Tag Archives: US Food and Drug Administration (FDA)

Going blind when your neural implant company flirts with bankruptcy (long read)

This story got me to thinking about what happens when any kind of implant company (pacemaker, deep brain stimulator, etc.) goes bankrupt or is acquired by another company with a different business model.

As I worked on this piece, more issues were raised and the scope expanded to include prosthetics along with implants while the focus narrowed to neuro as in, neural implants and neuroprosthetics. At the same time, I found salient examples for this posting in other medical advances such as gene editing.

In sum, all references to implants and prosthetics are to neural devices and some issues are illustrated with salient examples from other medical advances (specifically, gene editing).

Definitions (for those who find them useful)

The US Food and Drug Administration defines implants and prosthetics,

Medical implants are devices or tissues that are placed inside or on the surface of the body. Many implants are prosthetics, intended to replace missing body parts. Other implants deliver medication, monitor body functions, or provide support to organs and tissues.

As for what constitutes a neural implant/neuroprosthetic, there’s this from Emily Waltz’s January 20, 2020 article (How Do Neural Implants Work? Neural implants are used for deep brain stimulation, vagus nerve stimulation, and mind-controlled prostheses) for the Institute of Electrical and Electronics Engineers (IEEE) Spectrum magazine,

A neural implant, then, is a device—typically an electrode of some kind—that’s inserted into the body, comes into contact with tissues that contain neurons, and interacts with those neurons in some way.

Now, let’s start with the recent near bankruptcy of a retinal implant company.

The company goes bust (more or less)

From a February 25, 2022 Science Friday (a National Public Radio program) posting/audio file, Note: Links have been removed,

Barbara Campbell was walking through a New York City subway station during rush hour when her world abruptly went dark. For four years, Campbell had been using a high-tech implant in her left eye that gave her a crude kind of bionic vision, partially compensating for the genetic disease that had rendered her completely blind in her 30s. “I remember exactly where I was: I was switching from the 6 train to the F train,” Campbell tells IEEE Spectrum. “I was about to go down the stairs, and all of a sudden I heard a little ‘beep, beep, beep’ sound.’”

It wasn’t her phone battery running out. It was her Argus II retinal implant system powering down. The patches of light and dark that she’d been able to see with the implant’s help vanished.

Terry Byland is the only person to have received this kind of implant in both eyes. He got the first-generation Argus I implant, made by the company Second Sight Medical Products, in his right eye in 2004, and the subsequent Argus II implant in his left 11 years later. He helped the company test the technology, spoke to the press movingly about his experiences, and even met Stevie Wonder at a conference. “[I] went from being just a person that was doing the testing to being a spokesman,” he remembers.

Yet in 2020, Byland had to find out secondhand that the company had abandoned the technology and was on the verge of going bankrupt. While his two-implant system is still working, he doesn’t know how long that will be the case. “As long as nothing goes wrong, I’m fine,” he says. “But if something does go wrong with it, well, I’m screwed. Because there’s no way of getting it fixed.”

Science Friday and the IEEE [Institute of Electrical and Electronics Engineers] Spectrum magazine collaborated to produce this story. You’ll find the audio files and the transcript of interviews with the authors and one of the implant patients in this February 25, 2022 Science Friday (a National Public Radio program) posting.

Here’s more from the February 15, 2022 IEEE Spectrum article by Eliza Strickland and Mark Harris,

Ross Doerr, another Second Sight patient, doesn’t mince words: “It is fantastic technology and a lousy company,” he says. He received an implant in one eye in 2019 and remembers seeing the shining lights of Christmas trees that holiday season. He was thrilled to learn in early 2020 that he was eligible for software upgrades that could further improve his vision. Yet in the early months of the COVID-19 pandemic, he heard troubling rumors about the company and called his Second Sight vision-rehab therapist. “She said, ‘Well, funny you should call. We all just got laid off,’ ” he remembers. She said, ‘By the way, you’re not getting your upgrades.’ ”

These three patients, and more than 350 other blind people around the world with Second Sight’s implants in their eyes, find themselves in a world in which the technology that transformed their lives is just another obsolete gadget. One technical hiccup, one broken wire, and they lose their artificial vision, possibly forever. To add injury to insult: A defunct Argus system in the eye could cause medical complications or interfere with procedures such as MRI scans, and it could be painful or expensive to remove.

The writers included some information about what happened to the business, from the February 15, 2022 IEEE Spectrum article, Note: Links have been removed,

After Second Sight discontinued its retinal implant in 2019 and nearly went out of business in 2020, a public offering in June 2021 raised US $57.5 million at $5 per share. The company promised to focus on its ongoing clinical trial of a brain implant, called Orion, that also provides artificial vision. But its stock price plunged to around $1.50, and in February 2022, just before this article was published, the company announced a proposed merger with an early-stage biopharmaceutical company called Nano Precision Medical (NPM). None of Second Sight’s executives will be on the leadership team of the new company, which will focus on developing NPM’s novel implant for drug delivery.The company’s current leadership declined to be interviewed for this article but did provide an emailed statement prior to the merger announcement. It said, in part: “We are a recognized global leader in neuromodulation devices for blindness and are committed to developing new technologies to treat the broadest population of sight-impaired individuals.”

It’s unclear what Second Sight’s proposed merger means for Argus patients. The day after the merger was announced, Adam Mendelsohn, CEO of Nano Precision Medical, told Spectrum that he doesn’t yet know what contractual obligations the combined company will have to Argus and Orion patients. But, he says, NPM will try to do what’s “right from an ethical perspective.” The past, he added in an email, is “simply not relevant to the new future.”

There may be some alternatives, from the February 15, 2022 IEEE Spectrum article (Note: Links have been removed),

Second Sight may have given up on its retinal implant, but other companies still see a need—and a market—for bionic vision without brain surgery. Paris-based Pixium Vision is conducting European and U.S. feasibility trials to see if its Prima system can help patients with age-related macular degeneration, a much more common condition than retinitis pigmentosa.

Daniel Palanker, a professor of ophthalmology at Stanford University who licensed his technology to Pixium, says the Prima implant is smaller, simpler, and cheaper than the Argus II. But he argues that Prima’s superior image resolution has the potential to make Pixium Vision a success. “If you provide excellent vision, there will be lots of patients,” he tells Spectrum. “If you provide crappy vision, there will be very few.”

Some clinicians involved in the Argus II work are trying to salvage what they can from the technology. Gislin Dagnelie, an associate professor of ophthalmology at Johns Hopkins University School of Medicine, has set up a network of clinicians who are still working with Argus II patients. The researchers are experimenting with a thermal camera to help users see faces, a stereo camera to filter out the background, and AI-powered object recognition. These upgrades are unlikely to result in commercial hardware today but could help future vision prostheses.

The writers have carefully balanced this piece so it is not an outright condemnation of the companies (Second Sight and Nano Precision), from the February 15, 2022 IEEE Spectrum article,

Failure is an inevitable part of innovation. The Argus II was an innovative technology, and progress made by Second Sight may pave the way for other companies that are developing bionic vision systems. But for people considering such an implant in the future, the cautionary tale of Argus patients left in the lurch may make a tough decision even tougher. Should they take a chance on a novel technology? If they do get an implant and find that it helps them navigate the world, should they allow themselves to depend upon it?

Abandoning the Argus II technology—and the people who use it—might have made short-term financial sense for Second Sight, but it’s a decision that could come back to bite the merged company if it does decide to commercialize a brain implant, believes Doerr.

For anyone curious about retinal implant technology (specifically the Argus II), I have a description in a June 30, 2015 posting.

Speculations and hopes for neuroprosthetics

The field of neuroprosthetics is very active. Dr Arthur Saniotis and Prof Maciej Henneberg have written an article where they speculate about the possibilities of a neuroprosthetic that may one day merge with neurons in a February 21, 2022 Nanowerk Spotlight article,

For over a generation several types of medical neuroprosthetics have been developed, which have improved the lives of thousands of individuals. For instance, cochlear implants have restored functional hearing in individuals with severe hearing impairment.

Further advances in motor neuroprosthetics are attempting to restore motor functions in tetraplegic, limb loss and brain stem stroke paralysis subjects.

Currently, scientists are working on various kinds of brain/machine interfaces [BMI] in order to restore movement and partial sensory function. One such device is the ‘Ipsihand’ that enables movement of a paralyzed hand. The device works by detecting the recipient’s intention in the form of electrical signals, thereby triggering hand movement.

Another recent development is the 12 month BMI gait neurohabilitation program that uses a visual-tactile feedback system in combination with a physical exoskeleton and EEG operated AI actuators while walking. This program has been tried on eight patients with reported improvements in lower limb movement and somatic sensation.

Surgically placed electrode implants have also reduced tremor symptoms in individuals with Parkinson’s disease.

Although neuroprosthetics have provided various benefits they do have their problems. Firstly, electrode implants to the brain are prone to degradation, necessitating new implants after a few years. Secondly, as in any kind of surgery, implanted electrodes can cause post-operative infection and glial scarring. Furthermore, one study showed that the neurobiological efficacy of an implant is dependent on the rate of speed of its insertion.

But what if humans designed a neuroprosthetic, which could bypass the medical glitches of invasive neuroprosthetics? However, instead of connecting devices to neural networks, this neuroprosthetic would directly merge with neurons – a novel step. Such a neuroprosthetic could radically optimize treatments for neurodegenerative disorders and brain injuries, and possibly cognitive enhancement [emphasis mine].

A team of three international scientists has recently designed a nanobased neuroprosthetic, which was published in Frontiers in Neuroscience (“Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders“). [open access paper published in 2018]

An interesting feature of their nanobot neuroprosthetic is that it has been inspired from nature by way of endomyccorhizae – a type of plant/fungus symbiosis, which is over four hundred million years old. During endomyccorhizae, fungi use numerous threadlike projections called mycelium that penetrate plant roots, forming colossal underground networks with nearby root systems. During this process fungi take up vital nutrients while protecting plant roots from infections – a win-win relationship. Consequently, the nano-neuroprosthetic has been named ‘endomyccorhizae ligand interface’, or ‘ELI’ for short.

The Spotlight article goes on to describe how these nanobots might function. As for the possibility of cognitive enhancement, I wonder if that might come to be described as a form of ‘artificial intelligence’.

(Dr Arthur Saniotis and Prof Maciej Henneberg are both from the Department of Anthropology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences; and Biological Anthropology and Comparative Anatomy Research Unit, Adelaide Medical School, University of Adelaide. Abdul-Rahman Sawalma who’s listed as an author on the 2018 paper is from the Palestinian Neuroscience Initiative, Al-Quds University, Beit Hanina, Palestine.)

Saniotis and Henneberg’s Spotlight article presents an optimistic view of neuroprosthetics. It seems telling that they cite cochlear implants as a success story when it is viewed by many as ethically fraught (see the Cochlear implant Wikipedia entry; scroll down to ‘Criticism and controversy’).

Ethics and your implants

This is from an April 6, 2015 article by Luc Henry on technologist.eu,

Technologist: What are the potential consequences of accepting the “augmented human” in society?

Gregor Wolbring: There are many that we might not even envision now. But let me focus on failure and obsolescence [emphasis mine], two issues that are rarely discussed. What happens when the mechanisms fails in the middle of an action? Failure has hazardous consequences, but obsolescence has psychological ones. …. The constant surgical inter­vention needed to update the hardware may not be feasible. A person might feel obsolete if she cohabits with others using a newer version.

T. Are researchers working on prosthetics sometimes disconnected from reality?

G. W. Students engaged in the development of prosthetics have to learn how to think in societal terms and develop a broader perspective. Our education system provides them with a fascination for clever solutions to technological challenges but not with tools aiming at understanding the consequences, such as whether their product might increase or decrease social justice.

Wolbring is a professor at the University of Calgary’s Cumming School of Medicine (profile page) who writes on social issues to do with human enhancement/ augmentation. As well,

Some of his areas of engagement are: ability studies including governance of ability expectations, disability studies, governance of emerging and existing sciences and technologies (e.g. nanoscale science and technology, molecular manufacturing, aging, longevity and immortality, cognitive sciences, neuromorphic engineering, genetics, synthetic biology, robotics, artificial intelligence, automatization, brain machine interfaces, sensors), impact of science and technology on marginalized populations, especially people with disabilities he governance of bodily enhancement, sustainability issues, EcoHealth, resilience, ethics issues, health policy issues, human rights and sport.

He also maintains his own website here.

Not just startups

I’d classify Second Sight as a tech startup company and they have a high rate of failure, which may not have been clear to the patients who had the implants. Clinical trials can present problems too as this excerpt from my September 17, 2020 posting notes,

This October 31, 2017 article by Emily Underwood for Science was revelatory,

“In 2003, neurologist Helen Mayberg of Emory University in Atlanta began to test a bold, experimental treatment for people with severe depression, which involved implanting metal electrodes deep in the brain in a region called area 25 [emphases mine]. The initial data were promising; eventually, they convinced a device company, St. Jude Medical in Saint Paul, to sponsor a 200-person clinical trial dubbed BROADEN.

This month [October 2017], however, Lancet Psychiatry reported the first published data on the trial’s failure. The study stopped recruiting participants in 2012, after a 6-month study in 90 people failed to show statistically significant improvements between those receiving active stimulation and a control group, in which the device was implanted but switched off.

… a tricky dilemma for companies and research teams involved in deep brain stimulation (DBS) research: If trial participants want to keep their implants [emphases mine], who will take responsibility—and pay—for their ongoing care? And participants in last week’s meeting said it underscores the need for the growing corps of DBS researchers to think long-term about their planned studies.”

Symbiosis can be another consequence, as mentioned in my September 17, 2020 posting,

From a July 24, 2019 article by Liam Drew for Nature Outlook: The brain,

“It becomes part of you,” Patient 6 said, describing the technology that enabled her, after 45 years of severe epilepsy, to halt her disabling seizures. Electrodes had been implanted on the surface of her brain that would send a signal to a hand-held device when they detected signs of impending epileptic activity. On hearing a warning from the device, Patient 6 knew to take a dose of medication to halt the coming seizure.

“You grow gradually into it and get used to it, so it then becomes a part of every day,” she told Frederic Gilbert, an ethicist who studies brain–computer interfaces (BCIs) at the University of Tasmania in Hobart, Australia. “It became me,” she said. [emphasis mine]

Symbiosis is a term, borrowed from ecology, that means an intimate co-existence of two species for mutual advantage. As technologists work towards directly connecting the human brain to computers, it is increasingly being used to describe humans’ potential relationship with artificial intelligence. [emphasis mine]

It’s complicated

For a lot of people these devices are or could be life-changing. At the same time, there are a number of different issues related to implants/prosthetics; the following is not an exhaustive list. As Wolbring notes, issues that we can’t begin to imagine now are likely to emerge as these medical advances become more ubiquitous.

Ability/disability?

Assistive technologies are almost always portrayed as helpful. For example, a cochlear implant gives people without hearing the ability to hear. The assumption is that this is always a good thing—unless you’re a deaf person who wants to define the problem a little differently. Who gets to decide what is good and ‘normal’ and what is desirable?

While the cochlear implant is the most extreme example I can think of, there are variations of these questions throughout the ‘disability’ communities.

Also, as Wolbring notes in his interview with the Technologist.eu, the education system tends to favour technological solutions which don’t take social issues into account. Wolbring cites social justice issues when he mentions failure and obsolescence.

Technical failures and obsolescence

The story, excerpted earlier in this posting, opened with a striking example of a technical failure at an awkward moment; a blind woman depending on her retinal implant loses all sight as she maneuvers through a subway station in New York City.

Aside from being an awful way to find out the company supplying and supporting your implant is in serious financial trouble and can’t offer assistance or repair, the failure offers a preview of what could happen as implants and prosthetics become more commonly used.

Keeping up/fomo (fear of missing out)/obsolescence

It used to be called ‘keeping up with the Joneses, it’s the practice of comparing yourself and your worldly goods to someone else(‘s) and then trying to equal what they have or do better. Usually, people want to have more and better than the mythical Joneses.

These days, the phenomenon (which has been expanded to include social networking) is better known as ‘fomo’ or fear of missing out (see the Fear of missing out Wikipedia entry).

Whatever you want to call it, humanity’s competitive nature can be seen where technology is concerned. When I worked in technology companies, I noticed that hardware and software were sometimes purchased for features that were effectively useless to us. But, not upgrading to a newer version was unthinkable.

Call it fomo or ‘keeping up with the Joneses’, it’s a powerful force and when people (and even companies) miss out or can’t keep up, it can lead to a sense of inferiority in the same way that having an obsolete implant or prosthetic could.

Social consequences

Could there be a neural implant/neuroprosthetic divide? There is already a digital divide (from its Wikipedia entry),

The digital divide is a gap between those who have access to new technology and those who do not … people without access to the Internet and other ICTs [information and communication technologies] are at a socio-economic disadvantage because they are unable or less able to find and apply for jobs, shop and sell online, participate democratically, or research and learn.

After reading Wolbring’s comments, it’s not hard to imagine a neural implant/neuroprosthetic divide with its attendant psychological and social consequences.

What kind of human am I?

There are other issues as noted in my September 17, 2020 posting. I’ve already mentioned ‘patient 6’, the woman who developed a symbiotic relationship with her brain/computer interface. This is how the relationship ended,

… He [Frederic Gilbert, ethicist] is now preparing a follow-up report on Patient 6. The company that implanted the device in her brain to help free her from seizures went bankrupt. The device had to be removed.

… Patient 6 cried as she told Gilbert about losing the device. … “I lost myself,” she said.

“It was more than a device,” Gilbert says. “The company owned the existence of this new person.”

Above human

The possibility that implants will not merely restore or endow someone with ‘standard’ sight or hearing or motion or … but will augment or improve on nature was broached in this May 2, 2013 posting, More than human—a bionic ear that extends hearing beyond the usual frequencies and is one of many in the ‘Human Enhancement’ category on this blog.

More recently, Hugh Herr, an Associate Professor at the Massachusetts Institute of Technology (MIT), leader of the Biomechatronics research group at MIT’s Media Lab, a double amputee, and prosthetic enthusiast, starred in the recent (February 23, 2022) broadcast of ‘Augmented‘ on the Public Broadcasting Service (PBS) science programme, Nova.

I found ‘Augmented’ a little offputting as it gave every indication of being an advertisement for Herr’s work in the form of a hero’s journey. I was not able to watch more than 10 mins. This preview gives you a pretty good idea of what it was like although the part in ‘Augmented, where he says he’d like to be a cyborg hasn’t been included,

At a guess, there were a few talking heads (taking up from 10%-20% of the running time) who provided some cautionary words to counterbalance the enthusiasm in the rest of the programme. It’s a standard approach designed to give the impression that both sides of a question are being recognized. The cautionary material is usually inserted past the 1/2 way mark while leaving several minutes at the end for returning to the more optimistic material.

In a February 2, 2010 posting I have excerpts from an article featuring quotes from Herr that I still find startling,

Written by Paul Hochman for Fast Company, Bionic Legs, iLimbs, and Other Super-Human Prostheses [ETA March 23, 2022: an updated version of the article is now on Genius.com] delves further into the world where people may be willing to trade a healthy limb for a prosthetic. From the article,

There are many advantages to having your leg amputated.

Pedicure costs drop 50% overnight. A pair of socks lasts twice as long. But Hugh Herr, the director of the Biomechatronics Group at the MIT Media Lab, goes a step further. “It’s actually unfair,” Herr says about amputees’ advantages over the able-bodied. “As tech advancements in prosthetics come along, amputees can exploit those improvements. They can get upgrades. A person with a natural body can’t.”

Herr is not the only one who favours prosthetics (also from the Hochman article),

This influx of R&D cash, combined with breakthroughs in materials science and processor speed, has had a striking visual and social result: an emblem of hurt and loss has become a paradigm of the sleek, modern, and powerful. Which is why Michael Bailey, a 24-year-old student in Duluth, Georgia, is looking forward to the day when he can amputate the last two fingers on his left hand.

“I don’t think I would have said this if it had never happened,” says Bailey, referring to the accident that tore off his pinkie, ring, and middle fingers. “But I told Touch Bionics I’d cut the rest of my hand off if I could make all five of my fingers robotic.”

But Bailey is most surprised by his own reaction. “When I’m wearing it, I do feel different: I feel stronger. As weird as that sounds, having a piece of machinery incorporated into your body, as a part of you, well, it makes you feel above human.[emphasis mine] It’s a very powerful thing.”

My September 17, 2020 posting touches on more ethical and social issues including some of those surrounding consumer neurotechnologies or brain-computer interfaces (BCI). Unfortunately, I don’t have space for these issues here.

As for Paul Hochman’s article, Bionic Legs, iLimbs, and Other Super-Human Prostheses, now on Genius.com, it has been updated.

Money makes the world go around

Money and business practices have been indirectly referenced (for the most part) up to now in this posting. The February 15, 2022 IEEE Spectrum article and Hochman’s article, Bionic Legs, iLimbs, and Other Super-Human Prostheses, cover two aspects of the money angle.

In the IEEE Spectrum article, a tech start-up company, Second Sight, ran into financial trouble and is acquired by a company that has no plans to develop Second Sight’s core technology. The people implanted with the Argus II technology have been stranded as were ‘patient 6’ and others participating in the clinical trial described in the July 24, 2019 article by Liam Drew for Nature Outlook: The brain mentioned earlier in this posting.

I don’t know anything about the business bankruptcy mentioned in the Drew article but one of the business problems described in the IEEE Spectrum article suggests that Second Sight was founded before answering a basic question, “What is the market size for this product?”

On 18 July 2019, Second Sight sent Argus patients a letter saying it would be phasing out the retinal implant technology to clear the way for the development of its next-generation brain implant for blindness, Orion, which had begun a clinical trial with six patients the previous year. …

“The leadership at the time didn’t believe they could make [the Argus retinal implant] part of the business profitable,” Greenberg [Robert Greenberg, Second Sight co-founder] says. “I understood the decision, because I think the size of the market turned out to be smaller than we had thought.”

….

The question of whether a medical procedure or medicine can be profitable (or should the question be sufficiently profitable?) was referenced in my April 26, 2019 posting in the context of gene editing and personalized medicine

Edward Abrahams, president of the Personalized Medicine Coalition (US-based), advocates for personalized medicine while noting in passing, market forces as represented by Goldman Sachs in his May 23, 2018 piece for statnews.com (Note: A link has been removed),

Goldman Sachs, for example, issued a report titled “The Genome Revolution.” It argues that while “genome medicine” offers “tremendous value for patients and society,” curing patients may not be “a sustainable business model.” [emphasis mine] The analysis underlines that the health system is not set up to reap the benefits of new scientific discoveries and technologies. Just as we are on the precipice of an era in which gene therapies, gene-editing, and immunotherapies promise to address the root causes of disease, Goldman Sachs says that these therapies have a “very different outlook with regard to recurring revenue versus chronic therapies.”

The ‘Glybera’ story in my July 4, 2019 posting (scroll down about 40% of the way) highlights the issue with “recurring revenue versus chronic therapies,”

Kelly Crowe in a November 17, 2018 article for the CBC (Canadian Broadcasting Corporation) news writes about Glybera,

It is one of this country’s great scientific achievements.

“The first drug ever approved that can fix a faulty gene.

It’s called Glybera, and it can treat a painful and potentially deadly genetic disorder with a single dose — a genuine made-in-Canada medical breakthrough.

But most Canadians have never heard of it.

Here’s my summary (from the July 4, 2019 posting),

It cost $1M for a single treatment and that single treatment is good for at least 10 years.

Pharmaceutical companies make their money from repeated use of their medicaments and Glybera required only one treatment so the company priced it according to how much they would have gotten for repeated use, $100,000 per year over a 10 year period. The company was not able to persuade governments and/or individuals to pay the cost

In the end, 31 people got the treatment, most of them received it for free through clinical trials.

For rich people only?

Megan Devlin’s March 8, 2022 article for the Daily Hive announces a major research investment into medical research (Note: A link has been removed),

Vancouver [Canada] billionaire Chip Wilson revealed Tuesday [March 8, 2022] that he has a rare genetic condition that causes his muscles to waste away, and announced he’s spending $100 million on research to find a cure.

His condition is called facio-scapulo-humeral muscular dystrophy, or FSHD for short. It progresses rapidly in some people and more slowly in others, but is characterized by progressive muscle weakness starting the the face, the neck, shoulders, and later the lower body.

“I’m out for survival of my own life,” Wilson said.

“I also have the resources to do something about this which affects so many people in the world.”

Wilson hopes the $100 million will produce a cure or muscle-regenerating treatment by 2027.

“This could be one of the biggest discoveries of all time, for humankind,” Wilson said. “Most people lose muscle, they fall, and they die. If we can keep muscle as we age this can be a longevity drug like we’ve never seen before.”

According to rarediseases.org, FSHD affects between four and 10 people out of every 100,000 [emphasis mine], Right now, therapies are limited to exercise and pain management. There is no way to stall or reverse the disease’s course.

Wilson is best known for founding athleisure clothing company Lululemon. He also owns the most expensive home in British Columbia, a $73 million mansion in Vancouver’s Kitsilano neighbourhood.

Let’s see what the numbers add up to,

4 – 10 people out of 100,000

40 – 100 people out of 1M

1200 – 3,000 people out of 30M (let’s say this is Canada’s population)\

12,000 – 30,000 people out of 300M (let’s say this is the US’s population)

42,000 – 105,000 out of 1.115B (let’s say this is China’s population)

The rough total comes to 55,200 to 138,000 people between three countries with a combined population total of 1.445B. Given how business currently operates, it seems unlikely that any company will want to offer Wilson’s hoped for medical therapy although he and possibly others may benefit from a clinical trial.

Should profit or wealth be considerations?

The stories about the patients with the implants and the patients who need Glybera are heartbreaking and point to a question not often asked when medical therapies and medications are developed. Is the profit model the best choice and, if so, how much profit?

I have no answer to that question but I wish it was asked by medical researchers and policy makers.

As for wealthy people dictating the direction for medical research, I don’t have answers there either. I hope the research will yield applications and/or valuable information for more than Wilson’s disease.

It’s his money after all

Wilson calls his new venture, SolveFSHD. It doesn’t seem to be affiliated with any university or biomedical science organization and it’s not clear how the money will be awarded (no programmes, no application procedure, no panel of experts). There are three people on the team, Eva R. Chin, scientist and executive director, Chip Wilson, SolveFSHD founder/funder, and FSHD patient, and Neil Camarta, engineer, executive (fossil fuels and clean energy), and FSHD patient. There’s also a Twitter feed (presumably for the latest updates): https://twitter.com/SOLVEFSHD.

Perhaps unrelated but intriguing is news about a proposed new building in Kenneth Chan’s March 31, 2022 article for the Daily Hive,

Low Tide Properties, the real estate arm of Lululemon founder Chip Wilson [emphasis mine], has submitted a new development permit application to build a 148-ft-tall, eight-storey, mixed-use commercial building in the False Creek Flats of Vancouver.

The proposal, designed by local architectural firm Musson Cattell Mackey Partnership, calls for 236,000 sq ft of total floor area, including 105,000 sq ft of general office space, 102,000 sq ft of laboratory space [emphasis mine], and 5,000 sq ft of ground-level retail space. An outdoor amenity space for building workers will be provided on the rooftop.

[next door] The 2001-built, five-storey building at 1618 Station Street immediately to the west of the development site is also owned by Low Tide Properties [emphasis mine]. The Ferguson, the name of the existing building, contains about 79,000 sq ft of total floor area, including 47,000 sq ft of laboratory space and 32,000 sq ft of general office space. Biotechnology company Stemcell technologies [STEMCELL] Technologies] is the anchor tenant [emphasis mine].

I wonder if this proposed new building will house SolveFSHD and perhaps other FSHD-focused enterprises. The proximity of STEMCELL Technologies could be quite convenient. In any event, $100M will buy a lot (pun intended).

The end

Issues I’ve described here in the context of neural implants/neuroprosthetics and cutting edge medical advances are standard problems not specific to these technologies/treatments:

  • What happens when the technology fails (hopefully not at a critical moment)?
  • What happens when your supplier goes out of business or discontinues the products you purchase from them?
  • How much does it cost?
  • Who can afford the treatment/product? Will it only be for rich people?
  • Will this technology/procedure/etc. exacerbate or create new social tensions between social classes, cultural groups, religious groups, races, etc.?

Of course, having your neural implant fail suddenly in the middle of a New York City subway station seems a substantively different experience than having your car break down on the road.

There are, of course, there are the issues we can’t yet envision (as Wolbring notes) and there are issues such as symbiotic relationships with our implants and/or feeling that you are “above human.” Whether symbiosis and ‘implant/prosthetic superiority’ will affect more than a small number of people or become major issues is still to be determined.

There’s a lot to be optimistic about where new medical research and advances are concerned but I would like to see more thoughtful coverage in the media (e.g., news programmes and documentaries like ‘Augmented’) and more thoughtful comments from medical researchers.

Of course, the biggest issue I’ve raised here is about the current business models for health care products where profit is valued over people’s health and well-being. it’s a big question and I don’t see any definitive answers but the question put me in mind of this quote (from a September 22, 2020 obituary for US Supreme Court Justice Ruth Bader Ginsburg by Irene Monroe for Curve),

Ginsburg’s advocacy for justice was unwavering and showed it, especially with each oral dissent. In another oral dissent, Ginsburg quoted a familiar Martin Luther King Jr. line, adding her coda:” ‘The arc of the universe is long, but it bends toward justice,’” but only “if there is a steadfast commitment to see the task through to completion.” …

Martin Luther King Jr. popularized and paraphrased the quote (from a January 18, 2018 article by Mychal Denzel Smith for Huffington Post),

His use of the quote is best understood by considering his source material. “The arc of the moral universe is long, but it bends toward justice” is King’s clever paraphrasing of a portion of a sermon delivered in 1853 by the abolitionist minister Theodore Parker. Born in Lexington, Massachusetts, in 1810, Parker studied at Harvard Divinity School and eventually became an influential transcendentalist and minister in the Unitarian church. In that sermon, Parker said: “I do not pretend to understand the moral universe. The arc is a long one. My eye reaches but little ways. I cannot calculate the curve and complete the figure by experience of sight. I can divine it by conscience. And from what I see I am sure it bends toward justice.”

I choose to keep faith that people will get the healthcare products they need and that all of us need to keep working at making access more fair.

Asparagus spinal cord?

I love this picture,

Pelling in the kitchen with asparagus, the veggie that inspired his work on spinal cord injuries. Credit: Andrew Pelling?

The image accompanies Cari Shane’s August 4, 2021 article for Atlas Obscura’s Gastro Obscura about Andrew Pelling and his asparagus-based scaffolds for spinal cord stem cells (Note: A link has been removed),

Around 10 years ago, Pelling [Dr. Andrew Pelling at the University of Ottawa], a biophysicist, started thinking with his team about materials that could be used to reconstruct damaged or diseased human tissues. Surrounded by a rainbow of fresh fruits and vegetables at his University of Ottawa lab, Pelling and his team dismantle biological systems, mixing and matching parts, and put them back together in new and creative ways. It’s a little bit like a hacker who takes parts from a phone, a computer, and a car to build a robotic arm. Or like Mary Shelley’s Dr. Frankenstein, who built a monster out of cadavers. Except Pelling’s team has turned an apple into an ear and, most recently, a piece of asparagus into a scaffold for spinal-cord implants.

Pelling believes the future of regenerative medicine—which uses external therapies to help the body heal, the same way a cut heals by itself or a broken bone can mend without surgery—is in the supermarket produce aisle. He calls it “augmented biology,” and it’s a lot less expensive—by thousands and thousands of dollars—than implanting organs donated by humans, taken from animals, or manmade or bioengineered from animal tissue.

Decellularization as a process for implantation is fairly new, developed in the mid 1990s primarily by Doris Taylor. By washing out the genetic materials that make an apple an apple, for example, you are left with plant tissue, or a “cellulose mesh,” explains Pelling. “What we’re doing is washing out all the plant DNA, RNA proteins, all that sort of stuff that can cause immune responses, and rejection. And we’re just leaving behind the fiber in a plant—like literally the stuff that gets stuck in your teeth.”

When Pelling noticed the resemblance between a decellularized apple slice and an ear, he saw the true potential of his lab games. If he implanted the apple scaffolding into a living animal, he wondered, would it “be accepted” and vascularize? That is, would the test animal’s body glom onto the plant cells as if they weren’t a dangerous, foreign body and instead send out signals to create a blood supply, allowing the plant tissue to become a living part of the animal’s body? The answer was yes. “Suddenly, and by accident, we developed a material that has huge therapeutic and regenerative potential,” says Pelling. The apple ear does not enable hearing, and it remains in the animal-testing phase, but it may have applications for aesthetic implantation.

Soon after his breakthrough apple experiment, which was published in 2016 and earned him the moniker of “mad scientist,” Pelling shifted his focus to asparagus. The idea hit him when he was cooking. Looking at the end of a spear, he thought, “Hey, it looks like a spinal cord. What the hell? Maybe we can do something,” he says.

… Pelling implanted decellularized asparagus tissue under the skin of a lab rat. In just a few weeks, blood vessels flowed through the asparagus scaffolding; healthy cells from the animal moved into the tissue and turned the scaffold into living tissue. “The surprise here was that the body, instead of rejecting this material, it actually integrated into the material,” says Pelling. In the bioengineering world, getting that to happen has typically been a major challenge.

And then came the biggest surprise of all. Rats with severed spinal cords that had been implanted with the asparagus tissue were able to walk again, just a few weeks after implantation. …

While using asparagus tissue as scaffolding to repair spinal cords is not a “miracle cure,” says Pelling, it’s unlike the kinds of implants that have come before. Donated or manufactured organs are historically both more complicated and more expensive. Pelling’s implants were “done without stem cells or electrical stimulation or exoskeletons, or any of the usual approaches, but rather using very low cost, accessible materials that we honestly just bought at the grocery store,” he says, “and, we achieved the same level of recovery.” (At least in animal tests.) Plus, whereas patients usually need lifelong immunosuppressants, which can have negative side effects, to prevent their body from rejecting an implant, that doesn’t seem necessary with Pelling’s plant-based implants. And, so far, the plant-based implants don’t seem to break down over time like traditional spinal-cord implants. “The inertness of plant tissue is exactly why it’s so biocompatible,” says Pelling.

In October 2020, the asparagus implant was designated as a “breakthrough device” by the FDA [US Food and Drug Administration]. The designation means human trials will be fast-tracked and likely begin in a few years. …

Shane’s August 4, 2021 article is fascinating and well illustrated with a number of embedded images. If you have the time and the inclination, do read it.

More of Pelling’s work can be found here at the Pelling Lab website. He was mentioned (by name only as a participant in the second Canadian DIY Biology Summit organized by the Public Health Agency of Canada [PHAC]) here in an April 21, 2020 posting (my 10 year review of science culture in Canada). You’ll find the Pelling mention under the DIY Biology subhead about 20% of the way down the screen.

Sunscreens 2020 and the Environmental Working Group (EWG)

There must be some sweet satisfaction or perhaps it’s better described as relief for the Environmental Working Group (EWG) now that sunscreens with metallic (zinc oxide and/or titanium dioxide) nanoparticles are gaining wide acceptance. (More about the history and politics EWG and metallic nanoparticles at the end of this posting.)

This acceptance has happened alongside growing concerns about oxybenzone, a sunscreen ingredient that EWG has long warned against. Oxybenzone has been banned from use in Hawaii due to environmental concerns (see my July 6, 2018 posting; scroll down about 40% of the way for specifics about Hawaii). Also, it is one of the common sunscreen ingredients for which the US Food and Drug Administration (FDA) is completing a safety review.

Today, zinc oxide and titanium dioxide metallic nanoparticles are being called minerals, as in, “mineral-based” sunscreens. They are categorized as physical sunscreens as opposed to chemical sunscreens.

I believe the most recent sunscreen posting here was my 2018 update (uly 6, 2018 posting) so the topic is overdue for some attention here. From a May 21, 2020 EWG news release (received via email),

As states reopen and Americans leave their homes to venture outside, it’s important for them to remember to protect their skin from the sun’s harmful rays. Today the Environmental Working Group released its 14th annual Guide to Sunscreens.  

This year researchers rated the safety and efficacy of more than 1,300 SPF products – including sunscreens, moisturizers and lip balms – and found that only 25 percent offer adequate protection and do not contain worrisome ingredients such as oxybenzone, a potential hormone-disrupting chemical that is readily absorbed by the body.

Despite a delay in finalizing rules that would make all sunscreens on U.S. store shelves safer, the Food and Drug Administration, the agency that governs sunscreen safety, is completing tests that highlight concerns with common sunscreen ingredients. Last year, the agency published two studies showing that, with just a single application, six commonly used chemical active ingredients, including oxybenzone, are readily absorbed through the skin and could be detected in our bodies at levels that could cause harm.

“It’s quite concerning,” said Nneka Leiba, EWG’s vice president of Healthy Living science. “Those studies don’t prove whether the sunscreens are unsafe, but they do highlight problems with how these products are regulated.”

“EWG has been advocating for the FDA to review these chemical ingredients for 14 years,” Leiba said. “We slather these ingredients on our skin, but these chemicals haven’t been adequately tested. This is just one example of the backward nature of product regulation in the U.S.”

Oxybenzone remains a commonly used active ingredient, found in more than 40 percent of the non-mineral sunscreens in this year’s guide. Oxybenzone is allergenic and a potential endocrine disruptor, and has been detected in human breast milk, amniotic fluid, urine and blood.

According to EWG’s assessment, fewer than half of the products in this year’s guide contain active ingredients that the FDA has proposed are safe and effective.

“Based on the best current science and toxicology data, we continue to recommend sunscreens with the mineral active ingredients zinc dioxide and titanium dioxide, because they are the only two ingredients the FDA recognized as safe or effective in their proposed draft rules,” said Carla Burns, an EWG research and database analyst who manages the updates to the sunscreen guide.

Most people select sunscreen products based on their SPF, or sunburn protection factor, and mistakenly assume that bigger numbers offer better protection. According to the FDA, higher SPF values have not been shown to provide additional clinical benefit and may give users a false sense of protection. This may lead to overexposure to UVA rays that increase the risk of long-term skin damage and cancer. The FDA has proposed limiting SPF claims to 60+.

EWG continues to hone our recommendations by strengthening the criteria for assessing sunscreens, which are based on the latest findings in the scientific literature and commissioned tests of sunscreen product efficacy. This year EWG made changes to our methodology in order to strengthen our requirement that products provide the highest level of UVA protection.

“Our understanding of the dangers associated with UVA exposure is increasing, and they are of great concern,” said Burns. “Sunburn during early life, especially childhood, is very dangerous and a risk factor for all skin cancers, but especially melanoma. Babies and young children are especially vulnerable to sun damage. Just a few blistering sunburns early in life can double a person’s risk of developing melanoma later in life.”

EWG researchers found 180 sunscreens that meet our criteria for safety and efficacy and would likely meet the proposed FDA standards. Even the biggest brands now provide mineral options for consumers.  

Even for Americans continuing to follow stay-at-home orders, wearing an SPF product may still be important. If you’re sitting by a window, UVA and UVB rays can penetrate the glass.  

It is important to remember that sunscreen is only one part of a sun safety routine. People should also protect their skin by covering up with clothing, hats and sunglasses. And sunscreen must be reapplied at least every two hours to stay effective.

EWG’s Guide to Sunscreens helps consumers find products that get high ratings for providing adequate broad-spectrum protection and that are made with ingredients that pose fewer health concerns.

The new guide also includes lists of:

Here are more quick tips for choosing better sunscreens:

  • Check your products in EWG’s sunscreen database and avoid those with harmful ingredients.
  • Avoid products with oxybenzone. This chemical penetrates the skin, gets into the bloodstream and can affect normal hormone activities.
  • Steer clear of products with SPF higher than 50+. High SPF values do not necessarily provide increased UVA protection and may fool you into thinking you are safe from sun damage.
  • Avoid sprays. These popular products pose inhalation concerns, and they may not provide a thick and uniform coating on the skin.
  • Stay away from retinyl palmitate. Government studies link the use of retinyl palmitate, a form of vitamin A, to the formation of skin tumors and lesions when it is applied to sun-exposed skin.
  • Avoid intense sun exposure during the peak hours of 10 a.m. to 4 p.m.

Shoppers on the go can download EWG’s Healthy Living app to get ratings and safety information on sunscreens and other personal care products. Also be sure to check out EWG’s sunscreen label decoder.

One caveat, these EWG-recommended products might not be found in Canadian stores or your favourite product may not have been reviewed for inclusion, as a product to be sought out or avoided, in their database. For example, I use a sunscreen that isn’t listed in the database, although at least a few other of the company’s sunscreen products are. On the plus side, my sunscreen doesn’t include oxybenzone or retinyl palmitate as ingredients.

To sum up the situation with sunscreens containing metallic nanoparticles (minerals), they are considered to be relatively safe but should new research emerge that designation could change. In effect, all we can do is our best with the information at hand.

History and politics of metallic nanoparticles in sunscreens

In 2009 it was a bit of a shock when the EWG released a report recommending the use of sunscreens with metallic nanoparticles in the list of ingredients. From my July 9, 2009 posting,

The EWG (Environmental Working Group) is, according to Maynard [as of 20202: Dr. Andrew Maynard is a scientist and author, Associate Director of Faculty in the ASU {Arizona State University} School for the Future of Innovation in Society, also the director of the ASU Risk Innovation Lab, and leader of the Risk Innovation Nexus], not usually friendly to industry and they had this to say about their own predisposition prior to reviewing the data (from EWG),

When we began our sunscreen investigation at the Environmental Working Group, our researchers thought we would ultimately recommend against micronized and nano-sized zinc oxide and titanium dioxide sunscreens. After all, no one has taken a more expansive and critical look than EWG at the use of nanoparticles in cosmetics and sunscreens, including the lack of definitive safety data and consumer information on these common new ingredients, and few substances more dramatically highlight gaps in our system of public health protections than the raw materials used in the burgeoning field of nanotechnology. But many months and nearly 400 peer-reviewed studies later, we find ourselves drawing a different conclusion, and recommending some sunscreens that may contain nano-sized ingredients.

My understanding is that after this report, the EWG was somewhat ostracized by collegial organizations. Friends of the Earth (FoE) and the ETC Group both of which issued reports that were published after the EWG report and were highly critical of ‘nano sunscreens’.

The ETC Group did not continue its anti nanosunscreen campaign for long (I saw only one report) but FoE (in particular the Australian arm of the organization) more than made up for that withdrawal and to sad effect. My February 9, 2012 post title was this: Unintended consequences: Australians not using sunscreens to avoid nanoparticles?

An Australian government survey found that 13% of Australians were not using any sunscreen due to fears about nanoparticles. In a country with the highest incidence of skin cancer in the world and, which spent untold millions over decades getting people to cover up in the sun, it was devastating news.

FoE immediately withdrew all their anti nanosunscreen materials in Australia from circulation while firing broadsides at the government. The organization’s focus on sunscreens with metallic nanoparticles has diminished since 2012.

Research

I have difficulty trusting materials from FoE and you can see why here in this July 26, 2011 posting (Misunderstanding the data or a failure to research? Georgia Straight article about nanoparticles). In it, I analyze Alex Roslin’s profoundly problematic article about metallic nanoparticles and other engineered nanoparticles. All of Roslin’s article was based on research and materials produced by FoE which misrepresented some of the research. Roslin would have realized that if he had bothered to do any research for himself.

EWG impressed me mightily with their refusal to set aside or dismiss the research disputing their initial assumption that metallic nanoparticles in sunscreens were hazardous. (BTW, there is one instance where metallic nanoparticles in sunscreens are of concern. My October 13, 2013 posting about anatase and rutile forms of titanium dioxide at the nanoscale features research on that issue.)

EWG’s Wikipedia entry

Whoever and however many are maintaining this page, they don’t like EWG at all,

The accuracy of EWG reports and statements have been criticized, as has its funding by the organic food industry[2][3][4][5] Its warnings have been labeled “alarmist”, “scaremongering” and “misleading”.[6][7][8] Despite the questionable status of its work, EWG has been influential.[9]

This is the third paragraph in the Introduction. At its very best, the information is neutral, otherwise, it’s much like that third paragraph.

Even John D. Rockeller’s entry is more flattering and he was known as the ‘most hated man in America’ as this show description on the Public Broadcasting Service (PBS) website makes clear,

American Experience

The Rockefellers Chapter One

Clip: Season 13 Episode 1 | 9m 37s

John D. Rockefeller was the world’s first billionaire and the most hated man in America. Watch the epic story of the man who monopolized oil.

Fun in the sun

Have fun in the sun this summer. There’s EWG’s sunscreen database, the tips listed in the news release, and EWG also has a webpage where they describe their methodology for how they assess sunscreens. It gets a little technical (for me anyway) but it should answer any further safety questions you might have after reading this post.

It may require a bit of ingenuity given the concerns over COVID-19 but I’m constantly amazed at the inventiveness with which so many people have met this pandemic. (This June 15, 2020 Canadian Broadcasting Corporation article by Sheena Goodyear features a family that created a machine that won the 2020 Rube Goldberg Bar of Soap Video challenge. The article includes an embedded video of the winning machine in action.)

US Food and Drug Administration (FDA) gives first authorization for CRISPR (clustered regularly interspersed short palindromic repeats) use in COVID-19 crisis

Clustered regularly interspersed short palindromic repeats (CRISPR) gene editing has been largely confined to laboratory use or tested in agricultural trials. I believe that is true worldwide excepting the CRISPR twin scandal. (There are numerous postings about the CRISPR twins here including a Nov. 28, 2018 post, a May 17, 2019 post, and a June 20, 2019 post. Update: It was reported (3rd. para.) in December 2019 that He had been sentenced to three years jail time.)

Connie Lin in a May 7, 2020 article for Fast Company reports on this surprising decision by the US Food and Drug Administration (FDA), Note: A link has been removed),

The U.S. Food and Drug Administration has granted Emergency Use Authorization to a COVID-19 test that uses controversial gene-editing technology CRISPR.

This marks the first time CRISPR has been authorized by the FDA, although only for the purpose of detecting the coronavirus, and not for its far more contentious applications. The new test kit, developed by Cambridge, Massachusetts-based Sherlock Biosciences, will be deployed in laboratories certified to carry out high-complexity procedures and is “rapid,” returning results in about an hour as opposed to those that rely on the standard polymerase chain reaction method, which typically requires six hours.

The announcement was made in the FDA’s Coronavirus (COVID-19) Update: May 7, 2020 Daily Roundup (4th item in the bulleted list), Or, you can read the May 6, 2020 letter (PDF) sent to John Vozella of Sherlock Biosciences by the FDA.

As well, there’s the May 7, 2020 Sherlock BioSciences news release (the most informative of the lot),

Sherlock Biosciences, an Engineering Biology company dedicated to making diagnostic testing better, faster and more affordable, today announced the company has received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) for its Sherlock™ CRISPR SARS-CoV-2 kit for the detection of the virus that causes COVID-19, providing results in approximately one hour.

“While it has only been a little over a year since the launch of Sherlock Biosciences, today we have made history with the very first FDA-authorized use of CRISPR technology, which will be used to rapidly identify the virus that causes COVID-19,” said Rahul Dhanda, co-founder, president and CEO of Sherlock Biosciences. “We are committed to providing this initial wave of testing kits to physicians, laboratory experts and researchers worldwide to enable them to assist frontline workers leading the charge against this pandemic.”

The Sherlock™ CRISPR SARS-CoV-2 test kit is designed for use in laboratories certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. §263a, to perform high complexity tests. Based on the SHERLOCK method, which stands for Specific High-sensitivity Enzymatic Reporter unLOCKing, the kit works by programming a CRISPR molecule to detect the presence of a specific genetic signature – in this case, the genetic signature for SARS-CoV-2 – in a nasal swab, nasopharyngeal swab, oropharyngeal swab or bronchoalveolar lavage (BAL) specimen. When the signature is found, the CRISPR enzyme is activated and releases a detectable signal. In addition to SHERLOCK, the company is also developing its INSPECTR™ platform to create an instrument-free, handheld test – similar to that of an at-home pregnancy test – that utilizes Sherlock Biosciences’ Synthetic Biology platform to provide rapid detection of a genetic match of the SARS-CoV-2 virus.

“When our lab collaborated with Dr. Feng Zhang’s team to develop SHERLOCK, we believed that this CRISPR-based diagnostic method would have a significant impact on global health,” said James J. Collins, co-founder and board member of Sherlock Biosciences and Termeer Professor of Medical Engineering and Science for MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering. “During what is a major healthcare crisis across the globe, we are heartened that the first FDA-authorized use of CRISPR will aid in the fight against this global COVID-19 pandemic.”

Access to rapid diagnostics is critical for combating this pandemic and is a primary focus for Sherlock Biosciences co-founder and board member, David R. Walt, Ph.D., who co-leads the Mass [Massachusetts] General Brigham Center for COVID Innovation.

“SHERLOCK enables rapid identification of a single alteration in a DNA or RNA sequence in a single molecule,” said Dr. Walt. “That precision, coupled with its capability to be deployed to multiplex over 100 targets or as a simple point-of-care system, will make it a critical addition to the arsenal of rapid diagnostics already being used to detect COVID-19.”

This development is particularly interesting since there was a major intellectual property dispute over CRISPR between the Broad Institute (a Harvard University and Massachusetts Institute of Technology [MIT] joint initiative), and the University of California at Berkeley (UC Berkeley). The Broad Institute mostly won in the first round of the patent fight, as I noted in a March 15, 2017 post but, as far as I’m aware, UC Berkeley is still disputing that decision.

In the period before receiving authorization, it appears that Sherlock Biosciences was doing a little public relations and ‘consciousness raising’ work. Here’s a sample from a May 5, 2020 article by Sharon Begley for STAT (Note: Links have been removed),

The revolutionary genetic technique better known for its potential to cure thousands of inherited diseases could also solve the challenge of Covid-19 diagnostic testing, scientists announced on Tuesday. A team headed by biologist Feng Zhang of the McGovern Institute at MIT and the Broad Institute has repurposed the genome-editing tool CRISPR into a test able to quickly detect as few as 100 coronavirus particles in a swab or saliva sample.

Crucially, the technique, dubbed a “one pot” protocol, works in a single test tube and does not require the many specialty chemicals, or reagents, whose shortage has hampered the rollout of widespread Covid-19 testing in the U.S. It takes about an hour to get results, requires minimal handling, and in preliminary studies has been highly accurate, Zhang told STAT. He and his colleagues, led by the McGovern’s Jonathan Gootenberg and Omar Abudayyeh, released the protocol on their STOPCovid.science website.

Because the test has not been approved by the Food and Drug Administration, it is only for research purposes for now. But minutes before speaking to STAT on Monday, Zhang and his colleagues were on a conference call with FDA officials about what they needed to do to receive an “emergency use authorization” that would allow clinical use of the test. The FDA has used EUAs to fast-track Covid-19 diagnostics as well as experimental therapies, including remdesivir, after less extensive testing than usually required.

For an EUA, the agency will require the scientists to validate the test, which they call STOPCovid, on dozens to hundreds of samples. Although “it is still early in the process,” Zhang said, he and his colleagues are confident enough in its accuracy that they are conferring with potential commercial partners who could turn the test into a cartridge-like device, similar to a pregnancy test, enabling Covid-19 testing at doctor offices and other point-of-care sites.

“It could potentially even be used at home or at workplaces,” Zhang said. “It’s inexpensive, does not require a lab, and can return results within an hour using a paper strip, not unlike a pregnancy test. This helps address the urgent need for widespread, accurate, inexpensive, and accessible Covid-19 testing.” Public health experts say the availability of such a test is one of the keys to safely reopening society, which will require widespread testing, and then tracing and possibly isolating the contacts of those who test positive.

If you have time, do read Begley’s in full.

The CRISPR yogurt story and a hornless cattle update

Clustered regularly interspaced short palindromic repeats (CRISPR) does not and never has made much sense to me. I understand each word individually it’s just that I’ve never thought they made much sense strung together that way. It’s taken years but I’ve finally found out what the words (when strung together that way) mean and the origins for the phrase. Hint: it’s all about the phages.

Apparently, it all started with yogurt as Cynthia Graber and Nicola Twilley of Gastropod discuss on their podcast, “4 CRISPR experts on how gene editing is changing the future of food.” During the course of the podcast they explain the ‘phraseology’ issue, mention hornless cattle (I have an update to the information in the podcast later in this posting), and so much more.

CRISPR started with yogurt

You’ll find the podcast (almost 50 minutes long) here on an Oct. 11, 2019 posting on the Genetic Literacy Project. If you need a little more encouragement, here’s how the podcast is described,

To understand how CRISPR will transform our food, we begin our episode at Dupont’s yoghurt culture facility in Madison, Wisconsin. Senior scientist Dennis Romero tells us the story of CRISPR’s accidental discovery—and its undercover but ubiquitous presence in the dairy aisles today.

Jennifer Kuzma and Yiping Qi help us understand the technology’s potential, both good and bad, as well as how it might be regulated and labeled. And Joyce Van Eck, a plant geneticist at the Boyce Thompson Institute in Ithaca, New York, tells us the story of how she is using CRISPR, combined with her understanding of tomato genetics, to fast-track the domestication of one of the Americas’ most delicious orphan crops [groundcherries].

I featured Van Eck’s work with groundcherries last year in a November 28, 2018 posting and I don’t think she’s published any new work about the fruit since. As for Kuzma’s point that there should be more transparency where genetically modified food is concerned, Canadian consumers were surprised (shocked) in 2017 to find out that genetically modified Atlantic salmon had been introduced into the food market without any notification (my September 13, 2017 posting; scroll down to the Fish subheading; Note: The WordPress ‘updated version from Hell’ has affected some of the formatting on the page).

The earliest article on CRISPR and yogurt that I’ve found is a January 1, 2015 article by Kerry Grens for The Scientist,

Two years ago, a genome-editing tool referred to as CRISPR (clustered regularly interspaced short palindromic repeats) burst onto the scene and swept through laboratories faster than you can say “adaptive immunity.” Bacteria and archaea evolved CRISPR eons before clever researchers harnessed the system to make very precise changes to pretty much any sequence in just about any genome.

But life scientists weren’t the first to get hip to CRISPR’s potential. For nearly a decade, cheese and yogurt makers have been relying on CRISPR to produce starter cultures that are better able to fend off bacteriophage attacks. “It’s a very efficient way to get rid of viruses for bacteria,” says Martin Kullen, the global R&D technology leader of Health and Protection at DuPont Nutrition & Health. “CRISPR’s been an important part of our solution to avoid food waste.”

Phage infection of starter cultures is a widespread and significant problem in the dairy-product business, one that’s been around as long as people have been making cheese. Patrick Derkx, senior director of innovation at Denmark-based Chr. Hansen, one of the world’s largest culture suppliers, estimates that the quality of about two percent of cheese production worldwide suffers from phage attacks. Infection can also slow the acidification of milk starter cultures, thereby reducing creameries’ capacity by up to about 10 percent, Derkx estimates.
In the early 2000s, Philippe Horvath and Rodolphe Barrangou of Danisco (later acquired by DuPont) and their colleagues were first introduced to CRISPR while sequencing Streptococcus thermophilus, a workhorse of yogurt and cheese production. Initially, says Barrangou, they had no idea of the purpose of the CRISPR sequences. But as his group sequenced different strains of the bacteria, they began to realize that CRISPR might be related to phage infection and subsequent immune defense. “That was an eye-opening moment when we first thought of the link between CRISPR sequencing content and phage resistance,” says Barrangou, who joined the faculty of North Carolina State University in 2013.

One last bit before getting to the hornless cattle, scientist Yi Li has a November 15, 2018 posting on the GLP website about his work with gene editing and food crops,

I’m a plant geneticist and one of my top priorities is developing tools to engineer woody plants such as citrus trees that can resist the greening disease, Huanglongbing (HLB), which has devastated these trees around the world. First detected in Florida in 2005, the disease has decimated the state’s US$9 billion citrus crop, leading to a 75 percent decline in its orange production in 2017. Because citrus trees take five to 10 years before they produce fruits, our new technique – which has been nominated by many editors-in-chief as one of the groundbreaking approaches of 2017 that has the potential to change the world – may accelerate the development of non-GMO citrus trees that are HLB-resistant.

Genetically modified vs. gene edited

You may wonder why the plants we create with our new DNA editing technique are not considered GMO? It’s a good question.

Genetically modified refers to plants and animals that have been altered in a way that wouldn’t have arisen naturally through evolution. A very obvious example of this involves transferring a gene from one species to another to endow the organism with a new trait – like pest resistance or drought tolerance.

But in our work, we are not cutting and pasting genes from animals or bacteria into plants. We are using genome editing technologies to introduce new plant traits by directly rewriting the plants’ genetic code.

This is faster and more precise than conventional breeding, is less controversial than GMO techniques, and can shave years or even decades off the time it takes to develop new crop varieties for farmers.

There is also another incentive to opt for using gene editing to create designer crops. On March 28, 2018, U.S. Secretary of Agriculture Sonny Perdue announced that the USDA wouldn’t regulate new plant varieties developed with new technologies like genome editing that would yield plants indistinguishable from those developed through traditional breeding methods. By contrast, a plant that includes a gene or genes from another organism, such as bacteria, is considered a GMO. This is another reason why many researchers and companies prefer using CRISPR in agriculture whenever it is possible.

As the Gatropod’casters note, there’s more than one side to the gene editing story and not everyone is comfortable with the notion of cavalierly changing genetic codes when so much is still unknown.

Hornless cattle update

First mentioned here in a November 28, 2018 posting, hornless cattle have been in the news again. From an October 7, 2019 news item on ScienceDaily,

For the past two years, researchers at the University of California, Davis, have been studying six offspring of a dairy bull, genome-edited to prevent it from growing horns. This technology has been proposed as an alternative to dehorning, a common management practice performed to protect other cattle and human handlers from injuries.

UC Davis scientists have just published their findings in the journal Nature Biotechnology. They report that none of the bull’s offspring developed horns, as expected, and blood work and physical exams of the calves found they were all healthy. The researchers also sequenced the genomes of the calves and their parents and analyzed these genomic sequences, looking for any unexpected changes.

An October 7, 2019 UC Davis news release (also on EurekAlert), which originated the news item, provides more detail about the research (I have checked the UC Davis website here and the October 2019 update appears to be the latest available publicly as of February 5, 2020),

All data were shared with the U.S. Food and Drug Administration. Analysis by FDA scientists revealed a fragment of bacterial DNA, used to deliver the hornless trait to the bull, had integrated alongside one of the two hornless genetic variants, or alleles, that were generated by genome-editing in the bull. UC Davis researchers further validated this finding.

“Our study found that two calves inherited the naturally-occurring hornless allele and four calves additionally inherited a fragment of bacterial DNA, known as a plasmid,” said corresponding author Alison Van Eenennaam, with the UC Davis Department of Animal Science.

Plasmid integration can be addressed by screening and selection, in this case, selecting the two offspring of the genome-edited hornless bull that inherited only the naturally occurring allele.

“This type of screening is routinely done in plant breeding where genome editing frequently involves a step that includes a plasmid integration,” said Van Eenennaam.

Van Eenennaam said the plasmid does not harm the animals, but the integration technically made the genome-edited bull a GMO, because it contained foreign DNA from another species, in this case a bacterial plasmid.

“We’ve demonstrated that healthy hornless calves with only the intended edit can be produced, and we provided data to help inform the process for evaluating genome-edited animals,” said Van Eenennaam. “Our data indicates the need to screen for plasmid integration when they’re used in the editing process.”

Since the original work in 2013, initiated by the Minnesota-based company Recombinetics, new methods have been developed that no longer use donor template plasmid or other extraneous DNA sequence to bring about introgression of the hornless allele.

Scientists did not observe any other unintended genomic alterations in the calves, and all animals remained healthy during the study period. Neither the bull, nor the calves, entered the food supply as per FDA guidance for genome-edited livestock.

WHY THE NEED FOR HORNLESS COWS?

Many dairy breeds naturally grow horns. But on dairy farms, the horns are typically removed, or the calves “disbudded” at a young age. Animals that don’t have horns are less likely to harm animals or dairy workers and have fewer aggressive behaviors. The dehorning process is unpleasant and has implications for animal welfare. Van Eenennaam said genome-editing offers a pain-free genetic alternative to removing horns by introducing a naturally occurring genetic variant, or allele, that is present in some breeds of beef cattle such as Angus.

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

Genomic and phenotypic analyses of six offspring of a genome-edited hornless bull by Amy E. Young, Tamer A. Mansour, Bret R. McNabb, Joseph R. Owen, Josephine F. Trott, C. Titus Brown & Alison L. Van Eenennaam. Nature Biotechnology (2019) DOI: https://doi.org/10.1038/s41587-019-0266-0 Published 07 October 2019

This paper is open access.

Gene editing and personalized medicine: Canada

Back in the fall of 2018 I came across one of those overexcited pieces about personalized medicine and gene editing tha are out there. This one came from an unexpected source, an author who is a “PhD Scientist in Medical Science (Blood and Vasculature” (from Rick Gierczak’s LinkedIn profile).

It starts our promisingly enough although I’m beginning to dread the use of the word ‘precise’  where medicine is concerned, (from a September 17, 2018 posting on the Science Borealis blog by Rick Gierczak (Note: Links have been removed),

CRISPR-Cas9 technology was accidentally discovered in the 1980s when scientists were researching how bacteria defend themselves against viral infection. While studying bacterial DNA called clustered regularly interspaced short palindromic repeats (CRISPR), they identified additional CRISPR-associated (Cas) protein molecules. Together, CRISPR and one of those protein molecules, termed Cas9, can locate and cut precise regions of bacterial DNA. By 2012, researchers understood that the technology could be modified and used more generally to edit the DNA of any plant or animal. In 2015, the American Association for the Advancement of Science chose CRISPR-Cas9 as science’s “Breakthrough of the Year”.

Today, CRISPR-Cas9 is a powerful and precise gene-editing tool [emphasis mine] made of two molecules: a protein that cuts DNA (Cas9) and a custom-made length of RNA that works like a GPS for locating the exact spot that needs to be edited (CRISPR). Once inside the target cell nucleus, these two molecules begin editing the DNA. After the desired changes are made, they use a repair mechanism to stitch the new DNA into place. Cas9 never changes, but the CRISPR molecule must be tailored for each new target — a relatively easy process in the lab. However, it’s not perfect, and occasionally the wrong DNA is altered [emphasis mine].

Note that Gierczak makes a point of mentioning that CRISPR/Cas9 is “not perfect.” And then, he gets excited (Note: Links have been removed),

CRISPR-Cas9 has the potential to treat serious human diseases, many of which are caused by a single “letter” mutation in the genetic code (A, C, T, or G) that could be corrected by precise editing. [emphasis mine] Some companies are taking notice of the technology. A case in point is CRISPR Therapeutics, which recently developed a treatment for sickle cell disease, a blood disorder that causes a decrease in oxygen transport in the body. The therapy targets a special gene called fetal hemoglobin that’s switched off a few months after birth. Treatment involves removing stem cells from the patient’s bone marrow and editing the gene to turn it back on using CRISPR-Cas9. These new stem cells are returned to the patient ready to produce normal red blood cells. In this case, the risk of error is eliminated because the new cells are screened for the correct edit before use.

The breakthroughs shown by companies like CRISPR Therapeutics are evidence that personalized medicine has arrived. [emphasis mine] However, these discoveries will require government regulatory approval from the countries where the treatment is going to be used. In the US, the Food and Drug Administration (FDA) has developed new regulations allowing somatic (i.e., non-germ) cell editing and clinical trials to proceed. [emphasis mine]

The potential treatment for sickle cell disease is exciting but Gierczak offers no evidence that this treatment or any unnamed others constitute proof that “personalized medicine has arrived.” In fact, Goldman Sachs, a US-based investment bank, makes the case that it never will .

Cost/benefit analysis

Edward Abrahams, president of the Personalized Medicine Coalition (US-based), advocates for personalized medicine while noting in passing, market forces as represented by Goldman Sachs in his May 23, 2018 piece for statnews.com (Note: A link has been removed),

One of every four new drugs approved by the Food and Drug Administration over the last four years was designed to become a personalized (or “targeted”) therapy that zeros in on the subset of patients likely to respond positively to it. That’s a sea change from the way drugs were developed and marketed 10 years ago.

Some of these new treatments have extraordinarily high list prices. But focusing solely on the cost of these therapies rather than on the value they provide threatens the future of personalized medicine.

… most policymakers are not asking the right questions about the benefits of these treatments for patients and society. Influenced by cost concerns, they assume that prices for personalized tests and treatments cannot be justified even if they make the health system more efficient and effective by delivering superior, longer-lasting clinical outcomes and increasing the percentage of patients who benefit from prescribed treatments.

Goldman Sachs, for example, issued a report titled “The Genome Revolution.” It argues that while “genome medicine” offers “tremendous value for patients and society,” curing patients may not be “a sustainable business model.” [emphasis mine] The analysis underlines that the health system is not set up to reap the benefits of new scientific discoveries and technologies. Just as we are on the precipice of an era in which gene therapies, gene-editing, and immunotherapies promise to address the root causes of disease, Goldman Sachs says that these therapies have a “very different outlook with regard to recurring revenue versus chronic therapies.”

Let’s just chew on this one (contemplate)  for a minute”curing patients may not be ‘sustainable business model’!”

Coming down to earth: policy

While I find Gierczak to be over-enthused, he, like Abrahams, emphasizes the importance of new policy, in his case, the focus is Canadian policy. From Gierczak’s September 17, 2018 posting (Note: Links have been removed),

In Canada, companies need approval from Health Canada. But a 2004 law called the Assisted Human Reproduction Act (AHR Act) states that it’s a criminal offence “to alter the genome of a human cell, or in vitroembryo, that is capable of being transmitted to descendants”. The Actis so broadly written that Canadian scientists are prohibited from using the CRISPR-Cas9 technology on even somatic cells. Today, Canada is one of the few countries in the world where treating a disease with CRISPR-Cas9 is a crime.

On the other hand, some countries provide little regulatory oversight for editing either germ or somatic cells. In China, a company often only needs to satisfy the requirements of the local hospital where the treatment is being performed. And, if germ-cell editing goes wrong, there is little recourse for the future generations affected.

The AHR Act was introduced to regulate the use of reproductive technologies like in vitrofertilization and research related to cloning human embryos during the 1980s and 1990s. Today, we live in a time when medical science, and its role in Canadian society, is rapidly changing. CRISPR-Cas9 is a powerful tool, and there are aspects of the technology that aren’t well understood and could potentially put patients at risk if we move ahead too quickly. But the potential benefits are significant. Updated legislation that acknowledges both the risks and current realities of genomic engineering [emphasis mine] would relieve the current obstacles and support a path toward the introduction of safe new therapies.

Criminal ban on human gene-editing of inheritable cells (in Canada)

I had no idea there was a criminal ban on the practice until reading this January 2017 editorial by Bartha Maria Knoppers, Rosario Isasi, Timothy Caulfield, Erika Kleiderman, Patrick Bedford, Judy Illes, Ubaka Ogbogu, Vardit Ravitsky, & Michael Rudnicki for (Nature) npj Regenerative Medicine (Note: Links have been removed),

Driven by the rapid evolution of gene editing technologies, international policy is examining which regulatory models can address the ensuing scientific, socio-ethical and legal challenges for regenerative and personalised medicine.1 Emerging gene editing technologies, including the CRISPR/Cas9 2015 scientific breakthrough,2 are powerful, relatively inexpensive, accurate, and broadly accessible research tools.3 Moreover, they are being utilised throughout the world in a wide range of research initiatives with a clear eye on potential clinical applications. Considering the implications of human gene editing for selection, modification and enhancement, it is time to re-examine policy in Canada relevant to these important advances in the history of medicine and science, and the legislative and regulatory frameworks that govern them. Given the potential human reproductive applications of these technologies, careful consideration of these possibilities, as well as ethical and regulatory scrutiny must be a priority.4

With the advent of human embryonic stem cell research in 1978, the birth of Dolly (the cloned sheep) in 1996 and the Raelian cloning hoax in 2003, the environment surrounding the enactment of Canada’s 2004 Assisted Human Reproduction Act (AHRA) was the result of a decade of polarised debate,5 fuelled by dystopian and utopian visions for future applications. Rightly or not, this led to the AHRA prohibition on a wide range of activities, including the creation of embryos (s. 5(1)(b)) or chimeras (s. 5(1)(i)) for research and in vitro and in vivo germ line alterations (s. 5(1)(f)). Sanctions range from a fine (up to $500,000) to imprisonment (up to 10 years) (s. 60 AHRA).

In Canada, the criminal ban on gene editing appears clear, the Act states that “No person shall knowingly […] alter the genome of a cell of a human being or in vitro embryo such that the alteration is capable of being transmitted to descendants;” [emphases mine] (s. 5(1)(f) AHRA). This approach is not shared worldwide as other countries such as the United Kingdom, take a more regulatory approach to gene editing research.1 Indeed, as noted by the Law Reform Commission of Canada in 1982, criminal law should be ‘an instrument of last resort’ used solely for “conduct which is culpable, seriously harmful, and generally conceived of as deserving of punishment”.6 A criminal ban is a suboptimal policy tool for science as it is inflexible, stifles public debate, and hinders responsiveness to the evolving nature of science and societal attitudes.7 In contrast, a moratorium such as the self-imposed research moratorium on human germ line editing called for by scientists in December 20158 can at least allow for a time limited pause. But like bans, they may offer the illusion of finality and safety while halting research required to move forward and validate innovation.

On October 1st, 2016, Health Canada issued a Notice of Intent to develop regulations under the AHRA but this effort is limited to safety and payment issues (i.e. gamete donation). Today, there is a need for Canada to revisit the laws and policies that address the ethical, legal and social implications of human gene editing. The goal of such a critical move in Canada’s scientific and legal history would be a discussion of the right of Canadians to benefit from the advancement of science and its applications as promulgated in article 27 of the Universal Declaration of Human Rights9 and article 15(b) of the International Covenant on Economic, Social and Cultural Rights,10 which Canada has signed and ratified. Such an approach would further ensure the freedom of scientific endeavour both as a principle of a liberal democracy and as a social good, while allowing Canada to be engaged with the international scientific community.

Even though it’s a bit old, I still recommend reading the open access editorial in full, if you have the time.

One last thing abut the paper, the acknowledgements,

Sponsored by Canada’s Stem Cell Network, the Centre of Genomics and Policy of McGill University convened a ‘think tank’ on the future of human gene editing in Canada with legal and ethics experts as well as representatives and observers from government in Ottawa (August 31, 2016). The experts were Patrick Bedford, Janetta Bijl, Timothy Caulfield, Judy Illes, Rosario Isasi, Jonathan Kimmelman, Erika Kleiderman, Bartha Maria Knoppers, Eric Meslin, Cate Murray, Ubaka Ogbogu, Vardit Ravitsky, Michael Rudnicki, Stephen Strauss, Philip Welford, and Susan Zimmerman. The observers were Geneviève Dubois-Flynn, Danika Goosney, Peter Monette, Kyle Norrie, and Anthony Ridgway.

Competing interests

The authors declare no competing interests.

Both McGill and the Stem Cell Network pop up again. A November 8, 2017 article about the need for new Canadian gene-editing policies by Tom Blackwell for the National Post features some familiar names (Did someone have a budget for public relations and promotion?),

It’s one of the most exciting, and controversial, areas of health science today: new technology that can alter the genetic content of cells, potentially preventing inherited disease — or creating genetically enhanced humans.

But Canada is among the few countries in the world where working with the CRISPR gene-editing system on cells whose DNA can be passed down to future generations is a criminal offence, with penalties of up to 10 years in jail.

This week, one major science group announced it wants that changed, calling on the federal government to lift the prohibition and allow researchers to alter the genome of inheritable “germ” cells and embryos.

The potential of the technology is huge and the theoretical risks like eugenics or cloning are overplayed, argued a panel of the Stem Cell Network.

The step would be a “game-changer,” said Bartha Knoppers, a health-policy expert at McGill University, in a presentation to the annual Till & McCulloch Meetings of stem-cell and regenerative-medicine researchers [These meetings were originally known as the Stem Cell Network’s Annual General Meeting {AGM}]. [emphases mine]

“I’m completely against any modification of the human genome,” said the unidentified meeting attendee. “If you open this door, you won’t ever be able to close it again.”

If the ban is kept in place, however, Canadian scientists will fall further behind colleagues in other countries, say the experts behind the statement say; they argue possible abuses can be prevented with good ethical oversight.

“It’s a human-reproduction law, it was never meant to ban and slow down and restrict research,” said Vardit Ravitsky, a University of Montreal bioethicist who was part of the panel. “It’s a sort of historical accident … and now our hands are tied.”

There are fears, as well, that CRISPR could be used to create improved humans who are genetically programmed to have certain facial or other features, or that the editing could have harmful side effects. Regardless, none of it is happening in Canada, good or bad.

In fact, the Stem Cell Network panel is arguably skirting around the most contentious applications of the technology. It says it is asking the government merely to legalize research for its own sake on embryos and germ cells — those in eggs and sperm — not genetic editing of embryos used to actually get women pregnant.

The highlighted portions in the last two paragraphs of the excerpt were written one year prior to the claims by a Chinese scientist that he had run a clinical trial resulting in gene-edited twins, Lulu and Nana. (See my my November 28, 2018 posting for a comprehensive overview of the original furor). I have yet to publish a followup posting featuring the news that the CRISPR twins may have been ‘improved’ more extensively than originally realized. The initial reports about the twins focused on an illness-related reason (making them HIV ‘immune’) but made no mention of enhanced cognitive skills a side effect of eliminating the gene that would make them HIV ‘immune’. To date, the researcher has not made the bulk of his data available for an in-depth analysis to support his claim that he successfully gene-edited the twins. As well, there were apparently seven other pregnancies coming to term as part of the researcher’s clinical trial and there has been no news about those births.

Risk analysis innovation

Before moving onto the innovation of risk analysis, I want to focus a little more on at least one of the risks that gene-editing might present. Gierczak noted that CRISPR/Cas9 is “not perfect,” which acknowledges the truth but doesn’t convey all that much information.

While the terms ‘precision’ and ‘scissors’ are used frequently when describing the CRISPR technique, scientists actually mean that the technique is significantly ‘more precise’ than other techniques but they are not referencing an engineering level of precision. As for the ‘scissors’, it’s an analogy scientists like to use but in fact CRISPR is not as efficient and precise as a pair of scissors.

Michael Le Page in a July 16, 2018 article for New Scientist lays out some of the issues (Note: A link has been removed),

A study of CRIPSR suggests we shouldn’t rush into trying out CRISPR genome editing inside people’s bodies just yet. The technique can cause big deletions or rearrangements of DNA [emphasis mine], says Allan Bradley of the Wellcome Sanger Institute in the UK, meaning some therapies based on CRISPR may not be quite as safe as we thought.

The CRISPR genome editing technique is revolutionising biology, enabling us to create new varieties of plants and animals and develop treatments for a wide range of diseases.

The CRISPR Cas9 protein works by cutting the DNA of a cell in a specific place. When the cell repairs the damage, a few DNA letters get changed at this spot – an effect that can be exploited to disable genes.

At least, that’s how it is supposed to work. But in studies of mice and human cells, Bradley’s team has found that in around a fifth of cells, CRISPR causes deletions or rearrangements more than 100 DNA letters long. These surprising changes are sometimes thousands of letters long.

“I do believe the findings are robust,” says Gaetan Burgio of the Australian National University, an expert on CRISPR who has debunked previous studies questioning the method’s safety. “This is a well-performed study and fairly significant.”

I covered the Bradley paper and the concerns in a July 17, 2018 posting ‘The CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene-editing technique may cause new genetic damage kerfuffle‘. (The ‘kerfufle’ was in reference to a report that the CRISPR market was affected by the publication of Bradley’s paper.)

Despite Health Canada not moving swiftly enough for some researchers, they have nonetheless managed to release an ‘outcome’ report about a consultation/analysis started in October 2016. Before getting to the consultation’s outcome, it’s interesting to look at how the consultation’s call for response was described (from Health Canada’s Toward a strengthened Assisted Human Reproduction Act ; A Consultation with Canadians on Key Policy Proposals webpage),

In October 2016, recognizing the need to strengthen the regulatory framework governing assisted human reproduction in Canada, Health Canada announced its intention to bring into force the dormant sections of the Assisted Human Reproduction Act  and to develop the necessary supporting regulations.

This consultation document provides an overview of the key policy proposals that will help inform the development of regulations to support bringing into force Section 10, Section 12 and Sections 45-58 of the Act. Specifically, the policy proposals describe the Department’s position on the following:

Section 10: Safety of Donor Sperm and Ova

  • Scope and application
  • Regulated parties and their regulatory obligations
  • Processing requirements, including donor suitability assessment
  • Record-keeping and traceability

Section 12: Reimbursement

  • Expenditures that may be reimbursed
  • Process for reimbursement
  • Creation and maintenance of records

Sections 45-58: Administration and Enforcement

  • Scope of the administration and enforcement framework
  • Role of inspectors designated under the Act

The purpose of the document is to provide Canadians with an opportunity to review the policy proposals and to provide feedback [emphasis mine] prior to the Department finalizing policy decisions and developing the regulations. In addition to requesting stakeholders’ general feedback on the policy proposals, the Department is also seeking input on specific questions, which are included throughout the document.

It took me a while to find the relevant section (in particular, take note of ‘Federal Regulatory Oversight’),

3.2. AHR in Canada Today

Today, an increasing number of Canadians are turning to AHR technologies to grow or build their families. A 2012 Canadian studyFootnote 1 found that infertility is on the rise in Canada, with roughly 16% of heterosexual couples experiencing infertility. In addition to rising infertility, the trend of delaying marriage and parenthood, scientific advances in cryopreserving ova, and the increasing use of AHR by LGBTQ2 couples and single parents to build a family are all contributing to an increase in the use of AHR technologies.

The growing use of reproductive technologies by Canadians to help build their families underscores the need to strengthen the AHR Act. While the approach to regulating AHR varies from country to country, Health Canada has considered international best practices and the need for regulatory alignment when developing the proposed policies set out in this document. …

3.2.1 Federal Regulatory Oversight

Although the scope of the AHR Act was significantly reduced in 2012 and some of the remaining sections have not yet been brought into force, there are many important sections of the Act that are currently administered and enforced by Health Canada, as summarized generally below:

Section 5: Prohibited Scientific and Research Procedures
Section 5 prohibits certain types of scientific research and clinical procedures that are deemed unacceptable, including: human cloning, the creation of an embryo for non-reproductive purposes, maintaining an embryo outside the human body beyond the fourteenth day, sex selection for non-medical reasons, altering the genome in a way that could be transmitted to descendants, and creating a chimera or a hybrid. [emphasis mine]

….

It almost seems as if the they were hiding the section that broached the human gene-editing question. It doesn’t seem to have worked as it appears, there are some very motivated parties determined to reframe the discussion. Health Canada’s ‘outocme’ report, published March 2019, What we heard: A summary of scanning and consultations on what’s next for health product regulation reflects the success of those efforts,

1.0 Introduction and Context

Scientific and technological advances are accelerating the pace of innovation. These advances are increasingly leading to the development of health products that are better able to predict, define, treat, and even cure human diseases. Globally, many factors are driving regulators to think about how to enable health innovation. To this end, Health Canada has been expanding beyond existing partnerships and engaging both domestically and internationally. This expanding landscape of products and services comes with a range of new challenges and opportunities.

In keeping up to date with emerging technologies and working collaboratively through strategic partnerships, Health Canada seeks to position itself as a regulator at the forefront of health innovation. Following the targeted sectoral review of the Health and Biosciences Sector Regulatory Review consultation by the Treasury Board Secretariat, Health Canada held a number of targeted meetings with a broad range of stakeholders.

This report outlines the methodologies used to look ahead at the emerging health technology environment, [emphasis mine] the potential areas of focus that resulted, and the key findings from consultations.

… the Department identified the following key drivers that are expected to shape the future of health innovation:

  1. The use of “big data” to inform decision-making: Health systems are generating more data, and becoming reliant on this data. The increasing accuracy, types, and volume of data available in real time enable automation and machine learning that can forecast activity, behaviour, or trends to support decision-making.
  2. Greater demand for citizen agency: Canadians increasingly want and have access to more information, resources, options, and platforms to manage their own health (e.g., mobile apps, direct-to-consumer services, decentralization of care).
  3. Increased precision and personalization in health care delivery: Diagnostic tools and therapies are increasingly able to target individual patients with customized therapies (e.g., individual gene therapy).
  4. Increased product complexity: Increasingly complex products do not fit well within conventional product classifications and standards (e.g., 3D printing).
  5. Evolving methods for production and distribution: In some cases, manufacturers and supply chains are becoming more distributed, challenging the current framework governing production and distribution of health products.
  6. The ways in which evidence is collected and used are changing: The processes around new drug innovation, research and development, and designing clinical trials are evolving in ways that are more flexible and adaptive.

With these key drivers in mind, the Department selected the following six emerging technologies for further investigation to better understand how the health product space is evolving:

  1. Artificial intelligence, including activities such as machine learning, neural networks, natural language processing, and robotics.
  2. Advanced cell therapies, such as individualized cell therapies tailor-made to address specific patient needs.
  3. Big data, from sources such as sensors, genetic information, and social media that are increasingly used to inform patient and health care practitioner decisions.
  4. 3D printing of health products (e.g., implants, prosthetics, cells, tissues).
  5. New ways of delivering drugs that bring together different product lines and methods (e.g., nano-carriers, implantable devices).
  6. Gene editing, including individualized gene therapies that can assist in preventing and treating certain diseases.

Next, to test the drivers identified and further investigate emerging technologies, the Department consulted key organizations and thought leaders across the country with expertise in health innovation. To this end, Health Canada held seven workshops with over 140 representatives from industry associations, small-to-medium sized enterprises and start-ups, larger multinational companies, investors, researchers, and clinicians in Ottawa, Toronto, Montreal, and Vancouver. [emphases mine]

The ‘outocme’ report, ‘What we heard …’, is well worth reading in its entirety; it’s about 9 pp.

I have one comment, ‘stakeholders’ don’t seem to include anyone who isn’t “from industry associations, small-to-medium sized enterprises and start-ups, larger multinational companies, investors, researchers, and clinician” or from “Ottawa, Toronto, Montreal, and Vancouver.” Aren’t the rest of us stakeholders?

Innovating risk analysis

This line in the report caught my eye (from Health Canada’s Toward a strengthened Assisted Human Reproduction Act ; A Consultation with Canadians on Key Policy Proposals webpage),

There is increasing need to enable innovation in a flexible, risk-based way, with appropriate oversight to ensure safety, quality, and efficacy. [emphases mine]

It reminded me of the 2019 federal budget (from my March 22, 2019 posting). One comment before proceeding, regulation and risk are tightly linked and, so, by innovating regulation they are by exttension alos innovating risk analysis,

… Budget 2019 introduces the first three “Regulatory Roadmaps” to specifically address stakeholder issues and irritants in these sectors, informed by over 140 responses [emphasis mine] from businesses and Canadians across the country, as well as recommendations from the Economic Strategy Tables.

Introducing Regulatory Roadmaps

These Roadmaps lay out the Government’s plans to modernize regulatory frameworks, without compromising our strong health, safety, and environmental protections. They contain proposals for legislative and regulatory amendments as well as novel regulatory approaches to accommodate emerging technologies, including the use of regulatory sandboxes and pilot projects—better aligning our regulatory frameworks with industry realities.

Budget 2019 proposes the necessary funding and legislative revisions so that regulatory departments and agencies can move forward on the Roadmaps, including providing the Canadian Food Inspection Agency, Health Canada and Transport Canada with up to $219.1 million over five years, starting in 2019–20, (with $0.5 million in remaining amortization), and $3.1 million per year on an ongoing basis.

In the coming weeks, the Government will be releasing the full Regulatory Roadmaps for each of the reviews, as well as timelines for enacting specific initiatives, which can be grouped in the following three main areas:

What Is a Regulatory Sandbox? Regulatory sandboxes are controlled “safe spaces” in which innovative products, services, business models and delivery mechanisms can be tested without immediately being subject to all of the regulatory requirements.
– European Banking Authority, 2017

Establishing a regulatory sandbox for new and innovative medical products
The regulatory approval system has not kept up with new medical technologies and processes. Health Canada proposes to modernize regulations to put in place a regulatory sandbox for new and innovative products, such as tissues developed through 3D printing, artificial intelligence, and gene therapies targeted to specific individuals. [emphasis mine]

Modernizing the regulation of clinical trials
Industry and academics have expressed concerns that regulations related to clinical trials are overly prescriptive and inconsistent. Health Canada proposes to implement a risk-based approach [emphasis mine] to clinical trials to reduce costs to industry and academics by removing unnecessary requirements for low-risk drugs and trials. The regulations will also provide the agri-food industry with the ability to carry out clinical trials within Canada on products such as food for special dietary use and novel foods.

Does the government always get 140 responses from a consultation process? Moving on, I agree with finding new approaches to regulatory processes and oversight and, by extension, new approaches to risk analysis.

Earlier in this post, I asked if someone had a budget for public relations/promotion. I wasn’t joking. My March 22, 2019 posting also included these line items in the proposed 2019 budget,

Budget 2019 proposes to make additional investments in support of the following organizations:
Stem Cell Network: Stem cell research—pioneered by two Canadians in the 1960s [James Till and Ernest McCulloch]—holds great promise for new therapies and medical treatments for respiratory and heart diseases, spinal cord injury, cancer, and many other diseases and disorders. The Stem Cell Network is a national not-for-profit organization that helps translate stem cell research into clinical applications and commercial products. To support this important work and foster Canada’s leadership in stem cell research, Budget 2019 proposes to provide the Stem Cell Network with renewed funding of $18 million over three years, starting in 2019–20.

Genome Canada: The insights derived from genomics—the study of the entire genetic information of living things encoded in their DNA and related molecules and proteins—hold the potential for breakthroughs that can improve the lives of Canadians and drive innovation and economic growth. Genome Canada is a not-for-profit organization dedicated to advancing genomics science and technology in order to create economic and social benefits for Canadians. To support Genome Canada’s operations, Budget 2019 proposes to provide Genome Canada with $100.5 million over five years, starting in 2020–21. This investment will also enable Genome Canada to launch new large-scale research competitions and projects, in collaboration with external partners, ensuring that Canada’s research community continues to have access to the resources needed to make transformative scientific breakthroughs and translate these discoveries into real-world applications.

Years ago, I managed to find a webpage with all of the proposals various organizations were submitting to a government budget committee. It was eye-opening. You can tell which organizations were able to hire someone who knew the current government buzzwords and the things that a government bureaucrat would want to hear and the organizations that didn’t.

Of course, if the government of the day is adamantly against or uninterested, no amount of persusasion will work to get your organization more money in the budget.

Finally

Reluctantly, I am inclined to explore the topic of emerging technologies such as gene-editing not only in the field of agriculture (for gene-editing of plants, fish, and animals see my November 28, 2018 posting) but also with humans. At the very least, it needs to be discussed whether we choose to participate or not.

If you are interested in the arguments against changing Canada’s prohibition against gene-editing of humans, there’s an Ocotber 2, 2017 posting on Impact Ethics by Françoise Baylis, Professor and Canada Research Chair in Bioethics and Philosophy at Dalhousie University, and Alana Cattapan, Johnson Shoyama Graduate School of Public Policy at the University of Saskatchewan, which makes some compelling arguments. Of course, it was written before the CRISPR twins (my November 28, 2018 posting).

Recaliing CRISPR Therapeutics (mentioned by Gierczak), the company received permission to run clinical trials in the US in October 2018 after the FDA (US Food and Drug Administration) lifted an earlier ban on their trials according to an Oct. 10, 2018 article by Frank Vinhuan for exome,

The partners also noted that their therapy is making progress outside of the U.S. They announced that they have received regulatory clearance in “multiple countries” to begin tests of the experimental treatment in both sickle cell disease and beta thalassemia, …

It seems to me that the quotes around “multiple countries” are meant to suggest doubt of some kind. Generally speaking, company representatives make those kinds of generalizations when they’re trying to pump up their copy. E.g., 50% increase in attendance  but no whole numbers to tell you what that means. It could mean two people attended the first year and then brought a friend the next year or 100 people attended and the next year there were 150.

Despite attempts to declare personalized medicine as having arrived, I think everything is still in flux with no preordained outcome. The future has yet to be determined but it will be and I , for one, would like to have some say in the matter.

University of Toronto (Canada) researchers and lab-grown heart and liver tissue (person-on-a-chip)

Usually called ‘human-on-a-chip’, a team at the University of Toronto have developed a two-organ ‘person on a chip’ according to a March 7, 2016 news item on phys.org (Note: Links have been removed),

Researchers at U of T [University of Toronto] Engineering have developed a new way of growing realistic human tissues outside the body. Their “person-on-a-chip” technology, called AngioChip, is a powerful platform for discovering and testing new drugs, and could eventually be used to repair or replace damaged organs.

Professor Milica Radisic (IBBME, ChemE), graduate student Boyang Zhang and the rest of the team are among those research groups around the world racing to find ways to grow human tissues in the lab, under conditions that mimic a real person’s body. They have developed unique methods for manufacturing small, intricate scaffolds for individual cells to grow on. These artificial environments produce cells and tissues that resemble the real thing more closely than those grown lying flat in a petri dish.

The team’s recent creations have included BiowireTM—an innovative method of growing heart cells around a silk suture—as well as a scaffold for heart cells that snaps together like sheets of Velcro. But AngioChip takes tissue engineering to a whole new level. “It’s a fully three-dimensional structure complete with internal blood vessels,” says Radisic. “It behaves just like vasculature, and around it there is a lattice for other cells to attach and grow.” …

A March 7, 2016 University of Toronto news release (also on EurekAlert), which originated the news item, provides more detail about the AngioChip,

Zhang built the scaffold out of POMaC, a polymer that is both biodegradable and biocompatible. The scaffold is built out of a series of thin layers, stamped with a pattern of channels that are each about 50 to 100 micrometres wide. The layers, which resemble the computer microchips, are then stacked into a 3D structure of synthetic blood vessels. As each layer is added, UV light is used to cross-link the polymer and bond it to the layer below.

When the structure is finished, it is bathed in a liquid containing living cells. The cells quickly attach to the inside and outside of the channels and begin growing just as they would in the human body.

“Previously, people could only do this using devices that squish the cells between sheets of silicone and glass,” says Radisic. “You needed several pumps and vacuum lines to run just one chip. Our system runs in a normal cell culture dish, and there are no pumps; we use pressure heads to perfuse media through the vasculature. The wells are open, so you can easily access the tissue.”

Using the platform, the team has built model versions of both heart and liver tissues that function like the real thing. “Our liver actually produced urea and metabolized drugs,” says Radisic. They can connect the blood vessels of the two artificial organs, thereby modelling not just the organs themselves, but the interactions between them. They’ve even injected white blood cells into the vessels and watched as they squeezed through gaps in the vessel wall to reach the tissue on the other side, just as they do in the human body.

The news release also mentions potential markets and the work that needs to be accomplished before AngioChip is available for purchase,

AngioChip has great potential in the field of pharmaceutical testing. Current drug-testing methods, such as animal testing and controlled clinical trials, are costly and fraught with ethical concerns. Testing on lab-grown human tissues would provide a realistic model at a fraction of the cost, but this area of research is still in its infancy. “In the last few years, it has become possible to order cultures of human cells for testing, but they’re grown on a plate, a two-dimensional environment,” says Radisic. “They don’t capture all the functional hallmarks of a real heart muscle, for example.”

A more realistic platform like AngioChip could enable drug companies to detect dangerous side effects and interactions between organ compartments long before their products reach the market, saving countless lives. It could also be used to understand and validate the effectiveness of current drugs and even to screen libraries of chemical compounds to discover new drugs. Through TARA Biosystems Inc., a spin-off company co-founded by Radisic, the team is already working on commercializing the technology.

In future, Radisic envisions her lab-grown tissues being implanted into the body to repair organs damaged by disease. Because the cells used to seed the platform can come from anyone, the new tissues could be genetically identical to the intended host, reducing the risk of organ rejection. Even in its current form, the team has shown that the AngioChip can be implanted into a living animal, its artificial blood vessels connected to a real circulatory system. The polymer scaffolding itself simply biodegrades after several months.

The team still has much work to do. Each AngioChip is currently made by hand; if the platform is to be used industrially, the team will need to develop high-throughput manufacturing methods to create many copies at once. Still, the potential is obvious. “It really is multifunctional, and solves many problems in the tissue engineering space,” says Radisic. “It’s truly next-generation.”

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

Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis by Boyang Zhang, Miles Montgomery, M. Dean Chamberlain, Shinichiro Ogawa, Anastasia Korolj, Aric Pahnke, Laura A. Wells, Stéphane Massé, Jihye Kim, Lewis Reis, Abdul Momen, Sara S. Nunes, Aaron R. Wheeler, Kumaraswamy Nanthakumar, Gordon Keller, Michael V. Sefton, & Milica Radisic. Nature Materials (2016) doi:10.1038/nmat4570 Published online 07 March 2016

This paper is behind a paywall.

The researchers have made two images illustrating their work available. There’s this still image,

These tiny polymer scaffolds contain channels that are about 100 micrometres wide, about the same diameter as a human hair. When seeded with cells, the channels act as artificial blood vessels. By mimicking tissues in the human heart and other organs, these scaffolds provide a new way to test drugs for potentially dangerous side effects. (Image: Tyler Irving/Boyang Zhang/Kevin Soobrian)

These tiny polymer scaffolds contain channels that are about 100 micrometres wide, about the same diameter as a human hair. When seeded with cells, the channels act as artificial blood vessels. By mimicking tissues in the human heart and other organs, these scaffolds provide a new way to test drugs for potentially dangerous side effects. (Image: Tyler Irving/Boyang Zhang/Kevin Soobrian)

Perhaps more intriguing is this one,

UofT_AngioChipMoving

When seeded with heart cells, the flexible polymer scaffold contracts with a regular rhythm, just like real heart tissue. (Image: Boyang Zhang)

I have mentioned ‘human-on-a-chip’ projects many times here and as the news release writer notes, there is an international race. My July 1, 2015 posting (cross-posted from the June 30, 2015 posting [Testing times: the future of animal alternatives] on the International Innovation blog [a CORDIS-listed project dissemination partner for FP7 and H2020 projects]) notes a couple of those projects,

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

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

As for where the University of Toronto efforts fit into the race, I don’t know for sure. It’s the first time I’ve come across a reference to liver tissue producing urea but I believe there’s at least one other team in China which has achieved a three-dimensional, more lifelike aspect for liver tissue in my Jan. 29, 2016 posting ‘Constructing a liver’.