Tag Archives: Robert Langer

mRNA, COVID-19 vaccines, treating genetic diseases before birth, and the scientist who started it all

This post was going to be about new research into fetal therapeutics and mRNA.But, since I’ve been very intrigued by the therapeutic agent, mRNA, which has been a big part of the COVID-19 vaccine story; this seemed like a good opportunity to dive a little more deeply into that topic at the same time.

It’s called messenger ribonucleic acid (mRNA) and until seeing this video I had only the foggiest idea of how it works, which is troubling since at least two COVID-19 vaccines are based on this ‘new’ technology. From a November 10, 2020 article by Damian Garde for STAT,

Garde’s article offers detail about mRNA along with fascinating insight into how science and entreneurship works.

mRNA—it’s in the details, plus, the loneliness of pioneer researchers, a demotion, and squabbles

Garde’s November 10, 2020 article provides some explanation about how mRNA vaccines work and it takes a look at what can happen to pioneering scientists (Note: A link has been removed),

For decades, scientists have dreamed about the seemingly endless possibilities of custom-made messenger RNA, or mRNA.

Researchers understood its role as a recipe book for the body’s trillions of cells, but their efforts to expand the menu have come in fits and starts. The concept: By making precise tweaks to synthetic mRNA and injecting people with it, any cell in the body could be transformed into an on-demand drug factory. [emphasis mine]

But turning scientific promise into medical reality has been more difficult than many assumed. Although relatively easy and quick to produce compared to traditional vaccine-making, no mRNA vaccine or drug has ever won approval [until 2021].

Whether mRNA vaccines succeed or not, their path from a gleam in a scientist’s eye to the brink of government approval has been a tale of personal perseverance, eureka moments in the lab, soaring expectations — and an unprecedented flow of cash into the biotech industry.

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karikó spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

It all made sense on paper. In the natural world, the body relies on millions of tiny proteins to keep itself alive and healthy, and it uses mRNA to tell cells which proteins to make. If you could design your own mRNA, you could, in theory, hijack that process and create any protein you might desire — antibodies to vaccinate against infection, enzymes to reverse a rare disease, or growth agents to mend damaged heart tissue.

In 1990, researchers at the University of Wisconsin managed to make it work in mice. Karikó wanted to go further.

The problem, she knew, was that synthetic RNA was notoriously vulnerable to the body’s natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.

It was a real obstacle, and still may be, but Karikó was convinced it was one she could work around. Few shared her confidence.

“Every night I was working: grant, grant, grant,” Karikó remembered, referring to her efforts to obtain funding. “And it came back always no, no, no.”

By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

“Usually, at that point, people just say goodbye and leave because it’s so horrible,” Karikó said.

There’s no opportune time for demotion, but 1995 had already been uncommonly difficult. Karikó had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which she’d devoted countless hours was slipping through her fingers.

“I thought of going somewhere else, or doing something else,” Karikó said. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”

In time, those better experiments came together. After a decade of trial and error, Karikó and her longtime collaborator at Penn — Drew Weissman, an immunologist with a medical degree and Ph.D. from Boston University — discovered a remedy for mRNA’s Achilles’ heel.

The stumbling block, as Karikó’s many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response; the body sensed a chemical intruder, and went to war. The solution, Karikó and Weissman discovered, was the biological equivalent of swapping out a tire.

Every strand of mRNA is made up of four molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signaling the immune system. So Karikó and Weissman simply subbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the body’s defenses.

“That was a key discovery,” said Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. “Karikó and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone.”

That discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman, but it offered absolution to the mRNA researchers who had kept the faith during the technology’s lean years. And it was the starter pistol for the vaccine sprint to come.

Entrepreneurs rush in

Garde’s November 10, 2020 article shifts focus from Karikó, Weissman, and specifics about mRNA to the beginnings of what might be called an entrepreneurial gold rush although it starts sedately,

Derrick Rossi [emphasis mine], a native of Toronto who rooted for the Maple Leafs and sported a soul patch, was a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper. Not only did he recognize it as groundbreaking, he now says Karikó and Weissman deserve the Nobel Prize in chemistry.

“If anyone asks me whom to vote for some day down the line, I would put them front and center,” he said. “That fundamental discovery is going to go into medicines that help the world.”

But Rossi didn’t have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab.

He wondered whether modified messenger RNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells [emphasis mine].

In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinson’s disease to spinal cord injuries.

But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos.

Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.

He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create.

Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, the prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology.

On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend — and an ego-bruising squabble.

Langer is a towering figure in biotechnology and an expert on drug-delivery technology. At least 400 drug and medical device companies have licensed his patents. His office walls display many of his 250 major awards, including the Charles Stark Draper Prize, considered the equivalent of the Nobel Prize for engineers.

As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives.

“I think you can do a lot better than that,” Langer recalled telling Rossi, referring to stem cells. “I think you could make new drugs, new vaccines — everything.”

Within several months, Rossi, Langer, Afeyan [Noubar Afeyan, venture capitalist, founded and runs Flagship Ventures], and another physician-researcher at Harvard formed the firm Moderna — a new word combining modified and RNA.

Springer was the first investor to pledge money, Rossi said. In a 2012 Moderna news release, Afeyan said the firm’s “promise rivals that of the earliest biotechnology companies over 30 years ago — adding an entirely new drug category to the pharmaceutical arsenal.”

But although Moderna has made each of the founders hundreds of millions of dollars — even before the company had produced a single product — Rossi’s account is marked by bitterness. In interviews with the [Boston] Globe in October [2020], he accused Langer and Afeyan of propagating a condescending myth that he didn’t understand his discovery’s full potential until they pointed it out to him.

Garde goes on to explain how BioNTech came into the mRNA picture and contrasts the two companies’ approaches to biotechnology as a business. It seems BioNTech has not cashed in the same way as has Moderna. (For some insight into who’s making money from COVID-19 check out Giacomo Tognini’s December 23, 2020 article (Meet The 50 Doctors, Scientists And Healthcare Entrepreneurs Who Became Pandemic Billionaires In 2020) for Forbes.)

Garde ends his November 10, 2020 article on a mildly cautionary note,

“You have all these odd clinical and pathological changes caused by this novel bat coronavirus [emphasis mine], and you’re about to meet it with all of these vaccines with which you have no experience,” said Paul Offit, an infectious disease expert at Children’s Hospital of Philadelphia and an authority on vaccines.

What happened to Katalin Karikó?

Matthew Rosza’s January 25, 2021 article about Karikó and her pioneering work features an answer to my question and some advice,

“I want young people to feel — if my example, because I was demoted, rejected, terminated, I was even subject for deportation one point — [that] if they just pursue their thing, my example helps them to wear rejection as a badge,” Karikó, who today is a senior vice president at BioNTech RNA Pharmaceuticals, told Salon last month when discussing her story. “‘Okay, well, I was rejected. I know. Katalin was rejected and still [succeeded] at the end.’ So if it helps them, then it helps them.”

Despite her demotion, Karikó continued with her work and, along with a fellow immunologist named Dr. Drew Weissman, penned a series of influential articles starting in 2005. These articles argued that mRNA vaccines would not be neutralized by the human immune system as long as there were specific modifications to nucleosides, a compound commonly found in RNA.

By 2013, Karikó’s work had sufficiently impressed experts that she left the University of Pennsylvania for BioNTech RNA Pharmaceuticals.

Karikó tells Salon that the experience taught her one important lesson: In life there will be people who, for various reasons, will try to hold you back, and you can’t let them get you down.

“People that are in power, they can help you or block you,” Karikó told Salon. “And sometimes people select to make your life miserable. And now they cannot be happy with me because now they know that, ‘Oh, you know, we had the confrontation and…’ But I don’t spend too much time on these things.”

Before moving onto the genetic research which prompted this posting, I have an answer to the following questions:

Could an mRNA vaccine affect your DNA (deoxyribonucleic acid) and how do mRNA vaccines differ from the traditional ones?

No, DNA is not affected by the COVID-19 mRNA vaccines, according to a January 5, 2021 article by Jason Murdock for Newsweek,

The type of vaccines used against COVID-19 do not interact with or alter human genetic code, also known as DNA, scientists say.

In traditional vaccines, a piece of a virus, known as an “antigen,” would be injected into the body to force the immune system to make antibodies to fight off future infection. But mRNA-based methods do not use a live virus, and cannot give someone COVID.

Instead, mRNA vaccines give cells the instructions to make a “spike” protein also found on the surface of the virus that causes COVID. The body kickstarts its immune response by creating the antibodies needed to combat those specific virus proteins.

Once the spike protein is created, the cell breaks down the instructions provided by the mRNA molecule, leaving the human immune system prepared to combat infection. The mRNA vaccines are not a medicine—nor a cure—but a preventative measure.

Gavi, a vaccine alliance partnered with the World Health Organization (WHO), has said that mRNA instructions will become degraded in approximately 72 hours.

It says mRNA strands are “chemical intermediaries” between DNA in our chromosomes and the “cellular machinery that produces the proteins we need to function.”

But crucially, while mRNA vaccines will give the human body the blueprints on how to assemble proteins, the alliance said in a fact-sheet last month that “mRNA isn’t the same as DNA, and it can’t combine with our DNA to change our genetic code.”

It explained: “Some viruses like HIV can integrate their genetic material into the DNA of their hosts, but this isn’t true of all viruses… mRNA vaccines don’t carry these enzymes, so there is no risk of the genetic material they contain altering our DNA.”

The [US] Centers for Disease Control and Prevention (CDC) says on its website that mRNA vaccines that are rolling out don’t “interact with our DNA in any way,” and “mRNA never enters the nucleus of the cell, which is where our DNA (genetic material) is kept.”

Therapeutic fetal mRNA treatment

Rossi’s work on mRNA and embryonic stem cells bears a relationship of sorts to this work focusing on prebirth therapeutics. (From a January 13, 2021 news item on Nanowerk), Note: A link has been removed,

Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy.

The proof-of-concept study, published in Science Advances (“Ionizable Lipid Nanoparticles for In Utero mRNA Delivery”), engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.

A January 13, 2021 Children’s Hospital of Philadelphia (CHOP) news release (also on EurekAlert), which originated the news item, delves further into the research,

“This is an important first step in identifying nonviral mediated approaches for delivering cutting-edge therapies before birth,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at CHOP. “These lipid nanoparticles may provide a platform for in utero mRNA delivery, which would be used in therapies like fetal protein replacement and gene editing.”

Recent advances in DNA sequencing technology and prenatal diagnostics have made it possible to diagnose many genetic diseases before birth. Some of these diseases are treated by protein or enzyme replacement therapies after birth, but by then, some of the damaging effects of the disease have taken hold. Thus, applying therapies while the patient is still in the womb has the potential to be more effective for some conditions. The small fetal size allows for maximal therapeutic dosing, and the immature fetal immune system may be more tolerant of replacement therapy.

Of the potential vehicles for introducing therapeutic protein replacement, mRNA is distinct from other nucleic acids, such as DNA, because it does not need to enter the nucleus and can use the body’s own machinery to produce the desired proteins. Currently, the common methods of nucleic acid delivery include viral vectors and nonviral approaches. Although viral vectors may be well-suited to gene therapy, they come with the potential risk of unwanted integration of the transgene or parts of the viral vector in the recipient genome. Thus, there is an important need to develop safe and effective nonviral nucleic acid delivery technologies to treat prenatal diseases.

In order to identify potential nonviral delivery systems for therapeutic mRNA, the researchers engineered a library of lipid nanoparticles, small particles less than 100 nanometers in size that effectively enter cells in mouse fetal recipients. Each lipid nanoparticle formulation was used to encapsulate mRNA, which was administered to mouse fetuses. The researchers found that several of the lipid nanoparticles enabled functional mRNA delivery to fetal livers and that some of those lipid nanoparticles also delivered mRNA to the fetal lungs and intestines. They also assessed the lipid nanoparticles for toxicity and found them to be as safe or safer than existing formulations.

Having identified the lipid nanoparticles that were able to accumulate within fetal livers, lungs, and intestines with the highest efficiency and safety, the researchers also tested therapeutic potential of those designs by using them to deliver erythropoietin (EPO) mRNA, as the EPO protein is easily trackable. They found that EPO mRNA delivery to liver cells in mouse fetuses resulted in elevated levels of EPO protein in the fetal circulation, providing a model for protein replacement therapy via the liver using these lipid nanoparticles.

“A central challenge in the field of gene therapy is the delivery of nucleic acids to target cells and tissues, without causing side effects in healthy tissue. This is difficult to achieve in adult animals and humans, which have been studied extensively. Much less is known in terms of what is required to achieve in utero nucleic acid delivery,” said Mitchell. “We are very excited by the initial results of our lipid nanoparticle technology to deliver mRNA in utero in safe and effective manner, which could open new avenues for lipid nanoparticles and mRNA therapeutics to treat diseases before birth.”

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

Ionizable lipid nanoparticles for in utero mRNA delivery by Rachel S. Riley, Meghana V. Kashyap, Margaret M. Billingsley, Brandon White, Mohamad-Gabriel Alameh, Sourav K. Bose, Philip W. Zoltick, Hiaying Li, Rui Zhang, Andrew Y. Cheng, Drew Weissman, William H. Peranteau, Michael J. Mitchell. Science Advances 13 Jan 2021: Vol. 7, no. 3, eaba1028 DOI: 10.1126/sciadv.aba1028

This paper appears to be open access. BTW, I noticed Drew Weissman’s name as one of the paper’s authors and remembered him as one of the first to recognize Karikó’s pioneering work. I imagine that when he co-authored papers with Karikó he was risking his reputation.

Funny how a despised field of research has sparked a ‘gold rush’ for research and for riches, yes?.

7th annual Vancouver Nanomedicine Day, Sept. 17, 2020

Like so many events these days (COVID-19 days), this event put on by Canada’s NanoMedicines Innovation Network (NMIN) will be held virtually. Here’s more from the ‘Virtual’ Vancouver Nanomedicine Day 2020 event page on the NMIN website,

This world-class symposium, the sixth event of its kind, will bring together a record number (1000+) of renowned Canadian and international experts from across the nanomedicines field to:

  • highlight the discoveries and innovations in nanomedicines that are contributing to global progress in acute, chronic and orphan disease treatment and management;
  • present up-to-date diagnostic and therapeutic  nanomedicine approaches to addressing the challenges of COVID-19; and
  • facilitate discussion among nanomedicine researchers and innovators and UBC and NMIN clinician-scientists, basic researchers, trainees, and research partners.

Since 2014, Vancouver Nanomedicine Day has advanced nanomedicine research, knowledge mobilization and commercialization in Canada by sharing high-impact findings and facilitating interaction—among researchers, postdoctoral fellows, graduate students, and life science and startup biotechnology companies—to catalyze research collaboration.

Here are a few highlights from the ‘Virtual’ Vancouver Nanomedicine Day 2020 event page,

  • An introduction to nanomedicines by Dr. Emmanuel Ho (University of Waterloo)
  • A keynote address by an iconic nanomedicine innovator: Dr. Robert Langer (MIT, Department of Chemical Engineering)
  • Invited talks by internationally renowned experts, including Dr. Vito Foderà (The University of Copenhagen, Denmark); Dr. Lucia Gemma Delogu (University of Padova, Italy); and Dr. Christine Allen (University of Toronto)
  • A virtual poster competition, with cash prizes for the top posters
  • A debate on whether “nanomedicines are still the next big thing” between Marcel Bally (proponent) and Kishor Wasan (opponent)

You can get the Program in PDF.

Registration is free. But you must Register.

Here’s the event poster,

[downloaded from https://www.nanomedicines.ca/nmd-2020/]

I have a few observations, First, Robert Langer is a big deal. Here are a few highlights from his Wikipedia entry (Note: Links have been removed),

Robert Samuel Langer, Jr. FREng[2] (born August 29, 1948) is an American chemical engineer, scientist, entrepreneur, inventor and one of the twelve Institute Professors at the Massachusetts Institute of Technology.[3]

Langer holds over 1,350 granted or pending patents.[3][29] He is one of the world’s most highly cited researchers, having authored nearly 1,500 scientific papers, and has participated in the founding of multiple technology companies.[30][31]

Langer is the youngest person in history (at 43) to be elected to all three American science academies: the National Academy of Sciences, the National Academy of Engineering and the Institute of Medicine. He was also elected as a charter member of National Academy of Inventors.[32] He was elected as an International Fellow[2] of the Royal Academy of Engineering[2] in 2010.

It’s all about commercializing the research—or is it?

(This second observation is a little more complicated and requires a little context.) The NMIN is one of Canada’s Networks of Centres of Excellence (who thought that name up? …sigh), from the NMIN About page,

NMIN is funded by the Government of Canada through the Networks of Centres of Excellence (NCE) Program.

The NCEs seem to be firmly fixed on finding pathways to commercialization (from the NCE About page) Note: All is not as it seems,

Canada’s global economic competitiveness [emphasis mine] depends on making new discoveries and transforming them into products, services [emphasis mine] and processes that improve the lives of Canadians. To meet this challenge, the Networks of Centres of Excellence (NCE) offers a suite of programs that mobilize Canada’s best research, development and entrepreneurial [emphasis mine] expertise and focus it on specific issues and strategic areas.

NCE programs meet Canada’s needs to focus a critical mass of research resources on social and economic challenges, commercialize [emphasis mine] and apply more of its homegrown research breakthroughs, increase private-sector R&D, [emphasis mine] and train highly qualified people. As economic [emphasis mine] and social needs change, programs have evolved to address new challenges.

Interestingly, the NCE is being phased out,

As per the December 2018 NCE Program news, funding for the Networks of Centres of Excellence (NCE) Program will be gradually transferred to the New Frontiers in Research Fund (NFRF).

The new agency, NFRF, appears to have a completely different mandate, from the NFRF page on the Canada Research Coordinating Committee webspace,

The Canada Research Coordinating Committee designed the New Frontiers in Research Fund (NFRF) following a comprehensive national consultation, which involved Canadian researchers, research administrators, stakeholders and the public. NFRF is administered by the Tri-agency Institutional Programs Secretariat, which is housed within the Social Sciences and Humanities Research Council (SSHRC), on behalf of Canada’s three research granting agencies: the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council and SSHRC.

The fund will invest $275 million over the next 5 years beginning in fiscal 2018-19, and $65 million ongoing, to fund international, interdisciplinary, fast-breaking and high-risk research.

NFRF is composed of three streams to support groundbreaking research.

  • Exploration generates opportunities for Canada to build strength in high-risk, high-reward and interdisciplinary research;
  • Transformation provides large-scale support for Canada to build strength and leadership in interdisciplinary and transformative research; and
  • International enhances opportunities for Canadian researchers to participate in research with international partners.

As you can see there’s no reference to commercialization or economic challenges.

Personally

Here at last is the second observation, I find it hard to believe that the government of Canada has given up on the idea of commercializing research and increasing the country’s economic competitiveness through research. Certainly, Langer’s virtual appearance at Vancouver Nanomedicine Day 2020, suggests that at least some corners of the Canadian research establishment are remaining staunchly entrepreneurial.

After all, the only Canadian government ministry with science in its name is this one: Innovation, Science and Economic Development Canada (ISED), as of Sept. 11, 2020.. (The other ‘science’ ministries are Natural Resources Canada, Environment and Climate Change Canada, Fisheries and Oceans Canada, Health Canada, and Agriculture and Agri-Food Canada.) ISED is not exactly subtle. Intriguingly the latest review on the state of science and technology in Canada was released on April 10, 2018 (from the April 10, 2018 Council of Canadian Academies CCA] news release),

Canada remains strong in research output and impact, capacity for R&D and innovation at risk: New expert panel report

While Canada is a highly innovative country, with a robust research base and thriving communities of technology start-ups, significant barriers—such as a lack of managerial skills, the experience needed to scale-up companies, and foreign acquisition of high-tech firms—often prevent the translation of innovation into wealth creation.[emphasis mine] The result is a deficit of technology companies growing to scale in Canada, and a loss of associated economic and social benefits.This risks establishing a vicious cycle, where successful companies seek growth opportunities elsewhere due to a lack of critical skills and experience in Canada guiding companies through periods of rapid expansion.

According to the CCA’s [2018 report] Summary webpage, it was Innovation, Science and Economic Development Canada which requested the report. (I wrote up a two-part commentary under one of my favourite titles: “The Hedy Lamarr of international research: Canada’s Third assessment of The State of Science and Technology and Industrial Research and Development in Canada.” Part 1 and Part 2)

I will be fascinated to watch the NFRF and science commercialization situations as they develop.

In the meantime, you can sign up for free to attend the ‘Virtual’ Vancouver Nanomedicine Day 2020.

Editing the genome with CRISPR ((clustered regularly interspaced short palindromic repeats)-carrying nanoparticles

MIT (Massachusetts Institute of Technology) researchers have developed a new nonviral means of delivering CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene therapy according to a November 13, 2017 news item on Nanowerk,

In a new study, MIT researchers have developed nanoparticles that can deliver the CRISPR genome-editing system and specifically modify genes in mice. The team used nanoparticles to carry the CRISPR components, eliminating the need to use viruses for delivery.

Using the new delivery technique, the researchers were able to cut out certain genes in about 80 percent of liver cells, the best success rate ever achieved with CRISPR in adult animals.

In a new study, MIT researchers have developed nanoparticles that can deliver the CRISPR genome-editing system and specifically modify genes, eliminating the need to use viruses for delivery. Image: MIT News

A November 13, 2017 MIT news release (also on EurekAlert), which originated the news item, provides more details about the research and a good description of and comparison between using a viral system and using a nanoparticle-based system to deliver CRISPR-CAS9,

“What’s really exciting here is that we’ve shown you can make a nanoparticle that can be used to permanently and specifically edit the DNA in the liver of an adult animal,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

One of the genes targeted in this study, known as Pcsk9, regulates cholesterol levels. Mutations in the human version of the gene are associated with a rare disorder called dominant familial hypercholesterolemia, and the FDA recently approved two antibody drugs that inhibit Pcsk9. However these antibodies need to be taken regularly, and for the rest of the patient’s life, to provide therapy. The new nanoparticles permanently edit the gene following a single treatment, and the technique also offers promise for treating other liver disorders, according to the MIT team.

Anderson is the senior author of the study, which appears in the Nov. 13 [2017] issue of Nature Biotechnology. The paper’s lead author is Koch Institute research scientist Hao Yin. Other authors include David H. Koch Institute Professor Robert Langer of MIT, professors Victor Koteliansky and Timofei Zatsepin of the Skolkovo Institute of Science and Technology [Russia], and Professor Wen Xue of the University of Massachusetts Medical School.

Targeting disease

Many scientists are trying to develop safe and efficient ways to deliver the components needed for CRISPR, which consists of a DNA-cutting enzyme called Cas9 and a short RNA that guides the enzyme to a specific area of the genome, directing Cas9 where to make its cut.

In most cases, researchers rely on viruses to carry the gene for Cas9, as well as the RNA guide strand. In 2014, Anderson, Yin, and their colleagues developed a nonviral delivery system in the first-ever demonstration of curing a disease (the liver disorder tyrosinemia) with CRISPR in an adult animal. However, this type of delivery requires a high-pressure injection, a method that can also cause some damage to the liver.

Later, the researchers showed they could deliver the components without the high-pressure injection by packaging messenger RNA (mRNA) encoding Cas9 into a nanoparticle instead of a virus. Using this approach, in which the guide RNA was still delivered by a virus, the researchers were able to edit the target gene in about 6 percent of hepatocytes, which is enough to treat tyrosinemia.

While that delivery technique holds promise, in some situations it would be better to have a completely nonviral delivery system, Anderson says. One consideration is that once a particular virus is used, the patient will develop antibodies to it, so it couldn’t be used again. Also, some patients have pre-existing antibodies to the viruses being tested as CRISPR delivery vehicles.

In the new Nature Biotechnology paper, the researchers came up with a system that delivers both Cas9 and the RNA guide using nanoparticles, with no need for viruses. To deliver the guide RNAs, they first had to chemically modify the RNA to protect it from enzymes in the body that would normally break it down before it could reach its destination.

The researchers analyzed the structure of the complex formed by Cas9 and the RNA guide, or sgRNA, to figure out which sections of the guide RNA strand could be chemically modified without interfering with the binding of the two molecules. Based on this analysis, they created and tested many possible combinations of modifications.

“We used the structure of the Cas9 and sgRNA complex as a guide and did tests to figure out we can modify as much as 70 percent of the guide RNA,” Yin says. “We could heavily modify it and not affect the binding of sgRNA and Cas9, and this enhanced modification really enhances activity.”

Reprogramming the liver

The researchers packaged these modified RNA guides (which they call enhanced sgRNA) into lipid nanoparticles, which they had previously used to deliver other types of RNA to the liver, and injected them into mice along with nanoparticles containing mRNA that encodes Cas9.

They experimented with knocking out a few different genes expressed by hepatocytes, but focused most of their attention on the cholesterol-regulating Pcsk9 gene. The researchers were able to eliminate this gene in more than 80 percent of liver cells, and the Pcsk9 protein was undetectable in these mice. They also found a 35 percent drop in the total cholesterol levels of the treated mice.

The researchers are now working on identifying other liver diseases that might benefit from this approach, and advancing these approaches toward use in patients.

“I think having a fully synthetic nanoparticle that can specifically turn genes off could be a powerful tool not just for Pcsk9 but for other diseases as well,” Anderson says. “The liver is a really important organ and also is a source of disease for many people. If you can reprogram the DNA of your liver while you’re still using it, we think there are many diseases that could be addressed.”

“We are very excited to see this new application of nanotechnology open new avenues for gene editing,” Langer adds.

The research was funded by the National Institutes of Health (NIH), the Russian Scientific Fund, the Skoltech Center, and the Koch Institute Support (core) Grant from the National Cancer Institute.

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

Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing by Hao Yin, Chun-Qing Song, Sneha Suresh, Qiongqiong Wu, Stephen Walsh, Luke Hyunsik Rhym, Esther Mintzer, Mehmet Fatih Bolukbasi, Lihua Julie Zhu, Kevin Kauffman, Haiwei Mou, Alicia Oberholzer, Junmei Ding, Suet-Yan Kwan, Roman L Bogorad, Timofei Zatsepin, Victor Koteliansky, Scot A Wolfe, Wen Xue, Robert Langer, & Daniel G Anderson. Nature Biotechnology doi:10.1038/nbt.4005 Published online: 13 November 2017

This paper is behind a paywall.

Science innovation (nanomedicine) can be tough

Robert Langer is a well known researcher in the field of nanomedicine. Weirdly not included in a listing of prominent nanoscientists in a series by Slate.com writers (my Oct. 7, 2016 posting), it seems the English are making up for this oversight. Amy Fleming in an Oct. 17, 2016 article for the Guardian tells Langer’s story in the context of his recent award of the £1m Queen Elizabeth prize for engineering (Note: Links have been removed),

Robert Langer seems incredibly well adjusted for a man with transatlantic jetlag. And, for that matter, for someone who struggled for years to get his pioneering work in drug delivery accepted by the scientific establishment. As a young professor, his first nine research grant applications were turned down. Once, at a formal dinner in the early 80s, a senior colleague blew smoke in his eyes and told him to find another job.

And yet here he is, a good-natured nanotechnology trailblazer, swooping into the UK for duties associated with having won the £1m Queen Elizabeth prize for engineering. His work has improved the lives of 2 billion people and counting. He has collected awards from two US presidents, as well as the Queen. He has more than 1,000 patents on the go, and 30 companies have spun out from his vast lab at Massachusetts Institute of Technology (the largest biomedical lab in the world). At 68, he is still the future.

… the huge range of his research interests. There’s contraceptive microchip implants; a gel to repair damaged vocal cords; spinal cord repair tissue; an invisible “second skin” for conditions such as eczema (with the cosmetic side effect of rendering skin smooth and elastic); cutting-edge anti-frizz haircare; and what Langer calls “super-long-acting capsules or pills, that would last a week, a month, or even a year”. …

Fleming describes some of Langer’s innovations in more detail (Note: Links have been removed),

Commonly, when pharmaceuticals enter the body, they are coated in synthetic substances called polymers. These allow effective amounts of the drug to reach the body, slowly enough so as not to cause toxicity. Until Langer came along, this controlled method only worked for simpler, small-molecule drugs. Sophisticated large-molecule drugs, that can target diseases such as cancer, diabetes and mental illness, were too big to pass through polymers. “People wouldn’t think you could walk through a wall either,” he says. “But we built all these tortuous channels in what was the equivalent of the wall so somebody could get through, but they get through very slowly, like driving through London in rush hour.”

Langer also designed biologically tolerable polymer pellets – nanopellets, he calls them – that enable drugs to be implanted directly into cancer tumours. This enabled Langer and the cancer researcher Judah Folkman to isolate the first vascular inhibitors, which stop new blood vessels feeding tumours. “We thought it could be a new way of treating cancer,” Langer says, “and it’s become that. Drugs such as Avastin [bevacizumab] and Eylea [aflibercept] are based, in part, on our early research.” He also created new polymers that could dissolve like a bar of soap and release drugs in a very controlled way over months to years. And he and neurosurgeon Henry Brem developed implants (called gliadel wafers) that could be implanted in the brain to treat brain cancer. Trials in 1996 saw a 63% survival rate against just 19% in the control group.

If you have the time, it’s well worth reading Fleming’s article in its entirety.

Tightening the skin (and protecting it and removing wrinkles, temporarily)

“It’s an invisible layer that can provide a barrier, provide cosmetic improvement, and potentially deliver a drug locally to the area that’s being treated. Those three things together could really make it ideal for use in humans,” Daniel Anderson says. Photo: Melanie Gonick/MIT

“It’s an invisible layer that can provide a barrier, provide cosmetic improvement, and potentially deliver a drug locally to the area that’s being treated. Those three things together could really make it ideal for use in humans,” Daniel Anderson says. Photo: Melanie Gonick/MIT

It almost looks like he’s peeling off his own skin and I imagine that’s the secret to this polymer’s success. A May 9, 2016 news item on phys.org describes the work being done at the Massachusetts Institute of Technology (MIT) and elsewhere with collaborators,

Scientists at MIT, Massachusetts General Hospital, Living Proof, and Olivo Labs have developed a new material that can temporarily protect and tighten skin, and smooth wrinkles. With further development, it could also be used to deliver drugs to help treat skin conditions such as eczema and other types of dermatitis.

A May 9, 2016 MIT news release (also on EurekAlert), which originated the news item, provides more detail,

The material, a silicone-based polymer that could be applied on the skin as a thin, imperceptible coating, mimics the mechanical and elastic properties of healthy, youthful skin. In tests with human subjects, the researchers found that the material was able to reshape “eye bags” under the lower eyelids and also enhance skin hydration. This type of “second skin” could also be adapted to provide long-lasting ultraviolet protection, the researchers say.

“It’s an invisible layer that can provide a barrier, provide cosmetic improvement, and potentially deliver a drug locally to the area that’s being treated. Those three things together could really make it ideal for use in humans,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

Anderson is one of the authors of a paper describing the polymer in the May 9 online issue of Nature Materials. Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, is the paper’s senior author, and the paper’s lead author is Betty Yu SM ’98, ScD ’02, former vice president at Living Proof. Langer and Anderson are co-founders of Living Proof and Olivo Labs, and Yu earned her master’s and doctorate at MIT.

Mimicking skin

As skin ages, it becomes less firm and less elastic — problems that can be exacerbated by sun exposure. This impairs skin’s ability to protect against extreme temperatures, toxins, microorganisms, radiation, and injury. About 10 years ago, the research team set out to develop a protective coating that could restore the properties of healthy skin, for both medical and cosmetic applications.

“We started thinking about how we might be able to control the properties of skin by coating it with polymers that would impart beneficial effects,” Anderson says. “We also wanted it to be invisible and comfortable.”

The researchers created a library of more than 100 possible polymers, all of which contained a chemical structure known as siloxane — a chain of alternating atoms of silicon and oxygen. These polymers can be assembled into a network arrangement known as a cross-linked polymer layer (XPL). The researchers then tested the materials in search of one that would best mimic the appearance, strength, and elasticity of healthy skin.

“It has to have the right optical properties, otherwise it won’t look good, and it has to have the right mechanical properties, otherwise it won’t have the right strength and it won’t perform correctly,” Langer says.

The best-performing material has elastic properties very similar to those of skin. In laboratory tests, it easily returned to its original state after being stretched more than 250 percent (natural skin can be elongated about 180 percent). In laboratory tests, the novel XPL’s elasticity was much better than that of two other types of wound dressings now used on skin — silicone gel sheets and polyurethane films.

“Creating a material that behaves like skin is very difficult,” says Barbara Gilchrest, a dermatologist at MGH and an author of the paper. “Many people have tried to do this, and the materials that have been available up until this have not had the properties of being flexible, comfortable, nonirritating, and able to conform to the movement of the skin and return to its original shape.”

The XPL is currently delivered in a two-step process. First, polysiloxane components are applied to the skin, followed by a platinum catalyst that induces the polymer to form a strong cross-linked film that remains on the skin for up to 24 hours. This catalyst has to be added after the polymer is applied because after this step the material becomes too stiff to spread. Both layers are applied as creams or ointments, and once spread onto the skin, XPL becomes essentially invisible.

High performance

The researchers performed several studies in humans to test the material’s safety and effectiveness. In one study, the XPL was applied to the under-eye area where “eye bags” often form as skin ages. These eye bags are caused by protrusion of the fat pad underlying the skin of the lower lid. When the material was applied, it applied a steady compressive force that tightened the skin, an effect that lasted for about 24 hours.

In another study, the XPL was applied to forearm skin to test its elasticity. When the XPL-treated skin was distended with a suction cup, it returned to its original position faster than untreated skin.

The researchers also tested the material’s ability to prevent water loss from dry skin. Two hours after application, skin treated with the novel XPL suffered much less water loss than skin treated with a high-end commercial moisturizer. Skin coated with petrolatum was as effective as XPL in tests done two hours after treatment, but after 24 hours, skin treated with XPL had retained much more water. None of the study participants reported any irritation from wearing XPL.

“I think it has great potential for both cosmetic and noncosmetic applications, especially if you could incorporate antimicrobial agents or medications,” says Thahn Nga Tran, a dermatologist and instructor at Harvard Medical School, who was not involved in the research.

Living Proof has spun out the XPL technology to Olivo Laboratories, LLC, a new startup formed to focus on the further development of the XPL technology. Initially, Olivo’s team will focus on medical applications of the technology for treating skin conditions such as dermatitis.

 

This video supplied by MIT shows how to apply the polymer and offers a description and demonstration of its properties once applied,

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

An elastic second skin by Betty Yu, Soo-Young Kang, Ariya Akthakul, Nithin Ramadurai, Morgan Pilkenton, Alpesh Patel, Amir Nashat, Daniel G. Anderson, Fernanda H. Sakamoto, Barbara A. Gilchrest, R. Rox Anderson & Robert Langer. Nature Materials (2016) doi:10.1038/nmat4635 Published online 09 May 2016

This paper is behind a paywall.

One final comment, I wonder who’s lining up to invest in this product.

Nanomaterials and UV (ultraviolet) light for environmental cleanups

I think this is the first time I’ve seen anything about a technology that removes toxic materials from both water and soil; it’s usually one or the other. A July 22, 2015 news item on Nanowerk makes the announcement (Note: A link has been removed),

Many human-made pollutants in the environment resist degradation through natural processes, and disrupt hormonal and other systems in mammals and other animals. Removing these toxic materials — which include pesticides and endocrine disruptors such as bisphenol A (BPA) — with existing methods is often expensive and time-consuming.

In a new paper published this week in Nature Communications (“Nanoparticles with photoinduced precipitation for the extraction of pollutants from water and soil”), researchers from MIT [Massachusetts Institute of Technology] and the Federal University of Goiás in Brazil demonstrate a novel method for using nanoparticles and ultraviolet (UV) light to quickly isolate and extract a variety of contaminants from soil and water.

A July 21, 2015 MIT news release by Jonathan Mingle, which originated the news item, describes the inspiration and the research in more detail,

Ferdinand Brandl and Nicolas Bertrand, the two lead authors, are former postdocs in the laboratory of Robert Langer, the David H. Koch Institute Professor at MIT’s Koch Institute for Integrative Cancer Research. (Eliana Martins Lima, of the Federal University of Goiás, is the other co-author.) Both Brandl and Bertrand are trained as pharmacists, and describe their discovery as a happy accident: They initially sought to develop nanoparticles that could be used to deliver drugs to cancer cells.

Brandl had previously synthesized polymers that could be cleaved apart by exposure to UV light. But he and Bertrand came to question their suitability for drug delivery, since UV light can be damaging to tissue and cells, and doesn’t penetrate through the skin. When they learned that UV light was used to disinfect water in certain treatment plants, they began to ask a different question.

“We thought if they are already using UV light, maybe they could use our particles as well,” Brandl says. “Then we came up with the idea to use our particles to remove toxic chemicals, pollutants, or hormones from water, because we saw that the particles aggregate once you irradiate them with UV light.”

A trap for ‘water-fearing’ pollution

The researchers synthesized polymers from polyethylene glycol, a widely used compound found in laxatives, toothpaste, and eye drops and approved by the Food and Drug Administration as a food additive, and polylactic acid, a biodegradable plastic used in compostable cups and glassware.

Nanoparticles made from these polymers have a hydrophobic core and a hydrophilic shell. Due to molecular-scale forces, in a solution hydrophobic pollutant molecules move toward the hydrophobic nanoparticles, and adsorb onto their surface, where they effectively become “trapped.” This same phenomenon is at work when spaghetti sauce stains the surface of plastic containers, turning them red: In that case, both the plastic and the oil-based sauce are hydrophobic and interact together.

If left alone, these nanomaterials would remain suspended and dispersed evenly in water. But when exposed to UV light, the stabilizing outer shell of the particles is shed, and — now “enriched” by the pollutants — they form larger aggregates that can then be removed through filtration, sedimentation, or other methods.

The researchers used the method to extract phthalates, hormone-disrupting chemicals used to soften plastics, from wastewater; BPA, another endocrine-disrupting synthetic compound widely used in plastic bottles and other resinous consumer goods, from thermal printing paper samples; and polycyclic aromatic hydrocarbons, carcinogenic compounds formed from incomplete combustion of fuels, from contaminated soil.

The process is irreversible and the polymers are biodegradable, minimizing the risks of leaving toxic secondary products to persist in, say, a body of water. “Once they switch to this macro situation where they’re big clumps,” Bertrand says, “you won’t be able to bring them back to the nano state again.”

The fundamental breakthrough, according to the researchers, was confirming that small molecules do indeed adsorb passively onto the surface of nanoparticles.

“To the best of our knowledge, it is the first time that the interactions of small molecules with pre-formed nanoparticles can be directly measured,” they write in Nature Communications.

Nano cleansing

Even more exciting, they say, is the wide range of potential uses, from environmental remediation to medical analysis.

The polymers are synthesized at room temperature, and don’t need to be specially prepared to target specific compounds; they are broadly applicable to all kinds of hydrophobic chemicals and molecules.

“The interactions we exploit to remove the pollutants are non-specific,” Brandl says. “We can remove hormones, BPA, and pesticides that are all present in the same sample, and we can do this in one step.”

And the nanoparticles’ high surface-area-to-volume ratio means that only a small amount is needed to remove a relatively large quantity of pollutants. The technique could thus offer potential for the cost-effective cleanup of contaminated water and soil on a wider scale.

“From the applied perspective, we showed in a system that the adsorption of small molecules on the surface of the nanoparticles can be used for extraction of any kind,” Bertrand says. “It opens the door for many other applications down the line.”

This approach could possibly be further developed, he speculates, to replace the widespread use of organic solvents for everything from decaffeinating coffee to making paint thinners. Bertrand cites DDT, banned for use as a pesticide in the U.S. since 1972 but still widely used in other parts of the world, as another example of a persistent pollutant that could potentially be remediated using these nanomaterials. “And for analytical applications where you don’t need as much volume to purify or concentrate, this might be interesting,” Bertrand says, offering the example of a cheap testing kit for urine analysis of medical patients.

The study also suggests the broader potential for adapting nanoscale drug-delivery techniques developed for use in environmental remediation.

“That we can apply some of the highly sophisticated, high-precision tools developed for the pharmaceutical industry, and now look at the use of these technologies in broader terms, is phenomenal,” says Frank Gu, an assistant professor of chemical engineering at the University of Waterloo in Canada, and an expert in nanoengineering for health care and medical applications.

“When you think about field deployment, that’s far down the road, but this paper offers a really exciting opportunity to crack a problem that is persistently present,” says Gu, who was not involved in the research. “If you take the normal conventional civil engineering or chemical engineering approach to treating it, it just won’t touch it. That’s where the most exciting part is.”

The researchers have made this illustration of their work available,

Nanoparticles that lose their stability upon irradiation with light have been designed to extract endocrine disruptors, pesticides, and other contaminants from water and soils. The system exploits the large surface-to-volume ratio of nanoparticles, while the photoinduced precipitation ensures nanomaterials are not released in the environment. Image: Nicolas Bertrand Courtesy: MIT

Nanoparticles that lose their stability upon irradiation with light have been designed to extract endocrine disruptors, pesticides, and other contaminants from water and soils. The system exploits the large surface-to-volume ratio of nanoparticles, while the photoinduced precipitation ensures nanomaterials are not released in the environment.
Image: Nicolas Bertrand Courtesy: MIT

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

Nanoparticles with photoinduced precipitation for the extraction of pollutants from water and soil by Ferdinand Brandl, Nicolas Bertrand, Eliana Martins Lima & Robert Langer. Nature Communications 6, Article number: 7765 doi:10.1038/ncomms8765 Published 21 July 2015

This paper is open access.

Inspired by babies, scientists consider* popping nanoparticle pills and downing nanoparticle potions

Given the choice over injections or suppositories most of us will choose to take medication orally (pills or liquids). It may be a surprise to some but with all the talk about nanomedicine there has been a problem with using nanoparticles in an oral delivery system which scientists at the Brigham and Women’s Hospital (BWH) and Massachusetts Institute of Technology (MIT) have solved. From a Nov. 27, 2013 BWH news release, on EurekAlert,

… a study led by researchers at Brigham and Women’s Hospital (BWH) and Massachusetts Institute of Technology (MIT) is the first to report in the field of nanomedicine a new type of nanoparticle that can be successfully absorbed through the digestive tract. The findings may one day allow patients to simply take a pill instead of receiving injections.

Until recently, after being injected into the body, nanoparticles travelled to their destination, such as a tumor, by seeping through leaky vessels. The research team, led by Farokhzad [Omid Farokhzad, MD, director of the BWH Laboratory of Nanomedicine and Biomaterials, senior study author] and Robert Langer, ScD of MIT, developed nanoparticles that could reach the target site without relying on injection nor leaky vessels.

For nanoparticles to be taken orally they need to cross the intestinal lining. This lining is composed of a layer of epithelial cells joined together to form impenetrable barriers called tight junctions. To ensure that the nanoparticles could cross these barriers, the researchers took a cue from research on how babies absorb antibodies from their mothers’ milk. The antibodies would grab onto a receptor, known as neonatal Fc receptors, found on the cell surface. This gave them access across the cells of the intestinal lining into neighboring blood vessels.

Based on this knowledge, the researchers decorated nanoparticles with Fc proteins that targeted and bound to these receptors, which are also found in adult intestinal cells. After attaching to the receptors, the Fc-protein-decorated nanoparticles—toting their drug payload—are all absorbed into the intestinal lining and into the bloodstream at a high concentration.

According to the researchers, these receptors can be used to transport nanoparticles carrying different kinds of drugs and other materials—a feat that combines a versatile vehicle and an easily accessible passageway across cellular barriers.

To demonstrate how transport of Fc-targeted nanoparticles could impact the clinical space, the researchers focused on a diabetes treatment scenario, showing how oral delivery of insulin via these targeted nanoparticles could alter blood sugar levels in mice.

Insulin carried in nanoparticles decorated with Fc proteins reached the bloodstream more efficiently than those without the proteins. Moreover, the amount of insulin delivered was large enough to lower the mice’s blood sugar levels. Aside from insulin, the researchers note that the nanoparticles can be used to carry any kind of drug to treat many diseases.

“Being able to deliver nanomedicine orally would offer clinicians broad and novel ways to treat today’s many chronic diseases that require daily therapy, such as diabetes and cancer,” said Langer. “Imagine being able to take RNA or proteins orally; that would be paradigm shift.”

In terms of next steps, the researchers are working to enhance the nanoparticles’ drug-releasing abilities to prepare for future pre-clinical testing with insulin and other drugs. They also plan to design nanoparticles that can cross other barriers, such as the blood-brain barrier, which prevents many drugs from reaching the brain.

The Nov. 27, 2013 MIT news release by Anne Trafton on EurekAlert provides additional insight into the difficulties of getting nanoparticles past our digestive tracts (this is a bit repetitive but there’s enough new detail to make it worth my while to include it here),,

Several types of nanoparticles carrying chemotherapy drugs or short interfering RNA, which can turn off selected genes, are now in clinical trials to treat cancer and other diseases. These particles exploit the fact that tumors and other diseased tissues are surrounded by leaky blood vessels. After the particles are intravenously injected into patients, they seep through those leaky vessels and release their payload at the tumor site.

For nanoparticles to be taken orally, they need to be able to get through the intestinal lining, which is made of a layer of epithelial cells that join together to form impenetrable barriers called tight junctions.

“The key challenge is how to make a nanoparticle get through this barrier of cells. Whenever cells want to form a barrier, they make these attachments from cell to cell, analogous to a brick wall where the bricks are the cells and the mortar is the attachments, and nothing can penetrate that wall,” Farokhzad says.

Researchers have previously tried to break through this wall by temporarily disrupting the tight junctions, allowing drugs through. However, this approach can have unwanted side effects because when the barriers are broken, harmful bacteria can also get through.

To build nanoparticles that can selectively break through the barrier, the researchers took advantage of previous work that revealed how babies absorb antibodies from their mothers’ milk, boosting their own immune defenses. Those antibodies grab onto a cell surface receptor called the FcRN, granting them access through the cells of the intestinal lining into adjacent blood vessels.

The researchers coated their nanoparticles with Fc proteins — the part of the antibody that binds to the FcRN receptor, which is also found in adult intestinal cells. The nanoparticles, made of a biocompatible polymer called PLA-PEG, can carry a large drug payload, such as insulin, in their core.

After the particles are ingested, the Fc proteins grab on to the FcRN in the intestinal lining and gain entry, bringing the entire nanoparticle along with them.

“It illustrates a very general concept where we can use these receptors to traffic nanoparticles that could contain pretty much anything. Any molecule that has difficulty crossing the barrier could be loaded in the nanoparticle and trafficked across,” Karnik [Rohit Karnik, an MIT associate professor of mechanical engineering] says.

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

Transepithelial Transport of Fc-Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery by Eric M. Pridgen, Frank Alexis, Timothy T. Kuo, Etgar Levy-Nissenbaum, Rohit Karnik, Richard S. Blumberg, Robert Langer, and Omid C. Farokhzad.
Sci Transl Med 27 November 2013: Vol. 5, Issue 213, p. 213ra167 DOI: 10.1126/scitranslmed.3007049

This article is behind a paywall.

*  ‘consdier’ corrected to ‘consider’ on June 5, 2014.

Russia’s nanotechnology efforts falter?

The title for Leonid Bershidksy’s May 16, 2013 Bloomberg.com article, Power Grab Trumps Nanotechnology in Putin’s Russia, casts an ominous shadow over Rusnano’s situation (Note: Links have been removed),

The projects, known as Rusnano and Skolkovo, were meant to propel Russia’s raw-material economy into the technology age. They involved multibillion-dollar government investments, the first in nanotechnology and the second in a new city that would become Russia’s answer to Silicon Valley. They were supposed to provide the infrastructure and stability required to attract large amounts of foreign investment.

Now, both have become targets in Putin’s campaign to demonstrate that he’s being tough on corruption and mismanagement of government funds. As a result, their chances of succeeding are looking increasingly remote.

Trouble came in April [2013], when the Accounting Chamber, a body charged with auditing government spending, accused Rusnano of inefficient management in a report that received ample coverage on state-owned TV. It said that Rusnano had transferred about $40 million to shell companies and pointed out that a silicon factory in which Rusnano invested about $450 million was not functioning and was about to be declared insolvent. The report also highlighted the state company’s 2012 losses of 2.5 billion rubles ($80 million) and the 24.4-billion-ruble (about $800 million) in reserves Rusnano had formed against potential losses from risky ventures.

Anatoly Medetsky’s Apr. 29, 2013 article for The Moscow Times provides more insight into the situation,

The government’s Audit Chamber on Friday [April 26, 2013] accused state-owned Rusnano of multiple infractions in a blow to the high-tech corporation’s chief, Anatoly Chubais.

The chamber’s critical conclusions followed President Vladimir Putin’s reproof of the company during a live call-in show the previous day.

Auditors made their statement after examining Rusnano’s records in response to a request by Chubais’ political nemesis, the Communist Party.

“The audit’s materials attest that Rusnano’s performance was inappropriate to attain the goals that it was entrusted with, which are the development of the national nano industry,” the Audit Chamber said in a statement.

Auditor Sergei Agaptsov said separately that Rusnano is unlikely to achieve the goal of 300 billion rubles in annual sales of nano-tech products by the companies it co-owns in 2015 — the target that the government set for the company, Interfax reported.

I’m sorry to read about Rusnano’s difficulties especially in light my first piece about it where I compared the Canadian effort unfavourably to, what was then, a relatively new and promising organization in my Apr. 14, 2009 posting. About seventeen months later, officials with Rusnano signed a memorandum of understanding with John Varghese, CEO and Managing Partner of Toronto based venture capital firm, VentureLink Funds as noted in my Sept. 14, 2010 posting. Nothing further seemed to come of that agreement.

I have one last thought about Rusnano’s current travails, will they have an impact on US commercialization efforts? In my Oct. 28, 2011 posting where I was contrasting nanotechnology commercialization efforts by the US, Spain, and Rusnano, I mentioned this deal Rusnano had made with two US nanomedicine companies,

Then RUSNANO announced its investments in Selecta Biosciences and BIND Biosiences, from the Oct. 27, 2011 news item on Nanowerk,

BIND Biosciences and Selecta Biosciences, two leading nanomedicine companies, announced today that they have entered into investment agreements with RUSNANO, a $10-billion Russian Federation fund that supports high-tech and nanotechnology advances. [emphasis mine]

RUSNANO is co-investing $25 million in BIND and $25 million in Selecta, for a total RUSNANO investment of $50 million within the total financing rounds of $94.5 million in the two companies combined. …

The proprietary technology platforms of BIND and Selecta originated in laboratories at Harvard Medical School directed by Professor Omid Farokhzad, MD, and in laboratories at MIT directed by Professor Robert Langer, ScD, a renowned scientist who is a recipient of the US National Medal of Science, the highest US honor for scientists, and is an inventor of approximately 850 patents issued or pending worldwide. Drs. Langer and Farokhzad are founders of both companies.

Ripple effects, eh? Rusnano was very active internationally.

ETA June 14, 2013:  Nanowerk has a June 13, 2013 news item, which updates the situation with the news that Rusnano has opted out of presenting an ‘initial public offering’, aka, listing itself on a stock exchange in 2015 and will instead attract private investment.

Evolution is the best problem-solver

Dr. Jeffrey Karp of Brigham and Women’s Hospital says, “I truly believe evolution is the best problem-solver,” when discussing his medical biomimcry work in this video,

You can find the video and more in a Mar. 20, 2013 news item on Nanowerk which was originated by a Mar. 6, 2013 article by Alisa Zapp Machalek for the US National Institutes of Health (NIH) National Institute of General Medical Sciences (NGMS) Inside Life Science webpage,

Velcro® was inspired by the grappling hooks of burrs. Supersonic jets have structures that work like the nostrils of peregrine falcons in a speed dive. Full-body swimsuits, now banned from the Olympics, lend athletes a smooth, streamlined shape like fish.

Nature’s designs are also giving researchers funded by the National Institutes of Health ideas for new technologies that could help wounds heal, make injections less painful and provide new materials for a variety of purposes.

… scientists [Jeffrey Karp and Robert Langer] discovered, to their surprise, that a [porcupine] quill’s puncture power comes from its barbed tip. Barbs seem to work like the points on a serrated knife, concentrating pressure onto small areas to aid penetration. Because they require significantly less force to puncture skin, barbed shafts don’t hurt as much when they enter flesh as their smooth-tipped counterparts do.

Zapp Machalek goes on to detail work inspired by gecko feet and spider webs, as well as, porcupine quills.