Category Archives: human enhancement

Ethics of germline editing special CRISPR journal issue

Caption: The CRISPR Journal delivers groundbreaking multidisciplinary research, advances, and commentary on CRISPR, the extraordinary technology that gives scientists the power to cure disease and sculpt evolution. Credit: Mary Ann Liebert, Inc., publishers

The CRISPR Journal’s publisher, Mary Ann Liebert, Inc., released two notices about their special issue on ethics. I found this October 10, 2019 media alert on EurekAlert a little more informative than the other one,

Highlights from this Issue:

1. Human Germline Genome Editing: An Assessment
In the opening Perspective of the special issue on The Ethics of Human Genome Editing, Stanford Law professor Henry Greely argues that germline editing is not inherently bad or unethical, but the technology is unlikely to be particularly useful, at least in the near future. Greely takes issue with the notion that the human genome is “the heritage of humanity” – the equivalent of The Ark of the Covenant that “cannot be allowed to fall into the wrong hands.” He contrasts germline editing with the practical applications of preimplantation genetic testing and somatic gene therapy. Exceptions for germline editing might be found in the cases of rare couples where both partners have the same recessive disorder or one is homozygous for a dominant disease.

2. Pick Six: Democratic Governance of Germline Editing
Two international commissions, organized by the World Health Organization, the U.S. National Academies, and the Royal Society, have been launched to provide recommendations for the governance of human germline editing, prompted by the actions of He Jiankui and the 2018 CRISPR babies reports. In this Perspective, Jasanoff, Hurlbut, and Saha [Sheila Jasanoff, Harvard University {Cambridge, MA}, J. Benjamin Hurlbut, Arizona State University {Tempe, AZ}, and Krishanu Saha, University of Wisconsin-Madison] argue that such an approach is “premature and problematic.” Global democratic governance “demands a new mechanism for active, sustained reflection by scientists” in partnership with scholars from other disciplines and the public. The authors present six recommendations to promote democratic governance.

3. Just Say No to a Moratorium
In March 2019, Eric Lander, Francoise Baylis [emphasis mine], and colleagues issued a call for a temporary global moratorium on heritable genome editing. In this Perspective, Kerry Macintosh, author of Enhanced Beings, offers three reasons she opposes the imposition of a moratorium: the danger of a temporary ban becoming permanent; a disincentive to support appropriate research to make the technology safer and more effective; and the potential stigmatization of children born with edited genomes. Nations should regulate germline editing for safety and efficacy only, Macintosh says, without distinguishing between therapeutic applications and enhancement.

4. Who Speaks for Future Children?
Law professor Bartha Knoppers and Erika Kleiderman write that the recent calls for a moratorium on germline editing “may create an illusion of control over rogue science and stifle the necessary international debate surrounding an ethically responsible translational path forward.” Focusing efforts on enforcing current laws and fostering public dialogue is a better route, the authors suggest.

5. The Daunting Economics of Therapeutic Genome Editing
Ten years after the first gene editing clinical trial got underway, gene therapy is experiencing a renaissance. Recent approvals for some gene therapy drugs have been accompanied by exorbitant price tags, in one case exceeding $2 million. Looking ahead, Wilson [Ross C. Wilson, PhD, Innovative Genomics Institute, University of California, Berkeley] and Carroll [Dana Carroll, PhD, Department of Biochemistry, University of Utah School of Medicine] ask whether CRISPR can make good on its promise as “a great leveler” and “democratizing force in biomedicine”. They write: “Therapeutic genome editing must avoid several pitfalls that could substantially limit access to its transformative potential, especially in the developing world.” The costs of drug manufacture, testing, and delivery will have to come down to make the benefits of genome editing available to those most in need.

6. The Demand for Germline Editing: View from a Fertility Clinic
A common argument against human germline editing is that there is already a safe, proven technology to help couples have a healthy biological child — preimplantation genetic testing (PGT). In this Perspective, Manuel Viotti and colleagues from a leading IVF clinic in California strive to calculate the likely occurrence of cases where germline editing might offer couples opportunities to have a healthy biological child where PGT would not be applicable. The numbers are very small indeed.

7. Brave New World in the CRISPR Debate
In any discussion or warnings of designer babies and future dystopian societies based on genetic or reproductive technologies, exhibit A is invariably Aldous Huxley’s iconic 1932 novel, Brave New World. Indeed, David Baltimore referred to the novel at both of the international genome editing summits. In this Perspective, Derek So dissects the misuse of Brave New World, particularly regarding genome editing technology, enhancement, and eugenics. So [even offers a few less celebrated, but potentially more appropriate, examples from the sci-fi literature.

I highlighted Françoise Baylis’ name as she has been mentioned on this blog a few times and, if you’re curious, there’s an opportunity to hear her speak in Toronto (Ontario) tonight, Thursday, October 17, 2019. You can find out where and exactly when in my October 14, 2019 posting, under the first subheading, ‘… on the future of life forms …’.

The October 15, 2019 news release on EurekAlert offers much the same information but also includes this link to the journal issue where you can read it for free,

The Ethics of Human Genome Editing is the subject of intensive discussion and debate in a special issue of The CRISPR Journal, a new peer-reviewed journal from Mary Ann Liebert, Inc., publishers. Click here) to read the full-text issue free on The CRISPR Journal.

The issue contains 11 articles: nine Perspectives and two research articles on issues including human rights for the unborn, the economics of gene editing therapies, the pros and cons of a moratorium on genome editing, the real-world cases where germline editing could provide medical utility, and (on a lighter note) the use and misuse of “Brave New World.”

It looks like a very interesting and comprehensive lineup of topics related to ethics and editing the human germline. FYI, I covered the story about the CRISPR twins, Lulu and Nana, here in a November 28, 2018 posting, about the time the news first broke.

Detecting off-target effects of CRISPR gene-editing

In amidst all the hyperbole about CRISPR (clustered regularly interspaced short palindromic repeats), the gene editing technology, you will sometimes find a mild cautionary note. It seems that CRISPR is not as precise as you might think.

Some months ago there was a story about research into detecting possible unanticipated (off target) effects from using CRISPR, from an April 19, 2019 news item on ScienceDaily,

Since the CRISPR genome editing technology was invented in 2012, it has shown great promise to treat a number of intractable diseases. However, scientists have struggled to identify potential off-target effects in therapeutically relevant cell types, which remains the main barrier to moving therapies to the clinic. Now, a group of scientists at the Gladstone Institutes and the Innovative Genomics Institute (IGI), with collaborators at AstraZeneca, have developed a reliable method to do just that.

An April 19, 2019 Gladstone Institutes press release by Julie Langelier, which originated the press release, provides details,

CRISPR edits a person’s genome by cutting the DNA at a specific location. The challenge is to ensure the tool doesn’t also make cuts elsewhere along the DNA—damage referred to as “off-target effects,” which could have unforeseen consequences.

In a study published in the journal Science, the two first authors, Beeke Wienert and Stacia Wyman, found a new way to approach the problem.

“When CRISPR makes a cut, the DNA is broken,” says Wienert, PhD, who began the work in Jacob E. Corn’s IGI laboratory and who is now a postdoctoral scholar in Bruce R. Conklin’s laboratory at Gladstone. “So, in order to survive, the cell recruits many different DNA repair factors to that particular site in the genome to fix the break and join the cut ends back together. We thought that if we could find the locations of these DNA repair factors, we could identify the sites that have been cut by CRISPR.”

To test their idea, the researchers studied a panel of different DNA repair factors. They found that one of them, called MRE11, is one of the first responders to the site of the cut. Using MRE11, the scientists developed a new technique, named DISCOVER-Seq, that can identify the exact sites in the genome where a cut has been made by CRISPR.

“The human genome is extremely large—if you printed the entire DNA sequence, you would end up with a novel as tall as a 16-story building,” explains Conklin, MD, senior investigator at Gladstone and deputy director at IGI. “When we want to cut DNA with CRISPR, it’s like we’re trying to remove one specific word on a particular page in that novel.”

“You can think of the DNA repair factors as different types of bookmarks added to the book,” Conklin adds. “While some may bookmark an entire chapter, MRE11 is a bookmark that drills down to the exact letter than has been changed.”

Different methods currently exist to detect CRISPR off-target effects. However, they come with limitations that range from producing false-positive results to killing the cells they’re examining. In addition, the most common method used to date is currently limited to cultured cells in the laboratory, excluding its use in patient-derived stem cells or animal tissue.

“Because our method relies on the cell’s natural repair process to identify cuts, it has proven to be much less invasive and much more reliable,” says Corn, PhD, who now runs a laboratory at ETH Zurich. “We were able to test our new DISCOVER-Seq method in induced pluripotent stem cells, patient cells, and mice, and our findings indicate that this method could potentially be used in any system, rather than just in the lab.”

The DISCOVER-Seq method, by being applied to new cell types and systems, has also revealed new insights into the mechanisms used by CRISPR to edit the genome, which will lead to a better understanding of the biology of how this tool works.

“The new method greatly simplifies the process of identifying off-target effects while also increasing the accuracy of the results,” says Conklin, who is also a professor of medical genetics and molecular pharmacology at UC San Francisco (UCSF). “This could allow us to better predict how genome editing would work in a clinical setting. As a result, it represents an essential step in improving pre-clinical studies and bringing CRISPR-based therapies closer to the patients in need.”

###

About the Study

The paper “Unbiased detection of CRISPR off-targets in vivo 1 using DISCOVER-Seq” was published by the journal Science on April 19, 2019. Gladstone’s Hannah L. Watry and Luke M. Judge (who is also at UCSF) contributed to this study. Other authors also include Christopher D. Richardson, Jonathan T. Vu, and Katelynn R. Kazane from IGI, Charles D. Yeh from ETH Zurich, as well as Pinar Akcakaya, Michelle J. Porritt, and Michaela Morlock from AstraZeneca.

The work was supported by Gladstone, the National Institutes of Health (grants EY028249 and HL13535801), the Li Ka Shing Foundation, the Heritage Medical Research Institute, the Fanconi Anemia Research Foundation, a Sir Keith Murdoch Fellowship from the American Australian Association, and an Early Career Fellowship from the National Health and Medical Research Council.

About the Gladstone Institute

To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco.

Before getting to the link and citation that I usually offer you might find this July 17, 2018 posting, The CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene-editing technique may cause new genetic damage kerfuffle of interest. I wonder if this latest news affected the CRISPR market as the did the news in 2018.

In addition to the link in the press release, I am including a link and a citation for the study,

Unbiased detection of CRISPR off-targets in vivo using DISCOVER-Seq by Beeke Wienert, Stacia K. Wyman, Christopher D. Richardson, Charles D. Yeh, Pinar Akcakaya, Michelle J. Porritt, Michaela Morlock, Jonathan T. Vu, Katelynn R. Kazane, Hannah L. Watry, Luke M. Judge, Bruce R. Conklin, Marcello Maresca, Jacob E. Corn. Science 19 Apr 2019: Vol. 364, Issue 6437, pp. 286-289 DOI: 10.1126/science.aav9023

This paper is behind a paywall.

Money

Over the last 10 or more years, I have, on occasion made a point, of finding out about the funding for various non-profit agencies and projects. I find that sort of thing interesting and have hoped that my readers might feel the same way.

It seems that my readers and I might not be the only ones to care about the source of funding. Joi Ito who held appointments with Harvard University and the Massachusetts Institute of Technology (MIT) resigned from his various appointments on Sept. 7, 2019 after news of major donations from Jeffrey Epstein (a disgraced financier and sex offender) to MIT were revealed. From the Joi Ito’s entry on Wikipedia (Note: Links have been removed),

Joichi “Joi” Ito (伊藤 穰一 Itō Jōichi, born June 19, 1966) is a Japanese activist, entrepreneur and venture capitalist. He is the former director of the MIT Media Lab, and a former professor of the practice of media arts and sciences at MIT. He is a former visiting professor of practice at the Harvard Law School.[1][2]

Ito has received recognition for his role as an entrepreneur focused on Internet and technology companies and has founded, among other companies, PSINet Japan, Digital Garage and Infoseek Japan. Ito is a strategic advisor to Sony Corporation[3] and general partner of Neoteny Labs.[4] Ito writes a monthly column in the Ideas section of Wired.[5]

Ito resigned from his roles at MIT, Harvard, the John D. and Catherine T. MacArthur Foundation, the Knight Foundation, PureTech Health and The New York Times Company on September 7, 2019, following allegations of financial ties to sex offender and financier Jeffrey Epstein.[2][6][7]

Many, many institutions have accepted funds from sketchy characters and orgnaizations. It’s not new to academia, the sciences, or the arts. For a contemporary view of how some of this works, take a look at Anand Giridharadas’s 2018 book, Winners Take All. From the webepage for the book,

WINNERS TAKE ALL
The Elite Charade of Changing the World
 
An insider’s groundbreaking investigation of how the global elite’s efforts to “change the world” preserve the status quo and obscure their role in causing the problems they later seek to solve.

Former New York Times columnist Anand Giridharadas takes us into the inner sanctums of a new gilded age, where the rich and powerful fight for equality and justice any way they can–except ways that threaten the social order and their position atop it. We see how they rebrand themselves as saviors of the poor; how they lavishly reward “thought leaders” who redefine “change” in winner-friendly ways; and how they constantly seek to do more good, but never less harm. We hear the limousine confessions of a celebrated foundation boss; witness an American president hem and haw about his plutocratic benefactors; and attend a cruise-ship conference where entrepreneurs celebrate their own self-interested magnanimity.

I don’t recall any mention of Epstein in Giridharadas’s book but he did have this to say on Twitter about Epstein,

Anand Giridharadas‏Verified account @AnandWrites



Everything that made Epstein’s life possible remains in place after his arrest: the Caribbean tax havens, the hidden real-estate deals, the buying of politicians, the nonprofits that sell reputational glow, the editors who cover for people of their class.

7:34 PM – 8 Jul 2019

it can’t be easy to withstand the temptation to take the money and hope that the misdoings have been exaggerated or that they have stopped. I imagine Ito and others are under constant pressure to get funds.

AstraZeneca

One of the partners in this research about CRISPR, AstraZeneca, is a pharmaceutical company. In fact, it’s one of the largest in the world (from the AstraZeneca Wikipedia entry; Note: Links have been removed),

AstraZeneca plc[4] is a British-Swedish multinational pharmaceutical and biopharmaceutical company. In 2013, it moved its headquarters to Cambridge, UK, and concentrated its R&D in three sites: Cambridge; Gaithersburg, Maryland, USA (location of MedImmune) for work on biopharmaceuticals; and Mölndal (near Gothenburg) in Sweden, for research on traditional chemical drugs.[5] AstraZeneca has a portfolio of products for major disease areas including cancer, cardiovascular, gastrointestinal, infection, neuroscience, respiratory and inflammation.[6]

The company was founded in 1999 through the merger of the Swedish Astra AB and the British Zeneca Group[7][8] (itself formed by the demerger of the pharmaceutical operations of Imperial Chemical Industries in 1993). Since the merger it has been among the world’s largest pharmaceutical companies and has made numerous corporate acquisitions, including Cambridge Antibody Technology (in 2006), MedImmune (in 2007), Spirogen (in 2013) and Definiens (by MedImmune in 2014).

Controversies

Seroquel
In April 2010 AstraZeneca settled a qui tam lawsuit brought by Stefan P. Kruszewski for $520 million to settle allegations that the company defrauded Medicare, Medicaid, and other government-funded health care programs in connection with its marketing and promotional practices for the blockbuster atypical antipsychotic, Seroquel.[76]
In March 2011, AstraZeneca settled a lawsuit in the United States totalling $68.5 million to be divided up to 38 states.[77]
Nexium
The company’s most commercially successful medication is esomeprazole (Nexium). The primary uses are treatment of gastroesophageal reflux disease, treatment and maintenance of erosive esophagitis, treatment of duodenal ulcers caused by Helicobacter pylori, prevention of gastric ulcers in those on chronic NSAID therapy, and treatment of gastrointestinal ulcers associated with Crohn’s disease. When it is manufactured the result is a mixture of two mirror-imaged molecules, R and S. Two years before the omeprazole patent expired, AstraZeneca patented S-omeprazole in pure form, pointing out that since some people metabolise R-omeprazole slowly, pure S-omeprazole treatment would give higher dose efficiency and less variation between individuals.[78] In March 2001, the company began to market Nexium, as it would a brand new drug.[79]

In 2007, Marcia Angell, former editor-in-chief of the New England Journal of Medicine and a lecturer in social medicine at the Harvard Medical School, said in Stern, a German-language weekly newsmagazine, that AstraZeneca’s scientists had misrepresented their research on the drug’s efficiency, saying “Instead of using presumably comparable doses [of each drug], the company’s scientists used Nexium in higher dosages. They compared 20 and 40 mg Nexium with 20 mg Prilosec. With the cards having been marked in that way, Nexium looked like an improvement – which however was only small and shown in only two of the three studies.”[83]
Bildman fraud, and faithless servant clawback

Study
In 2004, University of Minnesota research participant Dan Markingson committed suicide while enrolled in an industry-sponsored pharmaceutical trial comparing three FDA-approved atypical antipsychotics: Seroquel (quetiapine), Zyprexa (olanzapine), and Risperdal (risperidone). University of Minnesota Professor of Bioethics Carl Elliott noted that Markingson was enrolled in the study against the wishes of his mother, Mary Weiss, and that he was forced to choose between enrolling in the study or being involuntarily committed to a state mental institution.[89] Further investigation revealed financial ties to AstraZeneca by Markingson’s psychiatrist, Stephen C. Olson, oversights and biases in AstraZeneca’s trial design, and the inadequacy of university Institutional Review Board (IRB) protections for research subjects.[90][unreliable source?] A 2005 FDA investigation cleared the university. Nonetheless, controversy around the case has continued. A Mother Jones article[89] resulted in a group of university faculty members sending a public letter to the university Board of Regents urging an external investigation into Markingson’s death.[91]

Is it ok to take money and/or other goods and services from them?

Innovative Genomics Institute (IGI)

Also mentioned as a partner in the research, is the Innovative Genomics Institute (IGI). Here’s more from the company’s Overview webpage (Note: Links have been removed),,

The IGI began in 2014 through the Li Ka Shing Center for Genetic Engineering, which was created thanks to a generous donation from the Li Ka Shing Foundation. [emphasis mine] The Innovative Genomics Initiative formed as a partnership between the University of California, Berkeley and the University of California, San Francisco. Combining the fundamental research expertise and the biomedical talent at UCB and UCSF, the Innovative Genomics Initiative focused on unraveling the mechanisms underlying CRISPR-based genome editing and applying this technology to improve human health. Early achievements include improving the efficiency of gene replacement and foundational work toward a treatment for sickle cell disease.

In late 2015, generous philanthropic donations enabled a bolder vision and broader mission for the IGI. With this expansion came a significant enhancement of the organization, and in January 2017, the IGI officially re-launched as the Innovative Genomics Institute.

As it turns out, there is a Li Ka-shing and he has a bit of a history with Vancouver (Canada). First, here’s more about him from the Li Ka-shing Wikipedia entry,(Note: Links have been removed),

Sir Li Ka-shing GBM KBE JP[4] (born 13 June 1928)[5][6] is a Hong Kong business magnate, investor, and philanthropist. As of June 2019, Li is the 30th richest person in the world, with an estimated net wealth of US$29.4 billion.[3] He is the senior advisor for CK Hutchison Holdings,[7] after he retired from the Chairman of the Board in May 2018;[8] through it, he is the world’s leading port investor, developer, and operator of the largest health and beauty retailer in Asia and Europe.[9]

Besides business through his flagship companies Cheung Kong Property Holdings and CK Hutchison Holdings Limited, Li Ka-shing has also personally invested extensively in real estate in Singapore and Canada. He was the single largest shareholder of Canadian Imperial Bank of Commerce (CIBC), the fifth largest bank in Canada, until the sale of his share in 2005 (with all proceedings donated, see below). He is also the majority shareholder of a major energy company, Husky Energy, based in Alberta, Canada.[48]

In January 2005, Li announced plans to sell his $1.2 billion CAD stake in the Canadian Imperial Bank of Commerce, with all proceeds going to private charitable foundations established by Li, including the Li Ka Shing Foundation in Hong Kong and the Li Ka Shing (Canada) Foundation based in Toronto, Ontario.[49]

His son Victor Li was kidnapped in 1996 on his way home after work by gangster “Big Spender” Cheung Tze-keung. Li Ka-shing paid a ransom of HK$1 billion, directly to Cheung who had come to his house.[53] A report was never filed with Hong Kong police. Instead the case was pursued by Mainland authorities, leading to Cheung’s execution in 1998, an outcome not possible under Hong Kong law. Rumours circulated of a deal between Li and the Mainland.[53] In interviews, when this rumor was brought up, Li brushed it off and dismissed it completely.

Li Ka-shing was well known here in Vancouver due to his purchase of a significant chunk of land in the city. This January 9, 2015 article by Glen Korstrum for Business in Vancouver notes some rather interesting news and contextualizes with Li’s Vancouver history,

Hong Kong billionaire Li Ka-shing is restructuring his empire and shifting his base to the Cayman Islands and away from the Chinese special administrative region.

His January 9 [2015] announcement came the same day that Forbes ranked him as Hong Kong’s richest man for the 17th consecutive year, with a total wealth of US$33.5 billion.

Li is best known in Vancouver for buying an 82.5-hectare parcel of land around False Creek for $328 million in 1988 along with partners, who included fellow Hong Kong tycoons, Lee Shau Kee and Cheng Yu Tung.

The group formed Concord Pacific, which redeveloped the site that had been home to Vancouver’s 1986 world’s fair, Expo ’86.

Li cashed out of Concord Pacific in the late 1990s and, in 2007, invested in Deltaport through his Hutchison Port Holdings.

Li’s biggest Canadian holding is his controlling stake in Husky Energy. …

Intriguing, yes? It also makes the prospect of deciding whose money you’re going to accept a bit more complicated than it might seem.

Gladstone Institutes

In what seems to be a decided contrast to the previous two partners, here’s more from the Gladstone Institutes, About Us, History webpage,

Born in London in 1910, J. David Gladstone was orphaned as a boy and came to North America at age 10. He began a career in real estate in Southern California at age 28, eventually making his fortune as the first developer to create the region’s enclosed shopping malls (such as the Northridge Fashion Center mall). His accidental death in 1971 left an estate valued at about $8 million to support medical students interested in research.

It soon became clear to the three trustees administering Mr. Gladstone’s trust that his legacy could support a far more substantial philanthropic enterprise. In 1979, they launched The J. David Gladstone Institutes under the leadership of Robert W. Mahley, MD, PhD, a leading cardiovascular scientist who at the time was working at the National Institutes of Health.

In 2010, after three decades of leading Gladstone, Dr. Mahley stepped down in order to return to more active research. That same year, R. Sanders “Sandy” Williams, MD, left Duke University, where he had been Dean of the School of Medicine—as well as Senior Vice Chancellor and Senior Advisor for International Strategy—to become Gladstone’s new president. The following year, the S.D. Bechtel, Jr. Foundation [emphasis mine] helped launch the Center for Comprehensive Alzheimer’s Disease Research with a generous $6M lead gift, while the Roddenberry Foundation [emphasis mine] gave $5 million to launch the Roddenberry Center for Stem Cell Biology and Medicine. Also in 2011, the independent and philanthropic Gladstone Foundation formed with the mission of expanding the financial resources available to drive’s Gladstone’s mission.

The S. D. Bechtel jr. mentioned is associated with Bechtel, an international engineering firm. I did not find any scandals or controversies in the Bechtel Wikipedia entry. That seemed improbable so I did a little digging and found a January 30, 2015 (?) article by Matthew Brunwasser for foreignpolicy.com (Note: A link has been removed),

Steamrolled; A special investigation into the diplomacy of doing business abroad.

One of Europe’s poorest countries wanted a road, so U.S. mega-contractor Bechtel sold it a $1.3 billion highway, with the backing of a powerful American ambassador. Funny thing is, the highway is barely being used—and the ambassador is now working for Bechtel.

Bechtel, the largest contractor by revenue in the United States and the third-largest internationally, according to an annual list compiled by the Engineering News-Record, has in recent years constructed expensive highways in Kosovo, Croatia, Romania, and Albania. A six-month investigation by the Investigative Reporting Program at the University of California at Berkeley Graduate School of Journalism has found that these highways were boondoggles for the countries in which they were constructed, and that members of governments and international institutions often saw problems coming before Bechtel (along with its Turkish joint venture partner, Enka) even began work on the roads.

My other source is a May 8, 1988 article by Walter Russell Mead for the Los Angeles Time,s

From San Francisco to Saudi Arabia, the Bechtel Group Inc. has left its mark around the world. Yet the privately owned Bechtel Group is one of the country’s most mysterious operations–or was, until the publication of Laton McCartney’s critical and controversial “Friends in High Places.”

Those who believe that “Dynasty” and “Falcon Crest” describe life at the top of America’s corporate pyramids will find a picture here that makes the most far-fetched TV plots look dull. One Bechtel executive was torn to pieces by an angry mob; another, kidnaped, survived two days in the trunk of a Mercedes that had been driven over the edge of a cliff but caught on an obstacle half way down. Wheeling and dealing from Beirut to the Bohemian Grove, Bechtel executives fought off Arab and Jewish nationalists, angry senators, bitter business rivals, and furious consumer groups to build the world’s largest construction and engineering firm.

Poor Bechtel sometimes seems damned if it does and damned if it doesn’t. No major corporation could undertake foreign operations on Bechtel’s scale without some cooperation from the U.S. government–and few companies could refuse a government request that, in return, they provide cover for intelligence agents. Given the enormous scope of Bechtel’s operations in global trouble spots–a $20-billion industrial development in Saudi Arabia, for example–it could only proceed with assurances that its relations with both Saudi and American governments were good. Where, exactly, is the line between right and wrong? [emphasis mine]

… The white elephants Bechtel scattered across the American landscape–particularly the nuclear power plants that threaten to bankrupt some of the country’s largest utility systems–are monuments to wasted talent and misdirected resources.

Finally, I get to the Roddenberry Foundation, which was founded by Gene Roddenberry’s (Star Trek) son. Here’s more from the About Us, Origin webpage,

Gene Roddenberry, creator of the Star Trek series, brought to his audiences meaningful and thought-provoking science fiction to “think, question, and challenge the status quo” with the intention of creating “a brighter future”. His work has touched countless lives and continues to entertain and inspire audiences worldwide. In 2010, Gene’s son Rod established the Roddenberry Foundation to build on his father’s legacy and philosophy of inclusion, diversity, and respect for life to drive social change and meaningfully improve the lives of people around the world.

While there are many criticisms of Mr. Roddenberry, there doesn’t seem to be anything that would be considered a serious scandal on the order of a Jeffrey Epstein or the whisper of scandal on the order of Sir Li Ka-shing or Bechtel.

Final comments

It’s a good thing when research is funded and being able to detect off-target effects from CRISPR is very good, assuming the research holds up to closer scrutiny.

As for vetting your donors, that’s tricky. Of course, Epstein was already a convicted sex offender when Ito accepted his funding for MIT but I cannot emphasize enough the amount of pressure these folks are under. Academia is always hungry for money. Hopefully this incident will introduce checks and balances in the donor process.

Needle-free tattoos, smart and otherwise

Before getting to the research news from the University of Twente (Netherlands), there’s this related event which took place on April 18, 2019 (from the Future Under Our Skin webpage (on the University of Twente website) Note: I have made some formatting changes,

Why this event?

Our skin can give information about our health, mood and surroundings. Medical and recreational tattoos have decorated humans for centuries. But we can inject other materials besides ink, such as sensing devices, nano- or bio-responsive materials. With the increased percentage of tattooed population in recent years new health challenges have emerged; but is also a unique possibility to “read from our own skin”, beyond an artistic design. 
 
We have invited scientists, innovators, entrepreneurs, dermatologists, cosmetic permanent make-up technicians, tattoo artists, philosophers, and other experts. They will share with us their vision of the current and future role our skin has for improving the quality of life.

Open Event

This event is open to students, citizens in general as well as societal and governmental organisations around the different uses of our skin. The presence of scientists, medical doctors, tattoo artists and industry representatives is guaranteed. Then, we will all explore together the potential for co-creation with healthy citizens, patients, entreprises and other stakeholders.


If you want to hear from experts and share your own ideas, feel free to come to this Open Event!
 
It is possible to take the dish of the day (‘goed gevulde noedels met kippendij en satésaus en kroepoek’) in restaurant The Gallery (same building as DesignLab) at own costs (€7,85). Of course it is also possible to eat à la carte in Grand Café 

Wanneer: : 18 april 2019
Tijd: :17:30 – 20:00
Organisator: University of Twente
Locatie: Design Lab University of Twente
Hengelosestraat 500
7521 AN Enschede

Just days before, the University of Twente announced this research in an April 16, 2019 news item on Naowerk (Note: A link has been removed),

A tattoo that is warning you for too many hours of sunlight exposure, or is alerting you for taking your medication? Next to their cosmetic role, tattoos could get new functionality using intelligent ink. That would require more precise and less invasive injection technique.

Researchers of the University of Twente now develop a micro-jet injection technology that doesn’t use needles at all. Instead, an ultrafast liquid jet with the thickness of a human hair penetrates the skin. It isn’t painful and there is less waste.

In their new publication in the American Journal of Physics (“High speed imaging of solid needle and liquid micro-jet injections”), the scientists compare both the needle and the fluid jet approach.

Here’s an image provided by the researchers which illustrates the technique they have developed,

Working principle of needle-free injection: laser heating the fluid.The growing bubble pushes out the fluid (medicine or ink) at very high speed. Courtesy: University of Twente

An April 15, 2019 University of Twente press release, which originated the news item, provides more detail about tattoos and the research leading to ‘need-free’ tattoos,

Ötzi the Iceman already had, over 5000 years ago, dozens of simple tattoos on his body, apparently for pain relief. Since the classic ‘anchor’ tattoo that sailors had on their arms, tattoos have become more and more common. About 44 million Europeans wear one or more of them. Despite its wider acceptance in society, the underlying technique didn’t change and still has health risks. One or more moving needles put ink underneath the skin surface. This is painful and can damage the skin. Apart from that, needles have to be disposed of in a responsible way, and quite some ink is wasted. The alternative that David Fernández Rivas and his colleagues are developing, doesn’t use any needles. In their new paper, they compare this new approach with classic needle technology, on an artificial skin material and using high speed images. Remarkably, according to Fernández Rivas, the classic needle technology has never been subject of research in such a thorough way, using high speed images.

Fast fluid jet

The new technique employs a laser for rapidly heating a fluid that is inside a microchannel on a glass chip. Heated above the boiling point, a vapour bubble forms and grows, pushing the liquid out at speeds up to 100 meter per second (360 km/h). The jet, about the diameter of a human hair, is capable of going through human skin. “You don’t feel much of it, no more than a mosquito bite”, say Fernandez Rivas.

The researchers did their experiments with a number of commercially available inks. Compared to a tattoo machine, the micro-jet consumes a small amount of energy. What’s more important, it minimizes skin damage and the injection efficiency is much higher, there is no loss of fluids. And there is no risk of contaminated needles. The current microjet is a single one, while tattooing is often done using multiple needles with different types or colours of ink. Also, the volume that can be ‘delivered’ by the microjet has to be increased. These are next steps in developing the needle-free technology.

Skin treatment

In today’s medical world, tattoo-resembling techniques are used for treatment of skin, masking scars, or treating hair diseases. These are other areas in which the new technique can be used, as well as in vaccination. A challenging idea is using tattoos for cosmetic purposes and as health sensors at the same time. What if ink is light-sensitive or responds to certain substances that are present in the skin or in sweat?

On this new approach, scientists, students, entrepreneurs and tattoo artists join a special event ‘The future under our skin’, organized by David Fernandez Rivas.

Research has been done in the Mesoscale Chemical Systems group, part of UT’s MESA+ Institute.

Here’s a link to an d a citation for the paper,

High speed imaging of solid needle and liquid micro-jet injections by Loreto Oyarte Gálveza, Maria Brió Pérez, and David Fernández Rivas. Journal of Applied Physics 125, 144504 (2019); Volume 125, Issue 14 DOI: 10.1063/1.5074176 https://doi.org/10.1063/1.5074176 Free Published Online: 09 April 2019

This paper appears to be open access.

Cyborgs based on melanin circuits

Pigments for biocompatible electronics? According to a March 26, 2019 news item on Nanowerk this is a distinct possibility (Note: A link has been removed),

The dark brown melanin pigment, eumelanin, colors hair and eyes, and protects our skin from sun damage. It has also long been known to conduct electricity, but too little for any useful application – until now.

In a landmark study published in Frontiers in Chemistry (“Evidence of Unprecedented High Electronic Conductivity in Mammalian Pigment Based Eumelanin Thin Films After Thermal Annealing in Vacuum”), Italian researchers subtly modified the structure of eumelanin by heating it in a vacuum.

“Our process produced a billion-fold increase in the electrical conductivity of eumelanin,” say study senior authors Dr. Alessandro Pezzella of University of Naples Federico II and Dr. Paolo Tassini of Italian National Agency for New Technologies, Energy and Sustainable Economic Development. “This makes possible the long-anticipated design of melanin-based electronics, which can be used for implanted devices due to the pigment’s biocompatibility.”

This is a rather dreamy image to illustrate the point,

Despite extensive research on the structure of melanin, nobody has yet managed to harness its potential in implantable electronics. Image: Shutterstock. [downloaded from https://blog.frontiersin.org/2019/03/26/will-cyborgs-circuits-be-made-from-melanin/]

A March 26, 2019 Frontiers in Chemistry (journal) press release (also on EurekAlert), which originated the news item, expands on the theme,

A young Pezzella had not even begun school when scientists first discovered that a type of melanin can conduct electricity. Excitement quickly rose around the discovery because eumelanin – the dark brown pigment found in hair, skin and eyes – is fully biocompatible.

“Melanins occur naturally in virtually all forms of life. They are non-toxic and do not elicit an immune reaction,” explains Pezzella. “Out in the environment, they are also completely biodegradable.”

Decades later, and despite extensive research on the structure of melanin, nobody has managed to harness its potential in implantable electronics.

“To date, conductivity of synthetic as well as natural eumelanin has been far too low for valuable applications,” he adds.

Some researchers tried to increase the conductivity of eumelanin by combining it with metals, or super-heating it into a graphene-like material – but what they were left with was not truly the biocompatible conducting material promised.

Determined to find the real deal, the Neapolitan group considered the structure of eumelanin.

“All of the chemical and physical analyses of eumelanin paint the same picture – of electron-sharing molecular sheets, stacked messily together. The answer seemed obvious: neaten the stacks and align the sheets, so they can all share electrons – then the electricity will flow.”

This process, called annealing, is used already to increase electrical conductivity and other properties in materials such as metals.

For the first time, the researchers put films of synthetic eumelanin through an annealing process under high vacuum to neaten them up – a little like hair straightening, but with only the pigment.

“We heated these eumelanin films – no thicker than a bacterium – under vacuum conditions, from 30 min up to 6 hours,” describes Tassini. “We call the resulting material High Vacuum Annealed Eumelanin, HVAE.”

The annealing worked wonders for eumelanin: the films slimmed down by more than half, and picked up quite a tan.

“The HVAE films were now dark brown and about as thick as a virus,” Tassini reports.

Crucially, the films had not simply been burnt to a crisp.

“All our various analyses agree that these changes reflect reorganization of eumelanin molecules from a random orientation to a uniform, electron-sharing stack. The annealing temperatures were too low to break up the eumelanin, and we detected no combustion to elemental carbon.”

Having achieved the intended structural changes to eumelanin, the researchers proved their hypothesis in spectacular fashion.

“The conductivity of the films increased billion-fold to an unprecedented value of over 300 S/cm, after annealing at 600°C for 2 hours,” Pezzella confirms.

Although well short of most metal conductors – copper has a conductivity of around 6 x 107 S/cm – this finding launches eumelanin well into a useful range for bioelectronics.

What’s more, the conductivity of HVAE was tunable according to the annealing conditions.

“The conductivity of the films increased with increasing temperature, from 1000-fold at 200°C. This opens the possibility of tailoring eumelanin for a wide range of applications in organic electronics and bioelectronics. It also strongly supports the conclusion from structural analysis that annealing reorganized the films, rather than burning them.”

There is one potential dampener: immersion of the films in water results in a marked decrease in conductivity.

“This contrasts with untreated eumelanin which, albeit in a much lower range, becomes more conductive with hydration (humidity) because it conducts electricity via ions as well as electrons. Further research is needed to fully understand the ionic vs. electronic contributions in eumelanin conductivity, which could be key to how eumelanin is used practically in implantable electronics.” concludes Pezzella.

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

Evidence of Unprecedented High Electronic Conductivity in Mammalian Pigment Based Eumelanin Thin Films After Thermal Annealing in Vacuum by Ludovico Migliaccio, Paola Manini, Davide Altamura, Cinzia Giannini, Paolo Tassini, Maria Grazia Maglione, Carla Minarini, and Alessandro Pezzella. Front. Chem., 26 March 2019 DOI: https://doi.org/10.3389/fchem.2019.00162

This paper is open access.

Ankle exoskeletons good for people who need to do a lot of walking or running on the job

For people who need a little extra ankle support, this might be useful in the, hopefully, not too distant future.

The new ankle exoskeleton design integrates into the shoe and under clothing. Submitted photo. Courtesy of Vanderbilt University Credit: Matthew Yandell

A March 22, 2019 news item on ScienceDaily announces this latest research,

A new lightweight, low-profile and inexpensive ankle exoskeleton could be widely used among elderly people, those with impaired lower-leg muscle strength and workers whose jobs require substantial walking or running.

Developed by Vanderbilt mechanical engineers, the device is believed to be the first ankle exoskeleton that could be worn under clothes without restricting motion. It does not require additional components such as batteries or actuators carried on the back or waist.

A March 21, 2019 Venderbilt University news release (also on EurekAlert but published March 22, 2019), offers more detail,

The study, published online by IEEE Transactions on Neural Systems & Rehabilitation Engineering, builds on a successful and widely cited ankle exoskeleton concept from other researchers in 2015.

“We’ve shown how an unpowered ankle exoskeleton could be redesigned to fit under clothing and inside/under shoes so it more seamlessly integrates into daily life,” said Matt Yandell, a mechanical engineering Ph.D. student and lead author of the study.

In a significant design advancement, the team invented an unpowered friction clutch mechanism that fits under the foot or shoe and is no thicker than a typical shoe insole. The complete device, which includes a soft shank sleeve and assistive spring, weighs just over one pound.

The unpowered ankle exoskeleton costs less than $100 to fabricate, without factoring in optimized design for manufacturing and economies of scale.

“Our design is lightweight, low profile, quiet, uses no motor or batteries, it is low cost to manufacture, and naturally adapts to different walking speeds to assist the ankle muscles,” said Karl Zelik, assistant professor of mechanical engineering and senior author on the study.

Zelik will be presenting this work next week at the Wearable Robotics Association Conference in Phoenix, Arizona [March 26-28, 2019].

The potential applications are broad, from helping aging people stay active to assisting recreational walkers, hikers or runners, he said.

“It could also help reduce fatigue in occupations that involve lots of walking, such as postal and warehouse workers, and soldiers in the field,” Zelik said.

Joshua Tacca, BE’18, also is a co-author. He is now a graduate student in the Integrative Physiology Department at the University of Colorado-Boulder. Several other Vanderbilt undergraduate engineering students also contributed to the device design and pilot testing.

I wonder if this device requires a particular kind of shoe. In any event, here’s a link to and a citation for the study,

Design of a Low Profile, Unpowered Ankle Exoskeleton That Fits Under Clothes: Overcoming Practical Barriers to Widespread Societal Adoption by Matthew B. Yandell, Joshua R. Tacca, and Karl E. Zelik. IEEE Transactions on Neural Systems & Rehabilitation Engineering 2019; 1 DOI: 10.1109/TNSRE.2019.2904924 Date of Publication: 14 March 2019 (early access)

This study appears to be behind a paywall

Iron oxide nanoparticles for artificial skin with super powers

A January 28, 2019 news item on ScienceDaily describes the possibilities for a skin replacement material,

A new type of sensor could lead to artificial skin that someday helps burn victims ‘feel’ and safeguards the rest of us, University of Connecticut researchers suggest in a paper in Advanced Materials.

Our skin’s ability to perceive pressure, heat, cold, and vibration is a critical safety function that most people take for granted. But burn victims, those with prosthetic limbs, and others who have lost skin sensitivity for one reason or another, can’t take it for granted, and often injure themselves unintentionally.

Chemists Islam Mosa from UConn [University of Connecticut], and James Rusling from UConn and UConn Health, along with University of Toronto engineer Abdelsalam Ahmed, wanted to create a sensor that can mimic the sensing properties of skin. Such a sensor would need to be able to detect pressure, temperature, and vibration. But perhaps it could do other things too, the researchers thought.

“It would be very cool if it had abilities human skin does not; for example, the ability to detect magnetic fields, sound waves, and abnormal behaviors,” said Mosa.

A January 22, 2019 UConn news release (also on EurekAlert but dated January 28, 2019), which originated the news item, give more detail about the work,

Mosa and his colleagues created such a sensor with a silicone tube wrapped in a copper wire and filled with a special fluid made of tiny particles of iron oxide just one billionth of a meter long, called nanoparticles. The nanoparticles rub around the inside of the silicone tube and create an electric current. The copper wire surrounding the silicone tube picks up the current as a signal. When this tube is bumped by something experiencing pressure, the nanoparticles move and the electric signal changes. Sound waves also create waves in the nanoparticle fluid, and the electric signal changes in a different way than when the tube is bumped.

The researchers found that magnetic fields alter the signal too, in a way distinct from pressure or sound waves. Even a person moving around while carrying the sensor changes the electrical current, and the team found they could distinguish between the electrical signals caused by walking, running, jumping, and swimming.

Metal skin might sound like a superhero power, but this skin wouldn’t make the wearer Colossus from the X-men. Rather, Mosa and his colleagues hope it could help burn victims “feel” again, and perhaps act as an early warning for workers exposed to dangerously high magnetic fields. Because the rubber exterior is completely sealed and waterproof, it could also serve as a wearable monitor to alert parents if their child fell into deep water in a pool, for example.

“The inspiration was to make something durable that would last for a very long time, and could detect multiple hazards,” Mosa says. The team has yet to test the sensor for its response to heat and cold, but they suspect it will work for those as well. The next step is to make the sensor in a flat configuration, more like skin, and see if it still works.

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

An Ultra‐Shapeable, Smart Sensing Platform Based on a Multimodal Ferrofluid‐Infused Surface by Abdelsalam Ahmed, Islam Hassan, Islam M. Mosa, Esraa Elsanadidy, Mohamed Sharafeldin, James F. Rusling, Shenqiang Ren. Advanced Materials DOI: https://doi.org/10.1002/adma.201807201 First published: 28 January 2019

This paper is behind a paywall.

Greater mortality for the CRISPR twins Lulu and Nana?

Every time I think this CRISPR (clustered regularly interspaced short palindromic repeats) story is winding down, something new happens. The latest (I think) is in a June 3, 2019 news item on ScienceDaily,

A genetic mutation that a Chinese scientist attempted to create in twin babies born last year, ostensibly to help them fend off HIV infection, is also associated with a 21% increase in mortality in later life, according to an analysis by University of California, Berkeley, scientists.

The researchers scanned more than 400,000 genomes and associated health records contained in a British database, UK Biobank, and found that people who had two mutated copies of the gene had a significantly higher death rate between ages 41 and 78 than those with one or no copies.

Sarah Zhang’s June 3, 2019 article for The Atlantic provides an overview of the situation before exploring the current controversy,

In the 1990s, virologists in New York learned of a genetic mutation that would become one of the most famous ever discovered. They found it in a man who could not be infected with HIV. He turned out to be missing just 32 letters in a gene called CCR5, and remarkably, it was enough to make him resistant to the virus killing so many others. About 1 percent of people of European descent carry two copies of this mutation, now known as CCR5-Δ32.

In 2018, a Chinese scientist named He Jiankui made the mutation infamous when he attempted to use CRISPR to edit CCR5-Δ32 (pronounced “CCR5-delta-32”) into human embryos. He chose this mutation, he said, because the babies’ father was HIV-positive, and he wanted to make the resulting twin girls resistant to the virus. CCR5-Δ32 is also, after all, one of the most studied mutations.

He’s work immediately provoked outrage among scientists, who knew enough to know how much they did not know about the risks of altering CCR5. And now a new study suggests that CCR5-Δ32 is indeed harmful overall.

The girls’ CCR5 genes were altered, according to data He presented, but they do not exactly match the 32-letter deletion; it’s unclear whether either of them is actually resistant to HIV. Even if they were unable to get HIV, a body of research already suggested that CCR5-Δ32 made people more vulnerable to the flu and West Nile virus. A “good” mutation in the context of HIV can be “bad” in another context. No one knew, exactly, the net effect of a CCR5-Δ32 mutation.

For some reason, Zhang makes no mention of the possibly enhanced cognitive abilities that the twins may have as a consequence of the gene editing assuming that He Jiankui successfully edited the genes. (To my knowledge, the results and data have not been released for review by colleagues.)

Regardless, Zhang’s article provides a handy overview and update.

For anyone who’s interested in more detail about this latest research into mortality and CCR5, there’s a June 3, 2019 University of California at Berkeley news release (also on EurekAlert) by Robert Sanders, which also originated the ScienceDaily news item, details the latest research,

Previous studies have associated two mutated copies of the gene, CCR5, with a fourfold increase in the death rate after influenza infection, and the higher overall mortality rate may reflect this greater susceptibility to death from the flu. But the researchers say there could be any number of explanations, since the protein that CCR5 codes for, and which no longer works in those having the mutation in both copies of the gene, is involved in many body functions.

“Beyond the many ethical issues involved with the CRISPR babies, the fact is that, right now, with current knowledge, it is still very dangerous to try to introduce mutations without knowing the full effect of what those mutations do,” said Rasmus Nielsen, a UC Berkeley professor of integrative biology. “In this case, it is probably not a mutation that most people would want to have. You are actually, on average, worse off having it.”

“Because one gene could affect multiple traits, and because, depending on the environment, the effects of a mutation could be quite different, I think there can be many uncertainties and unknown effects in any germline editing,” said postdoctoral fellow Xinzhu “April” Wei.
Wei is first author and Nielsen is senior author of a paper describing the research that will appear online on Monday, June 3, in the journal Nature Medicine.

Mutation prevents HIV infection

The gene CCR5 codes for a protein that, among other things, sits on the surface of immune cells and helps some strains of HIV, including the most common ones, to enter and infect them. Jiankui He, the Chinese scientist who last November shocked the world by announcing he had experimented with CCR5 on at least two babies, said he wanted to introduce a mutation in the gene that would prevent this. Naturally-occurring mutations that disable the protein are rare in Asians, but a mutation found in about 11% of Northern Europeans protects them against HIV infection.

The genetic mutation, ∆32 (Delta 32), refers to a missing 32-base-pair segment in the CCR5 gene. This mutation interferes with the localization on the cell surface of the protein for which CCR5 codes, thwarting HIV binding and infection. He was unable to duplicate the natural mutation, but appears to have generated a similar deletion that would also inactivate the protein. One of the twin babies reportedly had one copy of CCR5 modified by CRISPR-Cas9 gene editing, while the other baby had both copies edited.

But inactivating a protein found in all humans and most animals is likely to have negative effects, Nielsen said, especially when done to both copies of the gene — a so-called homozygous mutation

“Here is a functional protein that we know has an effect in the organism, and it is well-conserved among many different species, so it is likely that a mutation that destroys the protein is, on average, not good for you,” he said. “Otherwise, evolutionary mechanisms would have destroyed that protein a long time ago.”

After He’s experiment became public, Nielsen and Wei, who study current genetic variation to understand the origin of human, animal and plant traits, decided to investigate the effect of the CCR5-∆32 mutation using data from UK Biobank. The database houses genomic information on a half million U.K. citizens that is linked to their medical records. The genomic information is much like that acquired by Ancestry.com and 23andMe: details on nearly a million individual variations in the genetic sequence, so-called single nucleotide polymorphisms (SNPs).

Two independent measures indicated a higher mortality rate for those with two mutated genes. Fewer people than expected with two mutations enrolled in the database, indicating that they had died at a higher rate than the general population. And fewer than expected survived from ages 40 to 78.

“Both the proportions before enrollment and the survivorship after enrollment tell the same story, which is that you have lower survivability or higher mortality if you have two copies of the mutation,” Nielsen said. “There is simply a deficiency of individuals with two copies.”

Because the ∆32 mutation is relatively common in Northern Europeans, it must have been favored by natural selection at some point, Nielsen said, though probably not to protect against HIV, since the virus has circulated among humans only since the 1980s.

Wei said that some evidence links the mutation to increased survival after stroke and protection against smallpox and flaviviruses, a group that includes the dengue, Zika and West Nile viruses.

Despite these possible benefits, the potential unintended effects of creating genetic mutations, in both adult somatic cells and in embryonic, germline cells, argue for caution, the researchers said.

“I think there are a lot of things that are unknown at the current stage about genes’ functions,” Wei said. “The CRISPR technology is far too dangerous to use right now for germline editing.”

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

CCR5-∆32 is deleterious in the homozygous state in humans by Xinzhu Wei & Rasmus Nielsen. Nature Medicine (2019) DOI: https://doi.org/10.1038/s41591-019-0459-6 Published 03 June 2019

This paper is behind a paywall.

For those who have an insatiable appetite for detail, there’s my November 28, 2018 posting which covers what happened when the CRISPR twins, Lulu and Nana, was first announced, along with a few updates to January 23, 2019. The May 17, 2019 posting covers the news of possible cognitive advantages for the CCR5-Δ32 gene-edited twins and explores some of the social implications.

Two approaches to memristors

Within one day of each other in October 2018, two different teams working on memristors with applications to neuroprosthetics and neuromorphic computing (brainlike computing) announced their results.

Russian team

An October 15, 2018 (?) Lobachevsky University press release (also published on October 15, 2018 on EurekAlert) describes a new approach to memristors,

Biological neurons are coupled unidirectionally through a special junction called a synapse. An electrical signal is transmitted along a neuron after some biochemical reactions initiate a chemical release to activate an adjacent neuron. These junctions are crucial for cognitive functions, such as perception, learning and memory.

A group of researchers from Lobachevsky University in Nizhny Novgorod investigates the dynamics of an individual memristive device when it receives a neuron-like signal as well as the dynamics of a network of analog electronic neurons connected by means of a memristive device. According to Svetlana Gerasimova, junior researcher at the Physics and Technology Research Institute and at the Neurotechnology Department of Lobachevsky University, this system simulates the interaction between synaptically coupled brain neurons while the memristive device imitates a neuron axon.

A memristive device is a physical model of Chua’s [Dr. Leon Chua, University of California at Berkeley; see my May 9, 2008 posting for a brief description Dr. Chua’s theory] memristor, which is an electric circuit element capable of changing its resistance depending on the electric signal received at the input. The device based on a Au/ZrO2(Y)/TiN/Ti structure demonstrates reproducible bipolar switching between the low and high resistance states. Resistive switching is determined by the oxidation and reduction of segments of conducting channels (filaments) in the oxide film when voltage with different polarity is applied to it. In the context of the present work, the ability of a memristive device to change conductivity under the action of pulsed signals makes it an almost ideal electronic analog of a synapse.

Lobachevsky University scientists and engineers supported by the Russian Science Foundation (project No.16-19-00144) have experimentally implemented and theoretically described the synaptic connection of neuron-like generators using the memristive interface and investigated the characteristics of this connection.

“Each neuron is implemented in the form of a pulse signal generator based on the FitzHugh-Nagumo model. This model provides a qualitative description of the main neurons’ characteristics: the presence of the excitation threshold, the presence of excitable and self-oscillatory regimes with the possibility of a changeover. At the initial time moment, the master generator is in the self-oscillatory mode, the slave generator is in the excitable mode, and the memristive device is used as a synapse. The signal from the master generator is conveyed to the input of the memristive device, the signal from the output of the memristive device is transmitted to the input of the slave generator via the loading resistance. When the memristive device switches from a high resistance to a low resistance state, the connection between the two neuron-like generators is established. The master generator goes into the oscillatory mode and the signals of the generators are synchronized. Different signal modulation mode synchronizations were demonstrated for the Au/ZrO2(Y)/TiN/Ti memristive device,” – says Svetlana Gerasimova.

UNN researchers believe that the next important stage in the development of neuromorphic systems based on memristive devices is to apply such systems in neuroprosthetics. Memristive systems will provide a highly efficient imitation of synaptic connection due to the stochastic nature of the memristive phenomenon and can be used to increase the flexibility of the connections for neuroprosthetic purposes. Lobachevsky University scientists have vast experience in the development of neurohybrid systems. In particular, a series of experiments was performed with the aim of connecting the FitzHugh-Nagumo oscillator with a biological object, a rat brain hippocampal slice. The signal from the electronic neuron generator was transmitted through the optic fiber communication channel to the bipolar electrode which stimulated Schaffer collaterals (axons of pyramidal neurons in the CA3 field) in the hippocampal slices. “We are going to combine our efforts in the design of artificial neuromorphic systems and our experience of working with living cells to improve flexibility of prosthetics,” concludes S. Gerasimova.

The results of this research were presented at the 38th International Conference on Nonlinear Dynamics (Dynamics Days Europe) at Loughborough University (Great Britain).

This diagram illustrates an aspect of the work,

Caption: Schematic of electronic neurons coupling via a memristive device. Credit: Lobachevsky University

US team

The American Institute of Physics (AIP) announced the publication of a ‘memristor paper’ by a team from the University of Southern California (USC) in an October 16, 2018 news item on phys.org,

Just like their biological counterparts, hardware that mimics the neural circuitry of the brain requires building blocks that can adjust how they synapse, with some connections strengthening at the expense of others. One such approach, called memristors, uses current resistance to store this information. New work looks to overcome reliability issues in these devices by scaling memristors to the atomic level.

An October 16, 2018 AIP news release (also on EurekAlert), which originated the news item, delves further into the particulars of this particular piece of memristor research,

A group of researchers demonstrated a new type of compound synapse that can achieve synaptic weight programming and conduct vector-matrix multiplication with significant advances over the current state of the art. Publishing its work in the Journal of Applied Physics, from AIP Publishing, the group’s compound synapse is constructed with atomically thin boron nitride memristors running in parallel to ensure efficiency and accuracy.

The article appears in a special topic section of the journal devoted to “New Physics and Materials for Neuromorphic Computation,” which highlights new developments in physical and materials science research that hold promise for developing the very large-scale, integrated “neuromorphic” systems of tomorrow that will carry computation beyond the limitations of current semiconductors today.

“There’s a lot of interest in using new types of materials for memristors,” said Ivan Sanchez Esqueda, an author on the paper. “What we’re showing is that filamentary devices can work well for neuromorphic computing applications, when constructed in new clever ways.”

Current memristor technology suffers from a wide variation in how signals are stored and read across devices, both for different types of memristors as well as different runs of the same memristor. To overcome this, the researchers ran several memristors in parallel. The combined output can achieve accuracies up to five times those of conventional devices, an advantage that compounds as devices become more complex.

The choice to go to the subnanometer level, Sanchez said, was born out of an interest to keep all of these parallel memristors energy-efficient. An array of the group’s memristors were found to be 10,000 times more energy-efficient than memristors currently available.

“It turns out if you start to increase the number of devices in parallel, you can see large benefits in accuracy while still conserving power,” Sanchez said. Sanchez said the team next looks to further showcase the potential of the compound synapses by demonstrating their use completing increasingly complex tasks, such as image and pattern recognition.

Here’s an image illustrating the parallel artificial synapses,

Caption: Hardware that mimics the neural circuitry of the brain requires building blocks that can adjust how they synapse. One such approach, called memristors, uses current resistance to store this information. New work looks to overcome reliability issues in these devices by scaling memristors to the atomic level. Researchers demonstrated a new type of compound synapse that can achieve synaptic weight programming and conduct vector-matrix multiplication with significant advances over the current state of the art. They discuss their work in this week’s Journal of Applied Physics. This image shows a conceptual schematic of the 3D implementation of compound synapses constructed with boron nitride oxide (BNOx) binary memristors, and the crossbar array with compound BNOx synapses for neuromorphic computing applications. Credit: Ivan Sanchez Esqueda

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

Efficient learning and crossbar operations with atomically-thin 2-D material compound synapses by Ivan Sanchez Esqueda, Huan Zhao and Han Wang. The article will appear in the Journal of Applied Physics Oct. 16, 2018 (DOI: 10.1063/1.5042468).

This paper is behind a paywall.

*Title corrected from ‘Two approaches to memristors featuring’ to ‘Two approaches to memristors’ on May 31, 2019 at 1455 hours PDT.

Genes, intelligence, Chinese CRISPR (clustered regularly interspaced short palindromic repeats) babies, and other children

This started out as an update and now it’s something else. What follows is a brief introduction to the Chinese CRISPR twins; a brief examination of parents, children, and competitiveness; and, finally, a suggestion that genes may not be what we thought. I also include a discussion about how some think scientists should respond when they know beforehand that one of their kin is crossing an ethical line. Basically, this is a complex topic and I am attempting to interweave a number of competing lines of query into one narrative about human nature and the latest genetics obsession.

Introduction to the Chinese CRISPR twins

Back in November 2018 I covered the story about the Chinese scientist, He Jiankui , who had used CRISPR technology to edit genes in embryos that were subsequently implanted in a waiting mother (apparently there could be as many as eight mothers) with the babies being brought to term despite an international agreement (of sorts) not to do that kind of work. At this time, we know of the twins, Lulu and Nana but, by now, there may be more babies. (I have much more detail about the initial controversies in my November 28, 2018 posting.)

It seems the drama has yet to finish unfolding. There may be another consequence of He’s genetic tinkering.

Could the CRISPR babies, Lulu and Nana, have enhanced cognitive abilities?

Yes, according to Antonio Regalado’s February 21, 2019 article (behind a paywall) for MIT’s (Massachusetts Institute of Technology) Technology Review, those engineered babies may have enhanced abilities for learning and remembering.

For those of us who can’t get beyond the paywall, others have been successful. Josh Gabbatiss in his February 22, 2019 article for independent.co.uk provides some detail,

The world’s first gene edited babies may have had their brains unintentionally altered – and perhaps cognitively enhanced – as a result of the controversial treatment undertaken by a team of Chinese scientists.

Dr He Jiankui and his team allegedly deleted a gene from a number of human embryos before implanting them in their mothers, a move greeted with horror by the global scientific community. The only known successful birth so far is the case of twin girls Nana and Lulu.

The now disgraced scientist claimed that he removed a gene called CCR5 [emphasis mine] from their embroyos in an effort to make the twins resistant to infection by HIV.

But another twist in the saga has now emerged after a new paper provided more evidence that the impact of CCR5 deletion reaches far beyond protection against dangerous viruses – people who naturally lack this gene appear to recover more quickly from strokes, and even go further in school. [emphasis mine]

Dr Alcino Silva, a neurobiologist at the University of California, Los Angeles, who helped identify this role for CCR5 said the work undertaken by Dr Jiankui likely did change the girls’ brains.

“The simplest interpretation is that those mutations will probably have an impact on cognitive function in the twins,” he told the MIT Technology Review.

The connection immediately raised concerns that the gene was targeted due to its known links with intelligence, which Dr Silva said was his immediate response when he heard the news.

… there is no evidence that this was Dr Jiankui’s goal and at a press conference organised after the initial news broke, he said he was aware of the work but was “against using genome editing for enhancement”.

..

Claire Maldarelli’s February 22, 2019 article for Popular Science provides more information about the CCR5 gene/protein (Note: Links have been removed),

CCR5 is a protein that sits on the surface of white blood cells, a major component of the human immune system. There, it allows HIV to enter and infect a cell. A chunk of the human population naturally carries a mutation that makes CCR5 nonfunctional (one study found that 10 percent of Europeans have this mutation), which often results in a smaller protein size and one that isn’t located on the outside of the cell, preventing HIV from ever entering and infecting the human immune system.

The goal of the Chinese researchers’ work, led by He Jiankui of the Southern University of Science and Technology located in Shenzhen, was to tweak the embryos’ genome to lack CCR5, ensuring the babies would be immune to HIV.

But genetics is rarely that simple.

In recent years, the CCR5 gene has been a target of ongoing research, and not just for its relationship to HIV. In an attempt to understand what influences memory formation and learning in the brain, a group of researchers at UCLA found that lowering the levels of CCR5 production enhanced both learning and memory formation. This connection led those researchers to think that CCR5 could be a good drug target for helping stroke victims recover: Relearning how to move, walk, and talk is a key component to stroke rehabilitation.

… promising research, but it begs the question: What does that mean for the babies who had their CCR5 genes edited via CRISPR prior to their birth? Researchers speculate that the alternation will have effects on the children’s cognitive functioning. …

John Loeffler’s February 22, 2019 article for interestingengineering.com notes that there are still many questions about He’s (scientist’s name) research including, did he (pronoun) do what he claimed? (Note: Links have been removed),

Considering that no one knows for sure whether He has actually done as he and his team claim, the swiftness of the condemnation of his work—unproven as it is—shows the sensitivity around this issue.

Whether He did in fact edit Lulu and Nana’s genes, it appears he didn’t intend to impact their cognitive capacities. According to MIT Technology Review, not a single researcher studying CCR5’s role in intelligence was contacted by He, even as other doctors and scientists were sought out for advice about his project.

This further adds to the alarm as there is every expectation that He should have known about the connection between CCR5 and cognition.

At a gathering of gene-editing researchers in Hong Kong two days after the birth of the potentially genetically-altered twins was announced, He was asked about the potential impact of erasing CCR5 from the twins DNA on their mental capacity.

He responded that he knew about the potential cognitive link shown in Silva’s 2016 research. “I saw that paper, it needs more independent verification,” He said, before adding that “I am against using genome editing for enhancement.”

The problem, as Silva sees it, is that He may be blazing the trail for exactly that outcome, whether He intends to or not. Silva says that after his 2016 research was published, he received an uncomfortable amount of attention from some unnamed, elite Silicon Valley leaders who seem to be expressing serious interest in using CRISPR to give their children’s brains a boost through gene editing. [emphasis mine]

As such, Silva can be forgiven for not quite believing He’s claims that he wasn’t intending to alter the human genome for enhancement. …

The idea of designer babies isn’t new. As far back as Plato, the thought of using science to “engineer” a better human has been tossed about, but other than selective breeding, there really hasn’t been a path forward.

In the late 1800s, early 1900s, Eugenics made a real push to accomplish something along these lines, and the results were horrifying, even before Nazism. After eugenics mid-wifed the Holocaust in World War II, the concept of designer children has largely been left as fodder for science fiction since few reputable scientists would openly declare their intention to dabble in something once championed and pioneered by the greatest monsters of the 20th century.

Memories have faded though, and CRISPR significantly changes this decades-old calculus. CRISPR makes it easier than ever to target specific traits in order to add or subtract them from an embryos genetic code. Embryonic research is also a diverse enough field that some scientist could see pioneering designer babies as a way to establish their star power in academia while getting their names in the history books, [emphasis mine] all while working in relative isolation. They only need to reveal their results after the fact and there is little the scientific community can do to stop them, unfortunately.

When He revealed his research and data two days after announcing the births of Lulu and Nana, the gene-scientists at the Hong Kong conference were not all that impressed with the quality of He’s work. He has not provided access for fellow researchers to either his data on Lulu, Nana, and their family’s genetic data so that others can verify that Lulu and Nana’s CCR5 genes were in fact eliminated.

This almost rudimentary verification and validation would normally accompany a major announcement such as this. Neither has He’s work undergone a peer-review process and it hasn’t been formally published in any scientific journal—possibly for good reason.

Researchers such as Eric Topol, a geneticist at the Scripps Research Institute, have been finding several troubling signs in what little data He has released. Topol says that the editing itself was not precise and show “all kinds of glitches.”

Gaetan Burgio, a geneticist at the Australian National University, is likewise unimpressed with the quality of He’s work. Speaking of the slides He showed at the conference to support his claim, Burgio calls it amateurish, “I can believe that he did it because it’s so bad.”

Worse of all, its entirely possible that He actually succeeded in editing Lulu and Nana’s genetic code in an ad hoc, unethical, and medically substandard way. Sadly, there is no shortage of families with means who would be willing to spend a lot of money to design their idea of a perfect child, so there is certainly demand for such a “service.”

It’s nice to know (sarcasm icon) that the ‘Silicon Valley elite’ are willing to volunteer their babies for scientific experimentation in a bid to enhance intelligence.

The ethics of not saying anything

Natalie Kofler, a molecular biologist, wrote a February 26, 2019 Nature opinion piece and call to action on the subject of why scientists who were ‘in the know’ remained silent about He’s work prior to his announcements,

Millions [?] were shocked to learn of the birth of gene-edited babies last year, but apparently several scientists were already in the know. Chinese researcher He Jiankui had spoken with them about his plans to genetically modify human embryos intended for pregnancy. His work was done before adequate animal studies and in direct violation of the international scientific consensus that CRISPR–Cas9 gene-editing technology is not ready or appropriate for making changes to humans that could be passed on through generations.

Scholars who have spoken publicly about their discussions with He described feeling unease. They have defended their silence by pointing to uncertainty over He’s intentions (or reassurance that he had been dissuaded), a sense of obligation to preserve confidentiality and, perhaps most consistently, the absence of a global oversight body. Others who have not come forward probably had similar rationales. But He’s experiments put human health at risk; anyone with enough knowledge and concern could have posted to blogs or reached out to their deans, the US National Institutes of Health or relevant scientific societies, such as the Association for Responsible Research and Innovation in Genome Editing (see page 440). Unfortunately, I think that few highly established scientists would have recognized an obligation to speak up.

I am convinced that this silence is a symptom of a broader scientific cultural crisis: a growing divide between the values upheld by the scientific community and the mission of science itself.

A fundamental goal of the scientific endeavour is to advance society through knowledge and innovation. As scientists, we strive to cure disease, improve environmental health and understand our place in the Universe. And yet the dominant values ingrained in scientists centre on the virtues of independence, ambition and objectivity. That is a grossly inadequate set of skills with which to support a mission of advancing society.

Editing the genes of embryos could change our species’ evolutionary trajectory. Perhaps one day, the technology will eliminate heritable diseases such as sickle-cell anaemia and cystic fibrosis. But it might also eliminate deafness or even brown eyes. In this quest to improve the human race, the strengths of our diversity could be lost, and the rights of already vulnerable populations could be jeopardized.

Decisions about how and whether this technology should be used will require an expanded set of scientific virtues: compassion to ensure its applications are designed to be just, humility to ensure its risks are heeded and altruism to ensure its benefits are equitably distributed.

Calls for improved global oversight and robust ethical frameworks are being heeded. Some researchers who apparently knew of He’s experiments are under review by their universities. Chinese investigators have said He skirted regulations and will be punished. But punishment is an imperfect motivator. We must foster researchers’ sense of societal values.

Fortunately, initiatives popping up throughout the scientific community are cultivating a scientific culture informed by a broader set of values and considerations. The Scientific Citizenship Initiative at Harvard University in Cambridge, Massachusetts, trains scientists to align their research with societal needs. The Summer Internship for Indigenous Peoples in Genomics offers genomics training that also focuses on integrating indigenous cultural perspectives into gene studies. The AI Now Institute at New York University has initiated a holistic approach to artificial-intelligence research that incorporates inclusion, bias and justice. And Editing Nature, a programme that I founded, provides platforms that integrate scientific knowledge with diverse cultural world views to foster the responsible development of environmental genetic technologies.

Initiatives such as these are proof [emphasis mine] that science is becoming more socially aware, equitable and just. …

I’m glad to see there’s work being done on introducing a broader set of values into the scientific endeavour. That said, these programmes seem to be voluntary, i.e., people self-select, and those most likely to participate in these programmes are the ones who might be inclined to integrate social values into their work in the first place.

This doesn’t address the issue of how to deal with unscrupulous governments pressuring scientists to create designer babies along with hypercompetitive and possibly unscrupulous individuals such as the members of the ‘Silicon Valley insiders mentioned in Loeffler’s article, teaming up with scientists who will stop at nothing to get their place in the history books.

Like Kofler, I’m encouraged to see these programmes but I’m a little less convinced that they will be enough. What form it might take I don’t know but I think something a little more punitive is also called for.

CCR5 and freedom from HIV

I’ve added this piece about the Berlin and London patients because, back in November 2018, I failed to realize how compelling the idea of eradicating susceptibility to AIDS/HIV might be. Reading about some real life remissions helped me to understand some of He’s stated motivations a bit better. Unfortunately, there’s a major drawback described here in a March 5, 2019 news item on CBC (Canadian Broadcasting Corporation) online news attributed to Reuters,

An HIV-positive man in Britain has become the second known adult worldwide to be cleared of the virus that causes AIDS after he received a bone marrow transplant from an HIV-resistant donor, his doctors said.

The therapy had an early success with a man known as “the Berlin patient,” Timothy Ray Brown, a U.S. man treated in Germany who is 12 years post-transplant and still free of HIV. Until now, Brown was the only person thought to have been cured of infection with HIV, the virus that causes AIDS.

Such transplants are dangerous and have failed in other patients. They’re also impractical to try to cure the millions already infected.

In the latest case, the man known as “the London patient” has no trace of HIV infection, almost three years after he received bone marrow stem cells from a donor with a rare genetic mutation that resists HIV infection — and more than 18 months after he came off antiretroviral drugs.

“There is no virus there that we can measure. We can’t detect anything,” said Ravindra Gupta, a professor and HIV biologist who co-led a team of doctors treating the man.

Gupta described his patient as “functionally cured” and “in remission,” but cautioned: “It’s too early to say he’s cured.”

Gupta, now at Cambridge University, treated the London patient when he was working at University College London. The man, who has asked to remain anonymous, had contracted HIV in 2003, Gupta said, and in 2012 was also diagnosed with a type of blood cancer called Hodgkin’s lymphoma.

In 2016, when he was very sick with cancer, doctors decided to seek a transplant match for him.

“This was really his last chance of survival,” Gupta told Reuters.

Doctors found a donor with a gene mutation known as CCR5 delta 32, which confers resistance to HIV. About one per cent of people descended from northern Europeans have inherited the mutation from both parents and are immune to most HIV. The donor had this double copy of the mutation.

That was “an improbable event,” Gupta said. “That’s why this has not been observed more frequently.”

Most experts say it is inconceivable such treatments could be a way of curing all patients. The procedure is expensive, complex and risky. To do this in others, exact match donors would have to be found in the tiny proportion of people who have the CCR5 mutation.

Specialists said it is also not yet clear whether the CCR5 resistance is the only key [emphasis mine] — or whether the graft-versus-host disease may have been just as important. Both the Berlin and London patients had this complication, which may have played a role in the loss of HIV-infected cells, Gupta said.

Not only is there some question as to what role the CCR5 gene plays, there’s also a question as to whether or not we know what role genes play.

A big question: are genes what we thought?

Ken Richardson’s January 3, 2019 article for Nautilus (I stumbled across it on May 14, 2019 so I’m late to the party) makes and supports a startling statement, It’s the End of the Gene As We Know It We are not nearly as determined by our genes as once thought (Note: A link has been removed),

We’ve all seen the stark headlines: “Being Rich and Successful Is in Your DNA” (Guardian, July 12); “A New Genetic Test Could Help Determine Children’s Success” (Newsweek, July 10); “Our Fortunetelling Genes” make us (Wall Street Journal, Nov. 16); and so on.

The problem is, many of these headlines are not discussing real genes at all, but a crude statistical model of them, involving dozens of unlikely assumptions. Now, slowly but surely, that whole conceptual model of the gene is being challenged.

We have reached peak gene, and passed it.

The preferred dogma started to appear in different versions in the 1920s. It was aptly summarized by renowned physicist Erwin Schrödinger in a famous lecture in Dublin in 1943. He told his audience that chromosomes “contain, in some kind of code-script, the entire pattern of the individual’s future development and of its functioning in the mature state.”

Around that image of the code a whole world order of rank and privilege soon became reinforced. These genes, we were told, come in different “strengths,” different permutations forming ranks that determine the worth of different “races” and of different classes in a class-structured society. A whole intelligence testing movement was built around that preconception, with the tests constructed accordingly.

The image fostered the eugenics and Nazi movements of the 1930s, with tragic consequences. Governments followed a famous 1938 United Kingdom education commission in decreeing that, “The facts of genetic inequality are something that we cannot escape,” and that, “different children … require types of education varying in certain important respects.”

Today, 1930s-style policy implications are being drawn once again. Proposals include gene-testing at birth for educational intervention, embryo selection for desired traits, identifying which classes or “races” are fitter than others, and so on. And clever marketizing now sees millions of people scampering to learn their genetic horoscopes in DNA self-testing kits.[emphasis mine]

So the hype now pouring out of the mass media is popularizing what has been lurking in the science all along: a gene-god as an entity with almost supernatural powers. Today it’s the gene that, in the words of the Anglican hymn, “makes us high and lowly and orders our estate.”

… at the same time, a counter-narrative is building, not from the media but from inside science itself.

So it has been dawning on us is that there is no prior plan or blueprint for development: Instructions are created on the hoof, far more intelligently than is possible from dumb DNA. That is why today’s molecular biologists are reporting “cognitive resources” in cells; “bio-information intelligence”; “cell intelligence”; “metabolic memory”; and “cell knowledge”—all terms appearing in recent literature.1,2 “Do cells think?” is the title of a 2007 paper in the journal Cellular and Molecular Life Sciences.3 On the other hand the assumed developmental “program” coded in a genotype has never been described.


It is such discoveries that are turning our ideas of genetic causation inside out. We have traditionally thought of cell contents as servants to the DNA instructions. But, as the British biologist Denis Noble insists in an interview with the writer Suzan Mazur,1 “The modern synthesis has got causality in biology wrong … DNA on its own does absolutely nothing [ emphasis mine] until activated by the rest of the system … DNA is not a cause in an active sense. I think it is better described as a passive data base which is used by the organism to enable it to make the proteins that it requires.”

I highly recommend reading Richardson’s article in its entirety. As well, you may want to read his book, ” Genes, Brains and Human Potential: The Science and Ideology of Intelligence .”

As for “DNA on its own doing absolutely nothing,” that might be a bit of a eye-opener for the Silicon Valley elite types investigating cognitive advantages attributed to the lack of a CCR5 gene. Meanwhile, there are scientists inserting a human gene associated with brain development into monkeys,

Transgenic monkeys and human intelligence

An April 2, 2019 news item on chinadaily.com describes research into transgenic monkeys,

Researchers from China and the United States have created transgenic monkeys carrying a human gene that is important for brain development, and the monkeys showed human-like brain development.

Scientists have identified several genes that are linked to primate brain size. MCPH1 is a gene that is expressed during fetal brain development. Mutations in MCPH1 can lead to microcephaly, a developmental disorder characterized by a small brain.

In the study published in the Beijing-based National Science Review, researchers from the Kunming Institute of Zoology, Chinese Academy of Sciences, the University of North Carolina in the United States and other research institutions reported that they successfully created 11 transgenic rhesus monkeys (eight first-generation and three second-generation) carrying human copies of MCPH1.

According to the research article, brain imaging and tissue section analysis showed an altered pattern of neuron differentiation and a delayed maturation of the neural system, which is similar to the developmental delay (neoteny) in humans.

Neoteny in humans is the retention of juvenile features into adulthood. One key difference between humans and nonhuman primates is that humans require a much longer time to shape their neuro-networks during development, greatly elongating childhood, which is the so-called “neoteny.”

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

Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development by Lei Shi, Xin Luo, Jin Jiang, Yongchang Chen, Cirong Liu, Ting Hu, Min Li, Qiang Lin, Yanjiao Li, Jun Huang Hong Wang, Yuyu Niu, Yundi Shi, Martin Styner, Jianhong Wang, Yi Lu, Xuejin Sun, Hualin Yu, Weizhi Ji, Bing Su. National Science Review, nwz043, https://doi.org/10.1093/nsr/nwz043 Published: 27 March 2019

This appears to be an open access paper,

Transgenic monkeys and an ethical uproar

Predictably, this research set off alarms as Sharon Kirkey’s April 12, 2019 article for the National Post describes in detail (Note: A link has been removed)l,

Their brains may not be bigger than normal, but monkeys created with human brain genes are exhibiting cognitive changes that suggest they might be smarter — and the experiments have ethicists shuddering.

In the wake of the genetically modified human babies scandal, Chinese scientists [as a scientist from the US] are drawing fresh condemnation from philosophers and ethicists, this time over the announcement they’ve created transgenic monkeys with elements of a human brain.

Six of the monkeys died, however the five survivors “exhibited better short-term memory and shorter reaction time” compared to their wild-type controls, the researchers report in the journa.

According to the researchers, the experiments represent the first attempt to study the genetic basis of human brain origin using transgenic monkeys. The findings, they insist, “have the potential to provide important — and potentially unique — insights into basic questions of what actually makes humans unique.”

For others, the work provokes a profoundly moral and visceral uneasiness. Even one of the collaborators — University of North Carolina computer scientist Martin Styner — told MIT Technology Review he considered removing his name from the paper, which he said was unable to find a publisher in the West.

“Now we have created this animal which is different than it is supposed to be,” Styner said. “When we do experiments, we have to have a good understanding of what we are trying to learn, to help society, and that is not the case here.” l

In an email to the National Post, Styner said he has an expertise in medical image analysis and was approached by the researchers back in 2011. He said he had no input on the science in the project, beyond how to best do the analysis of their MRI data. “At the time, I did not think deeply enough about the ethical consideration.”

….

When it comes to the scientific use of nonhuman primates, ethicists say the moral compass is skewed in cases like this.

Given the kind of beings monkeys are, “I certainly would have thought you would have had to have a reasonable expectation of high benefit to human beings to justify the harms that you are going to have for intensely social, cognitively complex, emotional animals like monkeys,” said Letitia Meynell, an associate professor in the department of philosophy at Dalhousie University in Halifax.

“It’s not clear that this kind of research has any reasonable expectation of having any useful application for human beings,” she said.

The science itself is also highly dubious and fundamentally flawed in its logic, she said.
“If you took Einstein as a baby and you raised him in the lab he wouldn’t turn out to be Einstein,” Meynell said. “If you’re actually interested in studying the cognitive complexity of these animals, you’re not going to get a good representation of that by raising them in labs, because they can’t develop the kind of cognitive and social skills they would in their normal environment.”

The Chinese said the MCPH1 gene is one of the strongest candidates for human brain evolution. But looking at a single gene is just bad genetics, Meynell said. Multiple genes and their interactions affect the vast majority of traits.

My point is that there’s a lot of research focused on intelligence and genes when we don’t really know what role genes actually play and when there doesn’t seem to be any serious oversight.

Global plea for moratorium on heritable genome editing

A March 13, 2019 University of Otago (New Zealand) press release (also on EurekAlert) describes a global plea for a moratorium,

A University of Otago bioethicist has added his voice to a global plea for a moratorium on heritable genome editing from a group of international scientists and ethicists in the wake of the recent Chinese experiment aiming to produce HIV immune children.

In an article in the latest issue of international scientific journal Nature, Professor Jing-Bao Nie together with another 16 [17] academics from seven countries, call for a global moratorium on all clinical uses of human germline editing to make genetically modified children.

They would like an international governance framework – in which nations voluntarily commit to not approve any use of clinical germline editing unless certain conditions are met – to be created potentially for a five-year period.

Professor Nie says the scientific scandal of the experiment that led to the world’s first genetically modified babies raises many intriguing ethical, social and transcultural/transglobal issues. His main personal concerns include what he describes as the “inadequacy” of the Chinese and international responses to the experiment.

“The Chinese authorities have conducted a preliminary investigation into the scientist’s genetic misadventure and issued a draft new regulation on the related biotechnologies. These are welcome moves. Yet, by putting blame completely on the rogue scientist individually, the institutional failings are overlooked,” Professor Nie explains.

“In the international discourse, partly due to the mentality of dichotomising China and the West, a tendency exists to characterise the scandal as just a Chinese problem. As a result, the global context of the experiment and Chinese science schemes have been far from sufficiently examined.”

The group of 17 [18] scientists and bioethicists say it is imperative that extensive public discussions about the technical, scientific, medical, societal, ethical and moral issues must be considered before germline editing is permitted. A moratorium would provide time to establish broad societal consensus and an international framework.

“For germline editing to even be considered for a clinical application, its safety and efficacy must be sufficient – taking into account the unmet medical need, the risks and potential benefits and the existence of alternative approaches,” the opinion article states.

Although techniques have improved in recent years, germline editing is not yet safe or effective enough to justify any use in the clinic with the risk of failing to make the desired change or of introducing unintended mutations still unacceptably high, the scientists and ethicists say.

“No clinical application of germline editing should be considered unless its long-term biological consequences are sufficiently understood – both for individuals and for the human species.”

The proposed moratorium does not however, apply to germline editing for research uses or in human somatic (non-reproductive) cells to treat diseases.

Professor Nie considers it significant that current presidents of the UK Royal Society, the US National Academy of Medicine and the Director and Associate Director of the US National Institute of Health have expressed their strong support for such a proposed global moratorium in two correspondences published in the same issue of Nature. The editorial in the issue also argues that the right decision can be reached “only through engaging more communities in the debate”.

“The most challenging questions are whether international organisations and different countries will adopt a moratorium and if yes, whether it will be effective at all,” Professor Nie says.

A March 14, 2019 news item on phys.org provides a précis of the Comment in Nature. Or, you ,can access the Comment with this link

Adopt a moratorium on heritable genome editing; Eric Lander, Françoise Baylis, Feng Zhang, Emmanuelle Charpentier, Paul Berg and specialists from seven countries call for an international governance framework.signed by: Eric S. Lander, Françoise Baylis, Feng Zhang, Emmanuelle Charpentier, Paul Berg, Catherine Bourgain, Bärbel Friedrich, J. Keith Joung, Jinsong Li, David Liu, Luigi Naldini, Jing-Bao Nie, Renzong Qiu, Bettina Schoene-Seifert, Feng Shao, Sharon Terry, Wensheng Wei, & Ernst-Ludwig Winnacker. Nature 567, 165-168 (2019) doi: 10.1038/d41586-019-00726-5

This Comment in Nature is open access.

World Health Organization (WHO) chimes in

Better late than never, eh? The World Health Organization has called heritable gene editing of humans ‘irresponsible’ and made recommendations. From a March 19, 2019 news item on the Canadian Broadcasting Corporation’s Online news webpage,

A panel convened by the World Health Organization said it would be “irresponsible” for scientists to use gene editing for reproductive purposes, but stopped short of calling for a ban.

The experts also called for the U.N. health agency to create a database of scientists working on gene editing. The recommendation was announced Tuesday after a two-day meeting in Geneva to examine the scientific, ethical, social and legal challenges of such research.

“At this time, it is irresponsible for anyone to proceed” with making gene-edited babies since DNA changes could be passed down to future generations, the experts said in a statement.

Germline editing has been on my radar since 2015 (see my May 14, 2015 posting) and the probability that someone would experiment with viable embryos and bring them to term shouldn’t be that much of a surprise.

Slow science from Canada

Canada has banned germline editing but there is pressure to lift that ban. (I touched on the specifics of the campaign in an April 26, 2019 posting.) This March 17, 2019 essay on The Conversation by Landon J Getz and Graham Dellaire, both of Dalhousie University (Nova Scotia, Canada) elucidates some of the discussion about whether research into germline editing should be slowed down.

Naughty (or Haughty, if you prefer) scientists

There was scoffing from some, if not all, members of the scientific community about the potential for ‘designer babies’ that can be seen in an excerpt from an article by Ed Yong for The Atlantic (originally published in my ,August 15, 2017 posting titled: CRISPR and editing the germline in the US (part 2 of 3): ‘designer babies’?),

Ed Yong in an Aug. 2, 2017 article for The Atlantic offered a comprehensive overview of the research and its implications (unusually for Yong, there seems to be mildly condescending note but it’s worth ignoring for the wealth of information in the article; Note: Links have been removed),

” … the full details of the experiment, which are released today, show that the study is scientifically important but much less of a social inflection point than has been suggested. “This has been widely reported as the dawn of the era of the designer baby, making it probably the fifth or sixth time people have reported that dawn,” says Alta Charo, an expert on law and bioethics at the University of Wisconsin-Madison. “And it’s not.”

Then about 15 months later, the possibility seemed to be realized.

Interesting that scientists scoffed at the public’s concerns (you can find similar arguments about robots and artificial intelligence not being a potentially catastrophic problem), yes? Often, nonscientists’ concerns are dismissed as being founded in science fiction.

To be fair, there are times when concerns are overblown, the difficulty is that it seems the scientific community’s default position is to uniformly dismiss concerns rather than approaching them in a nuanced fashion. If the scoffers had taken the time to think about it, germline editing on viable embryos seems like an obvious and inevitable next step (as I’ve noted previously).

At this point, no one seems to know if He actually succeeded at removing CCR5 from Lulu’s and Nana’s genomes. In November 2018, scientists were guessing that at least one of the twins was a ‘mosaic’. In other words, some of her cells did not include CCR5 while others did.

Parents, children, competition

A recent college admissions scandal in the US has highlighted the intense competition to get into high profile educational institutions. (This scandal brought to mind the Silicon Valey elite who wanted to know more about gene editing that might result in improved cognitive skills.)

Since it can be easy to point the finger at people in other countries, I’d like to note that there was a Canadian parent among these wealthy US parents attempting to give their children advantages by any means, legal or not. (Note: These are alleged illegalities.) From a March 12, 2019 news article by Scott Brown, Kevin Griffin, and Keith Fraser for the Vancouver Sun,

Vancouver businessman and former CFL [Canadian Football League] player David Sidoo has been charged with conspiracy to commit mail and wire fraud in connection with a far-reaching FBI investigation into a criminal conspiracy that sought to help privileged kids with middling grades gain admission to elite U.S. universities.

In a 12-page indictment filed March 5 [2019] in the U.S. District Court of Massachusetts, Sidoo is accused of making two separate US$100,000 payments to have others take college entrance exams in place of his two sons.

Sidoo is also accused of providing documents for the purpose of creating falsified identification cards for the people taking the tests.

In what is being called the biggest college-admissions scam ever prosecuted by the U.S. Justice Department, Sidoo has been charged with nearly 50 other people. Nine athletic coaches and 33 parents including Hollywood actresses Felicity Huffman and Lori Loughlin. are among those charged in the investigation, dubbed Operation Varsity Blues.

According to the indictment, an unidentified person flew from Tampa, Fla., to Vancouver in 2011 to take the Scholastic Aptitude Test (SAT) in place of Sidoo’s older son and was directed not to obtain too high a score since the older son had previously taken the exam, obtaining a score of 1460 out of a possible 2400.

A copy of the resulting SAT score — 1670 out of 2400 — was mailed to Chapman University, a private university in Orange, Calif., on behalf of the older son, who was admitted to and ultimately enrolled in the university in January 2012, according to the indictment.

It’s also alleged that Sidoo arranged to have someone secretly take the older boy’s Canadian high school graduation exam, with the person posing as the boy taking the exam in June 2012.

The Vancouver businessman is also alleged to have paid another $100,000 to have someone take the SAT in place of his younger son.

Sidoo, an investment banker currently serving as CEO of Advantage Lithium, was awarded the Order of B.C. in 2016 for his philanthropic efforts.

He is a former star with the UBC [University of British Columbia] Thunderbirds football team and helped the school win its first Vanier Cup in 1982. He went on to play five seasons in the CFL with the Saskatchewan Roughriders and B.C. Lions.

Sidoo is a prominent donor to UBC and is credited with spearheading an alumni fundraising campaign, 13th Man Foundation, that resuscitated the school’s once struggling football team. He reportedly donated $2 million of his own money to support the program.

Sidoo Field at UBC’s Thunderbird Stadium is named in his honour.

In 2016, he received the B.C. [British Columbia] Sports Hall of Fame’s W.A.C. Bennett Award for his contributions to the sporting life of the province.

The question of whether or not these people like the ‘Silicon Valley elite’ (mentioned in John Loeffler’s February 22, 2019 article) would choose to tinker with their children’s genome if it gave them an advantage, is still hypothetical but it’s easy to believe that at least some might seriously consider the possibility especially if the researcher or doctor didn’t fully explain just how little is known about the impact of tinkering with the genome. For example, there’s a big question about whether those parents in China fully understood what they signed up for.

By the way, cheating scandals aren’t new (see Vanity Fair’s Schools For Scandal; The Inside Dramas at 16 of America’s Most Elite Campuses—Plus Oxford! Edited by Graydon Carter, published in August 2018 and covering 25 years of the magazine’s reporting). On a similar line, there’s this March13, 2019 essay which picks apart some of the hierarchical and power issues at play in the US higher educational system which led to this latest (but likely not last) scandal.

Scientists under pressure

While Kofler’s February 26, 2019 Nature opinion piece and call to action seems to address the concerns regarding germline editing by advocating that scientists become more conscious of how their choices impact society, as I noted earlier, the ideas expressed seem a little ungrounded in harsh realities. Perhaps it’s time to give some recognition to the various pressures put on scientists from their own governments and from an academic environment that fosters ‘success’ at any cost to peer pressure, etc. (For more about the costs of a science culture focused on success, read this March 2, 2019 blog posting by Jon Tennant on digital-science.com for a breakdown.)

One other thing I should mention, for some scientists getting into the history books, winning Nobel prizes, etc. is a very important goal. Scientists are people too.

Some thoughts

There seems to be a great disjunction between what Richardson presents as an alternative narrative to the ‘gene-god’ and how genetic research is being performed and reported on. What is clear to me is that no one really understands genetics and this business of inserting and deleting genes is essentially research designed to satisfy curiosity and/or allay fears about being left behind in a great scientific race to a an unknown destination.

I’d like to see some better reporting and a more agile response by the scientific community, the various governments, and international agencies. What shape or form a more agile response might take, I don’t know but I’d like to see some efforts.

Back to the regular programme

There’s a lot about CRISPR here on this blog. A simple search of ‘CRISPR ‘in the blog’s search engine should get you more than enough information about the technology and the various issues ranging from intellectual property to risks and more.

The three part series (CRISPR and editing the germline in the US …), mentioned previously, was occasioned by the publication of a study on germline editing research with nonviable embryos in the US. The 2017 research was done at the Oregon Health and Science University by Shoukhrat Mitalipov following similar research published by Chinese scientists in 2015. The series gives relatively complete coverage of the issues along with an introduction to CRISPR and embedded video describing the technique. Here’s part 1 to get you started..

Walking again with exoskeletons and brain-controlled, non-invasive muscle stimulation enabling people to walk

I have two news bits about paraplegics and the possibility of walking. The first is from Alberta, Canada and the second is from Brazil.

Alberta

The fellow in the video is wearing a robotic exoskeleton. As you can see, it’s not perfect but it represents an extraordinary breakthrough (from an April 16, 2019 article by Sarah Lawrynuik for the Canadian Broadcasting Corporation [CBC] Radio),

On his fifteenth birthday in December 2015, Calgary’s Alex McEwan was injured in a tobogganing accident with friends and lost the ability to walk. It’s the kind of change that could destroy a person, but Alex has thrived and is learning new skills. Watch him walk onstage, with some help from a powered exoskeleton, to receive his diploma. 1:21

Sometimes events conspire to move us in a completely unexpected ways. After his accident, Alex McEwan participated in a very special study (from an August 3, 2019 article by Colin Zak for Alberta Health Services),

Researchers at Foothills Medical Centre (FMC) are the first in Canada to examine the benefits of using an exoskeleton robotic device to rehabilitate patients with spinal cord injuries (SCI) in the days and weeks following their injury.

The device, known as the Ekso Bionic Exoskeleton, consists of a metal frame that supports and stabilizes a patient’s torso, core, legs and feet. It is moved robotically by a therapist, enabling patients with a spinal cord injury to get up and walk around. Although it is controlled by remote control, the device offers varying levels of physical control by the patient, depending on the nature and extent of their injury.

Dr. Ho [ Dr. Chester Ho, Head of Physical Medicine and Rehabilitation at FMC ] says exoskeletons may potentially promote recovery and reduce complications in SCI patients by reducing loss of bone and muscle mass caused by spending so much time lying down, and also improve breathing and bowel function.

The year-long study, which begins this summer, will include between five and 10 patients selected from across Calgary [Alberta]. It aims to examine whether treatment is safe and feasible in the days and weeks after an SCI. This study will be followed by larger studies involving more patients.

Participants in the study will receive 60-minute therapy sessions with the exoskeleton device two to three times a week, for a total of 25 training hours over an eight- to 10-week period. Safety and feasibility outcomes will be monitored and tracked by the research team throughout all sessions.

Before the advent of exoskeletons, rehabilitation for patients with an SCI required them to be hoisted with a physical therapist moving their legs.

“Every step is different with this device, so patients learn from their mistakes in real time. Patients really like to use the device; it gives them hope.”

Alex, [emphasis mine] 15, sustained a spinal cord injury while tobogganing last December.

He says rehabilitation sessions with the exoskeleton have made a difference in how he feels and gives him hope for the future.

Over 2 1/2 years later, the CBC has made a radio documentary about this study and the people who took part. Lawrynuik’s April 16, 2019 article describes some highlights from the radio documentary,

Imagine waking up in a hospital bed surrounded by the beeps and whirring sounds of the machines keeping you alive. The doctor tells you that you will likely never walk again.

But then, just as you begin to process that news, a physiotherapist shows up at your bedside and says, “Hold up. I might have a special opportunity for you.”

That’s the journey taken by a number of Albertans who landed in Calgary’s Foothills Medical Centre after accidents or trauma to their spine in the last three years. Three of those people are Alex McEwan, a university student in Lethbridge; Jean Ogilvie, a 77-year-old woman living in Calgary; and Josh Pelland, a former climber turned motivational speaker in Three Hills, Alta.

All three are united by a technology called an exoskeleton, created by a company called Ekso Bionics, that allowed them to walk despite no longer being able to use their legs. 

“The first time was a bit scary actually,” Ogilvie said. “It’s like a great big skeleton that sort of clasps you in its body. [It’s] black and all sorts of straps and sensors tell you how I’m doing.”

Pelland agrees about how daunting the experience is to start.

“They just said, ‘OK, the machine is going to assist you and lift you up.’ And I was a bit like, ‘OK, this is the strangest thing ever.'”

Once the frame of the exoskeleton is strapped along the outside of the patient’s legs and up their back, starting from the seated position, it does lift them completely without the help of their own muscles.

From there they shift their upper-body weight within the machine to hit certain targets — once your body weight is shifted forward and laterally enough, a beep sounds and the exoskeleton pulls each leg forward, one at a time. 

As patients learn to use the machine, they walk with the assistance of a walker. Then, as they progress, they upgrade to forearm crutches. The entire time, they’re accompanied by the man behind the machine, Kyle McIntosh.

McIntosh is a physiotherapist and he worked with the exoskeleton both to help patients and to conduct research into the machine’s impact on rehabilitation.

After being discharged and living once again without the exoskeleton, and therefore without the ability to walk — McEwan got an idea: maybe he’d be allowed to use the robot, just one last time.

“High school wasn’t high school for me. I only really got one semester of grade 10 before I broke my spine. So that first semester was great. I enjoyed it. I played sports. I was a good student. But then it was no longer about high school anymore. It was more about adjusting to my new life.”

McIntosh and McEwan hatched the plan together and kept it a closely guarded secret. Then, on the day McEwan was set to graduate from Grade 12, he asked to be placed last on the list of students to cross the stage.

“I remember taking a first few steps and not hearing very much. Hearing people cheer because I was the kid in the wheelchair at the high school, so it makes sense. But the second they saw the canes and my first few steps, just one kid erupted: ‘Yeah!’ And then everyone went crazy.”

“I think walking across the stage — just like I got to walk into my high school on the first day of Grade 10 — was a really good closing story. The chapter of me learning to live in a wheelchair was done. And it was now my turn to go live my life. So that’s why I think it was such an important day because it gave me a lot of closure. I got to walk into the high school, I got to walk out.”

If you have the time, you might want to read Lawrynuik’s April 16, 2019 article in its entirety. It turns out that the study did much more than give a people a chance to walk again, even if just for a short time.

Anyone interested in the robotic, wearable exoskeleton used in the study can go here to EksoHealth, the company that produces the EksoGT, a bionic exoskeleton. (Lawrynuik’s article has another name for the product, i.e., Ekso Bionic Exoskeleton but all I could find was the EksoGT.)

Brazil and Walk Again

The most recent post featuring the Walk Again project is my May 20, 2014 edition which was part of a larger series on ‘Brain research, ethics, and nanotechnology’. The May 20, 2014 posting covered Walk Again’s debut at the 2014 World Cup (soccer/football) in Brazil. Unfortunately,, the lead researcher Miguel Nicolelis oversold the technology. I think people were expecting someone with paraplegia to come bounding out onto the field and give a flashy opening kick for the tournament what they saw was something a great deal more restrained.

The person was wheeled out onto the field, stood up, shuffled a bit, and nudged the ball with his foot. It represented a huge breakthrough but it wasn’t flashy.

The latest from Walk Again is in a May 14, 2019 Associação Alberto Santos Dumont para Apoio à Pesquisa press release on EurekAlert,

In another major clinical breakthrough of the Walk Again Project, a non-profit international consortium aimed at developing new neuro-rehabilitation protocols, technologies and therapies for spinal cord injury, two patients with paraplegia regained the ability to walk with minimal assistance, through the employment of a fully non-invasive brain-machine interface that does not require the use of any invasive spinal cord surgical procedure. The results of this study appeared on the May 1 [2019] issue of the journal Scientific Reports.

The two patients with paraplegia (AIS C) used their own brain activity to control the non-invasive delivery of electrical pulses to a total of 16 muscles (eight in each leg), allowing them to produce a more physiological walk than previously reported, requiring only a conventional walker and a body weight support system as assistive devices. Overall, the two patients were able to produce more than 4,500 steps using this new technology, which combines a non-invasive brain-machine interface, based on a 16-channel EEG, to control a multi-channel functional electrical stimulation system (FES), tailored to produce a much smoother gait pattern than the state of the art of this technique.

“What surprised us was that, in addition to allowing these patients to walk with little help, one of them displayed a clear motor improvement by practicing with this new approach. Patients required approximatively [sic] 25 sessions to master the training before they were able to walk using this apparatus,” said Solaiman Shokur one of the authors of the study.

The two patients that used this new rehabilitation approach had previously participated in the long-term neurorehabilitation study carried out using the Walk Again Project Neurorehabilitation (WANR) protocol. As reported in a recent publication from the same team (Shokur et al., PLoS One, Nov. 2018), all seven patients who participated in that protocol for a period of 28 months improved their clinical status, from complete paraplegia (AIS A or B, meaning no motor functions below the level of the injury, according to the ASIA classification) to partial paraplegia (AIS C, meaning partial recovery of sensory and motor function below the injury level). This significant neurological recovery included major clinical improvements in sensory discrimination (tactile, nociception, vibration, and pressure), voluntary motor control of abdomen and leg muscles, and important gains in autonomic control, such as bladder, bowel, and sexual functions.

“The last two studies published by the Walk Again Project clearly indicate that partial neurological and functional recovery can be induced in chronic spinal cord injury patients by combining multiple non-invasive technologies that are based around the concept of using a brain-machine interface to control different types of actuators, like virtual avatars, robotic walkers, or muscle stimulating devices, to allow the total involvement of patients in their own rehabilitation routine,” said Miguel Nicolelis, scientific director of the Walk Again Project and one of the authors of the study.

In a recent report by another group, one AIS C and two AIS D patients were able to walk thanks to the employment of an invasive method for spinal cord electrical stimulation, which required a spinal surgical procedure. In contrast, in the present study two AIS C patients – which originally were AIS A (see Supplemental Material below)- and a third AIS B subject, who recently achieved similar results, were able to regain a significant degree of autonomous walking without the need for such invasive treatments. Instead, these patients only received electrical stimulation patterns delivered to the skin surface of their legs, so that a total of eight muscles in each limb could be electrically stimulated in a physiologically accurate sequence. This was done in order to produce a smoother and more natural pattern of locomotion.

“Crucial for this implementation was the development of a closed-loop controller that allowed real-time correction of the patients’ walking pattern, taking into account muscle fatigue and external perturbations, in order to produce a predefined gait trajectory. Another major component of our approach was the use of a wearable haptic display to deliver tactile feedback to the patients´ forearms in order to provide them with a continuous source of proprioceptive feedback related to their walking,” said Solaiman Shokur.

To control the pattern of electrical muscle stimulation in each leg, these patients utilized an EEG-based brain-machine interface. In this setup, patients learned to alternate the generation of “stepping motor imagery” activity in their right and left motor cortices, in order to create alternated movements of their left and right legs.

According to the authors, the patients exhibited not only “less dependency on walking assistance, but also partial neurological recovery, with substantial rates of motor improvement in one of them.” The improvement in motor control in this last AIS C patient was 9 points in the lower extremity motor score (LEMS), which was comparable with that observed using invasive spinal cord stimulation.

Based on the results obtained over the past 5 years, the WAP now intends to combine all its neurorehabilitation tools into a single integrated, non-invasive platform to treat spinal cord injury patients. This platform will allow patients to begin training soon after the injury occurs. It will also allow the employment of a multi-dimensional integrated brain-machine interface capable of simultaneously controlling virtual and robotic actuators (like a lowerlimb exoskeleton), a multi-channel non-invasive electrical muscle stimulation system (like the FES used in the present study), and a novel non-invasive spinal cord stimulation approach. In this final configuration, this WAP platform will incorporate all these technologies together in order to maximize neurological and functional recovery in the shortest possible time, without the need of any invasive procedure.

According to Dr. Nicolelis, “there is no silver bullet to treat spinal cord injuries. More and more, it looks like we need to implement multiple techniques simultaneously to achieve the best neurorehabilitation results. In this context, it is also imperative to consider the occurrence of cortical plasticity as a major component in the planning of our rehabilitation approach.”

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

Non-invasive, Brain-controlled Functional Electrical Stimulation for Locomotion Rehabilitation in Individuals with Paraplegia by Aurelie Selfslagh, Solaiman Shokur, Debora S. F. Campos, Ana R. C. Donati, Sabrina Almeida, Seidi Y. Yamauti, Daniel B. Coelho, Mohamed Bouri & Miguel A. L. Nicolelis. Scientific Reports volume 9, Article number: 6782 (2019) DOI: https://doi.org/10.1038/s41598-019-43041-9 Published 01 May 2019

This paper is open access.

There’s also a video for Walk Again,