Category Archives: medicine

A graphene ‘camera’ and your beating heart: say cheese

Comparing it to a ‘camera’, even with the quotes, is a bit of a stretch for my taste but I can’t come up with a better comparison. Here’s a video so you can judge for yourself,

Caption: This video repeats three times the graphene camera images of a single beat of an embryonic chicken heart. The images, separated by 5 milliseconds, were measured by a laser bouncing off a graphene sheet lying beneath the heart. The images are about 2 millimeters on a side. Credit: UC Berkeley images by Halleh Balch, Alister McGuire and Jason Horng

A June 16, 2021 news item on ScienceDaily announces the research,

Bay Area [San Francisco, California] scientists have captured the real-time electrical activity of a beating heart, using a sheet of graphene to record an optical image — almost like a video camera — of the faint electric fields generated by the rhythmic firing of the heart’s muscle cells.

A University of California at Berkeley (UC Berkeley) June 16, 2021 news release (also on EurekAlert) by Robert Sanders, which originated the news item, provides more detail,

The graphene camera represents a new type of sensor useful for studying cells and tissues that generate electrical voltages, including groups of neurons or cardiac muscle cells. To date, electrodes or chemical dyes have been used to measure electrical firing in these cells. But electrodes and dyes measure the voltage at one point only; a graphene sheet measures the voltage continuously over all the tissue it touches.

The development, published online last week in the journal Nano Letters, comes from a collaboration between two teams of quantum physicists at the University of California, Berkeley, and physical chemists at Stanford University.

“Because we are imaging all cells simultaneously onto a camera, we don’t have to scan, and we don’t have just a point measurement. We can image the entire network of cells at the same time,” said Halleh Balch, one of three first authors of the paper and a recent Ph.D. recipient in UC Berkeley’s Department of Physics.

While the graphene sensor works without having to label cells with dyes or tracers, it can easily be combined with standard microscopy to image fluorescently labeled nerve or muscle tissue while simultaneously recording the electrical signals the cells use to communicate.

“The ease with which you can image an entire region of a sample could be especially useful in the study of neural networks that have all sorts of cell types involved,” said another first author of the study, Allister McGuire, who recently received a Ph.D. from Stanford and. “If you have a fluorescently labeled cell system, you might only be targeting a certain type of neuron. Our system would allow you to capture electrical activity in all neurons and their support cells with very high integrity, which could really impact the way that people do these network level studies.”

Graphene is a one-atom thick sheet of carbon atoms arranged in a two-dimensional hexagonal pattern reminiscent of honeycomb. The 2D structure has captured the interest of physicists for several decades because of its unique electrical properties and robustness and its interesting optical and optoelectronic properties.

“This is maybe the first example where you can use an optical readout of 2D materials to measure biological electrical fields,” said senior author Feng Wang, UC Berkeley professor of physics. “People have used 2D materials to do some sensing with pure electrical readout before, but this is unique in that it works with microscopy so that you can do parallel detection.”

The team calls the tool a critically coupled waveguide-amplified graphene electric field sensor, or CAGE sensor.

“This study is just a preliminary one; we want to showcase to biologists that there is such a tool you can use, and you can do great imaging. It has fast time resolution and great electric field sensitivity,” said the third first author, Jason Horng, a UC Berkeley Ph.D. recipient who is now a postdoctoral fellow at the National Institute of Standards and Technology. “Right now, it is just a prototype, but in the future, I think we can improve the device.”

Graphene is sensitive to electric fields

Ten years ago, Wang discovered that an electric field affects how graphene reflects or absorbs light. Balch and Horng exploited this discovery in designing the graphene camera. They obtained a sheet of graphene about 1 centimeter on a side produced by chemical vapor deposition in the lab of UC Berkeley physics professor Michael Crommie and placed on it a live heart from a chicken embryo, freshly extracted from a fertilized egg. These experiments were performed in the Stanford lab of Bianxiao Cui, who develops nanoscale tools to study electrical signaling in neurons and cardiac cells.

The team showed that when the graphene was tuned properly, the electrical signals that flowed along the surface of the heart during a beat were sufficient to change the reflectance of the graphene sheet.

“When cells contract, they fire action potentials that generate a small electric field outside of the cell,” Balch said. “The absorption of graphene right under that cell is modified, so we will see a change in the amount of light that comes back from that position on the large area of graphene.”

In initial studies, however, Horng found that the change in reflectance was too small to detect easily. An electric field reduces the reflectance of graphene by at most 2%; the effect was much less from changes in the electric field when the heart muscle cells fired an action potential.

Together, Balch, Horng and Wang found a way to amplify this signal by adding a thin waveguide below graphene, forcing the reflected laser light to bounce internally about 100 times before escaping. This made the change in reflectance detectable by a normal optical video camera.

“One way of thinking about it is that the more times that light bounces off of graphene as it propagates through this little cavity, the more effects that light feels from graphene’s response, and that allows us to obtain very, very high sensitivity to electric fields and voltages down to microvolts,” Balch said.

The increased amplification necessarily lowers the resolution of the image, but at 10 microns, it is more than enough to study cardiac cells that are several tens of microns across, she said.

Another application, McGuire said, is to test the effect of drug candidates on heart muscle before these drugs go into clinical trials to see whether, for example, they induce an unwanted arrhythmia. To demonstrate this, he and his colleagues observed the beating chicken heart with CAGE and an optical microscope while infusing it with a drug, blebbistatin, that inhibits the muscle protein myosin. They observed the heart stop beating, but CAGE showed that the electrical signals were unaffected.

Because graphene sheets are mechanically tough, they could also be placed directly on the surface of the brain to get a continuous measure of electrical activity — for example, to monitor neuron firing in the brains of those with epilepsy or to study fundamental brain activity. Today’s electrode arrays measure activity at a few hundred points, not continuously over the brain surface.

“One of the things that is amazing to me about this project is that electric fields mediate chemical interactions, mediate biophysical interactions — they mediate all sorts of processes in the natural world — but we never measure them. We measure current, and we measure voltage,” Balch said. “The ability to actually image electric fields gives you a look at a modality that you previously had little insight into.”

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

Graphene Electric Field Sensor Enables Single Shot Label-Free Imaging of Bioelectric Potentials by Halleh B. Balch, Allister F. McGuire, Jason Horng, Hsin-Zon Tsai, Kevin K. Qi, Yi-Shiou Duh, Patrick R. Forrester, Michael F. Crommie, Bianxiao Cui, and Feng Wang. Nano Lett. 2021, XXXX, XXX, XXX-XXX OI: https://doi.org/10.1021/acs.nanolett.1c00543 Publication Date: June 8, 2021 © 2021 American Chemical Society

This paper is behind a paywall.

Nano-photosynthesis in your brain as a stroke treatment?

A May 19, 2021 news item on phys.org sheds some light on a new approach to stroke treatments,

Blocked blood vessels in the brains of stroke patients prevent oxygen-rich blood from getting to cells, causing severe damage. Plants and some microbes produce oxygen through photosynthesis. What if there was a way to make photosynthesis happen in the brains of patients? Now, researchers reporting in ACS’ Nano Letters have done just that in cells and in mice, using blue-green algae and special nanoparticles, in a proof-of-concept demonstration.

A May 19, 2021 American Chemical Society (ACS) news release, which originated the news item, provides more information on strokes and how this new approach may prove useful,

Strokes result in the deaths of 5 million people worldwide every year, according to the World Health Organization. Millions more survive, but they often experience disabilities, such as difficulties with speech, swallowing or memory. The most common cause is a blood vessel blockage in the brain, and the best way to prevent permanent brain damage from this type of stroke is to dissolve or surgically remove the blockage as soon as possible. However, those options only work within a narrow time window after the stroke happens and can be risky. Blue-green algae, such as Synechococcus elongatus, have been studied previously to treat the lack of oxygen in heart tissue and tumors using photosynthesis. But the visible light needed to trigger the microbes can’t penetrate the skull, and although near-infrared light can pass through, it is insufficient to directly power photosynthesis. “Up-conversion” nanoparticles, often used for imaging, can absorb near-infrared photons and emit visible light. So, Lin Wang, Zheng Wang, Guobin Wang and colleagues at Huazhong University of Science and Technology wanted to see if they could develop a new approach that could someday be used for stroke patients by combining these parts — S. elongatus, nanoparticles and near-infrared light — in a new “nano-photosynthetic” system.

The researchers paired S. elongatus with neodymium up-conversion nanoparticles that transform tissue-penetrating near-infrared light to a visible wavelength that the microbes can use to photosynthesize. In a cell study, they found that the nano-photosynthesis approach reduced the number of neurons that died after oxygen and glucose deprivation. They then injected the microbes and nanoparticles into mice with blocked cerebral arteries and exposed the mice to near-infrared light. The therapy reduced the number of dying neurons, improved the animals’ motor function and even helped new blood vessels to start growing. Although this treatment is still in the animal testing stage, it has promise to advance someday toward human clinical trials, the researchers say.

The authors acknowledge funding from the National Key Basic Research Program of China, the National Natural Science Foundation of China, the Chinese Ministry of Education’s Science and Technology Program, the Major Scientific and Technological Innovation Projects in Hubei Province, and the Joint Fund of Ministry of Education for Equipment Pre-research.

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

Oxygen-Generating Cyanobacteria Powered by Upconversion-Nanoparticles-Converted Near-Infrared Light for Ischemic Stroke Treatment by Jian Wang, Qiangfei Su, Qiying Lv, Bo Cai, Xiakeerzhati Xiaohalati, Guobin Wang, Zheng Wang, and Lin Wang. Nano Lett. 2021, 21, 11, 4654–4665 DOI: https://doi.org/10.1021/acs.nanolett.1c00719 Publication Date:May 19, 2021 © 2021 American Chemical Society

This paper is behind a paywall.

Who’s running the life science companies’ public relations campaign in British Columbia (Vancouver, Canada)?

I started writing this in the aftermath of the 2021 Canadian federal budget when most of the action (so far) occurred but if you keep going to the end of this post you’ll find updates for Precision Nanosystems and AcCellera and a few extra bits. Also, you may want to check out my August 20, 2021 posting (Getting erased from the mRNA/COVID-19 story) about Ian MacLachlan and some of the ‘rough and tumble’ of the biotechnology scene in BC/Canada. Now, onto my analysis of the life sciences public relations campaign in British Columbia.

Gordon Hoekstra’s May 7, 2021 article (also in print on May 8, 2021) about the British Columbia (mostly in Vancouver) biotechnology scene in the Vancouver Sun is the starting point for this story.

His entry (whether the reporter realizes it or not) into a communications (or public relations) campaign spanning federal, provincial, and municipal jurisdictions is well written and quite informative. While it’s tempting to attribute the whole thing to a single evil genius or mastermind in answer to the question posed in the head, the ‘campaign’ is likely a targeted effort by one or more groups and individuals enhanced with a little luck.

Federal and provincial money for life sciences and technology

The Business Council of British Columbia’s April 22, 2021 Federal & B.C. Budgets 2021 Analysis (PDF), notes this in its Highlights section,

•Another priority reflected in both budgets is boosting innovation and accelerating the growth of technology-producing companies. The federal budget [April 19, 2021] is spending billions more to support the life sciences and bio-manufacturing industry, clean technologies, the development of electric vehicles, the aerospace sector, quantum computing, AI, genomics, and digital technologies, among others.

•B.C.’s budget [April 20, 2021] also provides funding to spur innovation, support the technology sector and grow locally-based companies. In this area the main item is the new InBC Investment Corporation [emphasis mine], first announced last summer. Endowed with $500 million financed via an agency loan, the Corporation will establish a fund to invest in growing and “anchoring” high-growth [emphasis mine] B.C. businesses.

Their in-depth analysis does not provide more detail about the life sciences investments in the 2021 Canadian federal budget or the 2021 BC provincial budget.

My May 4, 2021 posting details many of the Canadian federal investments in life sciences and other technology areas of interest. The 2021 BC budget announcement is so vague, it didn’t merit much more than this mention until now.

InBC Investment Corporation (BC’s contribution)

InBC Investment Corporation was set up on or about April 27, 2021 as three news ‘references’ (brief summaries with a link) suggest: InBC Investment Corp. Act, InBC Announcement, $500-million investment fund paves way for StrongerBC.

While the corporation does not have a specific mandate to fund the biotechnology sector, given the current enthusiasm, it’s easy to believe they might be more inclined to fund them than not, regardless of any expertise they or may not have specifically in that field.

Of most interest to me was InBC’s Board of Directors, which I tracked down to a BC Ministry of Jobs, Economic Recovery and Innovation May 6, 2021 news release,

InBC Investment Corp. now has a full board of directors with backgrounds in finance, economics, impact investing and business to provide strategic guidance and accountability for the new Crown corporation.

InBC will support startups [emphasis mine], help promising companies scale up and work with a “triple bottom line” mandate that considers people, the planet and profits, to position British Columbia as a front-runner in the post-pandemic economy.

Christine Bergeron, president and chief executive officer of Vancity, will serve as the new board chair of InBC Investment Corp. The nine-member board of directors is made up of both public and private sector members who are responsible for oversight of the corporation, including its mission, policies and goals.

The InBC board members were selected through a comprehensive process, guided by the principles of the Crown Agencies and Board Resourcing Office. Candidates with a variety of relevant backgrounds were considered to form a strong board consisting of seven women and two men. The members appointed represent diversity as well as appropriate areas of expertise.

The following people were selected as members on the board of directors:

  • Christine Bergeron, president and CEO, Vancity
  • Kevin Campbell, managing director of investment banking, board of directors, Haywood Securities
  • Ingrid Leong, VP finance for JH Investments and chief investment officer, Houssian Foundation
  • Glen Lougheed, serial tech entrepreneur and angel investor
  • Suzanne Trottier, vice-president of Indigenous trust services, First Nations Bank Trust
  • Carole James, former minister of finance and deputy premier, Government of British Columbia
  • Iglika Ivanova, senior economist, public interest researcher, BC Office of the Canadian Centre for Policy Alternatives
  • Bobbi Plecas, deputy minister, B.C.’s Ministry of Jobs, Economic Recovery and Innovation
  • Heather Wood, deputy minister, B.C.’s Ministry of Finance

Legislation to provide the governance framework for InBC was introduced by the legislative assembly on April 27, 2021.

Board experience at growing a startup?

This group of people doesn’t seem to have a shred of experience with startups. Glen Lougheed’s “serial tech entrepreneur and angel investor” description means nothing to me and the description he provides in his LinkedIn profile doesn’t clear up matters,

I am a product and business development professional with an entrepreneurial attitude and strong technical skills. I have been building companies both mine and others since I was a teenager.

Having looked up the two companies for which he is currently acting as Chief Executive Officer, Lougheed’s interest appears to be focused on the use of ‘big data’ in marketing and communications campaigns.

Perhaps startup experience isn’t necessary since the board has been appointed to do this (from the BC Ministry of Jobs, Economic Recovery and Innovation May 6, 2021 news release; click on the Backgrounder),

Responsibilities of the InBC Investment Corp. board of directors

The board of directors will be responsible for oversight of the management of the affairs of the corporation. This includes:

  • selecting and approving the chief executive officer and chief innovation officer and monitoring performance and accountabilities;
  • reviewing and approving annual corporate financial statements;
  • oversight of policies that relate to InBC’s mandate and holding the executive to account for its accountabilities with respect to InBC’s mandate;
  • oversight of InBC’s operations; and
  • selection and appointment of InBC’s auditor.

Relationships

So, we have two government civil servants, Wood (Deputy Minister of B.C.’s Ministry of Finance) and Plecas (Deputy Minister of B.C.’s Ministry of Jobs, Economic Recovery and Innovation), and James, a BC Minister of Finance, who left the job several months ago. Then we have Lougheed, recently resigned (May 2021) as special advisor on innovation and technology to the BC Minister of Jobs, Economic Recovery and Innovation.

It would seem almost half of this new board is or has been affiliated with the government and, likely, know each other.

I expect there are more relationships to be found but my interest is in the overall picture as it pertains to the biotechnology scene. This board (except possibly for Lougheed) does not seem to have any experience in the biotechnology sector or growing any sort of startup business in any technology field.

Presumably, the new chief executive officer (CEO) and new chief innovation officer (CIO) will have some of the necessary experience. Still, biotechnology isn’t the same as digital technology, an area where the BC technology community is quite strong. (The Canadian federal government’s Digital Technology Supercluster is headquartered in BC.)

I imagine the politics around who gets hired as CEO and as CIO will be quite interesting.

See the ‘Updates and extras’ at the end of this posting for more mention of this ‘secretive’ government corporation.

The BC biotech gorillas

AbCellera was BC’s biggest biotech story in 2020/21 (see my Avo Media, Science Telephone, and a Canadian COVID-19 billionaire scientist post from December 30, 2020 for more. Do check out the subsection titled “Avo Media …” for a look at an unexpectedly interlaced relationship). Note: The AbCellera COVID-19 treatment is not a vaccine or a vaccine delivery system.

It was a bit surprising that Acuitas Therapeutics didn’t get more attention although Hoekstra seems to have addressed that shortcoming in his May 7, 2021 article by using Thomas Madden and Acuitas as the hook for the story,

By early 2020, concern was mounting about a new, deadly coronavirus first detected in Wuhan, China.

The World Health Organization had declared the coronavirus outbreak a global health emergency just days before. There had been more than 400 deaths and more than 20,000 cases, most of those in China.

But the virus was spreading around the world. Deaths had occurred in Hong Kong and the Philippines, and the virus had been detected in the U.S. and Canada.

By early January of 2020, scientists in China had already sequenced the virus’s genome and made it public, allowing scientists to begin the research for a vaccine.

Scientists expected that could take years.

But, as a second case was confirmed in B.C. in early February, Thomas Madden, a world-renowned expert in nanotechnology who heads Vancouver-based biotech company Acuitas Therapeutics, flew to Germany. [emphases mine]

Acuitas was in the business of creating lipid nanoparticles, microscopic biological vehicles that could deliver drugs [emphasis mine] — for example, to specifically target cancers in the body.

Scientists are already beginning to say it’s likely that a booster vaccine will be needed [emphasis mine] next year to deal with the virus variants.

Madden, the head of Acuitas, says it makes absolute sense to use the new biotechnology, for example, the use of messenger RNA vaccines, to prepare and fight future pandemics.

Says Madden [emphasis mine]: “The technology in terms of what it’s able to do is absolutely phenomenal. It’s just taken us 40 years to get here.”

So, Hoekstra reminds us of the international nature and urgency of the crisis, then, introduces Acuitas as a vital and local player in solutions deployed internationally, and, finally, brings us back to Acuitas after providing an overview of the BC biotech scene and the federal and provincial government’s latest moves,

AbCellera Biologics is more of a supporting player, along with a number of other companies, in Hoekstra’s story,

Sandwiched in the middle, you’ll find what I think is the point of the story,

LifeSciences BC and the provincial government’s commitments

From Hoekstra’s May 7, 2021 article,

The importance of the biotech sector in providing protection against pandemics has caught the attention of the federal and B.C. governments. It has also been noticed by the private markets.

In its budget [April 19, 2021] earlier this month [sic], the federal government promised more than $2 billion in the next seven years to support “promising” life sciences and bio-manufacturing firms, research, training, education and vaccine candidates.

Some companies, including Precision NanoSystems, have already got federal funding. The Vancouver company received $18.2 million last year to help develop its self-replicating mRNA vaccine and another $25 million in early 2021 to assist building a $50-million facility to produce the vaccine.

Last fall, Symvivo received $2.8 million from the National Research Council to help develop its oral COVID-19 vaccine.

AbCellera has also received a pledge of $175.6 million to help build an accredited manufacturing facility in Vancouver [emphasis mine] to produce antibody treatments.

AbCellera expects to double its 230-person workforce over the next two years as it expands its Vancouver campus.

When AbCellera became a publicly traded company late last year, it raised more than $500 million and had a recent market capitalization, the value of its stock, of about $8.5 billion.

When the B.C. government delivered its throne speech recently, the contribution of the province’s life sciences sector in the fight against the COVID-19 pandemic was highlighted, with Precision NanoSystems, AbCellera and StarFish Medical getting mentions. “Their work will not only help bring us out of the pandemic, it will position our province for success in the years ahead,” said B.C.’s Lt. Gov. Jane Austen in delivering the throne speech.

When the budget was released the following week [April 20, 2021], B.C. Finance Minister Selina Robinson said a new three-year, $500-million strategic investment fund would help support and scale up tech firms.

Despite their successes, B.C. biotech firms have faced challenges.

SaNOtize had to go to the U.K. to get support for clinical trials and AbCellera has been disappointed that despite Health Canada emergency approval of its COVID-19 treatment, provinces have been reluctant to use Bamlanivimab.

Hansen, AbCellera’s CEO and a former University of B.C. professor with a PhD in applied physics and biotechnology, said he believes that biotech is the most important frontier of technology.

In the past, while great science was launched from B.C.’s universities, not as great a job was done on turning that science into innovation, jobs [emphasis mine] and the capacity to bring new products to market, possibly because of a lack of entrepreneurship and polices to make it more attractive to companies to grow and thrive here and move here, notes Hansen.

Hurlburt [Wendy Hurlburt], the LifeSciences B.C. CEO, says that policies, including tax structure and patenting [emphasis mine], that encourages innovation companies are needed to support the biotech sector.

But, adds Hansen: “Here in Vancouver, I feel like we’re turning the corner. There’s probably never been a time when Vancouver’s biotech sector [emphasis mine] was stronger. And the future looks very good.”

Not only is the province involved but so is the City of Vancouver (more about that in a bit).

It’s not all about the cash

Hoekstra’s May 7, 2021 article helped answer a question I had in the title of another posting, January 22, 2021: Why is Precision Nanosystems Inc. in the local (Vancouver, Canada) newspaper? (See the ‘Updates and extras’ at the end of this posting for more to the answer.)

This campaign has been building for a while. In the “Is it magic or how does the federal budget get developed? subsection of my May 4, 2021 posting on the 2021 Canadian federal budget I speculated a little bit,

I believe most of the priorities are set by power players behind the scenes. We glimpsed some of the dynamics courtesy of the WE Charity scandal 2020/21 and the SNC-Lavalin scandal in 2019.

Access to special meetings and encounters are not likely to be given to any member of the ‘great unwashed’ but we do get to see the briefs that are submitted in anticipation of a new budget. These briefs and meetings with witnesses are available on the Parliament of Canada website (Standing Committee on Finance (FINA) webpage for pre-budget consultations.

AbCellera submitted a brief dated August 7, 2020 (PDF) detailing how they would like to see the Income Tax Act amended. It’s not always about getting cash, although that’s very important. In this brief, the company wants “… improved access to the enhanced Scientific Research & Experimental Development tax credit.”

There are many aspects to these campaigns including the federal Income Tax Act and, in this case, municipal involvement.

Vancouver (city government) and the biotech sector

About five weeks prior to the 2021 Canadian federal budget and BC provincial budget announcements, there was some news from the City of Vancouver (from a March 10, 2021 article by Kenneth Chan for dailyhive.com), Note: Links have been removed,

Major expansion plans are abound for AbCellera over the next few years to the extent that the Vancouver-based biotechnology company is now looking to build a massive purpose-built office and medical laboratory campus in Mount Pleasant (Vancouver neighbourhood).

It would be a redevelopment of the entire city block …

… earlier today, Vancouver City Council unanimously approved a rezoning enquiry allowing city staff to work with the proponent and accept a formal application for review.

This special additional pre-application step is required due to the temporary ban [emphasis mine] on most types of rezonings within the Broadway Plan’s planning area, until the plan is finalized at the end of 2021.

But city staff are willing to make this a rare exception due to the economic opportunity [emphasis mine] presented by the proposal and the healthcare-related aspects.

“The reasons for advancing this quickly are they are rapidly growing and would like to stay in Vancouver, and we would like them to… We’re very glad to have this company in Vancouver and want to provide them with a permanent home, but in order to scale up, the timeframe to produce their therapy [for viruses] is really time sensitive,” Gil Kelley, the chief urban planner of the City of Vancouver, told city council during today’s [March 10, 2021] meeting.

….

Roughly 10 days after the 2021 budgets are announced, there’s this from Kenneth Chan’s April 29,2021 article on dailyhive.com,

Plans for AbCellera Biologics’ major footprint expansion in Vancouver’s Mount Pleasant Industrial Area are moving forward quickly.

Based on the application submitted this week, the Vancouver-based biotechnology company is proposing to redevelop 110 West 4th Avenue …

It will be designated as the rapidly growing company’s global headquarters.

… city staff are providing AbCellera with the highly rare, expedited stream of combining the rezoning and development application processes into one.

By the middle of this decade, AbCellera will have four locations in the area, including its current 21,000 sq ft office at 2215 Yukon Street and a new 44,000 sq ft office nearing completion at 2131 Manitoba Street, just south of its future main hub.

“We’re building state-of-the-art facilities in Vancouver to accelerate the development of new antibody therapies with biotech and pharma partners from around the world,” said Carl Hansen, CEO and president of AbCellera, in a statement.

AbCellera has gained significant international attention over the past year after it co-developed the first authorized COVID-19 antibody therapy for emergency use in high-risk patients in Canada and the United States.

In late 2020, the company closed a successful initial public offering, bringing in $556 million after selling nearly 28 million shares, far exceeding its original goal of raising $250 million. It was the largest-ever IPO [initial public offering] by a Canadian biotech company.

“We see this new site as a creative hub for engineers, software developers, data scientists, biologists and bioinformaticians to collaborate, innovate, and push the frontiers of technology.” [said Veronique Lecault, the COO of AbCellera]

Additionally, AbCellera is also planning to build a clinical-grade, antibody manufacturing facility in Metro Vancouver, funded in part by the $176-million investment it received from the federal government in Spring 2020 [see May 3, 2020 AbCellera news release].

Not cash but AbCellera did get an expedited process for rezoning and I imagine there will be more special treatment as this progresses. (See the ‘Updates and extras’ at the end of this posting for news about the expedited process.)

It’s likely there are other companies in the BC’s life science sector that are eyeing this development with great interest and high hopes for themselves.

What it takes

COVID-19 seems to have galvanized interest and support almost everywhere in the world for life sciences.

I don’t believe that anyone in the life sciences planned for or rejoiced at news of this pandemic. However, the Canadian biotech sector has been working for decades to establish itself as an important economic resource. and, sadly, COVID-19 has been a timely development.

All those years of lobbying, also known as, government relations, marketing, investor relations, public relations and more served as preparation for what looks like a concerted effort and it has paid off in BC at the federal level, provincial level, and municipal level (at least one).

The campaigns continue. Here’s Wendy Hurlburt, president and CEO of LifeSciences BC in a May 14, 2021 Conversations That Matter Vancouver Sun podcast with Stuart McNish. Note: Hurlburt makes an odd comment at about the 7 min. 30 secs. mark regarding insulin and patents.

Her dismay over lost opportunities regarding the insulin patent is right in line with Canada’s current patent mania. See my May 13, 2021 posting, Not a pretty picture: Canada and a patent rights waiver for COVID-19 vaccines. As far as I’m aware, Canada’s stance has not changed. Interestingly, Hoekstra’s article doesn’t mention COVID-19 patent waivers.

By contrast, here’s what Frederick Banting (one of the discoverers) had to say about his patent, (from the Banting House Insulin Patents webpage),

About the sale of the patent of insulin for $1 Banting reportedly said, “Insulin belongs to the world, not to me.”

… On January 23rd, 1923 Banting, [Charles] Best, and [James] Collip were awarded the American patents for insulin which they sold to the University of Toronto for $1.00 each.

Hurlburt goes on to express dismay over taxes and notes that some companies may leave for other jurisdictions, which means we will lose ‘innovation’. This is a very common ploy coming from any of the technology sectors and can be dated back at least 30 years.

Unmentioned is the dream/business model that so many Canadian tech entrepreneurs have: grow the company, sell it for a lot of money, and retire, preferably before the age of 40.

Getting back to my point, the current situation is not attributable to one individual or to one company’s efforts or to one life science nonprofit or to one federal Network Centre for Excellence (NanoMedicines Innovation Network [NMIN] located at the University of British Columbia).

Note: I have more about the NMIN and Acuitas Therapeutics in a November 12, 2021 posting and there’s more about NMIN’s 7th annual conference and a very high profile guest in a September 11, 2020 posting.

Strategy at the federal, provincial, and local governments, with an eye to the international scene, has been augmented by luck and opportunism.

Updates and extras

Where updates are concerned I have one for Precision Nanosystems and one for AbCellera. I have extras with regard to Moderna and Canada and, BC’s special fund, inBC Investment Corporation. For anyone who’s curious about Banting and the high cost of insulin, I have a couple of links to further reading.

Precision Nanosystems

From an August 11, 2021 article by Kenneth Chan (Note: Links have been removed),

A homegrown pharmaceutical company has announced plans to significantly scale its operations with the opening of a new production facility in Vancouver’s False Creek Flats.

The new Evolution Block building will contain PNI’s new global headquarters and a new genetic medicine Good Manufacturing Practice (GMP) biomanufacturing centre, which would allow the company to expand its capabilities to include the clinical manufacturing of RNA vaccines and therapeutics.

Federal funding totalling $25.1 million for PNI was first announced in February 2021 towards covering part of the development costs of such a facility, as part of the federal government’s new strategy to better ensure Canada has the domestic capacity to secure its own COVID-19 vaccines and prepare the country for future pandemics. It is estimated the vaccine production capacity of the new facility will be 240 million doses annually.

PNI’s location in the False Creek Flats is strategic, given the close proximity to the new St. Paul’s Hospital campus and the growing concentration of tech and healthcare-based industrial businesses.

AbCellera

From a June 22, 2021 article by Kenneth Chan (Note: Links have been removed),

The rapidly growing Vancouver-based biotechnology company announced this morning their 130,000 sq ft Good Manufacturing Practices (GMP) facility will be located on a two-acre site at the 900 block of Evans Avenue, replacing the Urban Beach volleyball courts just next to the City of Vancouver’s Evans maintenance centre and the Regional Recycling Vancouver Bottle Depot.

GMP is partially funded by the $175 million in federal funding received by the company last year to support research into coronavirus treatment.

GMP adds to AbCellera’s major plans to build a new headquarters in close proximity at 110-150 West 4th Avenue in the Mount Pleasant Industrial Area — a city block-sized campus with a total of 380,000 sq ft of laboratory and office space for research and corporate uses.

Both campus buildings are being reviewed under the City of Vancouver’s rare streamlined, expedited process [emphasis mine] of combining the rezoning and development permit applications. AbCellera formally announced its campus plans in April 2021.

AbCellera gained significant international attention last year when it developed the world’s first monoclonal antibody therapy for COVID-19 to be authorized for emergency use in high-risk patients in Canada and the United States. According to the company, over 400,000 doses of its bamlanivimab drug have been administered around the world, and it is estimated to have kept more than 22,000 people out of hospital — saving at least 11,000 lives.

In late 2020, the company closed a successful initial public offering, bringing in $556 million after selling nearly 28 million shares, far exceeding its original goal of raising $250 million. It was the largest-ever IPO by a Canadian biotech company.

Moderna and Canada

It seems like yesterday that Derek Rossi (co-founder of Moderna) was talking about Canada’s need for a biotechnology hub. (see this June 17, 2021 article by Barbara Shecter for the Financial Post). Interestingly, there’s been an announcement of a memorandum of understanding (these things are announced all the time and don’t necessarily result in anything) between Moderna and the government of Canada according to an August 10, 2021 item on the Canadian Broadcasting Corporation (CBC) news website,

Massachusetts-based drug maker Moderna will build an mRNA vaccine manufacturing plant in Canada within the next two years, CEO Stephane Bancel said Tuesday [August 10, 2021; Note the timing, the writ for the next federal election was dropped on August 15, 2021].

The company has signed a memorandum of understanding with the federal government that will result in Canada becoming the home of Moderna’s first foreign operation. It’s not clear yet how much money Canada has offered to Moderna [emphasis mine] for the project.

Canada, whose life sciences industry has been decimated over the last three decades, wants in on the action. Prime Minister Justin Trudeau has promised to rebuild the industry, and the recent budget included a $2.2 billion, seven-year investment to grow the life science and biotech sectors.

Almost half of that targets companies that want to expand or set up vaccine and drug production in Canada. None of the COVID-19 vaccines to date have been made in Canada, leaving the country entirely reliant on imports to fill vaccine orders. As a result, Canada was slower out of the gate on immunizations than some of its counterparts with domestic production, and likely had to pay more per dose for some vaccines as well.

The location of the new facility hasn’t been finalized, but Bancel said the availability of an educated workforce will be the main deciding factor. He said the design is done and they’ll need to start hiring very soon so training can begin.

it’s not exactly a hub but who knows what the future will bring? I imagine there’s going to be some serious wrangling behind the scenes as the provinces battle to be the location for the facility. Note that Innovation Minister François-Philippe Champagne who made the announcement with Bancel in Montréal represents a federal riding in Québec. (BTW, Bancel is from France and seems to have spent much of his adult life in the US.) Of course anything can happen and I’m sure the BC contingent will make themselves felt but it would seem that Quebec is the front runner for now, assuming this memorandum of understanding leads to a facility. Given that we are in the midst of a federal election, it seems more probable than it might otherwise.

inBC Investment Corporation

Bob Mackin’s August 13, 2021 article for theBreaker.news sheds some light on how that corporation was formed so very quickly and more,

The B.C. NDP government rejigged the B.C. Immigrant Investor Fund last year, but refused to release the business case when it was rebranded as inBC Investment Corp. in late April [2021].

theBreaker.news requested the business case for the $500 million fund, which is overseen by a board of NDP patronage appointees, on May 6 [2021].

The 123-page document below is heavily censored — meaning the NDP cabinet is refusing to tell British Columbians the projected operating costs (including board expenses, salary and benefits, office space, operating and administration), full-time equivalents, and cash flows for the newest Crown corporation. inBC bills itself as a triple-bottom line organization, meaning it intends to invest on the basis of social, environmental and economic values.

When its enabling legislation was tabled, the NDP took steps to exempt inBC from the freedom of information law.

Thank you, Mr. Mackin.

More on Banting, insulin and patents

Caitlyn McClure’s 2016 article (Insulin’s Inventor Sold the Patent for $1. Then Drug Companies Got Hold of It.) for other98.com is a brief and pithy explanation for why insulin costs so much. Alanna Mitchell’s August 13, 2019 article for Maclean’s magazine investigates ‘insulin tourism’ and offers more detail as to how this situation has come about.

One last reminder, my August 20, 2021 posting (Getting erased from the mRNA/COVID-19 story) about Ian MacLachlan provides insight into how competitive and rough the bitotechnology scene can be here in BC/Canada.

Getting erased from the mRNA/COVID-19 story

Nathan Vardi’s August 17, 2021 article for Forbes magazine about Ian MacLachlan and the delivery system for mRNA vaccines tells a type of story I’ve more often seen in history books. It is reminiscent of the Thomas Edison and Nikola Tesla story of electricity. One gets all the glory while the other is largely forgotten.

I’m especially interested as much of this concerns players in the local (Vancouver, British Columbia, Canada) biotechnology scene. Vardi’s August 17, 2021 article sets the scene,

“The whole mRNA platform is not how to build an mRNA molecule; that’s the easy thing,” Bourla [Pfizer CEO Albert Bourla] says. “It is how to make sure the mRNA molecule will go into your cells and give the instructions.” 

Yet the story of how Moderna, BioNTech and Pfizer managed to create that vital delivery system has never been told. It’s a complicated saga involving 15 years of legal battles and accusations of betrayal and deceit. [emphases mine] What is clear is that when humanity needed a way to deliver mRNA to human cells to arrest the pandemic, there was only one reliable method available—and it wasn’t one originated in-house by Pfizer, Moderna, BioNTech or any of the other major vaccine companies. 

A months-long investigation by Forbes reveals that the scientist most responsible for this critical delivery method is a little-known 57-year-old Canadian biochemist named Ian MacLachlan. As chief scientific officer of two small companies, Protiva Biotherapeutics and Tekmira Pharmaceuticals, MacLachlan led the team that developed this crucial technology. Today, though, few people—and none of the big pharmaceutical companies—openly acknowledge his groundbreaking work, and MacLachlan earns nothing from the technology he pioneered. 

I have three stories (on this blog) mentioning Tekmira (all from 2014 or 2015) and none mentioning Protiva nor, for that matter, Ian MacLachlan.

Back to Vardi’s August 17, 2021 article,

Moderna Therapeutics vigorously disputes the idea that its mRNA vaccine uses MacLachlan’s delivery system, and BioNTech, the vaccine maker partnered with Pfizer, talks about it carefully. Legal proceedings are pending, and big money is at stake. 

Moderna, BioNTech and Pfizer are on their way to selling $45 billion worth of vaccines in 2021. They don’t pay a dime to MacLachlan. Other coronavirus vaccine makers, such as Gritstone Oncology, have recently licensed MacLachlan’s Protiva-Tekmira delivery technology for between 5% and 15% of product sales. MacLachlan no longer has a financial stake in the technology, but a similar royalty on the Moderna and Pfizer-BioNTech vaccines could yield as much as $6.75 billion in 2021 alone. …

Vardi provides evidence (Note: A link has been removed from the August 17, 2021 article excerpt,

Despite their denials, scientific papers and regulatory documents filed with the FDA [US Food and Drug Administration] show that both Moderna and Pfizer-BioNTech’s vaccines use a delivery system strikingly similar to what MacLachlan and his team created—a carefully formulated four-lipid component that encapsulates mRNA in a dense particle through a mixing process involving ethanol and a T-connector apparatus. 

For years, Moderna claimed it was using its own proprietary delivery system, but when it came time for the company to test its Covid-19 vaccine in mice, it used the same four kinds of lipids as MacLachlan’s technology, in identical ratios. 

According to Vardi’s LinkedIn profile: “I am a senior editor at Forbes, where I am responsible for the coverage of hedge funds, private equity, and other big investors. I lead investigative reporting efforts and have written 20 cover stories for Forbes Magazine,” he does not appear to have any medical or bioscience expertise (Bachelor of Journalism from Carleton University [Canada] and Masters of International Affairs from Columbia University [US].) Presumably someone he consulted or someone on his team provided the skills necessary for analyzing the scientific papers and documents.

You may recognize this scientist (from the August 17, 2021 article),

Not everyone ignores MacLachlan. “A lot of credit goes to Ian MacLachlan for the LNP [lipid nanoparticle],” says Katalin Karikó, [emphasis mine] the scientist who laid the groundwork for mRNA therapies before joining BioNTech in 2013. But Karikó, now a frontrunner for a Nobel Prize, is angry that MacLachlan didn’t do more to help her use his delivery system to build her own mRNA company years ago. “[MacLachlan] might be a great scientist, but he lacked vision,” she says.

I have more about Karikó and her role in the mRNA vaccine story here in a March 5, 2021 posting.

As for MacLachlan’s start (from the August 17, 2021 article),

… With a Ph.D. in biochemistry, MacLachlan joined Inex in 1996, his first job after completing a postdoctoral fellowship in a gene lab at the University of Michigan. 

Inex was cofounded by its chief scientific officer, Pieter Cullis, now 75, a long-haired physicist who taught at the University of British Columbia. From his perch there Cullis started several biotechs, cultivating an elite community of scientists that made Vancouver a hotbed of lipid chemistry. 

As companies rise and fall with intellectual property being assigned to one company or other, legal brawls ensue. This was the time that Karikó came knocking on the door, from the August 17, 2021 article,

It was in the midst of all this furious legal fighting that Hungarian biochemist Katalin Karikó first showed up at MacLachlan’s door. Karikó was early to grasp that MacLachlan’s delivery system held the key to unlocking the potential of mRNA therapies. As early as 2006, she began sending letters to MacLachlan urging him to encase her groundbreaking chemically altered mRNA in his four-lipid delivery system. Embroiled in litigation, MacLachlan passed on her offer. 

Karikó didn’t give up easily. In 2013, she flew to meet with Tekmira’s executives, offering to relocate to Vancouver and work directly under MacLachlan. Tekmira passed. “Moderna, BioNTech and CureVac all wanted me to work for them, but my number one choice, Tekmira, didn’t,” says Karikó, who took a job at BioNTech in 2013. 

By this time, Moderna CEO Stéphane Bancel [emphasis mine] was also trying to solve the delivery puzzle. Bancel held discussions with Tekmira about collaborating, but talks stalled. At one point, Tekmira indicated it wanted at least $100 million up front, plus royalties, to strike a deal.

Instead, Moderna partnered with Madden [Thomas Madden], who was still working with Cullis at their drug delivery company, Acuitas Therapeutics.  …

I have been wondering why Acuitas Therapeutics hasn’t been getting all that much attention in the hyperbolic discussions about British Columbia’s (or Vancouver’s) thriving biotechnology scene. (I’ll have more about the ‘scene’ in a later posting.) Perhaps all this legal wrangling is not considered helpful when bragging. (I do have a November 12, 2020 post, which features Acuitas, an interview with its president and chief executive office Dr. Thomas Madden, and an explanation of their technology.)

As for Moderna, I have a special interest as the company has announced plans to open a production facility here in Canada and one of Moderna’s founders is Canadian, Derek Rossi. (He too is mentioned in the March 5, 2021 posting, scroll down to the ‘Entrepreneurs rush in’ subhead; he is not an altogether happy camper.)

Rossi has opinions on how we should be doing things here as noted in a June 17, 2021 article by Barbara Shecter for the Financial Post (Moderna founder says Canada needs to build a biotech hub to avoid ‘getting caught with its pants down next time’). Thank you, Mr. Rossi. (I’m more familiar with clusters than hubs [hubs were a popular topic of conversation about 20 years ago but in Canada we seem more interested in clusters; see John Newbigin’s “Hubs, clusters and regions” on britishcouncil.org for a description of the differences].)

As for Moderna’s response to all of the legal wrangling over mRNA delivery systems, from Vardi’s August 17, 2021 article,

Moderna pursued a different strategy. It filed lawsuits with the U.S. Patent and Trademark Office seeking to nullify a series of patents related to MacLachlan’s delivery system, now controlled by Genevant. But in July 2020, as Moderna was pushing its vaccine through clinical trials, an adjudicative body largely upheld the most important patent claims. (Moderna is appealing.)

I highly recommend reading Vardi’s August 17, 2021 article as I have not done justice to all of the ‘ins and outs’ of the story.

You can see how thoroughly MacLachlan has been erased form the lipid nanoparticle delivery system/COVID-19 vaccine story in this May 24 ,2021 posting (Lipid nanoparticles: The underrated invention behind the vaccine revolution) by Nada Salem at the Science Borealis blog. It is largely a description of the technology and in the last two paragraphs a history of its development with no mention of MacLachlan or any of his companies.

One last thought, I wonder how Vardi found out about MacLachlan. Could someone have brought the story to his attention and who might that have been?

University of Alberta researchers 3D print nose cartilage

A May 4, 2021 news item on ScienceDaily announced work that may result the restoration of nasal cartilage for skin cancer patients,

A team of University of Alberta researchers has discovered a way to use 3-D bioprinting technology to create custom-shaped cartilage for use in surgical procedures. The work aims to make it easier for surgeons to safely restore the features of skin cancer patients living with nasal cartilage defects after surgery.

The researchers used a specially designed hydrogel — a material similar to Jell-O — that could be mixed with cells harvested from a patient and then printed in a specific shape captured through 3-D imaging. Over a matter of weeks, the material is cultured in a lab to become functional cartilage.

“It takes a lifetime to make cartilage in an individual, while this method takes about four weeks. So you still expect that there will be some degree of maturity that it has to go through, especially when implanted in the body. But functionally it’s able to do the things that cartilage does,” said Adetola Adesida, a professor of surgery in the Faculty of Medicine & Dentistry.

“It has to have certain mechanical properties and it has to have strength. This meets those requirements with a material that (at the outset) is 92 per cent water,” added Yaman Boluk, a professor in the Faculty of Engineering.

Who would have thought that nose cartilage would look like a worm?

Caption: 3-D printed cartilage is shaped into a curve suitable for use in surgery to rebuild a nose. The technology could eventually replace the traditional method of taking cartilage from the patient’s rib, a procedure that comes with complications. Credit: University of Alberta

A May 4, 2021 University of Alberta news release (also on EurekAlert) by Ross Neitz, which originated the news item, details why this research is important,

Adesida, Boluk and graduate student Xiaoyi Lan led the project to create the 3-D printed cartilage in hopes of providing a better solution for a clinical problem facing many patients with skin cancer.

Each year upwards of three million people in North America are diagnosed with non-melanoma skin cancer. Of those, 40 per cent will have lesions on their noses, with many requiring surgery to remove them. As part of the procedure, many patients may have cartilage removed, leaving facial disfiguration.

Traditionally, surgeons would take cartilage from one of the patient’s ribs and reshape it to fit the needed size and shape for reconstructive surgery. But the procedure comes with complications.

“When the surgeons restructure the nose, it is straight. But when it adapts to its new environment, it goes through a period of remodelling where it warps, almost like the curvature of the rib,” said Adesida. “Visually on the face, that’s a problem.

“The other issue is that you’re opening the rib compartment, which protects the lungs, just to restructure the nose. It’s a very vital anatomical location. The patient could have a collapsed lung and has a much higher risk of dying,” he added.

The researchers say their work is an example of both precision medicine and regenerative medicine. Lab-grown cartilage printed specifically for the patient can remove the risk of lung collapse, infection in the lungs and severe scarring at the site of a patient’s ribs.

“This is to the benefit of the patient. They can go on the operating table, have a small biopsy taken from their nose in about 30 minutes, and from there we can build different shapes of cartilage specifically for them,” said Adesida. “We can even bank the cells and use them later to build everything needed for the surgery. This is what this technology allows you to do.”

The team is continuing its research and is now testing whether the lab-grown cartilage retains its properties after transplantation in animal models. The team hopes to move the work to a clinical trial within the next two to three years.

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

Bioprinting of human nasoseptal chondrocytes-laden collagen hydrogel for cartilage tissue engineering by Xiaoyi Lan, Yan Liang, Esra J. N. Erkut, Melanie Kunze, Aillette Mulet-Sierra, Tianxing Gong, Martin Osswald, Khalid Ansari, Hadi Seikaly, Yaman Boluk, Adetola B. Adesida. The FASEB Journal Volume 35, Issue 3 March 2021 e21191 DOI: https://doi.org/10.1096/fj.202002081R First published online: 17 February 2021

This paper is open access.

Will you be my friend? Yes, after we activate our ultraminiature, wireless, battery-free, fully implantable devices

Perhaps I’m the only one who’s disconcerted?

Here’s the research (in text form) as to why we’re watching these scampering, momentary mouse friends, from a May 10, 2021 Northwestern University news release (also on EurekAlert) by Amanda Morris,

Northwestern University researchers are building social bonds with beams of light.

For the first time ever, Northwestern engineers and neurobiologists have wirelessly programmed — and then deprogrammed — mice to socially interact with one another in real time. The advancement is thanks to a first-of-its-kind ultraminiature, wireless, battery-free and fully implantable device that uses light to activate neurons.

This study is the first optogenetics (a method for controlling neurons with light) paper exploring social interactions within groups of animals, which was previously impossible with current technologies.

The research was published May 10 [2021] in the journal Nature Neuroscience.

The thin, flexible, wireless nature of the implant allows the mice to look normal and behave normally in realistic environments, enabling researchers to observe them under natural conditions. Previous research using optogenetics required fiberoptic wires, which restrained mouse movements and caused them to become entangled during social interactions or in complex environments.

“With previous technologies, we were unable to observe multiple animals socially interacting in complex environments because they were tethered,” said Northwestern neurobiologist Yevgenia Kozorovitskiy, who designed the experiment. “The fibers would break or the animals would become entangled. In order to ask more complex questions about animal behavior in realistic environments, we needed this innovative wireless technology. It’s tremendous to get away from the tethers.”

“This paper represents the first time we’ve been able to achieve wireless, battery-free implants for optogenetics with full, independent digital control over multiple devices simultaneously in a given environment,” said Northwestern bioelectronics pioneer John A. Rogers, who led the technology development. “Brain activity in an isolated animal is interesting, but going beyond research on individuals to studies of complex, socially interacting groups is one of the most important and exciting frontiers in neuroscience. We now have the technology to investigate how bonds form and break between individuals in these groups and to examine how social hierarchies arise from these interactions.”

Kozorovitskiy is the Soretta and Henry Shapiro Research Professor of Molecular Biology and associate professor of neurobiology in Northwestern’s Weinberg College of Arts and Sciences. She also is a member of the Chemistry of Life Processes Institute. Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery in the McCormick School of Engineering and Northwestern University Feinberg School of Medicine and the director of the Querrey Simpson Institute for Bioelectronics.

Kozorovitskiy and Rogers led the work with Yonggang Huang, the Jan and Marcia Achenbach Professor in Mechanical Engineering at McCormick, and Zhaoqian Xie, a professor of engineering mechanics at Dalian University of Technology in China. The paper’s co-first authors are Yiyuan Yang, Mingzheng Wu and Abraham Vázquez-Guardado — all at Northwestern.

Promise and problems of optogenetics

Because the human brain is a system of nearly 100 billion intertwined neurons, it’s extremely difficult to probe single — or even groups of — neurons. Introduced in animal models around 2005, optogenetics offers control of specific, genetically targeted neurons in order to probe them in unprecedented detail to study their connectivity or neurotransmitter release. Researchers first modify neurons in living mice to express a modified gene from light-sensitive algae. Then they can use external light to specifically control and monitor brain activity. Because of the genetic engineering involved, the method is not yet approved in humans.

“It sounds like sci-fi, but it’s an incredibly useful technique,” Kozorovitskiy said. “Optogenetics could someday soon be used to fix blindness or reverse paralysis.”

Previous optogenetics studies, however, were limited by the available technology to deliver light. Although researchers could easily probe one animal in isolation, it was challenging to simultaneously control neural activity in flexible patterns within groups of animals interacting socially. Fiberoptic wires typically emerged from an animal’s head, connecting to an external light source. Then a software program could be used to turn the light off and on, while monitoring the animal’s behavior.

“As they move around, the fibers tugged in different ways,” Rogers said. “As expected, these effects changed the animal’s patterns of motion. One, therefore, has to wonder: What behavior are you actually studying? Are you studying natural behaviors or behaviors associated with a physical constraint?”

Wireless control in real time

A world-renowned leader in wireless, wearable technology, Rogers and his team developed a tiny, wireless device that gently rests on the skull’s outer surface but beneath the skin and fur of a small animal. The half-millimeter-thick device connects to a fine, flexible filamentary probe with LEDs on the tip, which extend down into the brain through a tiny cranial defect.

The miniature device leverages near-field communication protocols, the same technology used in smartphones for electronic payments. Researchers wirelessly operate the light in real time with a user interface on a computer. An antenna surrounding the animals’ enclosure delivers power to the wireless device, thereby eliminating the need for a bulky, heavy battery.

Activating social connections

To establish proof of principle for Rogers’ technology, Kozorovitskiy and colleagues designed an experiment to explore an optogenetics approach to remote-control social interactions among pairs or groups of mice.

When mice were physically near one another in an enclosed environment, Kozorovitskiy’s team wirelessly synchronously activated a set of neurons in a brain region related to higher order executive function, causing them to increase the frequency and duration of social interactions. Desynchronizing the stimulation promptly decreased social interactions in the same pair of mice. In a group setting, researchers could bias an arbitrarily chosen pair to interact more than others.

“We didn’t actually think this would work,” Kozorovitskiy said. “To our knowledge, this is the first direct evaluation of a major long-standing hypothesis about neural synchrony in social behavior.”

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

Wireless multilateral devices for optogenetic studies of individual and social behaviors by Yiyuan Yang, Mingzheng Wu, Amy J. Wegener, Jose G. Grajales-Reyes, Yujun Deng, Taoyi Wang, Raudel Avila, Justin A. Moreno, Samuel Minkowicz, Vasin Dumrongprechachan, Jungyup Lee, Shuangyang Zhang, Alex A. Legaria, Yuhang Ma, Sunita Mehta, Daniel Franklin, Layne Hartman, Wubin Bai, Mengdi Han, Hangbo Zhao, Wei Lu, Yongjoon Yu, Xing Sheng, Anthony Banks, Xinge Yu, Zoe R. Donaldson, Robert W. Gereau IV, Cameron H. Good, Zhaoqian Xie, Yonggang Huang, Yevgenia Kozorovitskiy and John A. Rogers. Nature Neuroscience (2021)
DOI: https://doi.org/10.1038/s41593-021-00849-x Published 10 May 2021

This paper is behind a paywall.

This latest research seems to be the continuation of research featured here in a July 16, 2019 posting: “Controlling neurons with light: no batteries or wires needed.”

‘Nanotraps’ for catching and destroying coronavirus

‘Nanotraps’ are not vaccines although they do call the immune system into play. They represent a different way for dealing with COVID-19. (This work reminds of my June 24, 2020 posting Tiny sponges lure coronavirus away from lung cells where the researchers have a similar approach with what they call ‘nanosponges’.)

An April 27, 2021 news item on Nanowerk makes the announcement,

Researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have designed a completely novel potential treatment for COVID-19: nanoparticles that capture SARS-CoV-2 viruses within the body and then use the body’s own immune system to destroy it.

These “Nanotraps” attract the virus by mimicking the target cells the virus infects. When the virus binds to the Nanotraps, the traps then sequester the virus from other cells and target it for destruction by the immune system.

In theory, these Nanotraps could also be used on variants of the virus, leading to a potential new way to inhibit the virus going forward. Though the therapy remains in early stages of testing, the researchers envision it could be administered via a nasal spray as a treatment for COVID-19.

A scanning electron microscope image of a nanotrap (orange) binding a simulated SARS-CoV-2 virus (dots in green). Scientists at the University of Chicago created these nanoparticles as a potential treatment for COVID-19. Image courtesy Chen and Rosenberg et al.

An April 27, 2021 University of Chicago news release (also on EurekAlert) by Emily Ayshford, which originated the news item, describes the work in more detail,

“Since the pandemic began, our research team has been developing this new way to treat COVID-19,” said Asst. Prof. Jun Huang, whose lab led the research. “We have done rigorous testing to prove that these Nanotraps work, and we are excited about their potential.”

Designing the perfect trap

To design the Nanotrap, the research team – led by postdoctoral scholar Min Chen and graduate student Jill Rosenberg – looked into the mechanism SARS-CoV-2 uses to bind to cells: a spike-like protein on its surface that binds to a human cell’s ACE2 receptor protein.

To create a trap that would bind to the virus in the same way, they designed nanoparticles with a high density of ACE2 proteins on their surface. Similarly, they designed other nanoparticles with neutralizing antibodies on their surfaces. (These antibodies are created inside the body when someone is infected and are designed to latch onto the coronavirus in various ways).

Both ACE2 proteins and neutralizing antibodies have been used in treatments for COVID-19, but by attaching them to nanoparticles, the researchers created an even more robust system for trapping and eliminating the virus.

Made of FDA [US Food and Drug Administration]-approved polymers and phospholipids, the nanoparticles are about 500 nanometers in diameter – much smaller than a cell. That means the Nanotraps can reach more areas inside the body and more effectively trap the virus.

The researchers tested the safety of the system in a mouse model and found no toxicity. They then tested the Nanotraps against a pseudovirus – a less potent model of a virus that doesn’t replicate – in human lung cells in tissue culture plates and found that they completely blocked entry into the cells.

Once the pseudovirus bound itself to the nanoparticle – which in tests took about 10 minutes after injection – the nanoparticles used a molecule that calls the body’s macrophages to engulf and degrade the Nanotrap. Macrophages will generally eat nanoparticles within the body, but the Nanotrap molecule speeds up the process. The nanoparticles were cleared and degraded within 48 hours.

The researchers also tested the nanoparticles with a pseudovirus in an ex vivo lung perfusion system – a pair of donated lungs that is kept alive with a ventilator – and found that they completely blocked infection in the lungs.

They also collaborated with researchers at Argonne National Laboratory to test the Nanotraps with a live virus (rather than a pseudovirus) in an in vitro system. They found that their system inhibited the virus 10 times better than neutralizing antibodies or soluble ACE2 alone.

A potential future treatment for COVID-19 and beyond

Next the researchers hope to further test the system, including more tests with a live virus and on the many virus variants.

“That’s what is so powerful about this Nanotrap,” Rosenberg said. “It’s easily modulated. We can switch out different antibodies or proteins or target different immune cells, based on what we need with new variants.”

The Nanotraps can be stored in a standard freezer and could ultimately be given via an intranasal spray, which would place them directly in the respiratory system and make them most effective.

The researchers say it is also possible to serve as a vaccine by optimizing the Nanotrap formulation, creating an ultimate therapeutic system for the virus.

“This is the starting point,” Huang said. “We want to do something to help the world.”

The research involved collaborators across departments, including chemistry, biology, and medicine.

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

Nanotraps for the containment and clearance of SARS-CoV-2 by Min Chen, Jillian Rosenberg, Xiaolei Cai, Andy Chao Hsuan Lee, Jiuyun Shi, Mindy Nguyen, Thirushan Wignakumar, Vikranth Mirle, Arianna Joy Edobor, John Fung, Jessica Scott Donington, Kumaran Shanmugarajah, Yiliang Lin, Eugene Chang, Glenn Randall, Pablo Penaloza-MacMaster, Bozhi Tian, Maria Lucia Madariaga, Jun Huang. Matter, April 19, 2021, DOI: https://doi.org/10.1016/j.matt.2021.04.005

This paper appears to be open access.

Protocols for mouse-human chimeric embryos

This work on a type of species boundary-crossing could be very disturbing for some folks. That said, here’s more about the science from a July 2, 2021 news item on phys.org,

A year after University at Buffalo [in New York state] scientists demonstrated that it was possible to produce millions of mature human cells in a mouse embryo, they have published a detailed description of the method so that other laboratories can do it, too.

A July 2, 2021 University at Buffalo (UB) news release (also on EurekAlert) by Ellen Goldbaum, which originated the news item, explains why scientists have created these chimeras,

The ability to produce millions of mature human cells in a living organism, called a chimera, which contains the cells of two species, is critical if the ultimate promise of stem cells to treat or cure human disease is to be realized. But to produce those mature cells, human primed stem cells must be converted back into an earlier, less developed naive state so that the human stem cells can co-develop with the inner cell mass in a mouse blastocyst.

The protocol outlining how to do that has now been published in Nature Protocols by the UB scientists. They were invited to publish it because of the significant interest generated by the team’s initial publication describing their breakthrough last May [2020].

“This paper will enable many scientists to use this new platform to study the human disease of their interest,” said Jian Feng, PhD, professor of physiology and biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB and senior author. “Over time, it will transform biomedical research toward a more effective use of the human model system to directly study virtually any inborn condition of an individual. It will stimulate unforeseen discoveries and applications that may fundamentally change our understanding of human biology and medicine.”

The protocol will allow scientists to create animal models that Feng said provide a much more realistic picture of embryonic development than has ever been possible. These more realistic animal models also will have the potential to reveal the mechaniswms behind numerous diseases, especially those that afflict individuals from birth.

Better mouse models

“This step-by-step protocol will benefit the entire field by enabling other scientists to use our methods to generate chimeras to study human diseases that they are experts in,” said Feng. “It will lead to the generation of better mouse models for various human diseases, such as sickle cell anemia, COVID-19 and many others, or various human developmental disorders.” The paper demonstrates how to generate naive human pluripotent stem cells from existing induced pluripotent stem cells that may be derived from patients with various diseases, how to generate mouse-human chimeras using these cells and how to quantify the amount of human cells in the chimeras.

“Using our method, one can now track the development of naive human pluripotent stem cells in mouse-human chimeric embryos in real-time,” said Feng. These stem cells can then be manipulated either genetically or pharmacologically, providing valuable information about human development and disease.

“For example, one can label naive human pluripotent stem cells by inserting green fluorescent protein in a hemoglobin gene to study the development of human red blood cells in mouse-human chimeras,” said Feng.

Another application is to generate humanized mouse models to study many human diseases.

“These mice contain critical human cells, tissues or even organs so that they more accurately reflect the human condition,” said Feng. “With our method, the human cells are made along with the mouse during the development of the mouse embryo. There would be better matching and no rejections, because there are ways for the human cells to be made where there is no competition from their mouse counterparts.”

Organs for transplant in the future

By allowing others to improve and adapt the method to eventually generate chimeras in larger animals, this protocol may also lead to the generation of human organs to address the dire shortage of organs available for transplant, said Feng.

“If naive human pluripotent stem cells are able to generate significant amounts of mature human cells in other larger species, it could be possible to make human tissues or even human organs in chimeric animals,” Feng explained.

This would be possible using blastocyst complementation where, Feng explained, normal pluripotent stem cells from one species can reconstitute an organ for that species in a blastocyst of another species that been genetically modified not to grow that particular organ.

Feng added: “Ultimately, a better understanding of how human cells develop and grow in chimeras may enable the generation of human cells, tissues and organs in a completely artificial system and fundamentally change how we treat many human diseases. Research using chimeras is a bridge that must be crossed to reach that possibility.”

Here’s a link to and a citation for the 2021 article,

Generation of mouse–human chimeric embryos by Boyang Zhang, Hanqin Li, Zhixing Hu, Houbo Jiang, Aimee B. Stablewski, Brandon J. Marzullo, Donald A. Yergeau & Jian Feng. Nature Protocols (2021) DOI: https://doi.org/10.1038/s41596-021-00565-7 Published 02 July 2021

This article is behind a paywall.

Here’s a link to and citation for the 2020 work, which led to the publication of the protocols,

Transient inhibition of mTOR in human pluripotent stem cells enables robust formation of mouse-human chimeric embryos by Zhixing Hu, Hanqin Li, Houbo Jiang, Yong Ren, Xinyang Yu, Jingxin Qiu, Aimee B. Stablewski, Boyang Zhang, Michael J. Buck, Jian Feng. Science Advances 13 May 2020: Vol. 6, no. 20, eaaz0298 DOI: 10.1126/sciadv.aaz0298

This paper is open access.

Nanosensors use AI to explore the biomolecular world

EPFL scientists have developed AI-powered nanosensors that let researchers track various kinds of biological molecules without disturbing them. Courtesy: École polytechnique fédérale de Lausanne (EPFL)

If you look at the big orange dot (representing the nanosensors?), you’ll see those purplish/fuschia objects resemble musical notes (biological molecules?). I think that brainlike object to the left and in light blue is the artificial intelligence (AI) component. (If anyone wants to correct my guesses or identify the bits I can’t, please feel free to add to the Comments for this blog.)

Getting back to my topic, keep the ‘musical notes’ in mind as you read about some of the latest research from l’École polytechnique fédérale de Lausanne (EPFL) in an April 7, 2021 news item on Nanowerk,

The tiny world of biomolecules is rich in fascinating interactions between a plethora of different agents such as intricate nanomachines (proteins), shape-shifting vessels (lipid complexes), chains of vital information (DNA) and energy fuel (carbohydrates). Yet the ways in which biomolecules meet and interact to define the symphony of life is exceedingly complex.

Scientists at the Bionanophotonic Systems Laboratory in EPFL’s School of Engineering have now developed a new biosensor that can be used to observe all major biomolecule classes of the nanoworld without disturbing them. Their innovative technique uses nanotechnology, metasurfaces, infrared light and artificial intelligence.

To each molecule its own melody

In this nano-sized symphony, perfect orchestration makes physiological wonders such as vision and taste possible, while slight dissonances can amplify into horrendous cacophonies leading to pathologies such as cancer and neurodegeneration.

An April 7, 2021 EPFL press release, which originated the news item, provides more detail,

“Tuning into this tiny world and being able to differentiate between proteins, lipids, nucleic acids and carbohydrates without disturbing their interactions is of fundamental importance for understanding life processes and disease mechanisms,” says Hatice Altug, the head of the Bionanophotonic Systems Laboratory. 

Light, and more specifically infrared light, is at the core of the biosensor developed by Altug’s team. Humans cannot see infrared light, which is beyond the visible light spectrum that ranges from blue to red. However, we can feel it in the form of heat in our bodies, as our molecules vibrate under the infrared light excitation.

Molecules consist of atoms bonded to each other and – depending on the mass of the atoms and the arrangement and stiffness of their bonds – vibrate at specific frequencies. This is similar to the strings on a musical instrument that vibrate at specific frequencies depending on their length. These resonant frequencies are molecule-specific, and they mostly occur in the infrared frequency range of the electromagnetic spectrum. 

“If you imagine audio frequencies instead of infrared frequencies, it’s as if each molecule has its own characteristic melody,” says Aurélian John-Herpin, a doctoral assistant at Altug’s lab and the first author of the publication. “However, tuning into these melodies is very challenging because without amplification, they are mere whispers in a sea of sounds. To make matters worse, their melodies can present very similar motifs making it hard to tell them apart.” 

Metasurfaces and artificial intelligence

The scientists solved these two issues using metasurfaces and AI. Metasurfaces are man-made materials with outstanding light manipulation capabilities at the nano scale, thereby enabling functions beyond what is otherwise seen in nature. Here, their precisely engineered meta-atoms made out of gold nanorods act like amplifiers of light-matter interactions by tapping into the plasmonic excitations resulting from the collective oscillations of free electrons in metals. “In our analogy, these enhanced interactions make the whispered molecule melodies more audible,” says John-Herpin.

AI is a powerful tool that can be fed with more data than humans can handle in the same amount of time and that can quickly develop the ability to recognize complex patterns from the data. John-Herpin explains, “AI can be imagined as a complete beginner musician who listens to the different amplified melodies and develops a perfect ear after just a few minutes and can tell the melodies apart, even when they are played together – like in an orchestra featuring many instruments simultaneously.” 

The first biosensor of its kind

When the scientists’ infrared metasurfaces are augmented with AI, the new sensor can be used to analyze biological assays featuring multiple analytes simultaneously from the major biomolecule classes and resolving their dynamic interactions. 

“We looked in particular at lipid vesicle-based nanoparticles and monitored their breakage through the insertion of a toxin peptide and the subsequent release of vesicle cargos of nucleotides and carbohydrates, as well as the formation of supported lipid bilayer patches on the metasurface,” says Altug.

This pioneering AI-powered, metasurface-based biosensor will open up exciting perspectives for studying and unraveling inherently complex biological processes, such as intercellular communication via exosomesand the interaction of nucleic acids and carbohydrates with proteins in gene regulation and neurodegeneration. 

“We imagine that our technology will have applications in the fields of biology, bioanalytics and pharmacology – from fundamental research and disease diagnostics to drug development,” says Altug. 

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

Infrared Metasurface Augmented by Deep Learning for Monitoring Dynamics between All Major Classes of Biomolecules by Aurelian John‐Herpin, Deepthy Kavungal. Lea von Mücke, Hatice Altug. Advanced Materials Volume 33, Issue 14 April 8, 2021 2006054 DOI: https://doi.org/10.1002/adma.202006054 First published: 22 February 2021

This paper is open access.