Tag Archives: Broad Institute

Health/science journalists/editors: deadline is March 22, 2024 for media boot camp in Boston, Massachusetts

A February 14, 2023 Broad Institute news release presents an exciting opportunity for health/science journalists and editors,

The Broad Institute of MIT [Massachusetts Institute of Technology] and Harvard is now accepting applications for its 2024 Media Boot Camp.

This annual program connects health/science journalists and editors with faculty from the Broad Institute, Massachusetts Institute of Technology, Harvard University, and Harvard’s teaching hospitals for a two-day event exploring the latest advances in genomics and biomedicine. Journalists will explore possible future storylines, gain fundamental background knowledge, and build relationships with researchers. The program format includes presentations, discussions, and lab tours.

The 2024 Media Boot Camp will take place in person at the Broad Institute in Cambridge, MA on Thursday, May 16 and Friday, May 17 (with an evening welcome reception on Wednesday, May 15).

APPLICATION DEADLINE IS FRIDAY, MARCH 22 (5:00 PM US EASTERN TIME).

2024 Boot Camp topics include:

  • Gene editing
  • New approaches for therapeutic delivery  
  • Cancer biology, drug development
  • Data sciences, machine learning
  • Neurobiology (stem cell models of psychiatric disorders)
  • Antibiotic resistance, microbial biology
  • Medical and population genetics, genomic medicine

Current speakers include: Mimi Bandopadhayay, Clare Bernard,Roby Bhattacharyya, Todd Golub, Laura Kiessling, Eric Lander,David Liu, Ralda Nehme,Heidi Rehm, William Sellers, Feng Zhang, with potentially more to come.

This Media Boot Camp is an educational offering. All presentations are on-background.

Hotel accommodations and meals during the program will be provided by the Broad Institute. Attendees must cover travel costs to and from Boston.

Application Process

By Friday, March 22 [2024] (5:00 PM US Eastern time [2 pm PT]), please send at least one paragraph describing your interest in the program and how you hope it will benefit your reporting, as well as three recent news clips, to David Cameron, Director of External Communications, dcameron@broadinstitute.org

Please contact David at dcameron@broadinstitute.org, or 617-714-7184 with any questions.

I couldn’t find details about eligibility, that said, I wish you good luck with your ‘paragraph and three recent clips’ submission.

CRISPR-like system found in animals

I trust the eukaryotes will not be suing for intellectual property rights. (For anyone who’s interested in CRISPR [clustered regularly interspaced short palindromic repeats) and associated intellectual property (specifically, patent) issues, see my March 15, 2017 posting “CRISPR patent decision: Harvard’s and MIT’s Broad Institute victorious—for now.” It’s not up-to-date but as far as I know there haven’t been any major intellectual property developments since. If I’m wrong, please let me know in the Comments section of this posting.)

A june 28, 2023 news item on phys.org announces research suggesting there are naturally occurring CRISPR-like capabilities in some species,

A team of researchers led by Feng Zhang at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT [Massachusetts Institute of Technology] has uncovered the first programmable RNA-guided system in eukaryotes—organisms that include fungi, plants, and animals.

In a study in Nature, the team describes how the system is based on a protein called Fanzor. They showed that Fanzor proteins use RNA as a guide to target DNA precisely, and that Fanzors can be reprogrammed to edit the genome of human cells. The compact Fanzor systems have the potential to be more easily delivered to cells and tissues as therapeutics than CRISPR/Cas systems, and further refinements to improve their targeting efficiency could make them a valuable new technology for human genome editing

A june 28, 2023 Broad Institute of MIT and Harvard news release by Leah Eisenstadt (also on EurekAlert), which originated the news item, provides more context for the research,

CRISPR/Cas was first discovered in prokaryotes (bacteria and other single-cell organisms that lack nuclei) and scientists including Zhang’s lab have long wondered whether similar systems exist in eukaryotes. The new study demonstrates that RNA-guided DNA-cutting mechanisms are present across all kingdoms of life.

“CRISPR-based systems are widely used and powerful because they can be easily reprogrammed to target different sites in the genome,” said Zhang, senior author on the study and a core institute member at the Broad, an investigator at MIT’s McGovern Institute, the James and Patricia Poitras Professor of Neuroscience at MIT, and a Howard Hughes Medical Institute investigator. “This new system is another way to make precise changes in human cells, complementing the genome editing tools we already have.”

Searching the domains of life

A major aim of the Zhang lab is to develop genetic medicines using systems that can modulate human cells by targeting specific genes and processes. “A number of years ago, we started to ask, ‘What is there beyond CRISPR, and are there other RNA-programmable systems out there in nature?’” said Zhang.

Two years ago, Zhang lab members discovered a class of RNA-programmable systems in prokaryotes called OMEGAs, which are often linked with transposable elements, or “jumping genes”, in bacterial genomes and likely gave rise to CRISPR/Cas systems. That work also highlighted similarities between prokaryotic OMEGA systems and Fanzor proteins in eukaryotes, suggesting that the Fanzor enzymes might also use an RNA-guided mechanism to target and cut DNA.

In the new study, the researchers continued their study of RNA-guided systems by isolating Fanzors from fungi, algae, and amoeba species, in addition to a clam known as the Northern Quahog. Co-first author Makoto Saito of the Zhang lab led the biochemical characterization of the Fanzor proteins, showing that they are DNA-cutting endonuclease enzymes that use nearby non-coding RNAs known as ωRNAs to target particular sites in the genome. It is the first time this mechanism has been found in eukaryotes, such as animals.

Unlike CRISPR proteins, Fanzor enzymes are encoded in the eukaryotic genome within transposable elements and the team’s phylogenetic analysis suggests that the Fanzor genes have migrated from bacteria to eukaryotes through so-called horizontal gene transfer.

“These OMEGA systems are more ancestral to CRISPR and they are among the most abundant proteins on the planet, so it makes sense that they have been able to hop back and forth between prokaryotes and eukaryotes,” said Saito.

To explore Fanzor’s potential as a genome editing tool, the researchers demonstrated that it can generate insertions and deletions at targeted genome sites within human cells. The researchers found the Fanzor system to initially be less efficient at snipping DNA than CRISPR/Cas systems, but by systematic engineering, they introduced a combination of mutations into the protein that increased its activity 10-fold. Additionally, unlike some CRISPR systems and the OMEGA protein TnpB, the team found that a fungal-derived Fanzor protein did not exhibit “collateral activity,” where an RNA-guided enzyme cleaves its DNA target as well as degrading nearby DNA or RNA. The results suggest that Fanzors could potentially be developed as efficient genome editors.

Co-first author Peiyu Xu led an effort to analyze the molecular structure of the Fanzor/ωRNA complex and illustrate how it latches onto DNA to cut it. Fanzor shares structural similarities with its prokaryotic counterpart CRISPR-Cas12 protein, but the interaction between the ωRNA and the catalytic domains of Fanzor is more extensive, suggesting that the ωRNA might play a role in the catalytic reactions. “We are excited about these structural insights for helping us further engineer and optimize Fanzor for improved efficiency and precision as a genome editor,” said Xu.

Like CRISPR-based systems, the Fanzor system can be easily reprogrammed to target specific genome sites, and Zhang said it could one day be developed into a powerful new genome editing technology for research and therapeutic applications. The abundance of RNA-guided endonucleases like Fanzors further expands the number of OMEGA systems known across kingdoms of life and suggests that there are more yet to be found.

“Nature is amazing. There’s so much diversity,” said Zhang. “There are probably more RNA-programmable systems out there, and we’re continuing to explore and will hopefully discover more.”

The paper’s other authors include Guilhem Faure, Samantha Maguire, Soumya Kannan, Han Altae-Tran, Sam Vo, AnAn Desimone, and Rhiannon Macrae.

About Broad Institute of MIT and Harvard
Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard, Harvard-affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide.

About McGovern Institute for Brain Research at MIT
The McGovern Institute is an inclusive and collaborative community of MIT scientists, engineers, and support staff who work together to unravel the mysteries of the brain. Our researchers are committed to meeting two of the greatest challenges of modern science: understanding how the brain works and discovering new ways to prevent or treat brain disorders. To address this scientific challenge, we study the brain at many levels and collaborate with academic, clinical, and industry partners around the world.

The McGovern Institute was established in 2000 by technology entrepreneur Lore Harp McGovern and the late Patrick J. McGovern, former chairman of International Data Group (IDG). Our director is Robert Desimone, the Doris and Don Berkey Professor of Neuroscience at MIT and former head of intramural research at the National Institute of Mental Health. The McGovern Institute has grown from six founding faculty members to more than 20 distinguished investigators including one Nobel laureate and six members of the National Academy of Sciences.

.

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

Fanzor is a eukaryotic programmable RNA-guided endonuclease by Makoto Saito, Peiyu Xu, Guilhem Faure, Samantha Maguire, Soumya Kannan, Han Altae-Tran, Sam Vo, AnAn Desimone, Rhiannon K. Macrae & Feng Zhang. Nature (2023) DOI: https://doi.org/10.1038/s41586-023-06356-2 Published: 28 June 2023

This paper is behind a paywall.

A CRISPR (clustered regularly interspaced short palindromic repeats) anniversary

June 2022 was the 10th anniversary of the publication of a study the paved the way for CRISPR-Cas9 gene editing and Sophie Fessl’s June 28, 2022 article for The Scientist offers a brief history (Note: Links have been removed),

Ten years ago, Emmanuelle Charpentier and Jennifer Doudna published the study that paved the way for a new kind of genome editing: the suite of technologies now known as CRISPR. Writing in [the journal] Science, they adapted an RNA-mediated bacterial immune defense into a targeted DNA-altering system. “Our study . . . highlights the potential to exploit the system for RNA-programmable genome editing,” they conclude in the abstract of their paper—a potential that, in the intervening years, transformed the life sciences. 

From gene drives to screens, and diagnostics to therapeutics, CRISPR nucleic acids and the Cas enzymes with which they’re frequently paired have revolutionized how scientists tinker with DNA and RNA. … altering the code of life with CRISPR has been marred by ethical concerns. Perhaps the most prominent example was when Chinese scientist He Jiankui created the first gene edited babies using CRISPR/Cas9 genome editing. Doudna condemned Jiankui’s work, for which he was jailed, as “risky and medically unnecessary” and a “shocking reminder of the scientific and ethical challenges raised by this powerful technology.” 

There’s also the fact that legal battles over who gets to claim ownership of the system’s many applications have persisted almost as long as the technology has been around. Both Doudna and Charpentier’s teams from the University of California, Berkeley, and the University of Vienna and a team led by the Broad Institute’s Feng Zhang claim to be the first to have adapted CRISPR-Cas9 for gene editing in complex cells (eukaryotes). Patent offices in different countries have reached varying decisions, but in the US, the latest rulings say that the Broad Institute of MIT [Massachusetts Institute of Technology] and Harvard retains intellectual property of using CRISPR-Cas9 in eukaryotes, while Emmanuelle Charpentier, the University of California, and the University of Vienna maintain their original patent over using CRISPR-Cas9 for editing in vitro and in prokaryotes. 

Still, despite the controversies, the technique continues to be explored academically and commercially for everything from gene therapy to crop improvement. Here’s a look at seven different ways scientists have utilized CRISPR.

Fessl goes on to give a brief overview of CRISPR and gene drives, genetic screens, diagnostics, including COVID-19 tests, gene therapy, therapeutics, crop and livestock improvement, and basic research.

For anyone interested in the ethical issues (with an in depth look at the Dr. He Jiankui story), I suggest reading either or both Eben Kirksey’s 2020 book, “The Mutant Project; Inside the Global Race to Genetically Modify Humans,”

An anthropologist visits the frontiers of genetics, medicine, and technology to ask: Whose values are guiding gene editing experiments? And what does this new era of scientific inquiry mean for the future of the human species?

“That rare kind of scholarship that is also a page-turner.”
—Britt Wray, author of Rise of the Necrofauna

At a conference in Hong Kong in November 2018, Dr. He Jiankui announced that he had created the first genetically modified babies—twin girls named Lulu and Nana—sending shockwaves around the world. A year later, a Chinese court sentenced Dr. He to three years in prison for “illegal medical practice.”

As scientists elsewhere start to catch up with China’s vast genetic research program, gene editing is fueling an innovation economy that threatens to widen racial and economic inequality. Fundamental questions about science, health, and social justice are at stake: Who gets access to gene editing technologies? As countries loosen regulations around the globe, from the U.S. to Indonesia, can we shape research agendas to promote an ethical and fair society?

Eben Kirksey takes us on a groundbreaking journey to meet the key scientists, lobbyists, and entrepreneurs who are bringing cutting-edge genetic engineering tools like CRISPR—created by Nobel Prize-winning biochemists Jennifer Doudna and Emmanuelle Charpentier—to your local clinic. He also ventures beyond the scientific echo chamber, talking to disabled scholars, doctors, hackers, chronically-ill patients, and activists who have alternative visions of a genetically modified future for humanity.

and/or Kevin Davies’s 2020 book, “Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing,”

One of the world’s leading experts on genetics unravels one of the most important breakthroughs in modern science and medicine. 

If our genes are, to a great extent, our destiny, then what would happen if mankind could engineer and alter the very essence of our DNA coding? Millions might be spared the devastating effects of hereditary disease or the challenges of disability, whether it was the pain of sickle-cell anemia to the ravages of Huntington’s disease.

But this power to “play God” also raises major ethical questions and poses threats for potential misuse. For decades, these questions have lived exclusively in the realm of science fiction, but as Kevin Davies powerfully reveals in his new book, this is all about to change.

Engrossing and page-turning, Editing Humanity takes readers inside the fascinating world of a new gene editing technology called CRISPR, a high-powered genetic toolkit that enables scientists to not only engineer but to edit the DNA of any organism down to the individual building blocks of the genetic code.

Davies introduces readers to arguably the most profound scientific breakthrough of our time. He tracks the scientists on the front lines of its research to the patients whose powerful stories bring the narrative movingly to human scale.

Though the birth of the “CRISPR babies” in China made international news, there is much more to the story of CRISPR than headlines seemingly ripped from science fiction. In Editing Humanity, Davies sheds light on the implications that this new technology can have on our everyday lives and in the lives of generations to come.

Kevin Davies is the executive editor of The CRISPR Journal and the founding editor of Nature Genetics. He holds an MA in biochemistry from the University of Oxford and a PhD in molecular genetics from the University of London. He is the author of Cracking the Genome, The $1,000 Genome, and co-authored a new edition of DNA: The Story of the Genetic Revolution with Nobel Laureate James D. Watson and Andrew Berry. In 2017, Kevin was selected for a Guggenheim Fellowship in science writing.

I’ve read both books and while some of the same ground is covered, the perspectives diverge somewhat. Both authors offer a more nuanced discussion of the issues than was the case in the original reporting about Dr. He’s work.

Precision targeting of the liver for gene editing

Apparently the magic is in the lipid nanoparticles. A March 1, 2021 news item on Nanowerk announced research into lipid nanoparticles as a means to deliver CRISPR (clustered regularly interspaced short palindromic repeats) to specific organs (Note: A link has been removed),

The genome editing technology CRISPR has emerged as a powerful new tool that can change the way we treat disease. The challenge when altering the genetics of our cells, however, is how to do it safely, effectively, and specifically targeted to the gene, tissue and organ that needs treatment.

Scientists at Tufts University and the Broad Institute of Harvard [University] and MIT [Massachusetts Institute of Technology] have developed unique nanoparticles comprised of lipids — fat molecules — that can package and deliver gene editing machinery specifically to the liver.

In a study published in the Proceedings of the National Academy of Sciences [PNAS] (“Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3”), they have shown that they can use the lipid nanoparticles (LNPs) to efficiently deliver the CRISPR machinery into the liver of mice, resulting in specific genome editing and the reduction of blood cholesterol levels by as much as 57% — a reduction that can last for at least several months with just one shot.

A March 2, 2021 Tufts University news release (also on EurekAlert but published March 1, 2021), which originated the news item, provides greater insight into and technical detail about the research,

The problem of high cholesterol plagues more than 29 million Americans, according to the Centers for Disease Control and Prevention. The condition is complex and can originate from multiple genes as well as nutritional and lifestyle choices, so it is not easy to treat. The Tufts and Broad researchers, however, have modified one gene that could provide a protective effect against elevated cholesterol if it can be shut down by gene editing.

The gene that the researchers focused on codes for the angiopoietin-like 3 enzyme (Angptl3). That enzyme tamps down the activity of other enzymes – lipases – that help break down cholesterol. If researchers can knock out the Angptl3 gene, they can let the lipases do their work and reduce levels of cholesterol in the blood. It turns out that some lucky people have a natural mutation in their Angptl3 gene, leading to consistently low levels of triglycerides and low-density lipoprotein (LDL) cholesterol, commonly called “bad” cholesterol, in their bloodstream without any known clinical downsides.

“If we can replicate that condition by knocking out the angptl3 gene in others, we have a good chance of having a safe and long term solution to high cholesterol,” said Qiaobing Xu, associate professor of biomedical engineering at Tufts’ School of Engineering and corresponding author of the study. “We just have to make sure we deliver the gene editing package specifically to the liver so as not to create unwanted side effects.”

Xu’s team was able to do precisely that in mouse models. After a single injection of lipid nanoparticles packed with mRNA coding for CRISPR-Cas9 and a single-guide RNA targeting Angptl3, they observed a profound reduction in LDL cholesterol by as much as 57% and triglyceride levels by about 29 %, both of which remained at those lowered levels for at least 100 days. The researchers speculate that the effect may last much longer than that, perhaps limited only by the slow turnover of cells in the liver, which can occur over a period of about a year. The reduction of cholesterol and triglycerides is dose dependent, so their levels could be adjusted by injecting fewer or more LNPs in the single shot, the researchers said.

By comparison, an existing, FDA [US Food and Drug Administration]-approved version of CRISPR mRNA-loaded LNPs could only reduce LDL cholesterol by at most 15.7% and triglycerides by 16.3% when it was tested in mice, according to the researchers.

The trick to making a better LNP was in customizing the components – the molecules that come together to form bubbles around the mRNA. The LNPs are made up of long chain lipids that have a charged or polar head that is attracted to water, a carbon chain tail that points toward the middle of the bubble containing the payload, and a chemical linker between them. Also present are polyethylene glycol, and yes, even some cholesterol – which has a normal role in lipid membranes to make them less leaky – to hold their contents better.

The researchers found that the nature and relative ratio of these components appeared to have profound effects on the delivery of mRNA into the liver, so they tested LNPs with many combinations of heads, tails, linkers and ratios among all components for their ability to target liver cells. Because the in vitro potency of an LNP formulation rarely reflects its in vivo performance, they directly evaluated the delivery specificity and efficacy in mice that have a reporter gene in their cells that lights up red when genome editing occurs. Ultimately, they found a CRISPR mRNA-loaded LNP that lit up just the liver in mice, showing that it could specifically and efficiently deliver gene-editing tools into the liver to do their work.

The LNPs were built upon earlier work at Tufts, where Xu and his team developed LNPs with as much as 90% efficiency in delivering mRNA into cells. A unique feature of those nanoparticles was the presence of disulfide bonds between the long lipid chains. Outside the cells, the LNPs form a stable spherical structure that locks in their contents. When they are inside a cell, the environment within breaks the disulfide bonds to disassemble the nanoparticles. The contents are then quickly and efficiently released into the cell. By preventing loss outside the cell, the LNPs can have a much higher yield in delivering their contents.

“CRISPR is one of the most powerful therapeutic tools for the treatment of diseases with a genetic etiology. We have recently seen the first human clinical trail for CRISPR therapy enabled by LNP delivery to be administered systemically to edit genes inside the human body. Our LNP platform developed here holds great potential for clinical translation,” said Min Qiu, post-doctoral researcher in Xu’s lab at Tufts.  “We envision that with this LNP platform in hand, we could now make CRISPR a practical and safe approach to treat a broad spectrum of liver diseases or disorders,” said Zachary Glass, graduate student in the Xu lab. Qiu and Glass are co-first authors of the study.

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

Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3 by Min Qiu, Zachary Glass, Jinjin Chen, Mary Haas, Xin Jin, Xuewei Zhao, Xuehui Rui, Zhongfeng Ye, Yamin Li, Feng Zhang, and Qiaobing Xu. PNAS March 9, 2021 118 (10) e2020401118 DOI: https://doi.org/10.1073/pnas.2020401118

This paper appears to be behind a paywall.

The Broad Institute gives us another reason to love CRISPR

More and more, this resembles a public relations campaign. First, CRISPR (clustered regularly interspersed short palindromic repeats) gene editing is going to be helpful with COVID-19 and now it can help us to deal with conservation issues. (See my May 26, 2020 posting about the latest CRISPR doings as of May 7, 2020; included is a brief description of the patent dispute between Broad Institute and UC Berkeley and musings about a public relations campaign.)

A May 21, 2020 news item on ScienceDaily announces how CRISPR could be useful for conservation,

The gene-editing technology CRISPR has been used for a variety of agricultural and public health purposes — from growing disease-resistant crops to, more recently, a diagnostic test for the virus that causes COVID-19. Now a study involving fish that look nearly identical to the endangered Delta smelt finds that CRISPR can be a conservation and resource management tool, as well. The researchers think its ability to rapidly detect and differentiate among species could revolutionize environmental monitoring.

Caption: Longfin smelt can be difficult to differentiate from endangered Delta smelt. Here, a longfin smelt is swabbed for genetic identification through a CRISPR tool called SHERLOCK. Credit: Alisha Goodbla/UC Davis

A May 21, 2020 University of California at Davis (UC Davis) news release (also on EurekAlert) by Kat Kerlin, which originated the news item, provides more detail (Note: A link has been removed),

The study, published in the journal Molecular Ecology Resources, was led by scientists at the University of California, Davis, and the California Department of Water Resources in collaboration with MIT Broad Institute [emphasis mine].

As a proof of concept, it found that the CRISPR-based detection platform SHERLOCK (Specific High-sensitivity Enzymatic Reporter Unlocking) [emphasis mine] was able to genetically distinguish threatened fish species from similar-looking nonnative species in nearly real time, with no need to extract DNA.

“CRISPR can do a lot more than edit genomes,” said co-author Andrea Schreier, an adjunct assistant professor in the UC Davis animal science department. “It can be used for some really cool ecological applications, and we’re just now exploring that.”

WHEN GETTING IT WRONG IS A BIG DEAL

The scientists focused on three fish species of management concern in the San Francisco Estuary: the U.S. threatened and California endangered Delta smelt, the California threatened longfin smelt and the nonnative wakasagi. These three species are notoriously difficult to visually identify, particularly in their younger stages.

Hundreds of thousands of Delta smelt once lived in the Sacramento-San Joaquin Delta before the population crashed in the 1980s. Only a few thousand are estimated to remain in the wild.

“When you’re trying to identify an endangered species, getting it wrong is a big deal,” said lead author Melinda Baerwald, a project scientist at UC Davis at the time the study was conceived and currently an environmental program manager with California Department of Water Resources.

For example, state and federal water pumping projects have to reduce water exports if enough endangered species, like Delta smelt or winter-run chinook salmon, get sucked into the pumps. Rapid identification makes real-time decision making about water operations feasible.

FROM HOURS TO MINUTES

Typically to accurately identify the species, researchers rub a swab over the fish to collect a mucus sample or take a fin clip for a tissue sample. Then they drive or ship it to a lab for a genetic identification test and await the results. Not counting travel time, that can take, at best, about four hours.

SHERLOCK shortens this process from hours to minutes. Researchers can identify the species within about 20 minutes, at remote locations, noninvasively, with no specialized lab equipment. Instead, they use either a handheld fluorescence reader or a flow strip that works much like a pregnancy test — a band on the strip shows if the target species is present.

“Anyone working anywhere could use this tool to quickly come up with a species identification,” Schreier said.

OTHER CRYPTIC CRITTERS

While the three fish species were the only animals tested for this study, the researchers expect the method could be used for other species, though more research is needed to confirm. If so, this sort of onsite, real-time capability may be useful for confirming species at crime scenes, in the animal trade at border crossings, for monitoring poaching, and for other animal and human health applications.

“There are a lot of cryptic species we can’t accurately identify with our naked eye,” Baerwald said. “Our partners at MIT are really interested in pathogen detection for humans. We’re interested in pathogen detection for animals as well as using the tool for other conservation issues.”

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

Rapid and accurate species identification for ecological studies and monitoring using CRISPR‐based SHERLOCK by Melinda R. Baerwald, Alisha M. Goodbla, Raman P. Nagarajan, Jonathan S. Gootenberg, Omar O. Abudayyeh, Feng Zhang, Andrea D. Schreier. Molecular Ecology Resources https://doi.org/10.1111/1755-0998.13186 First published: 12 May 2020

This paper is behind a paywall.

The business of CRISPR

SHERLOCK™, is a trademark for what Sherlock Biosciences calls one of its engineering biology platforms. From the Sherlock Biosciences Technology webpage,

What is SHERLOCK™?

SHERLOCK is an evolution of CRISPR technology, which others use to make precise edits in genetic code. SHERLOCK can detect the unique genetic fingerprints of virtually any DNA or RNA sequence in any organism or pathogen. Developed by our founders and licensed exclusively from the Broad Institute, SHERLOCK is a method for single molecule detection of nucleic acid targets and stands for Specific High Sensitivity Enzymatic Reporter unLOCKing. It works by amplifying genetic sequences and programming a CRISPR molecule to detect the presence of a specific genetic signature in a sample, which can also be quantified. When it finds those signatures, the CRISPR enzyme is activated and releases a robust signal. This signal can be adapted to work on a simple paper strip test, in laboratory equipment, or to provide an electrochemical readout that can be read with a mobile phone.

However, things get a little more confusing when you look at the Broad Institute’s Developing Diagnostics and Treatments webpage,

Ensuring the SHERLOCK diagnostic platform is easily accessible, especially in the developing world, where the need for inexpensive, reliable, field-based diagnostics is the most urgent

SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) is a CRISPR-based diagnostic tool that is rapid, inexpensive, and highly sensitive, with the potential to have a transformative effect on research and global public health. The SHERLOCK platform can detect viruses, bacteria, or other targets in clinical samples such as urine or blood, and reveal results on a paper strip — without the need for extensive specialized equipment. This technology could potentially be used to aid the response to infectious disease outbreaks, monitor antibiotic resistance, detect cancer, and more. SHERLOCK tools are freely available [emphasis mine] for academic research worldwide, and the Broad Institute’s licensing framework [emphasis mine] ensures that the SHERLOCK diagnostic platform is easily accessible in the developing world, where inexpensive, reliable, field-based diagnostics are urgently needed.

Here’s what I suspect. as stated, the Broad Institute has free SHERLOCK licenses for academic institutions and not-for-profit organizations but Sherlock Biosciences, a Broad Institute spinoff company, is for-profit and has trademarked SHERLOCK for commercial purposes.

Final thoughts

This looks like a relatively subtle campaign to influence public perceptions. Genetic modification or genetic engineering as exemplified by the CRISPR gene editing technique is a force for the good of all. It will help us in our hour of need (COVID-19 pandemic) and it can help us save various species and better manage our resources.

This contrasts greatly with the publicity generated by the CRISPR twins situation where a scientist claimed to have successfully edited the germline for twins, Lulu and Nana. This was done despite a voluntary, worldwide moratorium on germline editing of viable embryos. (Search the terms [either here or on a standard search engine] ‘CRISPR twins’, ‘Lulu and Nana’, and/or ‘He Jiankui’ for details about the scandal.

In addition to presenting CRISPR as beneficial in the short term rather than the distant future, this publicity also subtly positions the Broad Institute as CRISPR’s owner.

Or, maybe I’m wrong. Regardless, I’m watching.

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.

I found it at the movies: a commentary on/review of “Films from the Future”

Kudos to anyone who recognized the reference to Pauline Kael (she changed film criticism forever) and her book “I Lost it at the Movies.” Of course, her book title was a bit of sexual innuendo, quite risqué for an important film critic in 1965 but appropriate for a period (the 1960s) associated with a sexual revolution. (There’s more about the 1960’s sexual revolution in the US along with mention of a prior sexual revolution in the 1920s in this Wikipedia entry.)

The title for this commentary is based on an anecdote from Dr. Andrew Maynard’s (director of the Arizona State University [ASU] Risk Innovation Lab) popular science and technology book, “Films from the Future: The Technology and Morality of Sci-Fi Movies.”

The ‘title-inspiring’ anecdote concerns Maynard’s first viewing of ‘2001: A Space Odyssey, when as a rather “bratty” 16-year-old who preferred to read science fiction, he discovered new ways of seeing and imaging the world. Maynard isn’t explicit about when he became a ‘techno nerd’ or how movies gave him an experience books couldn’t but presumably at 16 he was already gearing up for a career in the sciences. That ‘movie’ revelation received in front of a black and white television on January 1,1982 eventually led him to write, “Films from the Future.” (He has a PhD in physics which he is now applying to the field of risk innovation. For a more detailed description of Dr. Maynard and his work, there’s his ASU profile webpage and, of course, the introduction to his book.)

The book is quite timely. I don’t know how many people have noticed but science and scientific innovation is being covered more frequently in the media than it has been in many years. Science fairs and festivals are being founded on what seems to be a daily basis and you can now find science in art galleries. (Not to mention the movies and television where science topics are covered in comic book adaptations, in comedy, and in standard science fiction style.) Much of this activity is centered on what’s called ’emerging technologies’. These technologies are why people argue for what’s known as ‘blue sky’ or ‘basic’ or ‘fundamental’ science for without that science there would be no emerging technology.

Films from the Future

Isn’t reading the Table of Contents (ToC) the best way to approach a book? (From Films from the Future; Note: The formatting has been altered),

Table of Contents
Chapter One
In the Beginning 14
Beginnings 14
Welcome to the Future 16
The Power of Convergence 18
Socially Responsible Innovation 21
A Common Point of Focus 25
Spoiler Alert 26
Chapter Two
Jurassic Park: The Rise of Resurrection Biology 27
When Dinosaurs Ruled the World 27
De-Extinction 31
Could We, Should We? 36
The Butterfly Effect 39
Visions of Power 43
Chapter Three
Never Let Me Go: A Cautionary Tale of Human Cloning 46
Sins of Futures Past 46
Cloning 51
Genuinely Human? 56
Too Valuable to Fail? 62
Chapter Four
Minority Report: Predicting Criminal Intent 64
Criminal Intent 64
The “Science” of Predicting Bad Behavior 69
Criminal Brain Scans 74
Machine Learning-Based Precognition 77
Big Brother, Meet Big Data 79
Chapter Five
Limitless: Pharmaceutically-enhanced Intelligence 86
A Pill for Everything 86
The Seduction of Self-Enhancement 89
Nootropics 91
If You Could, Would You? 97
Privileged Technology 101
Our Obsession with Intelligence 105
Chapter Six
Elysium: Social Inequity in an Age of Technological
Extremes 110
The Poor Shall Inherit the Earth 110
Bioprinting Our Future Bodies 115
The Disposable Workforce 119
Living in an Automated Future 124
Chapter Seven
Ghost in the Shell: Being Human in an
Augmented Future 129
Through a Glass Darkly 129
Body Hacking 135
More than “Human”? 137
Plugged In, Hacked Out 142
Your Corporate Body 147
Chapter Eight
Ex Machina: AI and the Art of Manipulation 154
Plato’s Cave 154
The Lure of Permissionless Innovation 160
Technologies of Hubris 164
Superintelligence 169
Defining Artificial Intelligence 172
Artificial Manipulation 175
Chapter Nine
Transcendence: Welcome to the Singularity 180
Visions of the Future 180
Technological Convergence 184
Enter the Neo-Luddites 190
Techno-Terrorism 194
Exponential Extrapolation 200
Make-Believe in the Age of the Singularity 203
Chapter Ten
The Man in the White Suit: Living in a Material World 208
There’s Plenty of Room at the Bottom 208
Mastering the Material World 213
Myopically Benevolent Science 220
Never Underestimate the Status Quo 224
It’s Good to Talk 227
Chapter Eleven
Inferno: Immoral Logic in an Age of
Genetic Manipulation 231
Decoding Make-Believe 231
Weaponizing the Genome 234
Immoral Logic? 238
The Honest Broker 242
Dictating the Future 248
Chapter Twelve
The Day After Tomorrow: Riding the Wave of
Climate Change 251
Our Changing Climate 251
Fragile States 255
A Planetary “Microbiome” 258
The Rise of the Anthropocene 260
Building Resiliency 262
Geoengineering the Future 266
Chapter Thirteen
Contact: Living by More than Science Alone 272
An Awful Waste of Space 272
More than Science Alone 277
Occam’s Razor 280
What If We’re Not Alone? 283
Chapter Fourteen
Looking to the Future 288
Acknowledgments 293

The ToC gives the reader a pretty clue as to where the author is going with their book and Maynard explains how he chose his movies in his introductory chapter (from Films from the Future),

“There are some quite wonderful science fiction movies that didn’t make the cut because they didn’t fit the overarching narrative (Blade Runner and its sequel Blade Runner 2049, for instance, and the first of the Matrix trilogy). There are also movies that bombed with the critics, but were included because they ably fill a gap in the bigger story around emerging and converging technologies. Ultimately, the movies that made the cut were chosen because, together, they create an overarching narrative around emerging trends in biotechnologies, cybertechnologies, and materials-based technologies, and they illuminate a broader landscape around our evolving relationship with science and technology. And, to be honest, they are all movies that I get a kick out of watching.” (p. 17)

Jurassic Park (Chapter Two)

Dinosaurs do not interest me—they never have. Despite my profound indifference I did see the movie, Jurassic Park, when it was first released (someone talked me into going). And, I am still profoundly indifferent. Thankfully, Dr. Maynard finds meaning and a connection to current trends in biotechnology,

Jurassic Park is unabashedly a movie about dinosaurs. But it’s also a movie about greed, ambition, genetic engineering, and human folly—all rich pickings for thinking about the future, and what could possibly go wrong. (p. 28)

What really stands out with Jurassic Park, over twenty-five years later, is how it reveals a very human side of science and technology. This comes out in questions around when we should tinker with technology and when we should leave well enough alone. But there is also a narrative here that appears time and time again with the movies in this book, and that is how we get our heads around the sometimes oversized roles mega-entrepreneurs play in dictating how new tech is used, and possibly abused. These are all issues that are just as relevant now as they were in 1993, and are front and center of ensuring that the technologyenabled future we’re building is one where we want to live, and not one where we’re constantly fighting for our lives.  (pp. 30-1)

He also describes a connection to current trends in biotechnology,

De-Extinction

In a far corner of Siberia, two Russians—Sergey Zimov and his son Nikita—are attempting to recreate the Ice Age. More precisely, their vision is to reconstruct the landscape and ecosystem of northern Siberia in the Pleistocene, a period in Earth’s history that stretches from around two and a half million years ago to eleven thousand years ago. This was a time when the environment was much colder than now, with huge glaciers and ice sheets flowing over much of the Earth’s northern hemisphere. It was also a time when humans
coexisted with animals that are long extinct, including saber-tooth cats, giant ground sloths, and woolly mammoths.

The Zimovs’ ambitions are an extreme example of “Pleistocene rewilding,” a movement to reintroduce relatively recently extinct large animals, or their close modern-day equivalents, to regions where they were once common. In the case of the Zimovs, the
father-and-son team believe that, by reconstructing the Pleistocene ecosystem in the Siberian steppes and elsewhere, they can slow down the impacts of climate change on these regions. These areas are dominated by permafrost, ground that never thaws through
the year. Permafrost ecosystems have developed and survived over millennia, but a warming global climate (a theme we’ll come back to in chapter twelve and the movie The Day After Tomorrow) threatens to catastrophically disrupt them, and as this happens, the impacts
on biodiversity could be devastating. But what gets climate scientists even more worried is potentially massive releases of trapped methane as the permafrost disappears.

Methane is a powerful greenhouse gas—some eighty times more effective at exacerbating global warming than carbon dioxide— and large-scale releases from warming permafrost could trigger catastrophic changes in climate. As a result, finding ways to keep it in the ground is important. And here the Zimovs came up with a rather unusual idea: maintaining the stability of the environment by reintroducing long-extinct species that could help prevent its destruction, even in a warmer world. It’s a wild idea, but one that has some merit.8 As a proof of concept, though, the Zimovs needed somewhere to start. And so they set out to create a park for deextinct Siberian animals: Pleistocene Park.9

Pleistocene Park is by no stretch of the imagination a modern-day Jurassic Park. The dinosaurs in Hammond’s park date back to the Mesozoic period, from around 250 million years ago to sixty-five million years ago. By comparison, the Pleistocene is relatively modern history, ending a mere eleven and a half thousand years ago. And the vision behind Pleistocene Park is not thrills, spills, and profit, but the serious use of science and technology to stabilize an increasingly unstable environment. Yet there is one thread that ties them together, and that’s using genetic engineering to reintroduce extinct species. In this case, the species in question is warm-blooded and furry: the woolly mammoth.

The idea of de-extinction, or bringing back species from extinction (it’s even called “resurrection biology” in some circles), has been around for a while. It’s a controversial idea, and it raises a lot of tough ethical questions. But proponents of de-extinction argue
that we’re losing species and ecosystems at such a rate that we can’t afford not to explore technological interventions to help stem the flow.

Early approaches to bringing species back from the dead have involved selective breeding. The idea was simple—if you have modern ancestors of a recently extinct species, selectively breeding specimens that have a higher genetic similarity to their forebears can potentially help reconstruct their genome in living animals. This approach is being used in attempts to bring back the aurochs, an ancestor of modern cattle.10 But it’s slow, and it depends on
the fragmented genome of the extinct species still surviving in its modern-day equivalents.

An alternative to selective breeding is cloning. This involves finding a viable cell, or cell nucleus, in an extinct but well-preserved animal and growing a new living clone from it. It’s definitely a more appealing route for impatient resurrection biologists, but it does mean getting your hands on intact cells from long-dead animals and devising ways to “resurrect” these, which is no mean feat. Cloning has potential when it comes to recently extinct species whose cells have been well preserved—for instance, where the whole animal has become frozen in ice. But it’s still a slow and extremely limited option.

Which is where advances in genetic engineering come in.

The technological premise of Jurassic Park is that scientists can reconstruct the genome of long-dead animals from preserved DNA fragments. It’s a compelling idea, if you think of DNA as a massively long and complex instruction set that tells a group of biological molecules how to build an animal. In principle, if we could reconstruct the genome of an extinct species, we would have the basic instruction set—the biological software—to reconstruct
individual members of it.

The bad news is that DNA-reconstruction-based de-extinction is far more complex than this. First you need intact fragments of DNA, which is not easy, as DNA degrades easily (and is pretty much impossible to obtain, as far as we know, for dinosaurs). Then you
need to be able to stitch all of your fragments together, which is akin to completing a billion-piece jigsaw puzzle without knowing what the final picture looks like. This is a Herculean task, although with breakthroughs in data manipulation and machine learning,
scientists are getting better at it. But even when you have your reconstructed genome, you need the biological “wetware”—all the stuff that’s needed to create, incubate, and nurture a new living thing, like eggs, nutrients, a safe space to grow and mature, and so on. Within all this complexity, it turns out that getting your DNA sequence right is just the beginning of translating that genetic code into a living, breathing entity. But in some cases, it might be possible.

In 2013, Sergey Zimov was introduced to the geneticist George Church at a conference on de-extinction. Church is an accomplished scientist in the field of DNA analysis and reconstruction, and a thought leader in the field of synthetic biology (which we’ll come
back to in chapter nine). It was a match made in resurrection biology heaven. Zimov wanted to populate his Pleistocene Park with mammoths, and Church thought he could see a way of
achieving this.

What resulted was an ambitious project to de-extinct the woolly mammoth. Church and others who are working on this have faced plenty of hurdles. But the technology has been advancing so fast that, as of 2017, scientists were predicting they would be able to reproduce the woolly mammoth within the next two years.

One of those hurdles was the lack of solid DNA sequences to work from. Frustratingly, although there are many instances of well preserved woolly mammoths, their DNA rarely survives being frozen for tens of thousands of years. To overcome this, Church and others
have taken a different tack: Take a modern, living relative of the mammoth, and engineer into it traits that would allow it to live on the Siberian tundra, just like its woolly ancestors.

Church’s team’s starting point has been the Asian elephant. This is their source of base DNA for their “woolly mammoth 2.0”—their starting source code, if you like. So far, they’ve identified fifty plus gene sequences they think they can play with to give their modern-day woolly mammoth the traits it would need to thrive in Pleistocene Park, including a coat of hair, smaller ears, and a constitution adapted to cold.

The next hurdle they face is how to translate the code embedded in their new woolly mammoth genome into a living, breathing animal. The most obvious route would be to impregnate a female Asian elephant with a fertilized egg containing the new code. But Asian elephants are endangered, and no one’s likely to allow such cutting edge experimentation on the precious few that are still around, so scientists are working on an artificial womb for their reinvented woolly mammoth. They’re making progress with mice and hope to crack the motherless mammoth challenge relatively soon.

It’s perhaps a stretch to call this creative approach to recreating a species (or “reanimation” as Church refers to it) “de-extinction,” as what is being formed is a new species. … (pp. 31-4)

This selection illustrates what Maynard does so very well throughout the book where he uses each film as a launching pad for a clear, readable description of relevant bits of science so you understand why the premise was likely, unlikely, or pure fantasy while linking it to contemporary practices, efforts, and issues. In the context of Jurassic Park, Maynard goes on to raise some fascinating questions such as: Should we revive animals rendered extinct (due to obsolescence or inability to adapt to new conditions) when we could develop new animals?

General thoughts

‘Films for the Future’ offers readable (to non-scientific types) science, lively writing, and the occasional ‘memorish’ anecdote. As well, Dr. Maynard raises the curtain on aspects of the scientific enterprise that most of us do not get to see.  For example, the meeting  between Sergey Zimov and George Church and how it led to new ‘de-extinction’ work’. He also describes the problems that the scientists encountered and are encountering. This is in direct contrast to how scientific work is usually presented in the news media as one glorious breakthrough after the next.

Maynard does discuss the issues of social inequality and power and ownership. For example, who owns your transplant or data? Puzzlingly, he doesn’t touch on the current environment where scientists in the US and elsewhere are encouraged/pressured to start up companies commercializing their work.

Nor is there any mention of how universities are participating in this grand business experiment often called ‘innovation’. (My March 15, 2017 posting describes an outcome for the CRISPR [gene editing system] patent fight taking place between Harvard University’s & MIT’s [Massachusetts Institute of Technology] Broad Institute vs the University of California at Berkeley and my Sept. 11, 2018 posting about an art/science exhibit in Vancouver [Canada] provides an update for round 2 of the Broad Institute vs. UC Berkeley patent fight [scroll down about 65% of the way.) *To read about how my ‘cultural blindness’ shows up here scroll down to the single asterisk at the end.*

There’s a foray through machine-learning and big data as applied to predictive policing in Maynard’s ‘Minority Report’ chapter (my November 23, 2017 posting describes Vancouver’s predictive policing initiative [no psychics involved], the first such in Canada). There’s no mention of surveillance technology, which if I recall properly was part of the future environment, both by the state and by corporations. (Mia Armstrong’s November 15, 2018 article for Slate on Chinese surveillance being exported to Venezuela provides interesting insight.)

The gaps are interesting and various. This of course points to a problem all science writers have when attempting an overview of science. (Carl Zimmer’s latest, ‘She Has Her Mother’s Laugh: The Powers, Perversions, and Potential of Heredity’] a doorstopping 574 pages, also has some gaps despite his focus on heredity,)

Maynard has worked hard to give an comprehensive overview in a remarkably compact 279 pages while developing his theme about science and the human element. In other words, science is not monolithic; it’s created by human beings and subject to all the flaws and benefits that humanity’s efforts are always subject to—scientists are people too.

The readership for ‘Films from the Future’ spans from the mildly interested science reader to someone like me who’s been writing/blogging about these topics (more or less) for about 10 years. I learned a lot reading this book.

Next time, I’m hopeful there’ll be a next time, Maynard might want to describe the parameters he’s set for his book in more detail that is possible in his chapter headings. He could have mentioned that he’s not a cinéaste so his descriptions of the movies are very much focused on the story as conveyed through words. He doesn’t mention colour palates, camera angles, or, even, cultural lenses.

Take for example, his chapter on ‘Ghost in the Shell’. Focused on the Japanese animation film and not the live action Hollywood version he talks about human enhancement and cyborgs. The Japanese have a different take on robots, inanimate objects, and, I assume, cyborgs than is found in Canada or the US or Great Britain, for that matter (according to a colleague of mine, an Englishwoman who lived in Japan for ten or more years). There’s also the chapter on the Ealing comedy, The Man in The White Suit, an English film from the 1950’s. That too has a cultural (as well as, historical) flavour but since Maynard is from England, he may take that cultural flavour for granted. ‘Never let me go’ in Chapter Two was also a UK production, albeit far more recent than the Ealing comedy and it’s interesting to consider how a UK production about cloning might differ from a US or Chinese or … production on the topic. I am hearkening back to Maynard’s anecdote about movies giving him new ways of seeing and imagining the world.

There’s a corrective. A couple of sentences in Maynard’s introductory chapter cautioning that in depth exploration of ‘cultural lenses’ was not possible without expanding the book to an unreadable size followed by a sentence in each of the two chapters that there are cultural differences.

One area where I had a significant problem was with regard to being “programmed” and having  “instinctual” behaviour,

As a species, we are embarrassingly programmed to see “different” as “threatening,” and to take instinctive action against it. It’s a trait that’s exploited in many science fiction novels and movies, including those in this book. If we want to see the rise of increasingly augmented individuals, we need to be prepared for some social strife. (p. 136)

These concepts are much debated in the social sciences and there are arguments for and against ‘instincts regarding strangers and their possible differences’. I gather Dr. Maynard hies to the ‘instinct to defend/attack’ school of thought.

One final quandary, there was no sex and I was expecting it in the Ex Machina chapter, especially now that sexbots are about to take over the world (I exaggerate). Certainly, if you’re talking about “social strife,” then sexbots would seem to be fruitful line of inquiry, especially when there’s talk of how they could benefit families (my August 29, 2018 posting). Again, there could have been a sentence explaining why Maynard focused almost exclusively in this chapter on the discussions about artificial intelligence and superintelligence.

Taken in the context of the book, these are trifling issues and shouldn’t stop you from reading Films from the Future. What Maynard has accomplished here is impressive and I hope it’s just the beginning.

Final note

Bravo Andrew! (Note: We’ve been ‘internet acquaintances/friends since the first year I started blogging. When I’m referring to him in his professional capacity, he’s Dr. Maynard and when it’s not strictly in his professional capacity, it’s Andrew. For this commentary/review I wanted to emphasize his professional status.)

If you need to see a few more samples of Andrew’s writing, there’s a Nov. 15, 2018 essay on The Conversation, Sci-fi movies are the secret weapon that could help Silicon Valley grow up and a Nov. 21, 2018 article on slate.com, The True Cost of Stain-Resistant Pants; The 1951 British comedy The Man in the White Suit anticipated our fears about nanotechnology. Enjoy.

****Added at 1700 hours on Nov. 22, 2018: You can purchase Films from the Future here.

*Nov. 23, 2018: I should have been more specific and said ‘academic scientists’. In Canada, the great percentage of scientists are academic. It’s to the point where the OECD (Organization for Economic Cooperation and Development) has noted that amongst industrialized countries, Canada has very few industrial scientists in comparison to the others.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Medicine, healing, and big money

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Infections from pigs

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This paper is open access.

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

What is it to be human?

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

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

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

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

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

New wound dressings with nanofibres for tissue regeneration

The Rotary Jet-Spinning manufacturing system was developed specifically as a therapeutic for the wounds of war. The dressings could be a good option for large wounds, such as burns, as well as smaller wounds on the face and hands, where preventing scarring is important. Illustration courtesy of Michael Rosnach/Harvard University

This image really gets the idea of regeneration across to the viewer while also informing you that this is medicine that comes from the military. A March 19,2018 news item on phys.org announces the work,

Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and the Wyss Institute for Biologically Inspired Engineering have developed new wound dressings that dramatically accelerate healing and improve tissue regeneration. The two different types of nanofiber dressings, described in separate papers, use naturally-occurring proteins in plants and animals to promote healing and regrow tissue.

Our fiber manufacturing system was developed specifically for the purpose of developing therapeutics for the wounds of war,” said Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the research. “As a soldier in Afghanistan, I witnessed horrible wounds and, at times, the healing process for those wounds was a horror unto itself. This research is a years-long effort by many people on my team to help with these problems.”

Parker is also a Core Faculty Member of the Wyss Institute.

The most recent paper, published in Biomaterials, describes a wound dressing inspired by fetal tissue.

A March 19, 2018 Harvard University John A. Paulson School of Engineering and Applied Science news release by Leah Burrows (also on EurekAlert), which originated the news item, provides some background information before launching into more detail about this latest work,

In the late 1970s, when scientists first started studying the wound-healing process early in development, they discovered something unexpected: Wounds incurred before the third trimester left no scars. This opened a range of possibilities for regenerative medicine. But for decades, researchers have struggled to replicate those unique properties of fetal skin.

Unlike adult skin, fetal skin has high levels of a protein called fibronectin, which assembles into the extracellular matrix and promotes cell binding and adhesion. Fibronectin has two structures: globular, which is found in blood, and fibrous, which is found in tissue. Even though fibrous fibronectin holds the most promise for wound healing, previous research focused on the globular structure, in part because manufacturing fibrous fibronectin was a major engineering challenge.

But Parker and his team are pioneers in the field of nanofiber engineering.

The researchers made fibrous fibronectin using a fiber-manufacturing platform called Rotary Jet-Spinning (RJS), developed by Parker’s Disease Biophysics Group. RJS works likes a cotton-candy machine — a liquid polymer solution, in this case globular fibronectin dissolved in a solvent, is loaded into a reservoir and pushed out through a tiny opening by centrifugal force as the device spins. As the solution leaves the reservoir, the solvent evaporates and the polymers solidify. The centrifugal force unfolds the globular protein into small, thin fibers. These fibers — less than one micrometer in diameter — can be collected to form a large-scale wound dressing or bandage.

“The dressing integrates into the wound and acts like an instructive scaffold, recruiting different stem cells that are relevant for regeneration and assisting in the healing process before being absorbed into the body,” said Christophe Chantre, a graduate student in the Disease Biophysics Group and first author of the paper.

In in vivo testing, the researchers found that wounds treated with the fibronectin dressing showed 84 percent tissue restoration within 20 days, compared with 55.6 percent restoration in wounds treated with a standard dressing.

The researchers also demonstrated that wounds treated with the fibronectin dressing had almost normal epidermal thickness and dermal architecture, and even regrew hair follicles — often considered one of the biggest challenges in the field of wound healing.

“This is an important step forward,” said Chantre. “Most work done on skin regeneration to date involves complex treatments combining scaffolds, cells, and even growth factors. Here we were able to demonstrate tissue repair and hair follicle regeneration using an entirely material approach. This has clear advantages for clinical translation.”

In another paper published in Advanced Healthcare Materials, the Disease Biophysics Group demonstrated a soy-based nanofiber that also enhances and promotes wound healing.

Soy protein contains both estrogen-like molecules — which have been shown to accelerate wound healing — and bioactive molecules similar to those that build and support human cells.

“Both the soy- and fibronectin-fiber technologies owe their success to keen observations in reproductive medicine,” said Parker. “During a woman’s cycle, when her estrogen levels go high, a cut will heal faster. If you do a surgery on a baby still in the womb, they have scar-less wound healing. Both of these new technologies are rooted in the most fascinating of all the topics in human biology — how we reproduce.”

In a similar way to fibronectin fibers, the research team used RJS to spin ultrathin soy fibers into wound dressings. In experiments, the soy- and cellulose-based dressing demonstrated a 72 percent increase in healing over wounds with no dressing and a 21 percent increase in healing over wounds dressed without soy protein.

“These findings show the great promise of soy-based nanofibers for wound healing,” said Seungkuk Ahn, a graduate student in the Disease Biophysics Group and first author of the paper. “These one-step, cost-effective scaffolds could be the next generation of regenerative dressings and push the envelope of nanofiber technology and the wound-care market.”

Both kinds of dressing, according to researchers, have advantages in the wound-healing space. The soy-based nanofibers — consisting of cellulose acetate and soy protein hydrolysate — are inexpensive, making them a good option for large-scale use, such as on burns. The fibronectin dressings, on the other hand, could be used for smaller wounds on the face and hands, where preventing scarring is important.

Here’s are links and citations for both papers mentioned in the news release,

Soy Protein/Cellulose Nanofiber Scaffolds Mimicking Skin Extracellular Matrix for Enhanced Wound Healing by Seungkuk Ahn, Christophe O. Chantre, Alanna R. Gannon, Johan U. Lind, Patrick H. Campbell, Thomas Grevesse, Blakely B. O’Connor, Kevin Kit Parker. Advanced Healthcare Materials https://doi.org/10.1002/adhm.201701175 First published: 23 January 2018

Production-scale fibronectin nanofibers promote wound closure and tissue repair in a dermal mouse model by Christophe O. Chantre, Patrick H. Campbell, Holly M. Golecki, Adrian T. Buganza, Andrew K. Capulli, Leila F. Deravi, Stephanie Dauth, Sean P. Sheehy, Jeffrey A.Paten. KarlGledhill, Yanne S. Doucet, Hasan E.Abaci, Seungkuk Ahn, Benjamin D.Pope, Jeffrey W.Ruberti, Simon P.Hoerstrup, Angela M.Christiano, Kevin Kit Parker. Biomaterials Volume 166, June 2018, Pages 96-108 https://doi.org/10.1016/j.biomaterials.2018.03.006 Available online 5 March 2018

Both papers are behind paywalls although you may want to check with ResearchGate where many researchers make their papers available for free.

One last comment, I noticed this at the end of Burrows’ news release,

The Harvard Office of Technology Development has protected the intellectual property relating to these projects and is exploring commercialization opportunities.

It reminded me of the patent battle between the Broad Institute (a Harvard University and Massachusetts Institute of Technology joint venture) and the University of California at Berkeley over CRISPR (clustered regularly interspaced short palindromic repeats) technology. (My March 15, 2017 posting describes the battle’s outcome.)

Lest we forget, there could be major financial rewards from this work.

Santiago Ramón y Cajal and the butterflies of the soul

The Cajal exhibit of drawings was here in Vancouver (Canada) this last fall (2017) and I still carry the memory of that glorious experience (see my Sept. 11, 2017 posting for more about the show and associated events). It seems Cajal’s drawings had a similar response in New York city, from a January 18, 2018 article by Roberta Smith for the New York Times,

It’s not often that you look at an exhibition with the help of the very apparatus that is its subject. But so it is with “The Beautiful Brain: The Drawings of Santiago Ramón y Cajal” at the Grey Art Gallery at New York University, one of the most unusual, ravishing exhibitions of the season.

The show finished its run on March 31, 2018 and is now on its way to the Massachusetts Institute of Technology (MIT) in Boston, Massachusetts for its opening on May 3, 2018. It looks like they have an exciting lineup of events to go along with the exhibit (from MIT’s The Beautiful Brain: The Drawings of Santiago Ramón y Cajal exhibit and event page),

SUMMER PROGRAMS

ONGOING

Spotlight Tours
Explorations led by local and Spanish scientists, artists, and entrepreneurs who will share their unique perspectives on particular aspects of the exhibition. (2:00 pm on select Tuesdays and Saturdays)

Tue, May 8 – Mark Harnett, Fred and Carole Middleton Career Development Professor at MIT and McGovern Institute Investigator Sat, May 26 – Marion Boulicault, MIT Graduate Student and Neuroethics Fellow in the Center for Sensorimotor Neural Engineering Tue, June 5 – Kelsey Allen, Graduate researcher, MIT Center for Brains, Minds, and Machines Sat, Jun 23 – Francisco Martin-Martinez, Research Scientist in MIT’s Laboratory for Atomistic & Molecular Mechanics and President of the Spanish Foundation for Science and Technology Jul 21 – Alex Gomez-Marin, Principal Investigator of the Behavior of Organisms Laboratory in the Instituto de Neurociencias, Spain Tue, Jul 31– Julie Pryor, Director of Communications at the McGovern Institute for Brain Research at MIT Tue, Aug 28 – Satrajit Ghosh, Principal Research Scientist at the McGovern Institute for Brain Research at MIT, Assistant Professor in the Department of Otolaryngology at Harvard Medical School, and faculty member in the Speech and Hearing Biosciences and Technology program in the Harvard Division of Medical Sciences

Idea Hub
Drop in and explore expansion microscopy in our maker-space.

Visualizing Science Workshop
Experiential learning with micro-scale biological images. (pre-registration required)

Gallery Demonstrations
Researchers share the latest on neural anatomy, signal transmission, and modern imaging techniques.

EVENTS

Teen Science Café: Mindful Matters
MIT researchers studying the brain share their mind-blowing findings.

Neuron Paint Night
Create a painting of cerebral cortex neurons and learn about the EyeWire citizen science game.

Cerebral Cinema Series
Hear from researchers and then compare real science to depictions on the big screen.

Brainy Trivia
Test your brain power in a night of science trivia and short, snappy research talks.

Come back to see our exciting lineup for the fall!

If you don’t have a chance to see the show or if you’d like a preview, I encourage you to read Smith’s article as it has embedded several Cajal drawings and rendered them exceptionally well.

For those who like a little contemporary (and related) science with their art, there’s a March 30, 2018 Harvard Medical Schoo (HMS)l news release by Kevin Jang (also on EurekAlert), Note: All links save one have been removed,

Drawing of the cells of the chick cerebellum by Santiago Ramón y Cajal, from “Estructura de los centros nerviosos de las aves,” Madrid, circa 1905

 

Modern neuroscience, for all its complexity, can trace its roots directly to a series of pen-and-paper sketches rendered by Nobel laureate Santiago Ramón y Cajal in the late 19th and early 20th centuries.

His observations and drawings exposed the previously hidden composition of the brain, revealing neuronal cell bodies and delicate projections that connect individual neurons together into intricate networks.

As he explored the nervous systems of various organisms under his microscope, a natural question arose: What makes a human brain different from the brain of any other species?

At least part of the answer, Ramón y Cajal hypothesized, lay in a specific class of neuron—one found in a dazzling variety of shapes and patterns of connectivity, and present in higher proportions in the human brain than in the brains of other species. He dubbed them the “butterflies of the soul.”

Known as interneurons, these cells play critical roles in transmitting information between sensory and motor neurons, and, when defective, have been linked to diseases such as schizophrenia, autism and intellectual disability.

Despite more than a century of study, however, it remains unclear why interneurons are so diverse and what specific functions the different subtypes carry out.

Now, in a study published in the March 22 [2018] issue of Nature, researchers from Harvard Medical School, New York Genome Center, New York University and the Broad Institute of MIT and Harvard have detailed for the first time how interneurons emerge and diversify in the brain.

Using single-cell analysis—a technology that allows scientists to track cellular behavior one cell at a time—the team traced the lineage of interneurons from their earliest precursor states to their mature forms in mice. The researchers identified key genetic programs that determine the fate of developing interneurons, as well as when these programs are switched on or off.

The findings serve as a guide for efforts to shed light on interneuron function and may help inform new treatment strategies for disorders involving their dysfunction, the authors said.

“We knew more than 100 years ago that this huge diversity of morphologically interesting cells existed in the brain, but their specific individual roles in brain function are still largely unclear,” said co-senior author Gordon Fishell, HMS professor of neurobiology and a faculty member at the Stanley Center for Psychiatric Research at the Broad.

“Our study provides a road map for understanding how and when distinct interneuron subtypes develop, giving us unprecedented insight into the biology of these cells,” he said. “We can now investigate interneuron properties as they emerge, unlock how these important cells function and perhaps even intervene when they fail to develop correctly in neuropsychiatric disease.”

A hippocampal interneuron. Image: Biosciences Imaging Gp, Soton, Wellcome Trust via Creative CommonsA hippocampal interneuron. Image: Biosciences Imaging Gp, Soton, Wellcome Trust via Creative Commons

Origins and Fates

In collaboration with co-senior author Rahul Satija, core faculty member of the New York Genome Center, Fishell and colleagues analyzed brain regions in developing mice known to contain precursor cells that give rise to interneurons.

Using Drop-seq, a single-cell sequencing technique created by researchers at HMS and the Broad, the team profiled gene expression in thousands of individual cells at multiple time points.

This approach overcomes a major limitation in past research, which could analyze only the average activity of mixtures of many different cells.

In the current study, the team found that the precursor state of all interneurons had similar gene expression patterns despite originating in three separate brain regions and giving rise to 14 or more interneuron subtypes alone—a number still under debate as researchers learn more about these cells.

“Mature interneuron subtypes exhibit incredible diversity. Their morphology and patterns of connectivity and activity are so different from each other, but our results show that the first steps in their maturation are remarkably similar,” said Satija, who is also an assistant professor of biology at New York University.

“They share a common developmental trajectory at the earliest stages, but the seeds of what will cause them to diverge later—a handful of genes—are present from the beginning,” Satija said.

As they profiled cells at later stages in development, the team observed the initial emergence of four interneuron “cardinal” classes, which give rise to distinct fates. Cells were committed to these fates even in the early embryo. By developing a novel computational strategy to link precursors with adult subtypes, the researchers identified individual genes that were switched on and off when cells began to diversify.

For example, they found that the gene Mef2c—mutations of which are linked to Alzheimer’s disease, schizophrenia and neurodevelopmental disorders in humans—is an early embryonic marker for a specific interneuron subtype known as Pvalb neurons. When they deleted Mef2c in animal models, Pvalb neurons failed to develop.

These early genes likely orchestrate the execution of subsequent genetic subroutines, such as ones that guide interneuron subtypes as they migrate to different locations in the brain and ones that help form unique connection patterns with other neural cell types, the authors said.

The identification of these genes and their temporal activity now provide researchers with specific targets to investigate the precise functions of interneurons, as well as how neurons diversify in general, according to the authors.

“One of the goals of this project was to address an incredibly fascinating developmental biology question, which is how individual progenitor cells decide between different neuronal fates,” Satija said. “In addition to these early markers of interneuron divergence, we found numerous additional genes that increase in expression, many dramatically, at later time points.”

The association of some of these genes with neuropsychiatric diseases promises to provide a better understanding of these disorders and the development of therapeutic strategies to treat them, a particularly important notion given the paucity of new treatments, the authors said.

Over the past 50 years, there have been no fundamentally new classes of neuropsychiatric drugs, only newer versions of old drugs, the researchers pointed out.

“Our repertoire is no better than it was in the 1970s,” Fishell said.

“Neuropsychiatric diseases likely reflect the dysfunction of very specific cell types. Our study puts forward a clear picture of what cells to look at as we work to shed light on the mechanisms that underlie these disorders,” Fishell said. “What we will find remains to be seen, but we have new, strong hypotheses that we can now test.”

As a resource for the research community, the study data and software are open-source and freely accessible online.

A gallery of the drawings of Santiago Ramón y Cajal is currently on display in New York City, and will open at the MIT Museum in Boston in May 2018.

Christian Mayer, Christoph Hafemeister and Rachel Bandler served as co-lead authors on the study.

This work was supported by the National Institutes of Health (R01 NS074972, R01 NS081297, MH071679-12, DP2-HG-009623, F30MH114462, T32GM007308, F31NS103398), the European Molecular Biology Organization, the National Science Foundation and the Simons Foundation.

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

Developmental diversification of cortical inhibitory interneurons by Christian Mayer, Christoph Hafemeister, Rachel C. Bandler, Robert Machold, Renata Batista Brito, Xavier Jaglin, Kathryn Allaway, Andrew Butler, Gord Fishell, & Rahul Satija. Nature volume 555, pages 457–462 (22 March 2018) doi:10.1038/nature25999 Published: 05 March 2018

This paper is behind a paywall.