Tag Archives: NIH

Xenotransplantation—organs for transplantation in human patients—it’s a business and a science

The last time (June 18, 2018 post) I mentioned xenotransplantation (transplanting organs from one species into another species; see more here), it was in the context of an art/sci (or sciart) event coming to Vancouver (Canada).,

Patricia Piccinini’s Curious Imaginings Courtesy: Vancouver Biennale [downloaded from http://dailyhive.com/vancouver/vancouver-biennale-unsual-public-art-2018/]

The latest edition of the Vancouver Biennale was featured in a June 6, 2018 news item on the Daily Hive (Vancouver),

Melbourne artist Patricia Piccinini’s Curious Imaginings is expected to be one of the most talked about installations of the exhibit. Her style of “oddly captivating, somewhat grotesque, human-animal hybrid creature” is meant to be shocking and thought-provoking.

Piccinini’s interactive [emphasis mine] experience will “challenge us to explore the social impacts of emerging biotechnology and our ethical limits in an age where genetic engineering and digital technologies are already pushing the boundaries of humanity.”

Piccinini’s work will be displayed in the 105-year-old Patricia Hotel in Vancouver’s Strathcona neighbourhood. The 90-day ticketed exhibition [emphasis mine] is scheduled to open this September [2018].

(The show opens on Sept. 14, 2018.)

At the time, I had yet to stumble across Ingfei Chen’s thoughtful dive into the topic in her May 9, 2018 article for Slate.com,

In the United States, the clock is ticking for more than 114,700 adults and children waiting for a donated kidney or other lifesaving organ, and each day, nearly 20 of them die. Researchers are devising a new way to grow human organs inside other animals, but the method raises potentially thorny ethical issues. Other conceivable futuristic techniques sound like dystopian science fiction. As we envision an era of regenerative medicine decades from now, how far is society willing to go to solve the organ shortage crisis?

I found myself pondering this question after a discussion about the promises of stem cell technologies veered from the intriguing into the bizarre. I was interviewing bioengineer Zev Gartner, co-director and research coordinator of the Center for Cellular Construction at the University of California, San Francisco, about so-called organoids, tiny clumps of organlike tissue that can self-assemble from human stem cells in a Petri dish. These tissue bits are lending new insights into how our organs form and diseases take root. Some researchers even hope they can nurture organoids into full-size human kidneys, pancreases, and other organs for transplantation.

Certain organoid experiments have recently set off alarm bells, but when I asked Gartner about it, his radar for moral concerns was focused elsewhere. For him, the “really, really thought-provoking” scenarios involve other emerging stem cell–based techniques for engineering replacement organs for people, he told me. “Like blastocyst complementation,” he said.

Never heard of it? Neither had I. Turns out it’s a powerful new genetic engineering trick that researchers hope to use for growing human organs inside pigs or sheep—organs that could be genetically personalized for transplant patients, in theory avoiding immune-system rejection problems. The science still has many years to go, but if it pans out, it could be one solution to the organ shortage crisis. However, the prospect of creating hybrid animals with human parts and killing them to harvest organs has already raised a slew of ethical questions. In 2015, the National Institutes of Health placed a moratorium on federal funding of this nascent research area while it evaluated and discussed the issues.

As Gartner sees it, the debate over blastocyst complementation research—work that he finds promising—is just one of many conversations that society needs to have about the ethical and social costs and benefits of future technologies for making lifesaving transplant organs. “There’s all these weird ways that we could go about doing this,” he said, with a spectrum of imaginable approaches that includes organoids, interspecies organ farming, and building organs from scratch using 3D bioprinters. But even if it turns out we can produce human organs in these novel ways, the bigger issue, in each technological instance, may be whether we should.

Gartner crystallized things with a downright creepy example: “We know that the best bioreactor for tissues and organs for humans are human beings,” he said. Hypothetically, “the best way to get you a new heart would be to clone you, grow up a copy of yourself, and take the heart out.” [emphasis mine] Scientists could probably produce a cloned person with the technologies we already have, if money and ethics were of no concern. “But we don’t want to go there, right?” he added in the next breath. “The ethics involved in doing it are not compatible with who we want to be as a society.”

This sounds like Gartner may have been reading some science fiction, specifically, Lois McMaster Bujold and her Barrayar series where she often explored the ethics and possibilities of bioengineering. At this point, some of her work seems eerily prescient.

As for Chen’s article, I strongly encourage you to read it in its entirety if you have the time.

Medicine, healing, and big money

At about the same time, there was a May 31, 2018 news item on phys.org offering a perspective from some of the leaders in the science and the business (Note: Links have been removed),

Over the past few years, researchers led by George Church have made important strides toward engineering the genomes of pigs to make their cells compatible with the human body. So many think that it’s possible that, with the help of CRISPR technology, a healthy heart for a patient in desperate need might one day come from a pig.

“It’s relatively feasible to change one gene in a pig, but to change many dozens—which is quite clear is the minimum here—benefits from CRISPR,” an acronym for clustered regularly interspaced short palindromic repeats, said Church, the Robert Winthrop Professor of Genetics at Harvard Medical School (HMS) and a core faculty member of Harvard’s Wyss Institute for Biologically Inspired Engineering. Xenotransplantation is “one of few” big challenges (along with gene drives and de-extinction, he said) “that really requires the ‘oomph’ of CRISPR.”

To facilitate the development of safe and effective cells, tissues, and organs for future medical transplantation into human patients, Harvard’s Office of Technology Development has granted a technology license to the Cambridge biotech startup eGenesis.

Co-founded by Church and former HMS doctoral student Luhan Yang in 2015, eGenesis announced last year that it had raised $38 million to advance its research and development work. At least eight former members of the Church lab—interns, doctoral students, postdocs, and visiting researchers—have continued their scientific careers as employees there.

“The Church Lab is well known for its relentless pursuit of scientific achievements so ambitious they seem improbable—and, indeed, [for] its track record of success,” said Isaac Kohlberg, Harvard’s chief technology development officer and senior associate provost. “George deserves recognition too for his ability to inspire passion and cultivate a strong entrepreneurial drive among his talented research team.”

The license from Harvard OTD covers a powerful set of genome-engineering technologies developed at HMS and the Wyss Institute, including access to foundational intellectual property relating to the Church Lab’s 2012 breakthrough use of CRISPR, led by Yang and Prashant Mali, to edit the genome of human cells. Subsequent innovations that enabled efficient and accurate editing of numerous genes simultaneously are also included. The license is exclusive to eGenesis but limited to the field of xenotransplantation.

A May 30, 2018 Harvard University news release by Caroline Petty, which originated the news item, explores some of the issues associated with incubating humans organs in other species,

The prospect of using living, nonhuman organs, and concerns over the infectiousness of pathogens either present in the tissues or possibly formed in combination with human genetic material, have prompted the Food and Drug Administration to issue detailed guidance on xenotransplantation research and development since the mid-1990s. In pigs, a primary concern has been that porcine endogenous retroviruses (PERVs), strands of potentially pathogenic DNA in the animals’ genomes, might infect human patients and eventually cause disease. [emphases mine]

That’s where the Church lab’s CRISPR expertise has enabled significant advances. In 2015, the lab published important results in the journal Science, successfully demonstrating the use of genome engineering to eliminate all 62 PERVs in porcine cells. Science later called it “the most widespread CRISPR editing feat to date.”

In 2017, with collaborators at Harvard, other universities, and eGenesis, Church and Yang went further. Publishing again in Science, they first confirmed earlier researchers’ fears: Porcine cells can, in fact, transmit PERVs into human cells, and those human cells can pass them on to other, unexposed human cells. (It is still unknown under what circumstances those PERVs might cause disease.) In the same paper, they corrected the problem, announcing the embryogenesis and birth of 37 PERV-free pigs. [Note: My July 17, 2018 post features research which suggests CRISPR-Cas9 gene editing may cause greater genetic damage than had been thought.]

“Taken together, those innovations were stunning,” said Vivian Berlin, director of business development in OTD, who manages the commercialization strategy for much of Harvard’s intellectual property in the life sciences. “That was the foundation they needed, to convince both the scientific community and the investment community that xenotransplantation might become a reality.”

“After hundreds of tests, this was a critical milestone for eGenesis — and the entire field — and represented a key step toward safe organ transplantation from pigs,” said Julie Sunderland, interim CEO of eGenesis. “Building on this study, we hope to continue to advance the science and potential of making xenotransplantation a safe and routine medical procedure.”

Genetic engineering may undercut human diseases, but also could help restore extinct species, researcher says. [Shades of the Jurassic Park movies!]

It’s not, however, the end of the story: An immunological challenge remains, which eGenesis will need to address. The potential for a patient’s body to outright reject transplanted tissue has stymied many previous attempts at xenotransplantation. Church said numerous genetic changes must be achieved to make porcine organs fully compatible with human patients. Among these are edits to several immune functions, coagulation functions, complements, and sugars, as well as the PERVs.

“Trying the straight transplant failed almost immediately, within hours, because there’s a huge mismatch in the carbohydrates on the surface of the cells, in particular alpha-1-3-galactose, and so that was a showstopper,” Church explained. “When you delete that gene, which you can do with conventional methods, you still get pretty fast rejection, because there are a lot of other aspects that are incompatible. You have to take care of each of them, and not all of them are just about removing things — some of them you have to humanize. There’s a great deal of subtlety involved so that you get normal pig embryogenesis but not rejection.

“Putting it all together into one package is challenging,” he concluded.

In short, it’s the next big challenge for CRISPR.

Not unexpectedly, there is no mention of the CRISPR patent fight between Harvard/MIT’s (Massachusetts Institute of Technology) Broad Institute and the University of California at Berkeley (UC Berkeley). My March 15, 2017 posting featured an outcome where the Broad Institute won the first round of the fight. As I recall, it was a decision based on the principles associated with King Solomon, i.e., the US Patent Office, divided the baby and UCBerkeley got the less important part of the baby. As you might expect the decision has been appealed. In an April 30, 2018 piece, Scientific American reprinted an article about the latest round in the fight written by Sharon Begley for STAT (Note: Links have been removed),

All You Need to Know for Round 2 of the CRISPR Patent Fight

It’s baaaaack, that reputation-shredding, stock-moving fight to the death over key CRISPR patents. On Monday morning in Washington, D.C., the U.S. Court of Appeals for the Federal Circuit will hear oral arguments in University of California v. Broad Institute. Questions?

How did we get here? The patent office ruled in February 2017 that the Broad’s 2014 CRISPR patent on using CRISPR-Cas9 to edit genomes, based on discoveries by Feng Zhang, did not “interfere” with a patent application by UC based on the work of UC Berkeley’s Jennifer Doudna. In plain English, that meant the Broad’s patent, on using CRISPR-Cas9 to edit genomes in eukaryotic cells (all animals and plants, but not bacteria), was different from UC’s, which described Doudna’s experiments using CRISPR-Cas9 to edit DNA in a test tube—and it was therefore valid. The Patent Trial and Appeal Board concluded that when Zhang got CRISPR-Cas9 to work in human and mouse cells in 2012, it was not an obvious extension of Doudna’s earlier research, and that he had no “reasonable expectation of success.” UC appealed, and here we are.

For anyone who may not realize what the stakes are for these institutions, Linda Williams in a March 16, 1999 article for the LA Times had this to say about universities, patents, and money,

The University of Florida made about $2 million last year in royalties on a patent for Gatorade Thirst Quencher, a sports drink that generates some $500 million to $600 million a year in revenue for Quaker Oats Co.

The payments place the university among the top five in the nation in income from patent royalties.

Oh, but if some people on the Gainesville, Fla., campus could just turn back the clock. “If we had done Gatorade right, we would be getting $5 or $6 million (a year),” laments Donald Price, director of the university’s office of corporate programs. “It is a classic example of how not to handle a patent idea,” he added.

Gatorade was developed in 1965 when many universities were ill equipped to judge the commercial potential of ideas emerging from their research labs. Officials blew the university’s chance to control the Gatorade royalties when they declined to develop a professor’s idea.

The Gatorade story does not stop there and, even though it’s almost 20 years old, this article stands the test of time. I strongly encourage you to read it if the business end of patents and academia interest you or if you would like to develop more insight into the Broad Institute/UC Berkeley situation.

Getting back to the science, there is that pesky matter of diseases crossing over from one species to another. While, Harvard and eGenesis claim a victory in this area, it seems more work needs to be done.

Infections from pigs

An August 29, 2018 University of Alabama at Birmingham news release (also on EurekAlert) by Jeff Hansen, describes the latest chapter in the quest to provide more organs for transplantion,

A shortage of organs for transplantation — including kidneys and hearts — means that many patients die while still on waiting lists. So, research at the University of Alabama at Birmingham and other sites has turned to pig organs as an alternative. [emphasis mine]

Using gene-editing, researchers have modified such organs to prevent rejection, and research with primates shows the modified pig organs are well-tolerated.

An added step is needed to ensure the safety of these inter-species transplants — sensitive, quantitative assays for viruses and other infectious microorganisms in donor pigs that potentially could gain access to humans during transplantation.

The U.S. Food and Drug Administration requires such testing, prior to implantation, of tissues used for xenotransplantation from animals to humans. It is possible — though very unlikely — that an infectious agent in transplanted tissues could become an emerging infectious disease in humans.

In a paper published in Xenotransplantation, Mark Prichard, Ph.D., and colleagues at UAB have described the development and testing of 30 quantitative assays for pig infectious agents. These assays had sensitivities similar to clinical lab assays for viral loads in human patients. After validation, the UAB team also used the assays on nine sows and 22 piglets delivered from the sows through caesarian section.

“Going forward, ensuring the safety of these organs is of paramount importance,” Prichard said. “The use of highly sensitive techniques to detect potential pathogens will help to minimize adverse events in xenotransplantation.”

“The assays hold promise as part of the screening program to identify suitable donor animals, validate and release transplantable organs for research purposes, and monitor transplant recipients,” said Prichard, a professor in the UAB Department of Pediatrics and director of the Department of Pediatrics Molecular Diagnostics Laboratory.

The UAB researchers developed quantitative polymerase chain reaction, or qPCR, assays for 28 viruses sometimes found in pigs and two groups of mycoplasmas. They established reproducibility, sensitivity, specificity and lower limit of detection for each assay. All but three showed features of good quantitative assays, and the lower limit of detection values ranged between one and 16 copies of the viral or bacterial genetic material.

Also, the pig virus assays did not give false positives for some closely related human viruses.

As a start to understanding the infectious disease load in normal healthy animals and ensuring the safety of pig tissues used in xenotransplantation research, the researchers then screened blood, nasal swab and stool specimens from nine adult sows and 22 of their piglets delivered by caesarian section.

Mycoplasma species and two distinct herpesviruses were the most commonly detected microorganisms. Yet 14 piglets that were delivered from three sows infected with either or both herpesviruses were not infected with the herpesviruses, showing that transmission of these viruses from sow to the caesarian-delivery piglet was inefficient.

Prichard says the assays promise to enhance the safety of pig tissues for xenotransplantation, and they will also aid evaluation of human specimens after xenotransplantation.

The UAB researchers say they subsequently have evaluated more than 300 additional specimens, and that resulted in the detection of most of the targets. “The detection of these targets in pig specimens provides reassurance that the analytical methods are functioning as designed,” said Prichard, “and there is no a priori reason some targets might be more difficult to detect than others with the methods described here.”

As is my custom, here’s a link to and a citation for the paper,

Xenotransplantation panel for the detection of infectious agents in pigs by Caroll B. Hartline, Ra’Shun L. Conner, Scott H. James, Jennifer Potter, Edward Gray, Jose Estrada, Mathew Tector, A. Joseph Tector, Mark N. Prichard. Xenotransplantaion Volume 25, Issue 4 July/August 2018 e12427 DOI: https://doi.org/10.1111/xen.12427 First published: 18 August 2018

This paper is open access.

All this leads to questions about chimeras. If a pig is incubating organs with human cells it’s a chimera but then means the human receiving the organ becomes a chimera too. (For an example, see my Dec. 22, 2013 posting where there’s mention of a woman who received a trachea from a pig. Scroll down about 30% of the way.)

What is it to be human?

A question much beloved of philosophers and others, the question seems particularly timely with xenotransplantion and other developments such neuroprosthetics (cyborgs) and neuromorphic computing (brainlike computing).

As I’ve noted before, although not recently, popular culture offers a discourse on these issues. Take a look at the superhero movies and the way in which enhanced humans and aliens are presented. For example, X-Men comics and movies present mutants (humans with enhanced abilities) as despised and rejected. Video games (not really my thing but there is the Deus Ex series which has as its hero, a cyborg also offer insight into these issues.

Other than popular culture and in the ‘bleeding edge’ arts community, I can’t recall any public discussion on these matters arising from the extraordinary set of technologies which are being deployed or prepared for deployment in the foreseeable future.

(If you’re in Vancouver (Canada) from September 14 – December 15, 2018, you may want to check out Piccinini’s work. Also, there’s ” NCSU [North Carolina State University] Libraries, NC State’s Genetic Engineering and Society (GES) Center, and the Gregg Museum of Art & Design have issued a public call for art for the upcoming exhibition Art’s Work in the Age of Biotechnology: Shaping our Genetic Futures.” from my Sept. 6, 2018 posting. Deadline: Oct. 1, 2018.)

At a guess, there will be pushback from people who have no interest in debating what it is to be human as they already know, and will find these developments, when they learn about them, to be horrifying and unnatural.

Melting body fat with a microneedle patch

For many people this may seem like a dream come true but there is a proviso. So far researchers have gotten to the in vivo testing (mice)  with no word about human clinical trials, which means it could be quite a while, assuming human clinical trials go well, before any product comes to market. With that in mind, here’s more from a Sept.15, 2017 news item on Nanowerk,

Researchers have devised a medicated skin patch that can turn energy-storing white fat into energy-burning brown fat locally while raising the body’s overall metabolism. The patch could be used to burn off pockets of unwanted fat such as “love handles” and treat metabolic disorders like obesity and diabetes, according to researchers at Columbia University Medical Center (CUMC) and the University of North Carolina.

A Sept. 15, 2017 Columbia University Medical Center news release on EurekAlert, which originated the news item, describes the research further,

Humans have two types of fat. White fat stores excess energy in large triglyceride droplets. Brown fat has smaller droplets and a high number of mitochondria that burn fat to produce heat. Newborns have a relative abundance of brown fat, which protects against exposure to cold temperatures. But by adulthood, most brown fat is lost.

For years, researchers have been searching for therapies that can transform an adult’s white fat into brown fat–a process named browning–which can happen naturally when the body is exposed to cold temperatures–as a treatment for obesity and diabetes.

“There are several clinically available drugs that promote browning, but all must be given as pills or injections,” said study co-leader Li Qiang, PhD, assistant professor of pathology and cell biology at CUMC. “This exposes the whole body to the drugs, which can lead to side effects such as stomach upset, weight gain, and bone fractures. Our skin patch appears to alleviate these complications by delivering most drugs directly to fat tissue.”

To apply the treatment, the drugs are first encased in nanoparticles, each roughly 250 nanometers (nm) in diameter–too small to be seen by the naked eye. (In comparison, a human hair is about 100,000 nm wide.) The nanoparticles are then loaded into a centimeter-square skin patch containing dozens of microscopic needles. When applied to skin, the needles painlessly pierce the skin and gradually release the drug from nanoparticles into underlying tissue.

“The nanoparticles were designed to effectively hold the drug and then gradually collapse, releasing it into nearby tissue in a sustained way instead of spreading the drug throughout the body quickly,” said patch designer and study co-leader Zhen Gu, PhD, associate professor of joint biomedical engineering at the University of North Carolina at Chapel Hill and North Carolina State University.

The new treatment approach was tested in obese mice by loading the nanoparticles with one of two compounds known to promote browning: rosiglitazone (Avandia) or beta-adrenergic receptor agonist (CL 316243) that works well in mice but not in humans. Each mouse was given two patches–one loaded with drug-containing nanoparticles and another without drug–that were placed on either side of the lower abdomen. New patches were applied every three days for a total of four weeks. Control mice were also given two empty patches.

Mice treated with either of the two drugs had a 20 percent reduction in fat on the treated side compared to the untreated side. They also had significantly lower fasting blood glucose levels than untreated mice.

Tests in normal, lean mice revealed that treatment with either of the two drugs increased the animals’ oxygen consumption (a measure of overall metabolic activity) by about 20 percent compared to untreated controls.

Genetic analyses revealed that the treated side contained more genes associated with brown fat than on the untreated side, suggesting that the observed metabolic changes and fat reduction were due to an increase in browning in the treated mice.

“Many people will no doubt be excited to learn that we may be able to offer a noninvasive alternative to liposuction for reducing love handles,” says Dr. Qiang. “What’s much more important is that our patch may provide a safe and effective means of treating obesity and related metabolic disorders such as diabetes.” [emphasis mine]

The patch has not been tested in humans. The researchers are currently studying which drugs, or combination of drugs, work best to promote localized browning and increase overall metabolism.

The study was supported by grants from the North Carolina Translational and Clinical Sciences Institute and the National Institutes of Health (1UL1TR001111, R00DK97455, and P30DK063608).

Notice the emphasis on health and that the funding does not seem to be from industry (the National Institutes of Health is definitely a federal US agency but I’m not familiar with the North Carolina Translational and Clinical Sciences Institute).

Getting back to the research, here’s an animation featuring the work,

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

Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment by Yuqi Zhang†, Qiongming Liu, Jicheng Yu†, Shuangjiang Yu, Jinqiang Wang, Li Qiang, and Zhen Gu. ACS Nano, Article ASAP DOI: 10.1021/acsnano.7b04348 Publication Date (Web): September 15, 2017

Copyright © 2017 American Chemical Society

This paper is behind a paywall.

I would imagine that Qiang and his colleagues will find a number of business entities will be lining up to fund their work. While the researchers may be focused primarily on health issues, I imagine business types will be seeing dollar signs (very big ones with many zeroes).

The US White House and its Office of Science and Technology Policy (OSTP)

It’s been a while since I first wrote this but I believe this situation has not changed.

There’s some consternation regarding the US Office of Science and Technology Policy’s (OSTP) diminishing size and lack of leadership. From a July 3, 2017 article by Bob Grant for The Scientist (Note: Links have been removed),

Three OSTP staffers did leave last week, but it was because their prearranged tenures at the office had expired, according to an administration official familiar with the situation. “I saw that there were some tweets and what-not saying that it’s zero,” the official tells The Scientist. “That is not true. We have plenty of PhDs that are still on staff that are working on science. All of the work that was being done by the three who left on Friday had been transitioned to other staffers.”

At least one of the tweets that the official is referring to came from Eleanor Celeste, who announced leaving OSTP, where she was the assistant director for biomedical and forensic sciences. “science division out. mic drop,” she tweeted on Friday afternoon.

The administration official concedes that the OSTP is currently in a state of “constant flux” and at a “weird transition period” at the moment, and expects change to continue. “I’m sure that the office will look even more different in three months than it does today, than it did six months ago,” the official says.

Jeffrey Mervis in two articles for Science Magazine is able to provide more detail. From his July 11, 2017 article,

OSTP now has 35 staffers, says an administration official who declined to be named because they weren’t authorized to speak to the media. Holdren [John Holdren], who in January [2017] returned to Harvard University, says the plunge in staff levels is normal during a presidential transition. “But what’s shocking is that, this far into the new administration, the numbers haven’t gone back up.”

The office’s only political appointee is Michael Kratsios, a former aide to Trump confidant and Silicon Valley billionaire Peter Thiel. Kratsios is serving as OSTP’s deputy chief technology officer and de facto OSTP head. Eight new detailees have arrived from other agencies since the inauguration.

Although there has been no formal reorganization of OSTP, a “smaller, more collaborative staff” is now grouped around three areas—science, technology, and national security—according to the Trump aide. Three holdovers from Obama’s OSTP are leading teams focused on specific themes—Lloyd Whitman in technology, Chris Fall in national security, and Deerin Babb-Brott in environment and energy. They report to Kratsios and Ted Wackler, a career civil servant who was Holdren’s deputy chief of staff and who joined OSTP under former President George W. Bush.

“It’s a very flat structure,” says the Trump official, consistent with the administration’s view that “government should be looking for ways to do more with less.” Ultimately, the official adds, “the goal is [for OSTP] to have “probably closer to 50 [people].”

A briefing book prepared by Obama’s outgoing OSTP staff may be a small but telling indication of the office’s current status. The thick, three-ring binder, covering 100 issues, was modeled on one that Holdren received from John “Jack” Marburger, Bush’s OSTP director. “Jack did a fabulous job of laying out what OSTP does, including what reports it owes Congress, so we decided to do likewise,” Holdren says. “But nobody came [from Trump’s transition team] to collect it until a week before the inauguration.”

That person was Reed Cordish, the 43-year-old scion of billionaire real estate developer David Cordish. An English major in college, Reed Cordish was briefly a professional tennis player before joining the family business. He “spent an hour with us and took the book away,” Holdren says. “He told us, ‘This is an important operation and I’ll do my best to see that it flourishes.’ But we don’t know … whether he has the clout to make that happen.”

Cordish is now assistant to the president for intragovernmental and technology initiatives. He works in the new Office of American Innovation led by presidential son-in-law Jared Kushner. That office arranged a recent meeting with high-tech executives, and is also leading yet another White House attempt to “reinvent” government.

Trump has renewed the charter of the National Science and Technology Council, a multiagency group that carries out much of the day-to-day work of advancing the president’s science initiatives. … Still pending is the status of the President’s Council of Advisors on Science and Technology [emphasis mine], a body of eminent scientists and high-tech industry leaders that went out of business at the end of the Obama administration.

Mervis’ July 12, 2017 article is in the form of a Q&A (question and answer) session with the previously mentioned John Holdren, director of the OSTP in Barack Obama’s administration,

Q: Why did you have such a large staff?

A: One reason was to cover the bases. We knew from the start that the Obama administration thought cybersecurity would be an important issue and we needed to be capable in that space. We also knew we needed people who were capable in climate change, in science and technology for economic recovery and job creation and sustained economic growth, and people who knew about advanced manufacturing and nanotechnology and biotechnology.

We also recruited to carry out specific initiatives, like in precision medicine, or combating antibiotic resistance, or the BRAIN [Brain Research through Advancing Innovative Neurotechnologies] initiative. Most of the work will go on in the departments and agencies, but you need someone to oversee it.

The reason we ended up with 135 people at our peak, which was twice the number during its previous peak in the Clinton administration’s second term, was that this president was so interested in knowing what science could do to advance his agenda, on economic recovery, or energy and climate change, or national intelligence. He got it. He didn’t need to be tutored on why science and technology matters.

I feel I’ve been given undue credit for [Obama] being a science geek. It wasn’t me. He came that way. He was constantly asking what we could do to move the needle. When the first flu epidemic, H1N1, came along, the president immediately turned to me and said, “OK, I want [the President’s Council of Advisors on Science and Technology] to look in depth on this, and OSTP, and NIH [National Institutes of Health], and [the Centers for Disease Control and Prevention].” And he told us to coordinate my effort on this stuff—inform me on what can be done and assemble the relevant experts. It was the same with Ebola, with the Macondo oil spill in the Gulf, with Fukushima, where the United States stepped up to work with the Japanese.

It’s not that we had all the expertise. But our job was to reach out to those who did have the relevant expertise.

Q: OSTP now has 35 people. What does that level of staffing say to you?

A: I have to laugh.

Q: Why?

A: When I left, on 19 January [2017], we were down to 30 people. And a substantial fraction of the 30 were people who, in a sense, keep the lights on. They were the OSTP general counsel and deputy counsel, the security officer and deputy, the budget folks, the accounting folks, the executive director of NSTC [National Science and Technology Council].

There are some scientists left, and there are some scientists there still. But on 30 June the last scientist in the science division left.

Somebody said OSTP has shut down. But that’s not quite it. There was no formal decision to shut anything down. But they did not renew the contract of the last remaining science folks in the science division.

I saw somebody say, “Well, we still have some Ph.D.s left.” And that’s undoubtedly true. There are still some science Ph.D.s left in the national security and international affairs division. But because [OSTP] is headless, they have no direct connection to the president and his top advisers.

I don’t want to disparage the top people there. The top people there now are Michael Kratsios, who they named the deputy chief technology officer, and Ted Wackler, who was my deputy chief of staff and who was [former OSTP Director] Jack Marberger’s deputy, and who I kept because he’s a fabulously effective manager. And I believe that they are doing everything they can to make sure that OSTP, at the very least, does the things it has to do. … But right now I think OSTP is just hanging on.

Q: Why did some people choose to stay on?

A: A large portion of OSTP staff are borrowed from other agencies, and because the White House is the White House, we get the people we need. These are dedicated folks who want to get the job done. They want to see science and technology applied to advance the public interest. And they were willing to stay and do their best despite the considerable uncertainty about their future.

But again, most of the detailees, and the reason we went from 135 to 30 almost overnight, is that it’s pretty standard for the detailees to go back to their home agencies and wait for the next administration to decide what set of detailees it wants to advance their objects.

So there’s nothing shocking that most of the detailees went back to their home agencies. The people who stayed are mostly employed directly by OSTP. What’s shocking is that, this far into the new administration, that number hasn’t gone back up. That is, they have only five more people than they had on January 20 [2017].

As I had been wondering about the OSTP and about the President’s Council of Advisors on Science and Technology (PCAST), it was good to get an update.

On a more parochial note, we in Canada are still waiting for an announcement about who our Chief Science Advisor might be.

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.

Canada has a nanotechnology industry? and an overview of the US situation

It’s always interesting to get some insight into how someone else sees the nanotechnology effort in Canada.

First, there have been two basic approaches internationally. Some countries have chosen to fund nanotechnology/nanoscience research through a national initiative/project/council/etc. Notably the US, the UK, China, and Russia, amongst others, have followed this model. For example, the US National Nanotechnology Initiative (NNI)  (a type of hub for research, communication, and commercialization efforts) has been awarded a portion of the US budget every year since 2000. The money is then disbursed through the National Science Foundation.

Canada and its nanotechnology industry efforts

By contrast, Canada has no such line item in its national budget. There is a National Institute of Nanotechnology (NINT) but it is one of many institutes that help make up Canada’s National Research Council. I’m not sure if this is still true but when it was first founded, NINT was funded in part by the federal government and in part by the province of Alberta where it is located (specifically, in Edmonton at the University of Alberta). They claim the organization has grown since its early days although it looks like it’s been shrinking. Perhaps some organizational shuffles? In any event, support for the Canadian nanotechnology efforts are more provincial than federal. Alberta (NINT and other agencies) and Québec (NanoQuébec, a provincially funded nano effort) are the standouts, with Ontario (nano Ontario, a self-organized not-for-profit group) following closely. The scene in Canada has always seemed fragmented in comparison to the countries that have nanotechnology ‘hubs’.

Patrick Johnson in a Dec. 22, 2015 article for Geopolitical Monitor offers a view which provides an overview of nanotechnology in the US and Canada,  adds to the perspective offered here, and, at times, challenges it (Note: A link has been added),

The term ‘nanotechnology’ entered into the public vernacular quite suddenly around the turn of the century, right around the same time that, when announcing the US National Nanotechnology Initiative (NNI) in 2001 [2000; see the American Association for the Advancement of Science webpage on Historical Trends in Federal R&D, scroll down to the National Nanotechnology Initiative and click on the Jpg or Excel links], President Bill Clinton declared that it would one day build materials stronger than steel, detect cancer at its inception, and store the vast records of the Library of Congress in a device the size of a sugar cube. The world of science fiction took matters even further. In his 2002 book Prey, Michael Creighton [Michael Crichton; see Wikipedia entry] wrote of a cloud of self-replicating nanorobots [also known as, nanobots or self-assemblers] that terrorize the good people of Nevada when a science experiment goes terribly wrong.

Back then the hype was palpable. Federal money was funneled to promising nanotech projects as not to fall behind in the race to master this new frontier of science. And industry analysts began to shoot for the moon in their projections. The National Science Foundation famously predicted that the nanotechnology industry would be worth $1 trillion by the year 2015.

Well here we are in 2015 and the nanotechnology market was worth around $26 billion in [sic] last year, and there hasn’t even been one case of a murderous swarm of nanomachines terrorizing the American heartland. [emphasis mine]

Is this a failure of vision? No. If anything it’s only a failure of timing.

The nanotechnology industry is still well on its way to accomplishing the goals set out at the founding of the NNI, goals which at the time sounded utterly quixotic, and this fact is increasingly being reflected in year-on-year growth numbers. In other words, nanotechnology is still a game-changer in global innovation, it’s just taking a little longer than first expected.

The Canadian Connection

Although the Canadian government is not among the world’s top spenders on nanotechnology research, the industry still represents a bright spot in the future of the Canadian economy. The public-private engine [emphasis mine] at the center of Canada’s nanotech industry, the National Institute for Nanotechnology (NINT), was founded in 2001 with the stated goal of “increasing the competitiveness of Canadian companies; creating technology solutions to meet the needs of society; expanding training programs for researchers and entrepreneurs; and enhancing Canada’s stature in the world of nanotechnology.” This ambitious mandate that NINT set out for itself was to be accomplished over the course of two broad stages: first a ‘seeding’ phase of attracting promising personnel and coordinating basic research, and the then a ‘harvesting’ phase of putting the resulting nanotechnologies to the service of Canadian industry.

Recent developments in Canadian nanotechnology [emphasis mine] show that we have already entered that second stage where the concept of nanotechnology transitions from hopeful hypothetical to real-world economic driver

I’d dearly like to know which recent developments indicate Canada’s industry has entered a serious commercialization phase. (It’s one of the shortcomings of our effort that communication is not well supported.) As well, I’d like to know more about the  “… public-private engine at the center of Canada’s nanotech industry …” as Johnson seems to be referring to the NINT, which is jointly funded (I believe) by the federal government and the province of Alberta. There is no mention of private funding on their National Research Council webpage but it does include the University of Alberta as a major supporter.

I am intrigued and I hope there is more information to come.

US and its nanotechnology industry efforts

Dr. Ambika Bumb has written a Dec. 23, 2015 article for Tech Crunch which reflects on her experience as a researcher and entrepreneur in the context of the US NNI effort and includes a plea for future NNI funding [Note: One link added and one link removed],

Indeed, I am fortunate to be the CEO of a nanomedicine technology developer that extends the hands of doctors and scientists to the cellular and molecular level.

The first seeds of interest in bringing effective nano-tools into the hands of doctors and patients were planted in my mind when I did undergrad research at Georgia Tech.  That initial interest led to me pursuing a PhD at Oxford University to develop a tri-modal nanoparticle for imaging a variety of diseases ranging from cancers to autoimmune disorders.

My graduate research only served to increase my curiosity so I then did a pair of post-doctoral fellowships at the National Cancer Institute and the National Heart Lung and Blood Institute.  When it seemed that I was a shoe-in for a life-long academic career, our technology garnered much attention and I found myself in the Bay Area founding the now award-winning Bikanta [bikanta.com].

Through the National Nanotechnology Initiative (NNI) and Nanotechnology Research and Development Act of 2003, our federal government has invested $20 billion in nanoresearch in the past 13 years.  The return on that investment has resulted in 628 agency‐to‐agency collaborations, hundreds of thousands of publications, and more than $1 trillion in revenue generated from nano‐enabled products. [emphasis mine]

Given that medical innovations take a minimum of 10 years before they translate into a clinical product, already realizing a 50X return is an astounding achievement.  Slowing down would be counter-intuitive from an academic and business perspective.

Yet, that is what is happening.  Federal funding peaked half a decade ago in 2010.  [emphasis mine] NNI investments went from $1.58B in 2010 to $1.170B in 2015 (in constant dollars), a 26% drop.  The number of nano-related papers published in the US were roughly 25 thousand in 2013, while the EU and China produced 33 and 35 thousand, respectively.

History has shown repeatedly how the United States has lost an early competitive advantage in developing high‐value technologies to international competition when commercialization infrastructure was not adequately supported.

Examples include semiconductors, advanced batteries for vehicles, and cement‐based construction materials, all of which were originally developed in the United States, but are now manufactured elsewhere.

It is now time for a second era – NNI 2.0.  A return to higher and sustained investment, the purpose of NNI 2.0 should be not just foundational research but also necessary support for rapid commercialization of nanotechnology. The translation of bench science into commercial reality requires the partnership of academic, industrial, federal, and philanthropic players.

I’m not sure why there’s a difference between Johnson’s ” … worth around $26 billion in [sic] last year …] and Bumb’s “… return on that investment has resulted … more than $1 trillion in revenue generated from nano‐enabled products.” I do know there is some controversy as to what should or should not be included when estimating the value of the ‘nanotechnology enterprise’, for example, products that are only possible due to nanotechnology as opposed to products that already existed, such as golf clubs, but are enhanced by nanotechnology.

Bumb goes on to provide a specific example from her own experience to support the plea,

When I moved from the renowned NIH [US National Institutes of Health] on the east coast to the west coast to start Bikanta, one of the highest priority concerns was how we were going to develop nanodiamond technology without access to high-end characterization instrumentation to analyze the quality of our material.  Purchasing all that equipment was not financially viable or even wise for a startup.

We were extremely lucky because our proposal was accepted by the Molecular Foundry, one of five DOE [US Department of Energy]-funded nanoscience user facilities.  While the Foundry primarily facilitates basic nanoscience projects from academic and national laboratory users, Fortune 500 companies and startups like ours also take advantage of its capabilities to answer fundamental questions and conduct proof of concept studies (~10%).

Disregarding the dynamic intellectual community for a minute, there is probably more than $150M worth of instrumentation at the Foundry.  An early startup would never be able to dream of raising a first round that large.

One of the factors of Bikanta’s success is that the Molecular Foundry enabled us to make tremendous strides in R&D in just months instead of years.  More user facilities, incubator centers, and funding for commercializing nanotech are greatly needed.

Final comments

I have to thank Dr. Bumb for pointing out that 2010 was the peak for NNI funding (see the American Association for the Advancement of Science webpage on Historical Trends in Federal R&D, scroll down to the National Nanotechnology Initiative and click on the Jpg or Excel links). I erroneously believed (although I don’t appear to have written up my belief; if you find any such statement, please let me know so I can correct it) that the 2015 US budget was the first time the NNI experienced a drop in funding.

While I found Johnson’s article interesting I wasn’t able to determine the source for his numbers and some of his material had errors that can be identified immediately, e.g., Michael Creighton instead of Michael Crichton.

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?)

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.

Nanomedicine living up to its promise?

Michael Berger has written a March 10, 2015 Nanowerk spotlight article reviewing nanomedicine’s  progress or lack thereof (Note: Links have been removed),

In early 2003, the European Science Foundation launched its Scientific Forward Look on Nanomedicine, a foresight study (report here ;pdf) and in 2004, the U.S. National Institute[s] of Health (NIH) published its Roadmap (now Common Fund) of the Nanomedicine Initiative. This program began in 2005 with a national network of eight Nanomedicine Development Centers. Now, in the second half of this 10-year program, the four centers best positioned to effectively apply their findings to translational studies were selected to continue receiving support.

A generally accepted definition of nanomedicine refers to highly specific medical intervention at the molecular scale for curing disease or repairing damaged tissues, such as bone, muscle, or nerve.

Much of Berger’s article is based on Subbu Venkatraman’s, Director of the NTU (Nanyang Technological University)-Northwestern Nanomedicine Institute in Singapore, paper, Has nanomedicine lived up to its promise?, 2014 Nanotechnology 25 372501 doi:10.1088/0957-4484/25/37/372501 (Note: Links have been removed),

… Historically, the approval of Doxil as the very first nanotherapeutic product in 1995 is generally regarded as the dawn of nanomedicine for human use. Since then, research activity in this area has been frenetic, with, for example, 2000 patents being generated in 2003, in addition to 1200 papers [2]. In the same time period, a total of 207 companies were involved in developing nanomedicinal products in diagnostics, imaging, drug delivery and implants. About 38 products loosely classified as nanomedicine products were in fact approved by 2004. Out of these, however, a number of products (five in all) were based on PEG-ylated proteins, which strictly speaking, are not so much nanomedicine products as molecular therapeutics. Nevertheless, the promise of nanomedicine was being translated into funding for small companies, and into clinical success, so that by 2013, the number of approved products had reached 54 in all, with another 150 in various stages of clinical trials [3]. The number of companies and institutions had risen to 241 (including research centres that were working on nanomedicine). A PubMed search on articles relating to nanomedicine shows 7400 hits over 10 years, of which 1874 were published in 2013 alone. Similarly, the US patent office database shows 409 patents (since 1976) that were granted in nanomedicine, with another 679 applications awaiting approval. So judging by research activity and funding the field of nanomedicine has been very fertile; however, when we use the yardstick of clinical success and paradigm shifts in treatment, the results appear more modest.

Both Berger’s spotlight article and Venkatraman’s review provide interesting reading and neither is especially long.

Nanotechnology, tobacco plants, and the Ebola virus

Before presenting information about the current Ebola crisis and issues with vaccines and curatives, here’s a description of the disease from its Wikipedia entry,

Ebola virus disease (EVD) or Ebola hemorrhagic fever (EHF) is a disease of humans and other primates caused by an ebola virus. Symptoms start two days to three weeks after contracting the virus, with a fever, sore throat, muscle pain, and headaches. Typically nausea, vomiting, and diarrhea follow, along with decreased functioning of the liver and kidneys. Around this time, affected people may begin to bleed both within the body and externally. [1]

As for the current crisis in countries situated on the west coast of the African continent, there’s this from an Aug. 14, 2014 news item on ScienceDaily,

The outbreak of Ebola virus disease that has claimed more than 1,000 lives in West Africa this year poses a serious, ongoing threat to that region: the spread to capital cities and Nigeria — Africa’s most populous nation — presents new challenges for healthcare professionals. The situation has garnered significant attention and fear around the world, but proven public health measures and sharpened clinical vigilance will contain the epidemic and thwart a global spread, according to a new commentary by Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Dr. Fauci’s Aug. 13, 2014 commentary (open access) in the New England Journal of Medicine provides more detail (Note: A link has been removed),

An outbreak of Ebola virus disease (EVD) has jolted West Africa, claiming more than 1000 lives since the virus emerged in Guinea in early 2014 (see figure) Ebola Virus Cases and Deaths in West Africa (Guinea, Liberia, Nigeria, and Sierra Leone), as of August 11, 2014 (Panel A), and Over Time (Panel B).). The rapidly increasing numbers of cases in the African countries of Guinea, Liberia, and Sierra Leone have had public health authorities on high alert throughout the spring and summer. More recent events including the spread of EVD to Nigeria (Africa’s most populous country) and the recent evacuation to the United States of two American health care workers with EVD have captivated the world’s attention and concern. Health professionals and the general public are struggling to comprehend these unfolding dynamics and to separate misinformation and speculation from truth.

In early 2014, EVD emerged in a remote region of Guinea near its borders with Sierra Leone and Liberia. Since then, the epidemic has grown dramatically, fueled by several factors. First, Guinea, Sierra Leone, and Liberia are resource-poor countries already coping with major health challenges, such as malaria and other endemic diseases, some of which may be confused with EVD. Next, their borders are porous, and movement between countries is constant. Health care infrastructure is inadequate, and health workers and essential supplies including personal protective equipment are scarce. Traditional practices, such as bathing of corpses before burial, have facilitated transmission. The epidemic has spread to cities, which complicates tracing of contacts. Finally, decades of conflict have left the populations distrustful of governing officials and authority figures such as health professionals. Add to these problems a rapidly spreading virus with a high mortality rate, and the scope of the challenge becomes clear.

Although the regional threat of Ebola in West Africa looms large, the chance that the virus will establish a foothold in the United States or another high-resource country remains extremely small. Although global air transit could, and most likely will, allow an infected, asymptomatic person to board a plane and unknowingly carry Ebola virus to a higher-income country, containment should be readily achievable. Hospitals in such countries generally have excellent capacity to isolate persons with suspected cases and to care for them safely should they become ill. Public health authorities have the resources and training necessary to trace and monitor contacts. Protocols exist for the appropriate handling of corpses and disposal of biohazardous materials. In addition, characteristics of the virus itself limit its spread. Numerous studies indicate that direct contact with infected bodily fluids — usually feces, vomit, or blood — is necessary for transmission and that the virus is not transmitted from person to person through the air or by casual contact. Isolation procedures have been clearly outlined by the Centers for Disease Control and Prevention (CDC). A high index of suspicion, proper infection-control practices, and epidemiologic investigations should quickly limit the spread of the virus.

Fauci’s article makes it clear that public concerns are rising in the US and I imagine that’s true of Canada too and many other parts of the world, not to mention the countries currently experiencing the EVD outbreak. In the midst of all this comes a US Food and Drug Administration (FDA) warning as per an Aug. 15, 2014 news item (originated by Reuters reporter Toni Clarke) on Nanowerk,

The U.S. Food and Drug Administration said on Thursday [Aug. 14, 2014] it has become aware of products being sold online that fraudulently claim to prevent or treat Ebola.

The FDA’s warning comes on the heels of comments by Nigeria’s top health official, Onyebuchi Chukwu, who reportedly said earlier Thursday [Aug. 14, 2014] that eight Ebola patients in Lagos, the country’s capital, will receive an experimental treatment containing nano-silver.

Erica Jefferson, a spokeswoman for the FDA, said she could not provide any information about the product referenced by the Nigerians.

The Aug. 14,  2014 FDA warning reads in part,

The U.S. Food and Drug Administration is advising consumers to be aware of products sold online claiming to prevent or treat the Ebola virus. Since the outbreak of the Ebola virus in West Africa, the FDA has seen and received consumer complaints about a variety of products claiming to either prevent the Ebola virus or treat the infection.

There are currently no FDA-approved vaccines or drugs to prevent or treat Ebola. Although there are experimental Ebola vaccines and treatments under development, these investigational products are in the early stages of product development, have not yet been fully tested for safety or effectiveness, and the supply is very limited. There are no approved vaccines, drugs, or investigational products specifically for Ebola available for purchase on the Internet. By law, dietary supplements cannot claim to prevent or cure disease.

As per the FDA’s reference to experimental vaccines, an Aug. 6, 2014 article by Caroline Chen, Mark Niquette, Mark Langreth, and Marie French for Bloomberg describes the ZMapp vaccine/treatment (Note: Links have been removed),

On a small plot of land incongruously tucked amid a Kentucky industrial park sit five weather-beaten greenhouses. At the site, tobacco plants contain one of the most promising hopes for developing an effective treatment for the deadly Ebola virus.

The plants contain designer antibodies developed by San Diego-based Mapp Biopharmaceutical Inc. and are grown in Kentucky by a unit of Reynolds American Inc. Two stricken U.S. health workers received an experimental treatment containing the antibodies in Liberia last week. Since receiving doses of the drug, both patients’ conditions have improved.

Tobacco plant-derived medicines, which are also being developed by a company whose investors include Philip Morris International Inc., are part of a handful of cutting edge plant-based treatments that are in the works for everything from pandemic flu to rabies using plants such as lettuce, carrots and even duckweed. While the technique has existed for years, the treatments have only recently begun to reach the marketplace.

Researchers try to identify the best antibodies in the lab, before testing them on mice, then eventually on monkeys. Mapp’s experimental drug, dubbed ZMapp, has three antibodies, which work together to alert the immune system and neutralize the Ebola virus, she [Erica Ollman Saphire, a molecular biologist at the Scripps Research Institute,] said.

This is where the tobacco comes in: the plants are used as hosts to grow large amounts of the antibodies. Genes for the desired antibodies are fused to genes for a natural tobacco virus, Charles Arntzen, a plant biotechnology expert at Arizona State University, said in an Aug. 4 [2014] telephone interview.

The tobacco plants are then infected with this new artificial virus, and antibodies are grown inside the plant. Eventually, the tobacco is ground up and the antibody is extracted, Arntzen said.

The process of growing antibodies in mammals risks transferring viruses that could infect humans, whereas “plants are so far removed, so if they had some sort of plant virus we wouldn’t get sick because viruses are host-specific,” said Qiang Chen, a plant biologist at Arizona State University in Tempe, Arizona, in a telephone interview.

There is a Canadian (?) company working on a tobacco-based vaccines including one for EVD but as the Bloomberg writers note the project is highly secret,

Another tobacco giant-backed company working on biotech drugs grown in tobacco plants is Medicago Inc. in Quebec City, which is owned by Mitsubishi Tanabe Pharma Corp. and Philip Morris. [emphasis mine]

Medicago is working on testing a vaccine for pandemic influenza and has a production greenhouse facility in North Carolina, said Jean-Luc Martre, senior director for government affairs at Medicago. Medicago is planning a final stage trial of the pandemic flu vaccine for next year, he said in a telephone interview.

The plant method is flexible and capable of making antibodies and vaccines for numerous types of viruses, said Martre. In addition to influenza, the company’s website says it is in early stages of testing products for rabies and rotavirus.

Medicago ‘‘is currently closely working with partners for the production of an Ebola antibody as well as other antibodies that are of interest for bio-defense,” he said in an e-mail. He would not disclose who the partners were. [emphasis mine]

I have checked both the English and French language versions of Medicago’s website and cannot find any information about their work on ebola. (The Bloomberg article provides a good overview of the ebola situation and more. I recommend reading it and/or the Aug. 15, 2014 posting on CTV [Canadian Television Network] which originated from an Associated Press article by Malcolm Ritter).

Moving on to more research and ebola, Dexter Johnson in an Aug. 14, 2014 posting (on his Nanoclast blog on the IEEE [Institute of Electrical and Electronics Engineers] website,) describes some work from Northeastern University (US), Note: Links have been removed,

With the Ebola virus death toll now topping 1000 and even the much publicized experimental treatment ZMapp failing to save the life of a Spanish missionary priest who was treated with it, it is clear that scientists need to explore new ways of fighting the deadly disease. For researchers at Northeastern University in Boston, one possibility may be using nanotechnology.

“It has been very hard to develop a vaccine or treatment for Ebola or similar viruses because they mutate so quickly,” said Thomas Webster, the chair of Northeastern’s chemical engineering department, in a press release. “In nanotechnology we turned our attention to developing nanoparticles that could be attached chemically to the viruses and stop them from spreading.”

Webster, along with many researchers in the nanotechnology community, have been trying to use gold nanoparticles, in combination with near-infrared light, to kill cancer cells with heat. The hope is that the same approach could be used to kill the Ebola virus.

There is also an Aug. 6, 2014 Northeastern University news release by Joe O’Connell describing the technique being used by Webster’s team,

… According to Web­ster, gold nanopar­ti­cles are cur­rently being used to treat cancer. Infrared waves, he explained, heat up the gold nanopar­ti­cles, which, in turn, attack and destroy every­thing from viruses to cancer cells, but not healthy cells.

Rec­og­nizing that a larger sur­face area would lead to a quicker heat-​​up time, Webster’s team cre­ated gold nanos­tars. “The star has a lot more sur­face area, so it can heat up much faster than a sphere can,” Web­ster said. “And that greater sur­face area allows it to attack more viruses once they absorb to the par­ti­cles.” The problem the researchers face, how­ever, is making sure the hot gold nanopar­ti­cles attack the virus or cancer cells rather than the healthy cells.

At this point, there don’t seem to be any curative measures generally available although some are available experimentally in very small quantities.