neural integration by Lan Luan, Xiaoling Wei, Zhengtuo Zhao, Jennifer J. Siegel, Ojas Potnis, Catherine A Tuppen, Shengqing Lin, Shams Kazmi, Robert A. Fowler, Stewart Holloway, Andrew K. Dunn, Raymond A. Chitwood, and Chong Xie. Science Advances  15 Feb 2017: Vol. 3, no. 2, e1601966 DOI: 10.1126/sciadv.1601966

This paper is open access.

You can get more detail about the research in a Feb. 17, 2017 posting by Dexter Johnson on his Nanoclast blog (on the IEEE [International Institute for Electrical and Electronics Engineers] website).

Hopes for nanocellulose in the fields of medicine and green manufacturing

Initially this seemed like an essay extolling the possibilities for nanocellulose but it is also a research announcement. From a Nov. 7, 2016 news item on Nanowerk,

What if you could take one of the most abundant natural materials on earth and harness its strength to lighten the heaviest of objects, to replace synthetic materials, or use it in scaffolding to grow bone, in a fast-growing area of science in oral health care?

This all might be possible with cellulose nanocrystals, the molecular matter of all plant life. As industrial filler material, they can be blended with plastics and other synthetics. They are as strong as steel, tough as glass, lightweight, and green.

“Plastics are currently reinforced with fillers made of steel, carbon, Kevlar, or glass. There is an increasing demand in manufacturing for sustainable materials that are lightweight and strong to replace these fillers,” said Douglas M. Fox, associate professor of chemistry at American University.
“Cellulose nanocrystals are an environmentally friendly filler. If there comes a time that they’re used widely in manufacturing, cellulose nanocrystals will lessen the weight of materials, which will reduce energy.”

A Nov. 7, 2016 American University news release on EurekAlert, which originated the news item, continues into the research,

Fox has submitted a patent for his work with cellulose nanocrystals, which involves a simple, scalable method to improve their performance. Published results of his method can be found in the chemistry journal ACS Applied Materials and Interfaces. Fox’s method could be used as a biomaterial and for applications in transportation, infrastructure and wind turbines.

The power of cellulose

Cellulose gives stems, leaves and other organic material in the natural world their strength. That strength already has been harnessed for use in many commercial materials. At the nano-level, cellulose fibers can be broken down into tiny crystals, particles smaller than ten millionths of a meter. Deriving cellulose from natural sources such as wood, tunicate (ocean-dwelling sea cucumbers) and certain kinds of bacteria, researchers prepare crystals of different sizes and strengths.

For all of the industry potential, hurdles abound. As nanocellulose disperses within plastic, scientists must find the sweet spot: the right amount of nanoparticle-matrix interaction that yields the strongest, lightest property. Fox overcame four main barriers by altering the surface chemistry of nanocrystals with a simple process of ion exchange. Ion exchange reduces water absorption (cellulose composites lose their strength if they absorb water); increases the temperature at which the nanocrystals decompose (needed to blend with plastics); reduces clumping; and improves re-dispersal after the crystals dry.

Cell growth

Cellulose nanocrystals as a biomaterial is yet another commercial prospect. In dental regenerative medicine, restoring sufficient bone volume is needed to support a patient’s teeth or dental implants. Researchers at the National Institute of Standards and Technology [NIST], through an agreement with the National Institute of Dental and Craniofacial Research of the National Institutes of Health, are looking for an improved clinical approach that would regrow a patient’s bone. When researchers experimented with Fox’s modified nanocrystals, they were able to disperse the nanocrystals in scaffolds for dental regenerative medicine purposes.

“When we cultivated cells on the cellulose nanocrystal-based scaffolds, preliminary results showed remarkable potential of the scaffolds for both their mechanical properties and the biological response. This suggests that scaffolds with appropriate cellulose nanocrystal concentrations are a promising approach for bone regeneration,” said Martin Chiang, team leader for NIST’s Biomaterials for Oral Health Project.

Another collaboration Fox has is with Georgia Institute of Technology and Owens Corning, a company specializing in fiberglass insulation and composites, to research the benefits to replace glass-reinforced plastic used in airplanes, cars and wind turbines. He also is working with Vireo Advisors and NIST to characterize the health and safety of cellulose nanocrystals and nanofibers.

“As we continue to show these nanomaterials are safe, and make it easier to disperse them into a variety of materials, we get closer to utilizing nature’s chemically resistant, strong, and most abundant polymer in everyday products,” Fox said.

Here’s a link to and a citation for the paper,

Simultaneously Tailoring Surface Energies and Thermal Stabilities of Cellulose Nanocrystals Using Ion Exchange: Effects on Polymer Composite Properties for Transportation, Infrastructure, and Renewable Energy Applications by Douglas M. Fox, Rebeca S. Rodriguez, Mackenzie N. Devilbiss, Jeremiah Woodcock, Chelsea S. Davis, Robert Sinko, Sinan Keten, and Jeffrey W. Gilman. ACS Appl. Mater. Interfaces, 2016, 8 (40), pp 27270–27281 DOI: 10.1021/acsami.6b06083 Publication Date (Web): September 14, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

Tattoo therapy for chronic disease?

It’s good to wake up to something truly new. In this case, it’s using tattoos and nanoparticles for medical applications. From a Sept. 22, 2016 news item on ScienceDaily,

A temporary tattoo to help control a chronic disease might someday be possible, according to scientists at Baylor College of Medicine [Texas, US] who tested antioxidant nanoparticles created at Rice University [Texas, US].

A Sept. 22, 2016 Rice University news release, which originated the news item, provides more information and some good explanations of the terms used (Note: Links have been removed),

A proof-of-principle study led by Baylor scientist Christine Beeton published today by Nature’s online, open-access journal Scientific Reports shows that nanoparticles modified with polyethylene glycol are conveniently choosy as they are taken up by cells in the immune system.

That could be a plus for patients with autoimmune diseases like multiple sclerosis, one focus of study at the Beeton lab. “Placed just under the skin, the carbon-based particles form a dark spot that fades over about one week as they are slowly released into the circulation,” Beeton said.

T and B lymphocyte cells and macrophages are key components of the immune system. However, in many autoimmune diseases such as multiple sclerosis, T cells are the key players. One suspected cause is that T cells lose their ability to distinguish between invaders and healthy tissue and attack both.

In tests at Baylor, nanoparticles were internalized by T cells, which inhibited their function, but ignored by macrophages. “The ability to selectively inhibit one type of cell over others in the same environment may help doctors gain more control over autoimmune diseases,” Beeton said.

“The majority of current treatments are general, broad-spectrum immunosuppressants,” said Redwan Huq, lead author of the study and a graduate student in the Beeton lab. “They’re going to affect all of these cells, but patients are exposed to side effects (ranging) from infections to increased chances of developing cancer. So we get excited when we see something new that could potentially enable selectivity.” Since the macrophages and other splenic immune cells are unaffected, most of a patient’s existing immune system remains intact, he said.

The soluble nanoparticles synthesized by the Rice lab of chemist James Tour have shown no signs of acute toxicity in prior rodent studies, Huq said. They combine polyethylene glycol with hydrophilic carbon clusters, hence their name, PEG-HCCs. The carbon clusters are 35 nanometers long, 3 nanometers wide and an atom thick, and bulk up to about 100 nanometers in globular form with the addition of PEG. They have proven to be efficient scavengers of reactive oxygen species called superoxide molecules, which are expressed by cells the immune system uses to kill invading microorganisms.

T cells use superoxide in a signaling step to become activated. PEG-HCCs remove this superoxide from the T cells, preventing their activation without killing the cells.

Beeton became aware of PEG-HCCs during a presentation by former Baylor graduate student Taeko Inoue, a co-author of the new study. “As she talked, I was thinking, ‘That has to work in models of multiple sclerosis,’” Beeton said. “I didn’t have a good scientific rationale, but I asked for a small sample of PEG-HCCs to see if they affected immune cells.

“We found they affected the T lymphocytes and not the other splenic immune cells, like the macrophages. It was completely unexpected,” she said.

The Baylor lab’s tests on animal models showed that small amounts of PEG-HCCs injected under the skin are slowly taken up by T lymphocytes, where they collect and inhibit the cell’s function. They also found the nanoparticles did not remain in T cells and dispersed within days after uptake by the cells.

“That’s an issue because you want a drug that’s in the system long enough to be effective, but not so long that, if you have a problem, you can’t remove it,” Beeton said. “PEG-HCCs can be administered for slow release and don’t stay in the system for long. This gives us much better control over the circulating half-life.”

“The more we study the abilities of these nanoparticles, the more surprised we are at how useful they could be for medical applications,” Tour said. The Rice lab has published papers with collaborators at Baylor and elsewhere on using functionalized nanoparticles to deliver cancer drugs to tumors and to quench the overproduction of superoxides after traumatic brain injuries.

Beeton suggested delivering carbon nanoparticles just under the skin rather than into the bloodstream would keep them in the system longer, making them more available for uptake by T cells. And the one drawback – a temporary but visible spot on the skin that looks like a tattoo – could actually be a perk to some.

“We saw it made a black mark when we injected it, and at first we thought that’s going to be a real problem if we ever take it into the clinic,” Beeton said. “But we can work around that. We can inject into an area that’s hidden, or use micropattern needles and shape it.

“I can see doing this for a child who wants a tattoo and could never get her parents to go along,” she said. “This will be a good way to convince them.”

The research was supported by Baylor College of Medicine, the National Multiple Sclerosis Society, National Institutes of Health, the Dan L. Duncan Cancer Center, John S. Dunn Gulf Coast Consortium for Chemical Genomics and the U.S. Army-funded Traumatic Brain Injury Consortium.

That’s an interesting list of funders at the end of the news release.

Here’s a link to and a citation for the paper,

Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation by Redwan Huq, Errol L. G. Samuel, William K. A. Sikkema, Lizanne G. Nilewski, Thomas Lee, Mark R. Tanner, Fatima S. Khan, Paul C. Porter, Rajeev B. Tajhya, Rutvik S. Patel, Taeko Inoue, Robia G. Pautler, David B. Corry, James M. Tour, & Christine Beeton. Scientific Reports 6, Article number: 33808 (2016) doi:10.1038/srep33808 Published online: 22 September 2016

This paper is open access.

Here’s an image provided by the researchers,

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University) - See more at: http://news.rice.edu/2016/09/22/tattoo-therapy-could-ease-chronic-disease/#sthash.sIfs3b0S.dpuf

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University)

Cornell University researchers breach blood-brain barrier

There are other teams working on ways to breach the blood-brain barrier (my March 26, 2015 post highlights work from a team at the University of Montréal) but this team from  Cornell is working with a drug that has already been approved by the US Food and Drug Administration (FDA) according to an April 8, 2016 news item on ScienceDaily,

Cornell researchers have discovered a way to penetrate the blood brain barrier (BBB) that may soon permit delivery of drugs directly into the brain to treat disorders such as Alzheimer’s disease and chemotherapy-resistant cancers.

The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose and water, while keeping others out.

Cornell researchers report that an FDA-approved drug called Lexiscan activates receptors — called adenosine receptors — that are expressed on these BBB cells.

An April 4, 2016 Cornell University news release by Krishna Ramanujan, which originated the news item, expands on the theme,

“We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” said Margaret Bynoe, associate professor in the Department of Microbiology and Immunology in Cornell’s College of Veterinary Medicine. …

The researchers were able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper.

To test whether this drug delivery system has application to the human BBB, the lab engineered a BBB model using human primary brain endothelial cells. They observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice.

Bynoe and Kim discovered that a protein called P-glycoprotein is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Lexiscan acts on one of the adenosine receptors expressed on BBB endothelial cells specifically activating them. They showed that Lexiscan down-regulates P-glycoprotein expression and function on the BBB endothelial cells. It acts like a switch that can be turned on and off in a time dependent manner, which provides a measure of safety for the patient.

“We demonstrated that down-modulation of P-glycoprotein function coincides exquisitely with chemotherapeutic drug accumulation” in the brains of mice and across an engineered BBB using human endothelial cells, Bynoe said. “The amount of chemotherapeutic drugs that accumulated in the brain was significant.”

In addition to P-glycoprotein’s role in inhibiting foreign substances from penetrating the BBB, the protein is also expressed by many different types of cancers and makes these cancers resistant to chemotherapy.

“This finding has significant implications beyond modulation of the BBB,” Bynoe said. “It suggests that in the future, we may be able to modulate adenosine receptors to regulate P-glycoprotein in the treatment of cancer cells resistant to chemotherapy.”

Because Lexiscan is an FDA-approved drug, ”the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.

Another advantage is that these molecules (adenosine receptors  and P-glycoprotein are naturally expressed in mammals. “We don’t have to knock out a gene or insert one for a therapy to work,” Bynoe said.

The study was funded by the National Institutes of Health and the Kwanjung Educational Foundation.

Here’s a link to and a citation for the paper,

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier by Do-Geun Kim and Margaret S. Bynoe. J Clin Invest. doi:10.1172/JCI76207 First published April 4, 2016

Copyright © 2016, The American Society for Clinical Investigation.

This paper appears to be open access.

3D microtopographic scaffolds for transplantation and generation of reprogrammed human neurons

Should this technology prove successful once they start testing on people, the stated goal is to use it for the treatment of human neurodegenerative disorders such as Parkinson’s disease.  But, I can’t help wondering if they might also consider constructing an artificial brain.

Getting back to the 3D scaffolds for neurons, a March 17, 2016 US National Institutes of Health (NIH) news release (also on EurekAlert), makes the announcement,

National Institutes of Health-funded scientists have developed a 3D micro-scaffold technology that promotes reprogramming of stem cells into neurons, and supports growth of neuronal connections capable of transmitting electrical signals. The injection of these networks of functioning human neural cells — compared to injecting individual cells — dramatically improved their survival following transplantation into mouse brains. This is a promising new platform that could make transplantation of neurons a viable treatment for a broad range of human neurodegenerative disorders.

Previously, transplantation of neurons to treat neurodegenerative disorders, such as Parkinson’s disease, had very limited success due to poor survival of neurons that were injected as a solution of individual cells. The new research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of NIH.

“Working together, the stem cell biologists and the biomaterials experts developed a system capable of shuttling neural cells through the demanding journey of transplantation and engraftment into host brain tissue,” said Rosemarie Hunziker, Ph.D., director of the NIBIB Program in Tissue Engineering and Regenerative Medicine. “This exciting work was made possible by the close collaboration of experts in a wide range of disciplines.”

The research was performed by researchers from Rutgers University, Piscataway, New Jersey, departments of Biomedical Engineering, Neuroscience and Cell Biology, Chemical and Biochemical Engineering, and the Child Health Institute; Stanford University School of Medicine’s Institute of Stem Cell Biology and Regenerative Medicine, Stanford, California; the Human Genetics Institute of New Jersey, Piscataway; and the New Jersey Center for Biomaterials, Piscataway. The results are reported in the March 17, 2016 issue of Nature Communications.

The researchers experimented in creating scaffolds made of different types of polymer fibers, and of varying thickness and density. They ultimately created a web of relatively thick fibers using a polymer that stem cells successfully adhered to. The stem cells used were human induced pluripotent stem cells (iPSCs), which can be readily generated from adult cell types such as skin cells. The iPSCs were induced to differentiate into neural cells by introducing the protein NeuroD1 into the cells.

The space between the polymer fibers turned out to be critical. “If the scaffolds were too dense, the stem cell-derived neurons were unable to integrate into the scaffold, whereas if they are too sparse then the network organization tends to be poor,” explained Prabhas Moghe, Ph.D., distinguished professor of biomedical engineering & chemical engineering at Rutgers University and co-senior author of the paper. “The optimal pore size was one that was large enough for the cells to populate the scaffold but small enough that the differentiating neurons sensed the presence of their neighbors and produced outgrowths resulting in cell-to-cell contact. This contact enhances cell survival and development into functional neurons able to transmit an electrical signal across the developing neural network.”

To test the viability of neuron-seeded scaffolds when transplanted, the researchers created micro-scaffolds that were small enough for injection into mouse brain tissue using a standard hypodermic needle. They injected scaffolds carrying the human neurons into brain slices from mice and compared them to human neurons injected as individual, dissociated cells.

The neurons on the scaffolds had dramatically increased cell-survival compared with the individual cell suspensions. The scaffolds also promoted improved neuronal outgrowth and electrical activity. Neurons injected individually in suspension resulted in very few cells surviving the transplant procedure.

Human neurons on scaffolds compared to neurons in solution were then tested when injected into the brains of live mice. Similar to the results in the brain slices, the survival rate of neurons on the scaffold network was increased nearly 40-fold compared to injected isolated cells. A critical finding was that the neurons on the micro-scaffolds expressed proteins that are involved in the growth and maturation of neural synapses–a good indication that the transplanted neurons were capable of functionally integrating into the host brain tissue.

The success of the study gives this interdisciplinary group reason to believe that their combined areas of expertise have resulted in a system with much promise for eventual treatment of human neurodegenerative disorders. In fact, they are now refining their system for specific use as an eventual transplant therapy for Parkinson’s disease. The plan is to develop methods to differentiate the stem cells into neurons that produce dopamine, the specific neuron type that degenerates in individuals with Parkinson’s disease. The work also will include fine-tuning the scaffold materials, mechanics and dimensions to optimize the survival and function of dopamine-producing neurons, and finding the best mouse models of the disease to test this Parkinson’s-specific therapy.

Here’s a link to and a citation for the paper,

Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds by Aaron L. Carlson, Neal K. Bennett, Nicola L. Francis, Apoorva Halikere, Stephen Clarke, Jennifer C. Moore, Ronald P. Hart, Kenneth Paradiso, Marius Wernig, Joachim Kohn, Zhiping P. Pang, & Prabhas V. Moghe. Nature Communications 7, Article number: 10862  doi:10.1038/ncomms10862 Published 17 March 2016

This paper is open access.

North Carolina universities go beyond organ-on-a-chip

The researchers in the North Carolina universities involved in this project have high hopes according to an Oct. 9, 2015 news item on Nanowerk,

A team of researchers from the University of North Carolina at Chapel Hill and NC State University has received a $5.3 million, five-year Transformative Research (R01) Award from the National Institutes of Health (NIH) to create fully functioning versions of the human gut that fit on a chip the size of a dime.

Such “organs-on-a-chip” have become vital for biomedical research, as researchers seek alternatives to animal models for drug discovery and testing. The new grant will fund a technology that represents a major step forward for the field, overcoming limitations that have mired other efforts.

The technology will use primary cells derived directly from human biopsies, which are known to provide more relevant results than the immortalized cell lines used in current approaches. In addition, the device will sculpt these cells into the sophisticated architecture of the gut, rather than the disorganized ball of cells that are created in other miniature organ systems.

“We are building a device that goes far beyond the organ-on-a-chip,” said Nancy L. Allbritton, MD, PhD, professor and chair of the UNC-NC State joint department of biomedical engineering and one of four principle investigators on the NIH grant. “We call it a ‘simulacrum,’ [emphasis mine] a term used in science fiction to describe a duplicate. The idea is to create something that is indistinguishable from your own gut.”

I’ve come across the term ‘simulacrum’ in relation to philosophy so it’s a bit of a surprise to find it in a news release about an organ-on-a-chip where it seems to have been redefined somewhat. Here’s more from the Simulacrum entry on Wikipedia (Note: Links have been removed),

A simulacrum (plural: simulacra from Latin: simulacrum, which means “likeness, similarity”), is a representation or imitation of a person or thing.[1] The word was first recorded in the English language in the late 16th century, used to describe a representation, such as a statue or a painting, especially of a god. By the late 19th century, it had gathered a secondary association of inferiority: an image without the substance or qualities of the original.[2] Philosopher Fredric Jameson offers photorealism as an example of artistic simulacrum, where a painting is sometimes created by copying a photograph that is itself a copy of the real.[3] Other art forms that play with simulacra include trompe-l’œil,[4] pop art, Italian neorealism, and French New Wave.[3]

Philosophy

The simulacrum has long been of interest to philosophers. In his Sophist, Plato speaks of two kinds of image making. The first is a faithful reproduction, attempted to copy precisely the original. The second is intentionally distorted in order to make the copy appear correct to viewers. He gives the example of Greek statuary, which was crafted larger on the top than on the bottom so that viewers on the ground would see it correctly. If they could view it in scale, they would realize it was malformed. This example from the visual arts serves as a metaphor for the philosophical arts and the tendency of some philosophers to distort truth so that it appears accurate unless viewed from the proper angle.[5] Nietzsche addresses the concept of simulacrum (but does not use the term) in the Twilight of the Idols, suggesting that most philosophers, by ignoring the reliable input of their senses and resorting to the constructs of language and reason, arrive at a distorted copy of reality.[6]

Postmodernist French social theorist Jean Baudrillard argues that a simulacrum is not a copy of the real, but becomes truth in its own right: the hyperreal. Where Plato saw two types of representation—faithful and intentionally distorted (simulacrum)—Baudrillard sees four: (1) basic reflection of reality; (2) perversion of reality; (3) pretence of reality (where there is no model); and (4) simulacrum, which “bears no relation to any reality whatsoever”.[7] In Baudrillard’s concept, like Nietzsche’s, simulacra are perceived as negative, but another modern philosopher who addressed the topic, Gilles Deleuze, takes a different view, seeing simulacra as the avenue by which an accepted ideal or “privileged position” could be “challenged and overturned”.[8] Deleuze defines simulacra as “those systems in which different relates to different by means of difference itself. What is essential is that we find in these systems no prior identity, no internal resemblance”.[9]

Getting back to the proposed research, an Oct. (?), 2015 University of North Carolina news release, which originated the news item, describes the proposed work in more detail,

Allbritton is an expert at microfabrication and microengineering. Also on the team are intestinal stem cell expert Scott T. Magness, associate professor of medicine, biomedical engineering, and cell and molecular physiology in the UNC School of Medicine; microbiome expert Scott Bultman, associate professor of genetics in the UNC School of Medicine; and bioinformatics expert Shawn Gomez, associate professor of biomedical engineering in UNC’s College of Arts and Sciences and NC State.

The impetus for the “organ-on-chip” movement comes largely from the failings of the pharmaceutical industry. For just a single drug to go through the discovery, testing, and approval process can take as many as 15 years and as much as $5 billion dollars. Animal models are expensive to work with and often don’t respond to drugs and diseases the same way humans do. Human cells grown in flat sheets on Petri dishes are also a poor proxy. Three-dimensional “organoids” are an improvement, but these hollow balls are made of a mishmash of cells that doesn’t accurately mimic the structure and function of the real organ.

Basically, the human gut is a 30-foot long hollow tube made up of a continuous single-layer of specialized cells. Regenerative stem cells reside deep inside millions of small pits or “crypts” along the tube, and mature differentiated cells are linked to the pits and live further out toward the surface. The gut also contains trillions of microbes, which are estimated to outnumber human cells by ten to one. These diverse microbial communities – collectively known as the microbiota – process toxins and pharmaceuticals, stimulate immunity, and even release hormones to impact behavior.

To create a dime-sized version of this complex microenvironment, the UNC-NC State team borrowed fabrication technologies from the electronics and microfluidics world. The device is composed of a polymer base containing an array of imprinted or shaped “hydrogels,” a mesh of molecules that can absorb water like a sponge. These hydrogels are specifically engineered to provide the structural support and biochemical cues for growing cells from the gut. Plugged into the device will be various kinds of plumbing that bring in chemicals, fluids, and gases to provide cues that tell the cells how and where to differentiate and grow. For example, the researchers will engineer a steep oxygen gradient into the device that will enable oxygen-loving human cells and anaerobic microbes to coexist in close proximity.

“The underlying concept – to simply grow a piece of human tissue in a dish – doesn’t seem that groundbreaking,” said Magness. “We have been doing that for a long time with cancer cells, but those efforts do not replicate human physiology. Using native stem cells from the small intestine or colon, we can now develop gut tissue layers in a dish that contains stem cells and all the differentiated cells of the gut. That is the thing stem cell biologists and engineers have been shooting for, to make real tissue behave properly in a dish to create better models for drug screening and cell-based therapies. With this work, we made a big leap toward that goal.”

Right now, the team has a working prototype that can physically and chemically guide mouse intestinal stem cells into the appropriate structure and function of the gut. For several years, Magness has been isolating and banking human stem cells from samples from patients undergoing routine colonoscopies at UNC Hospitals.

As part of the grant, he will work with the rest of the team to apply these stem cells to the new device and create “simulacra” that are representative of each patient’s individual gut. The approach will enable researchers to explore in a personalized way how both the human and microbial cells of the gut behave during healthy and diseased states.

“Having a system like this will advance microbiota research tremendously,” said Bultman. “Right now microbiota studies involve taking samples, doing sequencing, and then compiling an inventory of all the microbes in the disease cases and healthy controls. These studies just draw associations, so it is difficult to glean cause and effect. This device will enable us to probe the microbiota, and gain a better understanding of whether changes in these microbial communities are the cause or the consequence of disease.”

I wish them good luck with their work and to end on another interesting note, the concept of organs-on-a-chip won a design award. From a June 22, 2015 article by Oliver Wainwright for the Guardian (Note: Links have been removed),

Meet the Lung-on-a-chip, a simulation of the biological processes inside the human lung, developed by the Wyss Institute for Biologically Inspired Engineering at Harvard University – and now crowned Design of the Year by London’s Design Museum.

Lined with living human cells, the “organs-on-chips” mimic the tissue structures and mechanical motions of human organs, promising to accelerate drug discovery, decrease development costs and potentially usher in a future of personalised medicine.

“This is the epitome of design innovation,” says Paola Antonelli, design curator at New York’s Museum of Modern Art [MOMA], who nominated the project for the award and recently acquired organs-on-chips for MoMA’s permanent collection. “Removing some of the pitfalls of human and animal testing means, theoretically, that drug trials could be conducted faster and their viable results disseminated more quickly.”

Whodathunkit? (Tor those unfamiliar with slang written in this form: Who would have thought it?)

Acoustofluidics and lab-on-a-chip for asthma and tuberculosis diagnostics

This is my first exposure to acoustofluidics (although it’s been around for a few years) and it concerns lab-on-a-chip diagnostics for asthma and tuberculosis. From an Aug. 3, 2015 news item on Azonano,

A device to mix liquids utilizing ultrasonics is the first and most difficult component in a miniaturized system for low-cost analysis of sputum from patients with pulmonary diseases such as tuberculosis and asthma.

The device, developed by engineers at Penn State in collaboration with researchers at the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, and the Washington University School of Medicine, will benefit patients in the U.S., where 12 percent of the population, or around 19 million people, have asthma, and in undeveloped regions where TB is still a widespread and often deadly contagion.

“To develop more accurate diagnosis and treatment approaches for patients with pulmonary diseases, we have to analyze sample cells directly from the lungs rather than by drawing blood,” said Tony Jun Huang, professor of engineering science and mechanics at Penn State and the inventor, with his group, of this and other acoustofluidic devices based on ultrasonic waves. “For instance, different drugs are used to treat different types of asthma patients. If you know what a person’s immunophenotype is, you can provide personalized medicine for their particular disease.

A July 29, 2015 Pennsylvania State University news release, which originated the news item, describes the disadvantages of the current sputum analyses techniques and explains how this new technique in an improvement,

There are several issues with the current standard method for sputum analysis. The first is that human specimens can be contagious, and sputum analysis requires handling of specimens in several discrete machines. With a lab on a chip device, all biospecimens are safely contained in a single disposable component.

Another issue is the sample size required for analysis in the current system, which is often larger than a person can easily produce. The acoustofluidic sputum liquefier created by Huang’s group requires 100 times less sample while still providing accuracy equivalent to the standard system.

A further issue is that current systems are difficult to use and require trained operators. With the lab on a chip system, a nurse can operate the device with a touch of a few buttons and get a read out, or the patient could even operate the device at home. In addition, the disposable portion of the device should cost less than a dollar to manufacture.

Po-Hsun Huang, a graduate student in the Huang group and the first author on the recent paper describing the device in the Royal Society of Chemistry journal Lab on a Chip, said “This will offer quick analysis of samples without having to send them out to a centralized lab. While I have been working on the liquefaction component of the device, my lab mates are working on the flow cytometry analysis component, which should be ready soon. This is the first on-chip sputum liquefier anyone has developed.”

Stewart J. Levine, a Senior Investigator and Chief of the Laboratory of Asthma and Lung Inflammation in the Division of Intramural Research at NHLBI, said “This on-chip sputum liquefier is a significant advance regarding our goal of developing a point-of-care diagnostic device that will determine the type of inflammation present in the lungs of asthmatics. This will allow health care providers to individualize asthma treatments for each patient and advance the goal of bringing precision medicine into clinical practice.”

Here’s a link to and a citation for the paper,

An acoustofluidic sputum liquefier by Po-Hsun Huang, Liqiang Ren, Nitesh Nama, Sixing Li, Peng Li, Xianglan Yao, Rosemarie A. Cuento, Cheng-Hsin Wei, Yuchao Chen, Yuliang Xie, Ahmad Ahsan Nawaz, Yael G. Alevy, Michael J. Holtzman, J. Philip McCoy, Stewart J. Levine, and  Tony Jun Huang. Lab Chip, 2015,15, 3125-3131 DOI: 10.1039/C5LC00539F

First published online 17 Jun 2015

This is an open access paper but you do need to register for a free (British) Royal Society of Chemistry publishing personal account.

A pragmatic approach to alternatives to animal testing

Retitled and cross-posted from the June 30, 2015 posting (Testing times: the future of animal alternatives) on the International Innovation blog (a CORDIS-listed project dissemination partner for FP7 and H2020 projects).

Maryse de la Giroday explains how emerging innovations can provide much-needed alternatives to animal testing. She also shares highlights of the 9th World Congress on Alternatives to Animal Testing.

‘Guinea pigging’ is the practice of testing drugs that have passed in vitro and in vivo tests on healthy humans in a Phase I clinical trial. In fact, healthy humans can make quite a bit of money as guinea pigs. The practice is sufficiently well-entrenched that there is a magazine, Guinea Pig Zero, devoted to professionals. While most participants anticipate some unpleasant side effects, guinea pigging can sometimes be a dangerous ‘profession’.

HARMFUL TO HEALTH

One infamous incident highlighting the dangers of guinea pigging occurred in 2006 at Northwick Park Hospital outside London. Volunteers were offered £2,000 to participate in a Phase I clinical trial to test a prospective treatment – a monoclonal antibody designed for rheumatoid arthritis and multiple sclerosis. The drug, called TGN1412, caused catastrophic systemic organ failure in participants. All six individuals receiving the drug required hospital treatment. One participant reportedly underwent amputation of fingers and toes. Another reacted with symptoms comparable to John Merrick, the Elephant Man.

The root of the disaster lay in subtle immune system differences between humans and cynomolgus monkeys – the model animal tested prior to the clinical trial. The drug was designed for the CD28 receptor on T cells. The monkeys’ receptors closely resemble those found in humans. However, unlike these monkeys, humans have other immune cells that carry CD28. The trial participants received a starting dosage that was 0.2 per cent of what the monkeys received in their final tests, but failure to take these additional receptors into account meant a dosage that was supposed to occupy 10 per cent of the available CD28 receptors instead occupied 90 per cent. After the event, a Russian inventor purchased the commercial rights to the drug and renamed it TAB08. It has been further developed by Russian company, TheraMAB, and TAB08 is reportedly in Phase II clinical trials.

HUMAN-ON-A-CHIP AND ORGANOID PROJECTS

While animal testing has been a powerful and useful tool for determining safe usage for pharmaceuticals and other types of chemicals, it is also a cruel and imperfect practice. Moreover, it typically only predicts 30-60 per cent of human responses to new drugs. Nanotechnology and other emerging innovations present possibilities for reducing, and in some cases eliminating, the use of animal models.

People for the Ethical Treatment of Animals (PETA), still better known for its publicity stunts, maintains a webpage outlining a number of alternatives including in silico testing (computer modelling), and, perhaps most interestingly, human-on-a-chip and organoid (tissue engineering) projects.

Organ-on-a-chip projects use stem cells to create human tissues that replicate the functions of human organs. Discussions about human-on-a-chip activities – a phrase used to describe 10 interlinked organ chips – were a highlight of the 9th World Congress on Alternatives to Animal Testing held in Prague, Czech Republic, last year. One project highlighted at the event was a joint US National Institutes of Health (NIH), US Food and Drug Administration (FDA) and US Defense Advanced Research Projects Agency (DARPA) project led by Dan Tagle that claimed it would develop functioning human-on-a-chip by 2017. However, he and his team were surprisingly close-mouthed and provided few details making it difficult to assess how close they are to achieving their goal.

By contrast, Uwe Marx – Leader of the ‘Multi-Organ-Chip’ programme in the Institute of Biotechnology at the Technical University of Berlin and Scientific Founder of TissUse, a human-on-a-chip start-up company – claims to have sold two-organ chips. He also claims to have successfully developed a four-organ chip and that he is on his way to building a human-on-a-chip. Though these chips remain to be seen, if they are, they will integrate microfluidics, cultured cells and materials patterned at the nanoscale to mimic various organs, and will allow chemical testing in an environment that somewhat mirrors a human.

Another interesting alternative for animal testing is organoids – a feature in regenerative medicine that can function as test sites. Engineers based at Cornell University recently published a paper on their functional, synthetic immune organ. Inspired by the lymph node, the organoid is comprised of gelatin-based biomaterials, which are reinforced with silicate nanoparticles (to keep the tissue from melting when reaching body temperature) and seeded with cells allowing it to mimic the anatomical microenvironment of a lymphatic node. It behaves like its inspiration converting B cells to germinal centres which activate, mature and mutate antibody genes when the body is under attack. The engineers claim to be able to control the immune response and to outperform 2D cultures with their 3D organoid. If the results are reproducible, the organoid could be used to develop new therapeutics.

Maryse de la Giroday is a science communications consultant and writer.

Full disclosure: Maryse de la Giroday received transportation and accommodation for the 9th World Congress on Alternatives to Animal Testing from SEURAT-1, a European Union project, making scientific inquiries to facilitate the transition to animal testing alternatives, where possible.

ETA July 1, 2015: I would like to acknowledge more sources for the information in this article,

Sources:

The guinea pigging term, the ‘professional aspect, the Northwick Park story, and the Guinea Pig Zero magazine can be found in Carl Elliot’s excellent 2006 story titled ‘Guinea-Pigging’ for New Yorker magazine.

http://www.newyorker.com/magazine/2008/01/07/guinea-pigging

Information about the drug used in the Northwick Park Hospital disaster, the sale of the rights to a Russian inventor, and the June 2015 date for the current Phase II clinical trials were found in this Wikipedia essay titled, TGN 1412.

http://en.wikipedia.org/wiki/TGN1412

Additional information about the renamed drug, TAB08 and its Phase II clinical trials was found on (a) a US government website for information on clinical trials, (b) in a Dec. 2014 (?) TheraMAB  advertisement in a Nature group magazine and a Jan. 2014 press release,

https://www.clinicaltrials.gov/ct2/show/NCT01990157?term=TAB08_RA01&rank=1

http://www.theramab.ru/TheraMAB_NAture.pdf

http://theramab.ru/en/news/phase_II

An April 2015 article (Experimental drug that injured UK volunteers resumes in human trials) by Owen Dyer for the British Medical Journal also mentioned the 2015 TheraMab Phase II clinical trials and provided information about the information about Macaque (cynomolgus) monkey tests.

http://www.bmj.com.proxy.lib.sfu.ca/content/350/bmj.h1831

BMJ 2015; 350 doi: http://dx.doi.org.proxy.lib.sfu.ca/10.1136/bmj.h1831 (Published 02 April 2015) Cite this as: BMJ 2015;350:h1831

A 2009 study by Christopher Horvath and Mark Milton somewhat contradicts the Dyer article’s contention that a species Macaque monkey was used as an animal model. (As the Dyer article is more recent and the Horvath/Milton analysis is more complex covering TGN 1412 in the context of other MAB drugs and their precursor tests along with specific TGN 1412 tests, I opted for the simple description.)

The TeGenero Incident [another name for the Northwick Park Accident] and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event? by Christopher J. Horvath and Mark N. Milton. Published online before print February 24, 2009, doi: 10.1177/0192623309332986 Toxicol Pathol April 2009 vol. 37 no. 3 372-383

http://tpx.sagepub.com/content/37/3/372.full

Philippa Roxbuy’s May 24, 2013 BBC news online article provided confirmation and an additional detail or two about the Northwick Park Hospital accident. It notes that other models, in addition to animal models, are being developed.

http://www.bbc.com/news/health-22556736

Anne Ju’s excellent June 10,2015 news release about the Cornell University organoid (synthetic immune organ) project was very helpful.

http://www.news.cornell.edu/stories/2015/06/engineers-synthetic-immune-organ-produces-antibodies

There will also be a magazine article in International Innovation, which will differ somewhat from the blog posting, due to editorial style and other requirements.

ETA July 22, 2015: I now have a link to the magazine article.