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Synthetic human embryos—what now? (2 of 2)

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The term they’re using in the Weizmann Institute of Science’s (Israel) announcement is “a generally accurate human embryo model.” This is in contrast to previous announcements including the one from the University of Cambridge team highlighted in Part 1.

From a September 6, 2023 news item on phys.org, Note: A link has been removed,

A research team headed by Prof. Jacob Hanna at the Weizmann Institute of Science has created complete models of human embryos from stem cells cultured in the lab—and managed to grow them outside the womb up to day 14. As reported today [September 6, 2023] in Nature, these synthetic embryo models had all the structures and compartments characteristic of this stage, including the placenta, yolk sac, chorionic sac and other external tissues that ensure the models’ dynamic and adequate growth.

Cellular aggregates derived from human stem cells in previous studies could not be considered genuinely accurate human embryo models, because they lacked nearly all the defining hallmarks of a post-implantation embryo. In particular, they failed to contain several cell types that are essential to the embryo’s development, such as those that form the placenta and the chorionic sac. In addition, they did not have the structural organization characteristic of the embryo and revealed no dynamic ability to progress to the next developmental stage.

Given their authentic complexity, the human embryo models obtained by Hanna’s group may provide an unprecedented opportunity to shed new light on the embryo’s mysterious beginnings. Little is known about the early embryo because it is so difficult to study, for both ethical and technical reasons, yet its initial stages are crucial to its future development. During these stages, the clump of cells that implants itself in the womb on the seventh day of its existence becomes, within three to four weeks, a well-structured embryo that already contains all the body organs.

“The drama is in the first month, the remaining eight months of pregnancy are mainly lots of growth,” Hanna says. “But that first month is still largely a black box. Our stem cell–derived human embryo model offers an ethical and accessible way of peering into this box. It closely mimics the development of a real human embryo, particularly the emergence of its exquisitely fine architecture.”

…

A stem cell–derived human embryo model at a developmental stage equivalent to that of a day 14 embryo. The model has all the compartments that define this stage: the yolk sac (yellow) and the part that will become the embryo itself, topped by the amnion (blue) – all enveloped by cells that will become the placenta (pink) Courtesy: Weizmann Institute of Science

A September 6, 2023 Weizmann Institute of Science press release, which originated the news item, offers a wealth of detail, Note: Links have been removed,

Letting the embryo model say “Go!”

Hanna’s team built on their previous experience in creating synthetic stem cell–based models of mouse embryos. As in that research, the scientists made no use of fertilized eggs or a womb. Rather, they started out with human cells known as pluripotent stem cells, which have the potential to differentiate into many, though not all, cell types. Some were derived from adult skin cells that had been reverted to “stemness.” Others were the progeny of human stem cell lines that had been cultured for years in the lab.

The researchers then used Hanna’s recently developed method to reprogram pluripotent stem cells so as to turn the clock further back: to revert these cells to an even earlier state – known as the naïve state – in which they are capable of becoming anything, that is, specializing into any type of cell. This stage corresponds to day 7 of the natural human embryo, around the time it implants itself in the womb. Hanna’s team had in fact been the first to start describing methods to generate human naïve stem cells, back in 2013; they continued to improve these methods, which stand at the heart of the current project, over the years.

The scientists divided the cells into three groups. The cells intended to develop into the embryo were left as is. The cells in each of the other groups were treated only with chemicals, without any need for genetic modification, so as to turn on certain genes, which was intended to cause these cells to differentiate toward one of three tissue types needed to sustain the embryo: placenta, yolk sac or the extraembryonic mesoderm membrane that ultimately creates the chorionic sac.

Soon after being mixed together under optimized, specifically developed conditions, the cells formed clumps, about 1 percent of which self-organized into complete embryo-like structures. “An embryo is self-driven by definition; we don’t need to tell it what to do – we must only unleash its internally encoded potential,” Hanna says. “It’s critical to mix in the right kinds of cells at the beginning, which can only be derived from naïve stem cells that have no developmental restrictions. Once you do that, the embryo-like model itself says, ‘Go!’”

The stem cell–based embryo-like structures (termed SEMs) developed normally outside the womb for 8 days, reaching a developmental stage equivalent to day 14 in human embryonic development. That’s the point at which natural embryos acquire the internal structures that enable them to proceed to the next stage: developing the progenitors of body organs.

Complete human embryo models match classic diagrams in terms of structure and cell identity

When the researchers compared the inner organization of their stem cell–derived embryo models with illustrations and microscopic anatomy sections in classical embryology atlases from the 1960s, they found an uncanny structural resemblance between the models and the natural human embryos at the corresponding stage. Every compartment and supporting structure was not only there, but in the right place, size and shape. Even the cells that make the hormone used in pregnancy testing were there and active: When the scientists applied secretions from these cells to a commercial pregnancy test, it came out positive.

In fact, the study has already produced a finding that may open a new direction of research into early pregnancy failure. The researchers discovered that if the embryo is not enveloped by placenta-forming cells in the right manner at day 3 of the protocol (corresponding to day 10 in natural embryonic development), its internal structures, such as the yolk sac, fail to properly develop.

“An embryo is not static. It must have the right cells in the right organization, and it must be able to progress – it’s about being and becoming,” Hanna says. “Our complete embryo models will help researchers address the most basic questions about what determines its proper growth.”

This ethical approach to unlocking the mysteries of the very first stages of embryonic development could open numerous research paths. It might help reveal the causes of many birth defects and types of infertility. It could also lead to new technologies for growing transplant tissues and organs. And it could offer a way around experiments that cannot be performed on live embryos – for example, determining the effects of exposure to drugs or other substances on fetal development.

For people who are visually inclined, there are two videos embedded in the September 6, 2023 Weizmann Institute of Science press release.

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

Complete human day 14 post-implantation embryo models from naïve ES cells by Bernardo Oldak, Emilie Wildschutz, Vladyslav Bondarenko, Mehmet-Yunus Comar, Cheng Zhao, Alejandro Aguilera-Castrejon, Shadi Tarazi, Sergey Viukov, Thi Xuan Ai Pham, Shahd Ashouokhi, Dmitry Lokshtanov, Francesco Roncato, Eitan Ariel, Max Rose, Nir Livnat, Tom Shani, Carine Joubran, Roni Cohen, Yoseph Addadi, Muriel Chemla, Merav Kedmi, Hadas Keren-Shaul, Vincent Pasque, Sophie Petropoulos, Fredrik Lanner, Noa Novershtern & Jacob H. Hanna. Nature (2023) DOI: https://doi.org/10.1038/s41586-023-06604-5 Published: 06 September 2023

This paper is behind a paywall.

As for the question I asked in the head “what now?” I have absolutely no idea.

Synthetic human embryos—what now? (1 of 2)

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Usually, there’s a rough chronological order to how I introduce the research, but this time I’m looking at the term used to describe it, following up with the various news releases and commentaries about the research, and finishing with a Canadian perspective.

After writing this post (but before it was published), the Weizmann Institute of Science (Israel) made their September 6, 2023 announcement and things changed a bit. That’s in Part two.

Say what you really mean (a terminology issue)

First, it might be useful to investigate the term, ‘synthetic human embryos’ as Julian Hitchcock does in his June 29, 2023 article on Bristows website (h/t Mondaq’s July 5, 2023 news item), Note: Links have been removed,

“Synthetic Embryos” are neither Synthetic nor Embryos. So why are editors giving that name to stem cell-based models of human development?

One of the less convincing aspects of the last fortnight’s flurry of announcements about advances in simulating early human development (see here) concerned their name. Headlines galore (in newspapers and scientific journals) referred to “synthetic embryos“.

But embryo models, however impressive, are not embryos. To claim that the fundamental stages of embryo development that we learnt at school – fertilisation, cleavage and compaction – could now be bypassed to achieve the same result would be wrong. Nor are these objects “synthesised”: indeed, their interest to us lies in the ways in which they organise themselves. The researchers merely place the stem cells in a matrix in appropriate conditions, then stand back and watch them do it. Scientists were therefore unhappy about this use of the term in news media, and relieved when the International Society for Stem Cell Research (ISSCR) stepped in with a press release:

“Unlike some recent media reports describing this research, the ISSCR advises against using the term “synthetic embryo” to describe embryo models, because it is inaccurate and can create confusion. Integrated embryo models are neither synthetic nor embryos. While these models can replicate aspects of the early-stage development of human embryos, they cannot and will not develop to the equivalent of postnatal stage humans. Further, the ISSCR Guidelines prohibit the transfer of any embryo model to the uterus of a human or an animal.”

Although this was the ISSCR’s first attempt to put that position to the public, it had already made that recommendation to the research community two years previously. Its 2021 Guidelines for Stem Cell Research and Clinical Translation had recommended researchers to “promote accurate, current, balanced, and responsive public representations of stem cell research”. In particular:

“While organoids, chimeras, embryo models, and other stem cell-based models are useful research tools offering possibilities for further scientific progress, limitations on the current state of scientific knowledge and regulatory constraints must be clearly explained in any communications with the public or media. Suggestions that any of the current in vitro models can recapitulate an intact embryo, human sentience or integrated brain function are unfounded overstatements that should be avoided and contradicted with more precise characterizations of current understanding.”

…

Here’s a little bit about Hitchcock from his Bristows profile page,

  • Diploma Medical School, University of Birmingham (1975-78)
  • LLB, University of Wolverhampton
  • Diploma in Intellectual Property Law & Practice, University of Bristol
  • Qualified 1998

Following an education in medicine at the University of Birmingham and a career as a BBC science producer, Julian has focused on the law and regulation of life science technologies since 1997, practising in England and Australia. He joined Bristows with Alex Denoon in 2018.

…

Hitchcock’s June 29, 2023 article comments on why this term is being used,

…

I have a lot of sympathy with the position of the science writers and editors incurring the scientists’ ire. First, why should journalists have known of the ISSCR’s recommendations on the use of the term “synthetic embryo”? A journalist who found Recommendation 4.1 of the ISSCR Guidelines would probably not have found them specific enough to address the point, and the academic introduction containing the missing detail is hard to find. …

My second reason for being sympathetic to the use of the terrible term is that no suitable alternative has been provided, other than in the Stem Cell Reports paper, which recommends the umbrella terms “embryo models” or “stem cell based embryo models”. …

When asked why she had used the term “synthetic embryo”, the journalist I contacted remarked that, “We’re still working out the right language and it’s something we’re discussing and will no doubt evolve along with the science”.

It is absolutely in the public’s interest (and in the interest of science), that scientific research is explained in terms that the public understands. There is, therefore, a need, I think, for the scientific community to supply a name to the media or endure the penalties of misinformation …

In such an intensely competitive field of research, disagreement among researchers, even as to names, is inevitable. In consequence, however, journalists and their audiences are confronted by a slew of terms which may or may not be synonymous or overlapping, with no agreed term [emphasis mine] for the overall class of stem cell based embryo models. We cannot blame them if they make up snappy titles of their own [emphasis mine]. …

The announcement

The earliest date for the announcement at the International Society for Stem Cell Researh meeting that I can find is Hannah Devlin’s June 14, 2023 article in The Guardian newspaper, Note: A link has been removed,

Scientists have created synthetic human embryos using stem cells, in a groundbreaking advance that sidesteps the need for eggs or sperm.

Scientists say these model embryos, which resemble those in the earliest stages of human development, could provide a crucial window on the impact of genetic disorders and the biological causes of recurrent miscarriage.

However, the work also raises serious ethical and legal issues as the lab-grown entities fall outside current legislation in the UK and most other countries.

The structures do not have a beating heart or the beginnings of a brain, but include cells that would typically go on to form the placenta, yolk sac and the embryo itself.

Prof Magdalena Żernicka-Goetz, of the University of Cambridge and the California Institute of Technology, described the work in a plenary address on Wednesday [June 14, 2023] at the International Society for Stem Cell Research’s annual meeting in Boston.

…

The (UK) Science Media Centre made expert comments available in a June 14, 2023 posting “expert reaction to Guardian reporting news of creation of synthetic embryos using stem cells.”

Two days later, this June 16, 2023 essay by Kathryn MacKay, Senior Lecturer in Bioethics, University of Sydney (Australia), appeared on The Conversation (h/t June 16, 2023 news item on phys.org), Note: Links have been removed,

Researchers have created synthetic human embryos using stem cells, according to media reports. Remarkably, these embryos have reportedly been created from embryonic stem cells, meaning they do not require sperm and ova.

This development, widely described as a breakthrough that could help scientists learn more about human development and genetic disorders, was revealed this week in Boston at the annual meeting of the International Society for Stem Cell Research.

The research, announced by Professor Magdalena Żernicka-Goetz of the University of Cambridge and the California Institute of Technology, has not yet been published in a peer-reviewed journal. But Żernicka-Goetz told the meeting these human-like embryos had been made by reprogramming human embryonic stem cells.

So what does all this mean for science, and what ethical issues does it present?

MacKay goes on to answer her own questions, from the June 16, 2023 essay, Note: A link has been removed,

…

One of these quandaries arises around whether their creation really gets us away from the use of human embryos.

Robin Lovell-Badge, the head of stem cell biology and developmental genetics at the Francis Crick Institute in London UK, reportedly said that if these human-like embryos can really model human development in the early stages of pregnancy, then we will not have to use human embryos for research.

At the moment, it is unclear if this is the case for two reasons.

First, the embryos were created from human embryonic stem cells, so it seems they do still need human embryos for their creation. Perhaps more light will be shed on this when Żernicka-Goetz’s research is published.

Second, there are questions about the extent to which these human-like embryos really can model human development.

…

Professor Magdalena Żernicka-Goetz’s research is published

Almost two weeks later the research from the Cambridge team (there are other teams and countries also racing; see Part two for the news from Sept. 6, 2023) was published, from a June 27, 2023 news item on ScienceDaily,

Cambridge scientists have created a stem cell-derived model of the human embryo in the lab by reprogramming human stem cells. The breakthrough could help research into genetic disorders and in understanding why and how pregnancies fail.

Published today [Tuesday, June 27, 2023] in the journal Nature, this embryo model is an organised three-dimensional structure derived from pluripotent stem cells that replicate some developmental processes that occur in early human embryos.

Use of such models allows experimental modelling of embryonic development during the second week of pregnancy. They can help researchers gain basic knowledge of the developmental origins of organs and specialised cells such as sperm and eggs, and facilitate understanding of early pregnancy loss.

…

A June 27, 2023 University of Cambridge press release (also on EurekAlert), which originated the news item, provides more detail about the work,

“Our human embryo-like model, created entirely from human stem cells, gives us access to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mother’s womb,” said Professor Magdalena Zernicka-Goetz in the University of Cambridge’s Department of Physiology, Development and Neuroscience, who led the work.

She added: “This exciting development allows us to manipulate genes to understand their developmental roles in a model system. This will let us test the function of specific factors, which is difficult to do in the natural embryo.”

In natural human development, the second week of development is an important time when the embryo implants into the uterus. This is the time when many pregnancies are lost.

The new advance enables scientists to peer into the mysterious ‘black box’ period of human development – usually following implantation of the embryo in the uterus – to observe processes never directly observed before.

Understanding these early developmental processes holds the potential to reveal some of the causes of human birth defects and diseases, and to develop tests for these in pregnant women.

Until now, the processes could only be observed in animal models, using cells from zebrafish and mice, for example.

Legal restrictions in the UK currently prevent the culture of natural human embryos in the lab beyond day 14 of development: this time limit was set to correspond to the stage where the embryo can no longer form a twin. [emphasis mine]

Until now, scientists have only been able to study this period of human development using donated human embryos. This advance could reduce the need for donated human embryos in research.

Zernicka-Goetz says the while these models can mimic aspects of the development of human embryos, they cannot and will not develop to the equivalent of postnatal stage humans.

Over the past decade, Zernicka-Goetz’s group in Cambridge has been studying the earliest stages of pregnancy, in order to understand why some pregnancies fail and some succeed.

In 2021 and then in 2022 her team announced in Developmental Cell, Nature and Cell Stem Cell journals that they had finally created model embryos from mouse stem cells that can develop to form a brain-like structure, a beating heart, and the foundations of all other organs of the body.

The new models derived from human stem cells do not have a brain or beating heart, but they include cells that would typically go on to form the embryo, placenta and yolk sac, and develop to form the precursors of germ cells (that will form sperm and eggs).

Many pregnancies fail at the point when these three types of cells orchestrate implantation into the uterus begin to send mechanical and chemical signals to each other, which tell the embryo how to develop properly.

There are clear regulations governing stem cell-based models of human embryos and all researchers doing embryo modelling work must first be approved by ethics committees. Journals require proof of this ethics review before they accept scientific papers for publication. Zernicka-Goetz’s laboratory holds these approvals.

“It is against the law and FDA regulations to transfer any embryo-like models into a woman for reproductive aims. These are highly manipulated human cells and their attempted reproductive use would be extremely dangerous,” said Dr Insoo Hyun, Director of the Center for Life Sciences and Public Learning at Boston’s Museum of Science and a member of Harvard Medical School’s Center for Bioethics.

Zernicka-Goetz also holds position at the California Institute of Technology and is NOMIS Distinguished Scientist and Scholar Awardee.

The research was funded by the Wellcome Trust and Open Philanthropy.

(There’s more about legal concerns further down in this post.)

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

Pluripotent stem cell-derived model of the post-implantation human embryo by Bailey A. T. Weatherbee, Carlos W. Gantner, Lisa K. Iwamoto-Stohl, Riza M. Daza, Nobuhiko Hamazaki, Jay Shendure & Magdalena Zernicka-Goetz. Nature (2023) DOI: https://doi.org/10.1038/s41586-023-06368-y Published: 27 June 2023

This paper is open access.

Published the same day (June 27, 2023) is a paper (citation and link follow) also focused on studying human embryonic development using stem cells. First, there’s this from the Abstract,

Investigating human development is a substantial scientific challenge due to the technical and ethical limitations of working with embryonic samples. In the face of these difficulties, stem cells have provided an alternative to experimentally model inaccessible stages of human development in vitro …

This time the work is from a US/German team,

Self-patterning of human stem cells into post-implantation lineages by Monique Pedroza, Seher Ipek Gassaloglu, Nicolas Dias, Liangwen Zhong, Tien-Chi Jason Hou, Helene Kretzmer, Zachary D. Smith & Berna Sozen. Nature (2023) DOI: https://doi.org/10.1038/s41586-023-06354-4 Published: 27 June 2023

The paper is open access.

Legal concerns and a Canadian focus

A July 25, 2023 essay by Françoise Baylis and Jocelyn Downie of Dalhousie University (Nova Scotia, Canada) for The Conversation (h/t July 25, 2023 article on phys.org) covers the advantages of doing this work before launching into a discussion of legislation and limits in the UK and, more extensively, in Canada, Note: Links have been removed,

…

This research could increase our understanding of human development and genetic disorders, help us learn how to prevent early miscarriages, lead to improvements in fertility treatment, and — perhaps — eventually allow for reproduction without using sperm and eggs.

Synthetic human embryos — also called embryoid bodies, embryo-like structures or embryo models — mimic the development of “natural human embryos,” those created by fertilization. Synthetic human embryos include the “cells that would typically go on to form the embryo, placenta and yolk sac, and develop to form the precursors of germ cells (that will form sperm and eggs).”

Though research involving natural human embryos is legal in many jurisdictions, it remains controversial. For some people, research involving synthetic human embryos is less controversial because these embryos cannot “develop to the equivalent of postnatal stage humans.” In other words, these embryos are non-viable and cannot result in live births.

…

Now, for a closer look at the legalities in the UK and in Canada, from the July 25, 2023 essay, Note: Links have been removed,

The research presented by Żernicka-Goetz at the ISSCR meeting took place in the United Kingdom. It was conducted in accordance with the Human Fertilization and Embryology Act, 1990, with the approval of the U.K. Stem Cell Bank Steering Committee.

U.K. law limits the research use of human embryos to 14 days of development. An embryo is defined as “a live human embryo where fertilisation is complete, and references to an embryo include an egg in the process of fertilisation.”

Synthetic embryos are not created by fertilization and therefore, by definition, the 14-day limit on human embryo research does not apply to them. This means that synthetic human embryo research beyond 14 days can proceed in the U.K.

The door to the touted potential benefits — and ethical controversies — seems wide open in the U.K.

…

While the law in the U.K. does not apply to synthetic human embryos, the law in Canada clearly does. This is because the legal definition of an embryo in Canada is not limited to embryos created by fertilization [emphasis mine].

The Assisted Human Reproduction Act (the AHR Act) defines an embryo as “a human organism during the first 56 days of its development following fertilization or creation, excluding any time during which its development has been suspended.”

Based on this definition, the AHR Act applies to embryos created by reprogramming human embryonic stem cells — in other words, synthetic human embryos — provided such embryos qualify as human organisms.

A synthetic human embryo is a human organism. It is of the species Homo sapiens, and is thus human. It also qualifies as an organism — a life form — alongside other organisms created by means of fertilization, asexual reproduction, parthenogenesis or cloning.

…

Given that the AHR Act applies to synthetic human embryos, there are legal limits on their creation and use in Canada.

First, human embryos — including synthetic human embryos – can only be created for the purposes of “creating a human being, improving or providing instruction in assisted reproduction procedures.”

Given the state of the science, it follows that synthetic human embryos could legally be created for the purpose of improving assisted reproduction procedures.

Second, “spare” or “excess” human embryos — including synthetic human embryos — originally created for one of the permitted purposes, but no longer wanted for this purpose, can be used for research. This research must be done in accordance with the consent regulations which specify that consent must be for a “specific research project.”

Finally, all research involving human embryos — including synthetic human embryos — is subject to the 14-day rule. The law stipulates that: “No person shall knowingly… maintain an embryo outside the body of a female person after the fourteenth day of its development following fertilization or creation, excluding any time during which its development has been suspended.”

Putting this all together, the creation of synthetic embryos for improving assisted human reproduction procedures is permitted, as is research using “spare” or “excess” synthetic embryos originally created for this purpose — provided there is specific consent and the research does not exceed 14 days.

This means that while synthetic human embryos may be useful for limited research on pre-implantation embryo development, they are not available in Canada for research on post-implantation embryo development beyond 14 days.

The authors close with this comment about the prospects for expanding Canada’s14-day limit, from the July 25, 2023 essay,

… any argument will have to overcome the political reality that the federal government is unlikely to open up the Pandora’s box of amending the AHR Act.

It therefore seems likely that synthetic human embryo research will remain limited in Canada for the foreseeable future.

As mentioned, in September 2023 there was a new development. See: Part two.

Nanoparticle drug delivery could reduce rejection rates for corneal transplants

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I like pictures of happy researchers and, as these pictures go, the researchers seem pretty relaxed,

Caption: Qingguo Xu, D.Phil., associate professor of pharmaceutics and ophthalmology at VCU School of Pharmacy, (right) in the lab with Tuo Meng, Ph.D., (left) and Vineet Kulkarni. (School of Pharmacy) Credit: VCU School of Pharmacy

A March 23, 2023 Virginia Commonwealth University (VCU) news release (also on EurekAlert) announces work into making corneal transplants more successful, Note: A link has been removed,

Corneal transplants can be the last step to returning clear vision to many patients suffering from eye disease. Each year, approximately 80,000 corneal transplantations take place in the U.S. Worldwide, more than 184,000 corneal transplantation surgeries are performed annually. 

However, rejection rates for the corneal grafts can be as high as 10%. This is largely due to poor patient compliance to the medications, which require frequent administrations of topical eyedrops over a long period of time. 

This becomes especially acute when patients show signs of early rejection of the transplanted corneas. When this occurs, patients need to apply topical eyedrops [sic] hourly to rescue the corneal grafts from failure. 

The tedious process of eyedrop [sic] dosing causes a tremendous burden for patients. The resulting noncompliance to medication treatment can lead to even higher graft-rejection rates. 

Research led by a team at Virginia Commonwealth University may make the corneal grafts more successful by using nanoparticles to encapsulate the medication. The novel approach could significantly improve patient compliance, according to a paper recently published in Science Advances, “Six-month effective treatment of corneal graft rejection.”

Each nanoparticle encapsulates a drug called dexamethasone sodium phosphate, one of the most commonly used corticosteroids for various ocular diseases treatment such as ocular inflammation, non-infectious uveitis, macular edema and corneal neovascularization. By using the nanoparticles to control the release of the medicine over time, patients would require only one injection right after the corneal transplantation surgery without the frequent eye drops. Our studies have shown that using this method the medication maintains its efficacy for six months on a corneal graft rejection model. 

In addition, because the medicine is released slowly and directly where it is most needed, the approach requires much lower doses than current standard eyedrop treatment while providing better efficacy and safety profiles.

Qingguo Xu, D.Phil., the principal investigator of this project and an associate professor of pharmaceutics and ophthalmology at VCU School of Pharmacy, collaborated with Justin Hanes, Ph.D., the Lewis J. Ort professor of ophthalmology at Johns Hopkins University.

Xu said, “To improve patient compliance and treatment efficacy, we developed a tiny nanoparticle (around 200 nanometers) that in animal studies enables the release of the drug up to six months after a single subconjunctival injection along the eyeball.”

Tuo Meng, Ph.D., who worked on the project as a doctoral student at VCU and is the first author of this paper, said: “In our preclinical corneal graft rejection model, the single dosing of the nanoparticle successfully prevented corneal graft rejection for six months.” 

More importantly, the nanoparticle approach reversed signs of early rejection and maintained corneal grafts for six months without rejection. 

This work was supported by the National Eye Institute, National Institutes of Health, through the R01 grant R01EY027827. 

Xu’s lab focuses on developing nanotherapeutics for safer and more effective treatment of various eye diseases.

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

Six-month effective treatment of corneal graft rejection by Tuo Meng, Jinhua Zheng, Min Chen, Yang Zhao, Hadi Sudarjat, Aji Alex M.R., Vineet Kulkarni, Yumin Oh, Shiyu Xia, Zheng Ding, Hyounkoo Han, Nicole Anders, Michelle A. Rudek, Woon Chow, Walter Stark, Laura M. Ensign, Justin Hanes, and Qingguo Xu. Science Advances 22 Mar 2023 Vol 9, Issue 12 DOI: 10.1126/sciadv.adf4608

This paper is open access.

Nanobiotics and artificial intelligence (AI)

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Antibiotics at the nanoscale = nanobiotics. For a more complete explanation, there’s this (Note: the video runs a little longer than most of the others embedded on this blog),

Before pushing further into this research, a note about antibiotic resistance. In a sense, we’ve created the problem we (those scientists in particular) are trying to solve.

Antibiotics and cleaning products kill 99.9% of the bacteria, leaving 0.1% that are immune. As so many living things on earth do, bacteria reproduce. Now, a new antibiotic is needed and discovered; it too kills 99.9% of the bacteria. The 0.1% left are immune to two antibiotics. And,so it goes.

As the scientists have made clear, we’re running out of options using standard methods and they’re hoping this ‘nanoparticle approach’ as described in a June 5, 2023 news item on Nanowerk will work, Note: A link has been removed,

Identifying whether and how a nanoparticle and protein will bind with one another is an important step toward being able to design antibiotics and antivirals on demand, and a computer model developed at the University of Michigan can do it.

The new tool could help find ways to stop antibiotic-resistant infections and new viruses—and aid in the design of nanoparticles for different purposes.

“Just in 2019, the number of people who died of antimicrobial resistance was 4.95 million. Even before COVID, which worsened the problem, studies showed that by 2050, the number of deaths by antibiotic resistance will be 10 million,” said Angela Violi, an Arthur F. Thurnau Professor of mechanical engineering, and corresponding author of the study that made the cover of Nature Computational Science (“Domain-agnostic predictions of nanoscale interactions in proteins and nanoparticles”).

In my ideal scenario, 20 or 30 years from now, I would like—given any superbug—to be able to quickly produce the best nanoparticles that can treat it.”

…

A June 5, 2023 University of Michigan news release (also on EurekAlert), which originated the news item, provides more technical details, Note: A link has been removed,

Much of the work within cells is done by proteins. Interaction sites on their surfaces can stitch molecules together, break them apart and perform other modifications—opening doorways into cells, breaking sugars down to release energy, building structures to support groups of cells and more. If we could design medicines that target crucial proteins in bacteria and viruses without harming our own cells, that would enable humans to fight new and changing diseases quickly.

The new [computer] model, named NeCLAS [NeCLAS (Nanoparticle-Computed Ligand Affinity Scoring)], uses machine learning—the AI technique that powers the virtual assistant on your smartphone and ChatGPT. But instead of learning to process language, it absorbs structural models of proteins and their known interaction sites. From this information, it learns to extrapolate how proteins and nanoparticles might interact, predict binding sites and the likelihood of binding between them—as well as predicting interactions between two proteins or two nanoparticles.

“Other models exist, but ours is the best for predicting interactions between proteins and nanoparticles,” said Paolo Elvati, U-M associate research scientist in mechanical engineering.

AlphaFold, for example, is a widely used tool for predicting the 3D structure of a protein based on its building blocks, called amino acids. While this capacity is crucial, this is only the beginning: Discovering how these proteins assemble into larger structures and designing practical nanoscale systems are the next steps.

“That’s where NeCLAS comes in,” said Jacob Saldinger, U-M doctoral student in chemical engineering and first author of the study. “It goes beyond AlphaFold by showing how nanostructures will interact with one another, and it’s not limited to proteins. This enables researchers to understand the potential applications of nanoparticles and optimize their designs.”

The team tested three case studies for which they had additional data: 

  • Molecular tweezers, in which a molecule binds to a particular site on another molecule. This approach can stop harmful biological processes, such as the aggregation of protein plaques in diseases of the brain like Alzheimer’s.
  • How graphene quantum dots break up the biofilm produced by staph bacteria. These nanoparticles are flakes of carbon, no more than a few atomic layers thick and 0.0001 millimeters to a side. Breaking up biofilms is likely a crucial tool in fighting antibiotic-resistant infections—including the superbug methicillin-resistant Staphylococcus aureus (MRSA), commonly acquired at hospitals.
  • Whether graphene quantum dots would disperse in water, demonstrating the model’s ability to predict nanoparticle-nanoparticle binding even though it had been trained exclusively on protein-protein data.

While many protein-protein models set amino acids as the smallest unit that the model must consider, this doesn’t work for nanoparticles. Instead, the team set the size of that smallest feature to be roughly the size of the amino acid but then let the computer model decide where the boundaries between these minimum features were. The result is representations of proteins and nanoparticles that look a bit like collections of interconnected beads, providing more flexibility in exploring small scale interactions.

“Besides being more general, NeCLAS also uses way less training data than AlphaFold. We only have 21 nanoparticles to look at, so we have to use protein data in a clever way,” said Matt Raymond, U-M doctoral student in electrical and computer engineering and study co-author.  

Next, the team intends to explore other biofilms and microorganisms, including viruses.

The Nature Computational Science study was funded by the University of Michigan Blue Sky Initiative, the Army Research Office and the National Science Foundation. 

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

Domain-agnostic predictions of nanoscale interactions in proteins and nanoparticles by Jacob Charles Saldinger, Matt Raymond, Paolo Elvati & Angela Violi. Nature Computational Science volume 3, pages 393–402 (2023) DOI: https://doi.org/10.1038/s43588-023-00438-x Published: 01 May 2023 Issue Date: May 2023

This paper is behind a paywall.

Dealing with mosquitos: a robot story and an engineered human tissue story

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I have two ‘mosquito and disease’ stories, the first concerning dengue fever and the second, malaria.

Dengue fever in Taiwan

A June 8, 2023 news item on phys.org features robotic vehicles, dengue fever, and mosquitoes,

Unmanned ground vehicles can be used to identify and eliminate the breeding sources of mosquitos that carry dengue fever in urban areas, according to a new study published in PLOS Neglected Tropical Diseases by Wei-Liang Liu of the Taiwan National Mosquito-Borne Diseases Control Research Center, and colleagues.

It turns out sewers are a problem according to this June 8, 2023 PLOS (Public Library of Science) news release on EurekAlert, provides more context and detail,

Dengue fever is an infectious disease caused by the dengue virus and spread by several mosquito species in the genus Aedes, which also spread chikungunya, yellow fever and zika. Through the process of urbanization, sewers have become easy breeding grounds for Aedes mosquitos and most current mosquito monitoring programs struggle to monitor and analyze the density of mosquitos in these hidden areas.

In the new control effort, researchers combined a crawling robot, wire-controlled cable car and real-time monitoring system into an unmanned ground vehicle system (UGV) that can take high-resolution, real-time images of areas within sewers. From May to August 2018, the system was deployed in five administrative districts in Kaohsiung city, Taiwan, with covered roadside sewer ditches suspected to be hotspots for mosquitos. Mosquito gravitraps were places above the sewers to monitor effects of the UGV intervention on adult mosquitos in the area.

In 20.7% of inspected sewers, the system found traces of Aedes mosquitos in stages from larvae to adult. In positive sewers, additional prevention control measures were carried out, using either insecticides or high-temperature water jets.  Immediately after these interventions, the gravitrap index (GI)—  a measure of the adult mosquito density nearby— dropped significantly from 0.62 to 0.19.

“The widespread use of UGVs can potentially eliminate some of the breeding sources of vector mosquitoes, thereby reducing the annual prevalence of dengue fever in Kaohsiung city,” the authors say.

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

Use of unmanned ground vehicle systems in urbanized zones: A study of vector Mosquito surveillance in Kaohsiung by Yu-Xuan Chen, Chao-Ying Pan, Bo-Yu Chen, Shu-Wen Jeng, Chun-Hong Chen, Joh-Jong Huang, Chaur-Dong Chen, Wei-Liang Liu. PLOS Neglected Tropical Diseases DOI: https://doi.org/10.1371/journal.pntd.0011346 Published: June 8, 2023

This paper is open access.

Dengue on the rise

Like many diseases, dengue is one where you may not have symptoms (asymptomatic), or they’re relatively mild and can be handled at home, or you may need care in a hospital and, in some cases, it can be fatal.

The World Health Organization (WHO) notes that dengue fever cases have increased exponentially since 2000 (from the March 17, 2023 version of the WHO’s “Dengue and severe dengue” fact sheet),

Global burden

The incidence of dengue has grown dramatically around the world in recent decades, with cases reported to WHO increased from 505 430 cases in 2000 to 5.2 million in 2019. A vast majority of cases are asymptomatic or mild and self-managed, and hence the actual numbers of dengue cases are under-reported. Many cases are also misdiagnosed as other febrile illnesses (1).

One modelling estimate indicates 390 million dengue virus infections per year of which 96 million manifest clinically (2). Another study on the prevalence of dengue estimates that 3.9 billion people are at risk of infection with dengue viruses.

The disease is now endemic in more than 100 countries in the WHO Regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. The Americas, South-East Asia and Western Pacific regions are the most seriously affected, with Asia representing around 70% of the global disease burden.

Dengue is spreading to new areas including Europe, [emphasis mine] and explosive outbreaks are occurring. Local transmission was reported for the first time in France and Croatia in 2010 [emphasis mine] and imported cases were detected in 3 other European countries.

The largest number of dengue cases ever reported globally was in 2019. All regions were affected, and dengue transmission was recorded in Afghanistan for the first time. The American Region reported 3.1 million cases, with more than 25 000 classified as severe. A high number of cases were reported in Bangladesh (101 000), Malaysia (131 000) Philippines (420 000), Vietnam (320 000) in Asia.

Dengue continues to affect Brazil, Colombia, the Cook Islands, Fiji, India, Kenya, Paraguay, Peru, the Philippines, the Reunion Islands and Vietnam as of 2021. 

There’s information from an earlier version of the fact sheet, in my July 2, 2013 posting, highlighting different aspects of the disease, e.g., “About 2.5% of those affected die.”

A July 21, 2023 United Nations press release warns that the danger from mosquitoes spreading dengue fever could increase along with the temperature,

Global warming marked by higher average temperatures, precipitation and longer periods of drought, could prompt a record number of dengue infections worldwide, the World Health Organization (WHO) warned on Friday [July 21, 2023].

Despite the absence of mosquitoes infected with the dengue virus in Canada, the government has a Dengue fever information page. At this point, the concern is likely focused on travelers who’ve contracted the disease from elsewhere. However, I am guessing that researchers are keeping a close eye on Canadian mosquitoes as these situations can change.

Malaria in Florida (US)

The researchers from the University of Central Florida (UCF) couldn’t have known when they began their project to study mosquito bites and disease that Florida would register its first malaria cases in 20 years this summer, from a July 26, 2023 article by Stephanie Colombini for NPR ([US] National Public Radio), Note: Links have been removed,

…

First local transmission in U.S. in 20 years

Heath [Hannah Heath] is one of eight known people in recent months who have contracted malaria in the U.S., after being bitten by a local mosquito, rather than while traveling abroad. The cases comprise the nation’s first locally transmitted outbreak in 20 years. The last time this occurred was in 2003, when eight people tested positive for malaria in Palm Beach, Fla.

One of the eight cases is in Texas; the rest occurred in the northern part of Sarasota County.

The Florida Department of Health recorded the most recent case in its weekly arbovirus report for July 9-15 [2023].

For the past month, health officials have issued a mosquito-borne illness alert for residents in Sarasota and neighboring Manatee County. Mosquito management teams are working to suppress the population of the type of mosquito that carries malaria, Anopheles.

Sarasota Memorial Hospital has treated five of the county’s seven malaria patients, according to Dr. Manuel Gordillo, director of infection control.

“The cases that are coming in are classic malaria, you know they come in with fever, body aches, headaches, nausea, vomiting, diarrhea,” Gordillo said, explaining that his hospital usually treats just one or two patients a year who acquire malaria while traveling abroad in Central or South America, or Africa.

…

All the locally acquired cases were of Plasmodium vivax malaria, a strain that typically produces milder symptoms or can even be asymptomatic, according to the Centers for Disease Control and Prevention. But the strain can still cause death, and pregnant people and children are particularly vulnerable.

…

Malaria does not spread from human-to-human contact; a mosquito carrying the disease has to bite someone to transmit the parasites.

Workers with Sarasota County Mosquito Management Services have been especially busy since May 26 [2023], when the first local case was confirmed.

Like similar departments across Florida, the team is experienced in responding to small outbreaks of mosquito-borne illnesses such as West Nile virus or dengue. They have protocols for addressing travel-related cases of malaria as well, but have ramped up their efforts now that they have confirmation that transmission is occurring locally between mosquitoes and humans.

…

While organizations like the World Health Organization have cautioned climate change could lead to more global cases and deaths from malaria and other mosquito-borne diseases, experts say it’s too soon to tell if the local transmission seen these past two months has any connection to extreme heat or flooding.

“We don’t have any reason to think that climate change has contributed to these particular cases,” said Ben Beard, deputy director of the CDC’s US Centers for Disease Control and Prevention] division of vector-borne diseases and deputy incident manager for this year’s local malaria response.

“In a more general sense though, milder winters, earlier springs, warmer, longer summers – all of those things sort of translate into mosquitoes coming out earlier, getting their replication cycles sooner, going through those cycles faster and being out longer,” he said. And so we are concerned about the impact of climate change and environmental change in general on what we call vector-borne diseases.”.

Beard co-authored a 2019 report that highlights a significant increase in diseases spread by ticks and mosquitoes in recent decades. Lyme disease and West Nile virus were among the top five most prevalent.

“In the big picture it’s a very significant concern that we have,” he said.

…

Engineered tissue and bloodthirsty mosquitoes

A June 8, 2023 University of Central Florida (UCF) news release (also on EurekAlert) by Eric Eraso describes the research into engineered human tissue and features a ‘bloodthirsty’ video. First, the video,

Note: A link has been removed,

A UCF research team has engineered tissue with human cells that mosquitoes love to bite and feed upon — with the goal of helping fight deadly diseases transmitted by the biting insects.

A multidisciplinary team led by College of Medicine biomedical researcher Bradley Jay Willenberg with Mollie Jewett (UCF Burnett School of Biomedical Sciences) and Andrew Dickerson (University of Tennessee) lined 3D capillary gel biomaterials with human cells to create engineered tissue and then infused it with blood. Testing showed mosquitoes readily bite and blood feed on the constructs. Scientists hope to use this new platform to study how pathogens that mosquitoes carry impact and infect human cells and tissues. Presently, researchers rely largely upon animal models and cells cultured on flat dishes for such investigations.

Further, the new system holds great promise for blood feeding mosquito species that have proven difficult to rear and maintain as colonies in the laboratory, an important practical application. The Willenberg team’s work was published Friday in the journal Insects.

Mosquitos have often been called the world’s deadliest animal, as vector-borne illnesses, including those from mosquitos cause more than 700,000 deaths worldwide each year. Malaria, dengue, Zika virus and West Nile virus are all transmitted by mosquitos. Even for those who survive these illnesses, many are left suffering from organ failure, seizures and serious neurological impacts.

“Many people get sick with mosquito-borne illnesses every year, including in the United States. The toll of such diseases can be especially devastating for many countries around the world,” Willenberg says.

This worldwide impact of mosquito-borne disease is what drives Willenberg, whose lab employs a unique blend of biomedical engineering, biomaterials, tissue engineering, nanotechnology and vector biology to develop innovative mosquito surveillance, control and research tools. He said he hopes to adapt his new platform for application to other vectors such as ticks, which spread Lyme disease.

“We have demonstrated the initial proof-of-concept with this prototype” he says. “I think there are many potential ways to use this technology.”

Captured on video, Willenberg observed mosquitoes enthusiastically blood feeding from the engineered tissue, much as they would from a human host. This demonstration represents the achievement of a critical milestone for the technology: ensuring the tissue constructs were appetizing to the mosquitoes.

“As one of my mentors shared with me long ago, the goal of physicians and biomedical researchers is to help reduce human suffering,” he says. “So, if we can provide something that helps us learn about mosquitoes, intervene with diseases and, in some way, keep mosquitoes away from people, I think that is a positive.”

Willenberg came up with the engineered tissue idea when he learned the National Institutes of Health (NIH) was looking for new in vitro 3D models that could help study pathogens that mosquitoes and other biting arthropods carry.

“When I read about the NIH seeking these models, it got me thinking that maybe there is a way to get the mosquitoes to bite and blood feed [on the 3D models] directly,” he says. “Then I can bring in the mosquito to do the natural delivery and create a complete vector-host-pathogen interface model to study it all together.”

As this platform is still in its early stages, Willenberg wants to incorporate addition types of cells to move the system closer to human skin. He is also developing collaborations with experts that study pathogens and work with infected vectors, and is working with mosquito control organizations to see how they can use the technology.

“I have a particular vision for this platform, and am going after it. My experience too is that other good ideas and research directions will flourish when it gets into the hands of others,” he says. “At the end of the day, the collective ideas and efforts of the various research communities propel a system like ours to its full potential. So, if we can provide them tools to enable their work, while also moving ours forward at the same time, that is really exciting.”

Willenberg received his Ph.D. in biomedical engineering from the University of Florida and continued there for his postdoctoral training and then in scientist, adjunct scientist and lecturer positions. He joined the UCF College of Medicine in 2014, where he is currently an assistant professor of medicine.

Willenberg is also a co-founder, co-owner and manager of Saisijin Biotech, LLC and has a minor ownership stake in Sustained Release Technologies, Inc. Neither entity was involved in any way with the work presented in this story. Team members may also be listed as inventors on patent/patent applications that could result in royalty payments. This technology is available for licensing. To learn more, please visit ucf.flintbox.com/technologies/44c06966-2748-4c14-87d7-fc40cbb4f2c6.

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

Engineered Human Tissue as A New Platform for Mosquito Bite-Site Biology Investigations by Corey E. Seavey, Mona Doshi, Andrew P. Panarello, Michael A. Felice, Andrew K. Dickerson, Mollie W. Jewett and Bradley J. Willenberg. Insects 2023, 14(6), 514; https://doi.org/10.3390/insects14060514 Published: 2 June 2023

This paper is open access.

That final paragraph in the news release is new to me. I’ve seen them list companies where the researchers have financial interests but this is the first time I’ve seen a news release that offers a statement attempting to cover all the bases including some future possibilities such as: “Team members may also be listed as inventors on patent/patent applications that could result in royalty payments.“

It seems pretty clear that there’s increasing concern about mosquito-borne diseases no matter where you live.

Georges Canguilhem’s influence on life sciences philosophy and ‘it’s all about Kant’

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This July 5, 2023 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) press release by José Tadeu Arantes (also on EurekAlert but published on July 3, 2023) slow walks us through a listing of French intellectuals and some history (which I enjoyed) before making a revelation,

The constitution of the World Health Organization (WHO) defines health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”. The definition dates from the 1940s, but even then the thinking behind it was hardly novel. Similar concepts can be found in antiquity, in Eastern as well as Western societies, but in Europe, the cradle of Western culture, the view that mental well-being was part of health enjoyed little prestige in the eighteenth and nineteenth centuries owing to a reductionist understanding of disease as strictly somatic (relating only to the body). This outlook eventually began to be questioned. One of its leading critics in the twentieth century was French philosopher and physician Georges Canguilhem (1904-1995).

A disciple of Gaston Bachelard (1884-1962), a colleague of Jean-Paul Sartre (1905-1980), Paul Nizan (1905-1940) and Raymond Aron (1905-1983), and a major influence on Michel Foucault (1926-1984), Canguilhem was one of the foremost French intellectuals of the postwar years. Jacques Lacan (1901-1981), Gilles Deleuze (1925-1995) and Jacques Derrida (1930-2004) were among the thinkers who took inspiration from his ideas.

Canguilhem began studying medicine in the mid-thirties and earned his medical doctorate in 1943, by which time he had already taught philosophy in high schools for many years (having qualified in 1927). Another significant tack in his life course occurred during World War Two. He had long been both a pacifist and an antifascist. Following the French surrender in 1940, he refused to continue teaching under the Vichy regime and joined the Resistance, fighting with the rural guerrillas of the Maquis. In this historically and politically complex period, he apparently set out to train as a physician in order to have practical experience as well as book learning and to work on the history of the life sciences. He was awarded the Croix de Guerre and the Médaille da la Résistance for organizing a field hospital while under attack in the Auvergne.

In an article published in the journal History and Philosophy of the Life Sciences, Emiliano Sfara, who has a PhD in philosophy from the University of Montpellier and was a postdoctoral fellow at the University of São Paulo (USP) in Brazil from 2018 to 2022, argues that Canguilhem’s concepts of “technique”, “technical activity” and “practice” derived from Immanuel Kant’s Critique of Judgment (1790) and influenced Canguilhem’s decision to study medicine.

“Earlier historiographical research showed how Kant influenced Canguilhem, especially the concept of ‘knowledge’ developed in Kant’s Critique of Pure Reason as the unification of heterogeneous data by an organizing intellect, and the idea of the ‘organism’ as a totality of interdependent and interacting parts, inspired by the Critique of Judgment. I tried to show in the article the importance, and roots in Kant, of a third cluster of ideas relating to the concept of ‘technique’ in Canguilhem’s work, beginning in mid-thirties,” said Sfara, currently a researcher at the National Institute of Science and Technology for Interdisciplinary and Transdisciplinary Studies in Ecology and Evolution (INCT IN-TREE), hosted by the Federal University of Bahia (UFBA).

“Section 43 of Kant’s Critique of Judgment makes a distinction between technical capacity and science as a theoretical faculty. Technique is the subject’s concrete practice operating in a certain context, a vital movement of construction or manufacturing of objects and tools that enable a person to live in their environment. This is not reducible to science. Analogously, Canguilhem postulates that science is posterior to technique. Practice comes first; theory arises later. This movement is evident in art. True, the artist starts out with a project. But the development of the artwork isn’t confined to the project, which is reconstructed as the process unfolds. This practical element of the subject’s interaction with the environment, which has its roots in Kant’s theories, was very important to the evolution of Canguilhem’s thought. It even influenced his decision to study medicine, as well as the conception of medicine he developed.”

Sfara explained that while Canguilhem espoused the values of the Parti Radical in his youth, in the mid-thirties he moved left, without becoming a pro-Soviet Stalinist. Later on, according to some scholars who knew him and are still active (such as the Moroccan philosopher and mathematician Hourya Benis Sinaceur), Canguilhem gave primacy to the egalitarian principles symbolized by the French Republic’s motto Liberté, Egalité, Fraternité.

His main contributions were to medicine and philosophy of science. His most important work, The Normal and the Pathological (1966), is basically an expansion of his 1943 doctoral thesis. “In his original thesis, Canguilhem broke with part of eighteenth- and nineteenth-century French medical tradition and formulated ideas that are very much part of medicine today. [emphasis mine] Taking a purely analytical and quantitative approach, physicians like François Broussais (1772-1838) believed disease resulted from a surplus or lack of some organic substance, such as blood. Bloodletting was regularly used as a form of treatment. France imported 33 million leeches from southern Europe in the first half of the nineteenth century. Canguilhem saw the organism as a totality that interacted with its environment [emphasis mine] rather than a mere aggregation of parts whose functioning depended only on a ‘normal’ amount of the right organic substances,” Safra said.

In Canguilhem, the movement changes. Instead of transiting from the part to the whole, he moves from the whole to the part (as does Kant in the Critique of Judgment). He views the organism not as a machine but as an integral self-regulating totality. Life cannot be deduced from physical and chemical laws. One must start from the living being to understand life. Practice is the bridge that connects this totality to the environment. At the same time as it changes the environment, practice changes the organism and helps determine its physiological states.

“So Canguilhem implies that in order to find a state called normal, i.e. healthy, a given organism has to adapt its own operating rules to the outside world in the course of interacting concretely and practically with the environment. A human organism, for example, is in a ‘normal’ state when its pulse slows sharply after a period of long daily running. A case in point is the long-distance runner, who has to train every day,” Safra said.

“For Canguilhem, disease is due to inadaptation between the part, the organism and the environment, and often manifests itself as a feeling of malaise. Adaptive mechanisms in the organism can correct pathological dysfunctions.”

The article resulted from Sfara’s postdoctoral research supervised by Márcio Suzuki and supported by FAPESP.

The article “From technique to normativity: the influence of Kant on Georges Canguilhem’s philosophy of life” is at: link.springer.com/article/10.1007/s40656-023-00573-8.

This text was originally published by FAPESP Agency according to Creative Commons license CC-BY-NC-ND. Read the original here.https://agencia.fapesp.br/republicacao_frame?url=https://agencia.fapesp.br/study-shows-kants-influence-on-georges-canguilhem-who-anticipated-concepts-current-in-medicine-today/41794/&utm_source=republish&utm_medium=republish&utm_content=https://agencia.fapesp.br/study-shows-kants-influence-on-georges-canguilhem-who-anticipated-concepts-current-in-medicine-today/41794/

Even though you can find a link to the paper in the press release, here’s my version of a citation complete with link,

From technique to normativity: the influence of Kant on Georges Canguilhem’s philosophy of life by Emiliano Sfara .History and Philosophy of the Life Sciences volume 45, Article number: 16 (2023) DOI: https://doi.org/10.1007/s40656-023-00573-8 Published: 06 April 2023

This paper is open access.

PAINT wound-healing ink into your cuts with a 3D-printing pen

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This screams tattoo to me but it’s not,

Caption This 3-D printing pen is painting a gel that can help wounds of all shapes heal quickly and effectively. Credit: Adapted from ACS Applied Materials & Interfaces, 2023, DOI: 10.1021/acsami.3c03630

A June 1, 2023 American Chemical Society (ACS) news release (also on EurekAlert), announces a new approach to wound healing,

The body is pretty good at healing itself, though more severe wounds can require bandages or stitches. But researchers publishing in ACS Applied Materials & Interfaces have developed a wound-healing ink that can actively encourage the body to heal by exposing the cut to immune-system vesicles. The ink can be spread into a cut of any shape using a 3D-printing pen, and in mice, the technology nearly completely repaired wounds in just 12 days.

When the skin is cut or torn, the body’s natural “construction crew” kicks in to fix it back up — clearing out any bacterial invaders, regrowing broken blood vessels and eventually forming a scar. Many techniques used to heal wounds can’t do much beyond helping the body do its job better. Bandages or stitches are used to prevent further bleeding, while antibiotics work to prevent complications from infections. But by adding members of the construction crew to a wound-healing treatment or bandage, it could actually accelerate the natural healing process. Specifically, white blood cells or the extracellular vesicles (EVs) secreted from them play important roles in promoting blood vessel formation and reducing inflammation during healing. So, Dan Li, Xianguang Ding and Lianhui Wang wanted to incorporate these EVs into a hydrogel-based wound healing ink that could be painted into cuts of any shape.

The team developed a system called PAINT, or “portable bioactive ink for tissue healing,” using EVs secreted from macrophages combined with sodium alginate. These components were combined in a 3D-printing pen, where they mixed at the pen’s tip and formed a sturdy gel at the site of injury within three minutes. The EVs promoted blood vessel formation and reduced inflammatory markers in human epithelial cells, shifting them into the “proliferative,” or growth, phase of healing. PAINT was also tested on injured mice, where it promoted collagen fiber formation. Mice treated with PAINT had almost healed completely from a large wound after 12 days, compared to mice that didn’t receive the treatment, who were not nearly as far along in the healing process at this time point. The researchers say that this work could help heal a wide variety of cuts quickly and easily, without the need for complex procedures.

The authors acknowledge funding from the Leading-Edge Technology Programme of Jiangsu Natural Science Foundation, the Natural Science Foundation, the Natural Science Foundation of Jiangsu Province, the CAS [Chinese Academy of Sciences] Key Laboratory of Nano-Bio Interface, the Key Laboratory of Nanodevices and Applications, and the Postgraduate Research & Practice Innovation Program of Jiangsu Province.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS’ mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and all its people. The Society is a global leader in promoting excellence in science education and providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a leader in scientific information solutions, its CAS division partners with global innovators to accelerate breakthroughs by curating, connecting and analyzing the world’s scientific knowledge. ACS’ main offices are in Washington, D.C., and Columbus, Ohio.

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

Paintable Bioactive Extracellular Vesicle Ink for Wound Healing by Li Li, Zhiyu Wang, Kepeng Wang, Siyuan Fu, Dan Li, Mao Wang, Yi Cao, Houjuan Zhu, Ziyan Li, Lixing Weng, Zhiyang Li, Xianguang Ding, and Lianhui Wang. ACS Appl. Mater. Interfaces 2023, 15, 21, 25427–25436 DOI: https://doi.org/10.1021/acsami.3c03630 Publication Date:May 19, 2023 Copyright © 2023 American Chemical Society

This paper is behind a paywall.

A new lipid nanoparticle (LNP) delivery system for CRISPR-Cas9) gene editing

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The first time lipid nanoparticles were mentioned here as a delivery system for CRISPR-Cas9 editing was in a January 26, 2018 posting featuring work at the Massachusetts Institute of Technology (MIT). This latest research on the topic comes from Japan according to a March 2, 2023 news item on phys.org,

Gene therapy is a potential mode of treatment for a wide variety of diseases caused by genetic mutations. While it has been an area of diverse and intense research, historically, only a very few patients have been treated using gene therapy—and fewer still cured. The advent of the genetic modification technique called CRISPR-Cas9 in 2012 has revolutionized gene therapy—as well as biology as a whole—and it has recently entered clinical trials for the treatment of some diseases in humans.

Haruno Onuma, Yusuke Sato and Hideyoshi Harashima at Hokkaido University have developed a new delivery system for CRISPR-Cas9, based on lipid nanoparticles (LNPs), that could greatly increases the efficiency of in vivo gene therapy. Their findings were published in the Journal of Controlled Release.

…

A March 2, 2023 Hokkaido University press release (also on EurekAlert), which originated the news item, provides details about the researchers’ new technique,

“There are broadly two ways of treating diseases with gene therapy,” Sato explained, “ex vivo, where cells are subjected to the desired modifications in the laboratory and then introduced into the patient, and in vivo, where the treatment is administered to the patient to change the cells in their body. Safe and effective in vivo treatment is the ultimate aspiration of gene therapy, as it would be a straightforward process for patients and healthcare providers. LNPs can function as a vehicle for the safe and effective delivery of such therapies.”

CRISPR-Cas9 consists of a large molecule composed of the Cas9 protein and guide RNA. The guide RNA binds to a specific, complementary DNA sequence, and the Cas9 protein cuts that sequence, allowing it to be modified. The guide RNA can be altered to target specific DNA sequences to be modified.

“In a previous study, we discovered that additional DNA molecules, called ssODNs, ensure that the CRISPR-Cas9 molecule is loaded into the LNPs (CRISPR-LNPs),” Harashima elucidated. “In this study,  we again used ssODNs, but they were carefully designed so that they would not inhibit the function of the guide RNA.” 

Using a guide RNA targeting the expression of a protein called transthyretin, they evaluated the effectiveness of the CRISPR-LNPs in mice models. CRISPR-LNPs with ssODNs that dissociated from the guide RNA at room temperature were most effective at reducing serum transthyretin: two consecutive doses, one day apart, reduced it by 80%.

“We have demonstrated the optimal ssODN sequence affinity that ensures the loading and the release of CRISPR-Cas9 at the target location; and that this system can be used to edit cells in vivo,” concluded Onuma. “We will continue to improve the design of ssODNs, as well as to develop optimal lipid formulations to increase the effectiveness of delivery.” 

The image and caption helped me with better understanding the technique described in the press release,

The RNP-ssODN is designed to ensure the CRISPR-Cas9 molecule is encapsulated by the LNP. Once inside the cells, the ssODN dissociates and CRISPR-Cas9 can carry out its effect. (Haruno Onuma, Yusuke Sato, Hideyoshi Harashima. Journal of Controlled Release. February 10, 2023).

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

Lipid nanoparticle-based ribonucleoprotein delivery for in vivo genome editing by Haruno Onuma, Yusuke Sato, Hideyoshi Harashima. Journal of Controlled Release Volume 355, March 2023, Pages 406-416 DOI: https://doi.org/10.1016/j.jconrel.2023.02.008

This paper is behind a paywall.

Biodegradable electronics: a seaweed biosensor

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By combining seaweed and graphene, scientists have been able to create sensors that can be worn like a ‘second skin’ and outperform other similar biosensors, according to a March 3, 2023 news item on ScienceDaily,

Scientists at the University of Sussex have successfully trialed new biodegradable health sensors that could change the way we experience personal healthcare and fitness monitoring technology.

The team at Sussex have developed the new health sensors — such as those worn by runners or patients to monitor heart rate and temperature — using natural elements like rock salt, water and seaweed, combined with graphene. Because they are solely made with ingredients found in nature, the sensors are fully biodegradable, making them more environmentally friendly than commonly used rubber and plastic-based alternatives. Their natural composition also places them within the emerging scientific field of edible electronics — electronic devices that are safe for a person to consume.

Better still, the researchers found that their sustainable seaweed-based sensors actually outperform existing synthetic based hydrogels and nanomaterials, used in wearable health monitors, in terms of sensitivity. Therefore, improving the accuracy, as the more sensitive a sensor, the more accurately it will record a person’s vital signs.

…

A March 2, 2023 University of Sussex press release (also on EurekAlert) by Poppy Luckett, which originated the news item, describes the inspiration for the research,

Dr Conor Boland, a materials physics lecturer in the School of Mathematical and Physical Sciences, said:  “I was first inspired to use seaweed in the lab after watching MasterChef during lockdown. Seaweed, when used to thicken deserts, gives them a soft and bouncy structure – favored by vegans and vegetarians as an alternative to gelatin. It got me thinking: “what if we could do that with sensing technology?”.

“For me, one of the most exciting aspects to this development is that we have a sensor that is both fully biodegradable and highly effective. The mass production of unsustainable rubber and plastic based health technology could, ironically, pose a risk to human health through microplastics leeching into water sources as they degrade.  

“As a new parent, I see it as my responsibility to ensure my research enables the realisation of a cleaner world for all our children.” 

Seaweed is first and foremost an insulator, but by adding a critical amount of graphene to a seaweed mixture the scientists were able to create an electrically conductive film. When soaked in a salt bath, the film rapidly absorbs water, resulting in a soft, spongy, electrically conductive hydrogel.  

The development has the potential to revolutionise health monitoring technology, as future applications of the clinical grade wearable sensors would look something like a second skin or a temporary tattoo: lightweight, easy to apply, and safe, as they are made with all natural ingredients. This would significantly improve the overall patient experience, without the need for more commonly used and potentially invasive hospital instruments, wires and leads.  

Dr Sue Baxter, Director of Innovation and Business Partnerships at the University of Sussex, is excited about the potential benefits of this technology:  “At the University of Sussex, we are committed to protecting the future of the planet through sustainability research, expertise and innovation. What’s so exciting about this development from Dr Conor Boland and his team is that it manages to be all at once truly sustainable, affordable, and highly effective – out-performing synthetic alternatives.  

“What’s also remarkable for this stage of research – and I think this speaks to the meticulous ground-work that Dr Boland and his team put in when they created their blueprint – is that it’s more than a proof of principle development. Our Sussex scientists have created a device that has real potential for industry development into a product from which you or I could benefit in the relatively near future.” 

This latest  research breakthrough follows the publication of a blueprint for nanomaterial development from the Sussex scientists in 2019, which presented a method for researchers to follow in order to optimise the development of nanomaterial sensors.  

…

Kevin Doty, a Masters student in the School of Mathematical and Physical Sciences, at the University of Sussex, said:  “I taught chemistry previously, but decided I wanted to learn more about nanoscience. My gamble paid off, and not only did I enjoy it more than I expected, but I also ended up with an opportunity to utilize the information I had learned to work on a novel idea that has evolved into a first author publication as an MSc student. Learning about nanoscience showed me just how varied and multidisciplinary the field is. Any science background can bring knowledge that can be applied to this field in a unique way. This has led to further studies in a PhD studentship, opening up an all new career path I could not have previously considered.” 

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

Food-Inspired, High-Sensitivity Piezoresistive Graphene Hydrogels by Adel A. K. Aljarid, Kevin L. Doty, Cencen Wei, Jonathan P. Salvage, and Conor S. Boland. ACS Sustainable Chem. Eng. 2023, 11, 5, 1820–1827 DOI: https://doi.org/10.1021/acssuschemeng.2c06101 Publication Date:January 25, 2023 Copyright © 2023 The Authors. Published by American Chemical Society

This paper appears to be open access.

Artificially-grown mini-brains (organoids)—without animal components— offer opportunities for neuroscience

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There’s a good (brief) description of how these fibres become organoids in the photo caption,

Engineered extracellular matrices composed of fibrillar fibronectin are suspended over a porous polymer framework and provide the niche for stem cells to attach, differentiate, and mature into organoids. Credit: Ayse Muñiz Courtesy: Michigan Medicine – University of Michigan

A July 13 ,2023 University of Michigan (Michigan Medicine) news release by Noah Fromson (also on EurekAlert) announces ‘kinder, gentler’ brain organoids. Coincidentally, these organoids more closely resemble human brains, Note: Links have been removed,

Researchers at University of Michigan developed a method to produce artificially grown miniature brains — called human brain organoids — free of animal cells that could greatly improve the way neurodegenerative conditions are studied and, eventually, treated.

Over the last decade of researching neurologic diseases, scientists have explored the use of human brain organoids as an alternative to mouse models. These self-assembled, 3D tissues derived from embryonic or pluripotent stem cells more closely model the complex brain structure compared to conventional two-dimensional cultures.

Until now, the engineered network of proteins and molecules that give structure to the cells in brain organoids, known as extracellular matrices, often used a substance derived from mouse sarcomas called Matrigel. That method suffers significant disadvantages, with a relatively undefined composition and batch-to-batch variability.

The latest U-M research, published in Annals of Clinical and Translational Neurology, offers a solution to overcome Matrigel’s weaknesses. Investigators created a novel culture method that uses an engineered extracellular matrix for human brain organoids — without the presence of animal components – and enhanced the neurogenesis of brain organoids compared to previous studies.

“This advancement in the development of human brain organoids free of animal components will allow for significant strides in the understanding of neurodevelopmental biology,” said senior author Joerg Lahann, Ph.D., director of the U-M Biointerfaces Institute and Wolfgang Pauli Collegiate Professor of Chemical Engineering at U-M.

“Scientists have long struggled to translate animal research into the clinical world, and this novel method will make it easier for translational research to make its way from the lab to the clinic.”

The foundational extracellular matrices of the research team’s brain organoids were comprised of human fibronectin, a protein that serves as a native structure for stem cells to adhere, differentiate and mature. They were supported by a highly porous polymer scaffold.

The organoids were cultured for months, while lab staff was unable to enter the building due to the COVID 19-pandemic.

Using proteomics, researchers found their brain organoids developed cerebral spinal fluid, a clear liquid that flows around healthy brain and spinal cords. This fluid more closely matched human adult CSF compared to a landmark study of human brain organoids developed in Matrigel.

“When our brains are naturally developing in utero, they are of course not growing on a bed of extracellular matrix produced by mouse cancer cells,” said first author Ayşe Muñiz, Ph.D., who was a graduate student in the U-M Macromolecular Science and Engineering Program at the time of the work.  

“By putting cells in an engineered niche that more closely resembles their natural environment, we predicted we would observe differences in organoid development that more faithfully mimics what we see in nature.”

The success of these xenogeneic-free human brain organoids opens the door for reprogramming with cells from patients with neurodegenerative diseases, says co-author Eva Feldman, M.D., Ph.D., director of the ALS Center of Excellence at U-M and James W. Albers Distinguished Professor of Neurology at U-M Medical School.

“There is a possibility to take the stem cells from a patient with a condition such as ALS or Alzheimer’s and, essentially, build an avatar mini brain of that patients to investigate possible treatments or model how their disease will progress,” Feldman said. “These models would create another avenue to predict disease and study treatment on a personalized level for conditions that often vary greatly from person to person.”

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

Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells by Ayşe J. Muñiz, Tuğba Topal, Michael D. Brooks, Angela Sze, Do Hoon Kim, Jacob Jordahl, Joe Nguyen, Paul H. Krebsbach, Masha G. Savelieff, Eva L. Feldman, Joerg Lahann. Annals of Clinical and Translational Neurology DOI: https://doi.org/10.1002/acn3.51820 First published: 07 June 2023

This paper is open access.