U of Waterloo startups rank second in North America for investor ROI


Investor coin

Waterloo companies power past Stanford, MIT and Harvard in key metric

Ahhh …. Those wily Canadians! Surpassing MIT, Stanford and Silicon Valley 

Investors looking for higher returns might be wiser to look to Waterloo companies than ventures started by alumni at Stanford, MIT and Harvard.

A new report from a U.S. platform for investors and startups has found that ventures founded by Waterloo alumni produce a higher-than-expected return on investment than their counterparts at the three American institutions.

The data from AngelList Venture show Waterloo startups generate outsized ROI for their investors, with an average excess markup rate 13 per cent higher than the baseline at 12 and 36 months.

Only the University of Washington ranked higher with a rate of 21 per cent, while Brown University came in third with an 11.5 per cent excess markup rate.  Two other Canadian universities made the ranking, with University of Toronto coming in at 16th and McGill University at 19th.

The platform considers an investment on its list to be marked up if it does an equity round at a higher price per share in a future fundraise. The rate is a strong indication of how an investment is performing, the company says.

“This speaks highly of Waterloo founders’ ability to thrive here in southwestern Ontario, well outside of Silicon Valley, New-York or Boston,” said Vivek Goel, president and vice-chancellor of the University. “Waterloo companies like ApplyBoard, Vidyard and Clearco are paving the way for future founders who want to grow within Canada, helping to increase the prominence of the Toronto-Waterloo tech ecosystem on the global stage.”

The Toronto-Waterloo corridor ranked 18th globally in a Startup Genome’s 2020 Global Startup Ecosystem Ranking and first in Canada.

u of waterlooThe findings indicate that Waterloo founders are being underestimated or undervalued by investors, said Alex Norman, a partner at N49P and co-founder of TechTO. “As investors see more and more University of Waterloo founders succeed, this may lead to more teams being funded or higher valuations for early-stage companies.”

While Canadian founders might be initially passed over by U.S. investors, great results for Waterloo founders over time are allowing early supporters to reap outsized rewards.

“It is no longer a secret that the University of Waterloo is a top school for innovative talent in North America,” said John Dick, director of Concept, the University’s experiential entrepreneurship program.

Young companies will continue to flourish in Waterloo Region through the University’s Campus Innovation Ecosystem and Velocity Incubator, which offer many problem-solving and venture-building opportunities, he said.

While founders with Waterloo pedigrees might not see the same level of investor demand as those at larger institutions in the U.S. AngelList says that can make them undervalued, “meaning that investors willing to back the founders from these institutions may have an opportunity to capture some excess returns.”

The findings come at an eventful time for Velocity, the University’s flagship entrepreneurial incubator, which announced recently that the total amount of funding raised by Velocity companies surpassed $2.4 billion. The incubator took almost a decade to reach the $1-billion mark but less than two years to reach $2 billion, showing an acceleration in both deal numbers and sizes. Velocity is expecting an alumni company to go through IPO for the first time later this year.

Velocity started its own pre-seed venture fund in 2019, and 18 out of 19 companies they have invested in so far received meaningful follow-on investments, highlighting the program’s ability to support early-stage founders and help them turn ideas and prototypes into marketable, scalable companies.

New DNA-based chip can be programmed to solve complex math problems – Are DNA Based CPU’s vs Electronic CPU’s in Our Future?


The term ‘DNA’ immediately calls to mind the double-stranded helix that contains all our genetic information. But the individual units of its two strands are pairs of molecules bonded with each other in a selective, complementary fashion. Turns out, one can take advantage of this pairing property to perform complex mathematical calculations, and this forms the basis of DNA nanotechnology and DNA computing.
Since DNA has only two strands, performing even a simple calculation requires multiple chemical reactions using different sets of DNA. In most existing research, the DNA for each reaction are added manually, one by one, into a single reaction tube, which makes the process very cumbersome.
Microfluidic chips, which consist of narrow channels etched onto a material like plastic, offer a way to automate the process. But despite their promise, the use of microfluidic chips for DNA computing remains underexplored.
In a recent article in ACS Nano (“Programmable DNA-Based Boolean Logic Microfluidic Processing Unit”), a team of scientists from Incheon National University (INU), Korea, present a programmable DNA-based microfluidic chip that can be controlled by a personal computer to perform DNA calculations.
“Our hope is that DNA-based CPUs will replace electronic CPUs in the future because they consume less power, which will help with global warming. DNA-based CPUs also provide a platform for complex calculations like deep learning solutions and mathematical modelling,” says Dr. Youngjun Song from INU, who led the study.
Dr. Song and team used 3D printing to fabricate their microfluidic chip, which can execute Boolean logic, one of the fundamental logics of computer programming. Boolean logic is a type of true-or-false logic that compares inputs and returns a value of ‘true’ or ‘false’ depending on the type of operation, or ‘logic gate,’ used. The logic gate in this experiment consisted of a single-stranded DNA template.
Different single-stranded DNA were then used as inputs. If part of an input DNA had a complementary Watson-Crick sequence to the template DNA, it paired to form double-stranded DNA. The output was considered true or false based on the size of the final DNA.
What makes the designed chip extraordinary is a motor-operated valve system that can be operated using a PC or smartphone. The chip and software set-up together form a microfluidic processing unit (MPU). Thanks to the valve system, the MPU could perform a series of reactions to execute a combination of logic operations in a rapid and convenient manner.
This unique valve system of the programmable DNA-based MPU paves the way for more complex cascades of reactions that can code for extended functions. “Future research will focus on a total DNA computing solution with DNA algorithms and DNA storage systems,” says Dr. Song.
Source: Incheon National University

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Engineers create nanoparticles that deliver gene-editing tools to specific tissues and organs


Credit: CC0 Public Domain

One of the most remarkable recent advances in biomedical research has been the development of highly targeted gene-editing methods such as CRISPR that can add, remove, or change a gene within a cell with great precision. The method is already being tested or used for the treatment of patients with sickle cell anemia and cancers such as multiple myeloma and liposarcoma, and today, its creators Emmanuelle Charpentier and Jennifer Doudna received the Nobel Prize in chemistry.

While gene editing is remarkably precise in finding and altering genes, there is still no way to target treatment to specific locations in the body. The treatments tested so far involve removing blood stem cells or immune system T cells from the body to modify them, and then infusing them back into a patient to repopulate the bloodstream or reconstitute an immune response—an expensive and time-consuming process.

Building on the accomplishments of Charpentier and Doudna, Tufts researchers have for the first time devised a way to directly deliver gene-editing packages efficiently across the blood brain barrier and into specific regions of the brain, into immune system cells, or to specific tissues and organs in mouse models. These applications could open up an entirely new line of strategy in the treatment of neurological conditions, as well as cancer, infectious disease, and autoimmune diseases.

A team of Tufts biomedical engineers, led by associate professor Qiaobing Xu, sought to find a way to package the gene editing “kit” so it could be injected to do its work inside the body on targeted cells, rather than in a lab.

They used lipid nanoparticles (LNPs)—tiny “bubbles” of lipid molecules that can envelop the editing enzymes and carry them to specific cells, tissues, or organs. Lipids are molecules that include a long carbon tail, which helps give them an “oily” consistency, and a hydrophilic head, which is attracted to a watery environment.

There is also typically a nitrogen, sulfur, or oxygen-based link between the head and tail. The lipids arrange themselves around the bubble nanoparticles with the heads facing outside and the tails facing inward toward the center.

Xu’s team was able to modify the surface of these LNPs so they can eventually “stick” to certain cell types, fuse with their membranes, and release the gene-editing enzymes into the cells to do their work.

Making a targeted LNP takes some chemical crafting.

By creating a mix of different heads, tails, and linkers, the researchers can screen— first in the lab—a wide variety of candidates for their ability to form LNPs that target specific cells. The best candidates can then be tested in mouse models, and further modified chemically to optimize targeting and delivery of the gene-editing enzymes to the same cells in the mouse.

“We created a method around tailoring the delivery package for a wide range of potential therapeutics, including gene editing,” said Xu. “The methods draw upon combinatorial chemistry used by the pharmaceutical industry for designing the drugs themselves, but instead we are applying the approach to designing the components of the delivery vehicle.”

In an ingenious bit of chemical modeling, Xu and his team used a neurotransmitter at the head of some lipids to assist the particles in crossing the blood-brain barrier, which would otherwise be impermeable to molecule assemblies as large as an LNP.

The ability to safely and efficiently deliver drugs across the barrier and into the brain has been a long-standing challenge in medicine. In a first, Xu’s lab delivered an entire complex of messenger RNAs and enzymes making up the CRISPR kit into targeted areas of the brain in a living animal.

Some slight modifications to the lipid linkers and tails helped create LNPs that could deliver into the brain the small molecule antifungal drug amphotericin B (for treatment of meningitis) and a DNA fragment that binds to and shuts down the gene producing the tau protein linked to Alzheimer’s disease.

More recently, Xu and his team have created LNPs to deliver gene-editing packages into T cells in mice. T cells can help in the production of antibodies, destroy infected cells before viruses can replicate and spread, and regulate and suppress other cells of the immune system.

The LNPs they created fuse with T cells in the spleen or liver—where they typically reside—to deliver the gene-editing contents, which can then alter the molecular make-up and behavior of the T cell. It’s a first step in the process of not just training the immune system, as one might do with a vaccine, but actually engineering it to fight disease better.

Xu’s approach to editing T cell genomes is much more targeted, efficient, and likely to be safer than methods tried so far using viruses to modify their genome.

“By targeting T cells, we can tap into a branch of the immune system that has tremendous versatility in fighting off infections, protecting against cancer, and modulating inflammation and autoimmunity,” said Xu.

Xu and his team explored further the mechanism by which LNPs might find their way to their targets in the body. In experiments aimed at cells in the lungs, they found that the nanoparticles picked up specific proteins in the bloodstream after injection.

The proteins, now incorporated into the surface of the LNPs, became the main component that helped the LNPs to latch on to their target. This information could help improve the design of future delivery particles.

While these results have been demonstrated in mice, Xu cautioned that more studies and clinical trials will be needed to determine the efficacy and safety of the delivery method in humans.


Explore furtherNovel drug delivery particles use neurotransmitters as a ‘passport’ into the brain


More information: Xuewei Zhao et al. Imidazole‐Based Synthetic Lipidoids for In Vivo mRNA Delivery into Primary T Lymphocytes, Angewandte Chemie International Edition (2020). DOI: 10.1002/anie.202008082Journal information:Angewandte Chemie International EditionProvided by Tufts University

Spinal carbon nanotube implants restore motor functions


A new study conducted by SISSA and the University of Trieste shows the efficacy of carbon nanotube implants to restore motor functions and paves the way for a new therapeutic approach for spinal cord injuries.
Re-establishing motor skills and neuronal connectivity thanks to the implantation of carbon nanotubes in the injury site. This is the result of a new study conducted by SISSA – Scuola Internazionale Superiore di Studi Avanzati and the University of Trieste that rewards a ten years interdisciplinary collaboration. For the first time, the researchers have used nanomaterial implants in animals with spinal injury, observing the regrowth of nerve fibres and the restoration of motor functions.
The research, published in PNAS (“Functional rewiring across spinal injuries via biomimetic nanofiber scaffolds”), shows the potential of therapeutic approaches that use the mechanical and electric properties of regenerative scaffolds to treat the injured area.
“We have been studying the interaction between neurons and carbon nanotubes for 15 years. Finally, we have been able to challenge their function in vivo”, say Laura Ballerini, neurophysiologist at SISSA, and Maurizio Prato, chemist at the University of Trieste, who have been investigating nerve cell growth when interfaced to smart materials, such as carbon nanotubes in the last decade, using increasingly complex systems. “In recent years, we passed from single neurons to brain tissue explants and from single nanotubes to two-dimensional structures and, now, three dimensional ones.”
“We studied the effect of the carbon nanotube implant in small mammals with a disease model of incomplete spinal cord injury,” explains Sadaf Usmani, PhD in neurobiology and lead author of the study. “We observed their motor recovery during the next six months through standard protocols for locomotor evaluation which revealed a greater recovery of motor skills when compared to non-implanted animals”.
This phenomenon is associated with nerve fibre regrowth through the injury site, as shown by the magnetic resonance experiments carried out in collaboration with the Center for Cooperative Research in Biomaterials (CIC biomaGUNE). A regrowth that is certainly favoured by nanotube implantation, explain Ballerini and Prato.
“Nerve fibre regeneration is promoted by the physical characteristics of nanomaterials. These implants are able to guarantee mechanical support and, at the same time, interact electrically with neurons.”
“The functionality of the regenerated tissue was not taken for granted, just as the biocompatibility of the implants” continue the researchers “And yet, not only there have been no cases of rejection, but electron microscope observations and the use of specific markers have confirmed that there is no real boundary between the tissue surrounding the injury, the regenerated tissue and the nanomaterials.”
These results not only confirm the possible applications of the nanomaterials in the biomedical sector but also pave the way to new therapeutic approaches which use the physical, mechanical and electrical properties in particular, of the injured zone to favour functional recovery.
Source: SISSA

Copper-based Nanomaterials can KILL Cancer Cells in Mice


Cancer cell during cell division. Credit: National Institutes of Health

An interdisciplinary team of scientists from KU Leuven, the University of Bremen, the Leibniz Institute of Materials Engineering, and the University of Ioannina has succeeded in killing tumour cells in mice using nano-sized copper compounds together with immunotherapy. After the therapy, the cancer did not return.

Recent advances in  therapy use one’s own immunity to fight the cancer. However, in some cases, immunotherapy has proven unsuccessful.

The team of biomedical researchers, physicists, and chemical engineers found that tumours are sensitive to copper oxide nanoparticles—a compound composed of copper and oxygen. Once inside a living organism, these nanoparticles dissolve and become toxic.

By creating the nanoparticles using iron oxide, the researchers were able to control this process to eliminate , while healthy cells were not affected.

“Any material that you create at a nanoscale has slightly different characteristics than its normal-sized counterpart,” explain Professor Stefaan Soenen and Dr. Bella B. Manshian from the Department of Imaging and Pathology, who worked together on the study.

“If we would ingest  in large quantities, they can be dangerous, but at a nanoscale and at controlled, safe, concentrations, they can actually be beneficial.”

As the researchers expected, the cancer returned after treating with only the nanoparticles. Therefore, they combined the nanoparticles with immunotherapy. “We noticed that the copper compounds not only could kill the tumour cells directly, they also could assist those cells in the  that fight foreign substances, like tumours,” says Dr. Manshian.

The combination of the nanoparticles and immunotherapy made the tumours disappear entirely and, as a result, works as a vaccine for lung and colon cancer—the two types that were investigated in the study. To confirm their finding, the researchers injected tumour cells back into the mice. These cells were immediately eliminated by the immune system, which was on the lookout for any new, similar, cells invading the body.

The authors state that the novel technique can be used for about sixty percent of all cancers, given that the cancer cells stem from a mutation in the p53 gene. Examples include lung, breast, ovarian, and colon cancer.

A  is that the tumours disappeared without the use of chemotherapy, which typically comes with major side-effects. Chemotherapeutic drugs not only attack cancer cells, they often damage healthy cells along the way.

For example, some of these drugs wipe out white blood cells, abolishing the immune system.

“As far as I’m aware, this is the first time that metal oxides are used to efficiently fight cancer  with long-lasting immune effects in live models,” Professor Soenen says. “As a next step, we want to create other metal , and identify which particles affect which types of cancer. This should result in a comprehensive database.”

The team also plans to test  derived from cancer patient tissue. If the results remain the same, Professor Soenen plans to set up a clinical trial. For that to happen, however, there are still some hurdles along the way.

He explains: “Nanomedicine is on the rise in the U.S. and Asia, but Europe is lagging behind. It’s a challenge to advance in this field, because doctors and engineers often speak a different language. We need more interdisciplinary collaboration, so that we can understand each other better and build upon each other’s knowledge.”

More information: 
Hendrik Naatz et al, Model-Based Nanoengineered Pharmacokinetics of Iron-Doped Copper Oxide for Nanomedical Applications, Angewandte Chemie International Edition (2019).  DOI: 10.1002/anie.201912312

Journal information: Angewandte Chemie International Edition

Provided by KU Leuven

Study finds Salt Nanoparticles (Sodium Chloride or SCNP’s) are Toxic to Cancer Cells – University of Georgia


A new study at the University of Georgia has found a way to attack cancer cells that is potentially less harmful to the patient.

Sodium chloride nanoparticles—more commonly known as salt—are toxic to cancer cells and offer the potential for therapies that have fewer negative side effects than current treatments.

Led by Jin Xie, associate professor of chemistry, the study found that SCNPs can be used as a Trojan horse to deliver ions into cells and disrupt their internal environment, leading to cell death. SCNPs become salt when they degrade, so they’re not harmful to the body.

“This technology is well suited for localized destruction of cancer cells,” said Xie, a faculty member in the Franklin College of Arts and Sciences. “We expect it to find wide applications in treatment of bladder, prostate, liver, and head and neck cancer.”

Nanoparticles are the key to delivering SCNPs into cells, according to Xie and the team of researchers. Cell membranes maintain a gradient that keeps relatively low sodium concentrations inside cells and relatively high sodium concentrations outside cells.

The plasma membrane prevents sodium from entering a cell, but SCNPs are able to pass through because the cell doesn’t recognize them as sodium ions.

Once inside a cell, SCNPs dissolve into millions of sodium and chloride ions that are trapped inside by the gradient and overwhelm protective mechanisms, inducing rupture of the plasma membrane and cell death. When the plasma membrane ruptures, the molecules that leak out signal the immune system that there’s tissue damage, inducing an inflammatory response that helps the body fight pathogens.

“This mechanism is actually more toxic to cancer cells than normal cells, because cancer cells have relatively high sodium concentrations to start with,” Xie said.

Using a mouse model, Xie and the team tested SCNPs as a potential cancer therapeutic, injecting SCNPs into tumors. They found that SCNP treatment suppressed tumor growth by 66 percent compared to the control group, with no drop in body weight and no sign of toxicity to major organs.

They also performed a vaccination study, inoculating mice with cancer cells that had been killed via SCNPs or freeze thaw. These mice showed much greater resistance to a subsequent live cancer cell challenge, with all animals remaining tumor free for more than two weeks.

The researchers also explored anti-cancer immunity in a tumor model. After injecting primary tumors with SCNPs and leaving secondary tumors untreated, they found that the secondary tumors grew at a much lower speed than the control, showing a tumor inhibition rate of 53 percent.

Collectively, the results suggest that SCNPs killed cancer cells and converted the dying cancer cells to an in situ vaccine.

SCNPs are unique in the world of inorganic particles because they are made of a benign material, and their toxicity is based on the nanoparticle form, according to Xie.

“With a relatively short half-life in aqueous solutions, SCNPs are best suited for localized rather than systemic therapy. The treatment will cause immediate and immunogenic cancer cell death,” he said. “After the treatment, the nanoparticles are reduced to salts, which are merged with the body’s fluid system and cause no systematic or accumulative toxicity. No sign of systematic toxicity was observed with SCNPs injected at high doses.”

The study was published in Advanced Materials.

MIT: Study Furthers Radically New View of Gene Control


  • MIT researchers have developed a new model of gene control, in which the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates.

  • Image: Steven H. Lee

  • Along the genome, proteins form liquid-like droplets that appear to boost the expression of particular genes.

    In recent years, MIT scientists have developed a new model for how key genes are controlled that suggests the cellular machinery that transcribes DNA into RNA forms specialized droplets called condensates. These droplets occur only at certain sites on the genome, helping to determine which genes are expressed in different types of cells.

    In a new study that supports that model, researchers at MIT and the Whitehead Institute for Biomedical Research have discovered physical interactions between proteins and with DNA that help explain why these droplets, which stimulate the transcription of nearby genes, tend to cluster along specific stretches of DNA known as super enhancers. These enhancer regions do not encode proteins but instead regulate other genes.

    “This study provides a fundamentally important new approach to deciphering how the ‘dark matter’ in our genome functions in gene control,” says Richard Young, an MIT professor of biology and member of the Whitehead Institute.

    Young is one of the senior authors of the paper, along with Phillip Sharp, an MIT Institute Professor and member of MIT’s Koch Institute for Integrative Cancer Research; and Arup K. Chakraborty, the Robert T. Haslam Professor in Chemical Engineering, a professor of physics and chemistry, and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MGH, MIT, and Harvard.

    Graduate student Krishna Shrinivas and postdoc Benjamin Sabari are the lead authors of the paper, which appears in Molecular Cell on Aug. 8.

    “A biochemical factory”

    Every cell in an organism has an identical genome, but cells such as neurons or heart cells express different subsets of those genes, allowing them to carry out their specialized functions. Previous research has shown that many of these genes are located near super enhancers, which bind to proteins called transcription factors that stimulate the copying of nearby genes into RNA.

    About three years ago, Sharp, Young, and Chakraborty joined forces to try to model the interactions that occur at enhancers.

    In a 2017 Cell paper, based on computational studies, they hypothesized that in these regions, transcription factors form droplets called phase-separated condensates. Similar to droplets of oil suspended in salad dressing, these condensates are collections of molecules that form distinct cellular compartments but have no membrane separating them from the rest of the cell.

    In a 2018 Science paper, the researchers showed that these dynamic droplets do form at super enhancer locations. Made of clusters of transcription factors and other molecules, these droplets attract enzymes such as RNA polymerases that are needed to copy DNA into messenger RNA, keeping gene transcription active at specific sites.

    “We had demonstrated that the transcription machinery forms liquid-like droplets at certain regulatory regions on our genome, however we didn’t fully understand how or why these dewdrops of biological molecules only seemed to condense around specific points on our genome,” Shrinivas says.

    As one possible explanation for that site specificity, the research team hypothesized that weak interactions between intrinsically disordered regions of transcription factors and other transcriptional molecules, along with specific interactions between transcription factors and particular DNA elements, might determine whether a condensate forms at a particular stretch of DNA. Biologists have traditionally focused on “lock-and-key” style interactions between rigidly structured protein segments to explain most cellular processes, but more recent evidence suggests that weak interactions between floppy protein regions also play an important role in cell activities.

    In this study, computational modeling and experimentation revealed that the cumulative force of these weak interactions conspire together with transcription factor-DNA interactions to determine whether a condensate of transcription factors will form at a particular site on the genome. Different cell types produce different transcription factors, which bind to different enhancers. When many transcription factors cluster around the same enhancers, weak interactions between the proteins are more likely to occur. Once a critical threshold concentration is reached, condensates form.

    “Creating these local high concentrations within the crowded environment of the cell enables the right material to be in the right place at the right time to carry out the multiple steps required to activate a gene,” Sabari says. “Our current study begins to tease apart how certain regions of the genome are capable of pulling off this trick.”

    These droplets form on a timescale of seconds to minutes, and they blink in and out of existence depending on a cell’s needs.

    “It’s an on-demand biochemical factory that cells can form and dissolve, as and when they need it,” Chakraborty says. “When certain signals happen at the right locus on a gene, the condensates form, which concentrates all of the transcription molecules. Transcription happens, and when the cells are done with that task, they get rid of them.”

    “A functional condensate has to be more than the sum of its parts, and how the protein and DNA components work together is something we don’t fully understand,” says Rohit Pappu, director of the Center for Science and Engineering of Living Systems at Washington University, who was not involved in the research. “This work gets us on the road to thinking about the interplay among protein-protein, protein-DNA, and possibly DNA-DNA interactions as determinants of the outputs of condensates.”

    A new view

    Weak cooperative interactions between proteins may also play an important role in evolution, the researchers proposed in a 2018 Proceedings of the National Academy of Sciences paper.

    The sequences of intrinsically disordered regions of transcription factors need to change only a little to evolve new types of specific functionality. In contrast, evolving new specific functions via “lock-and-key” interactions requires much more significant changes.

    “If you think about how biological systems have evolved, they have been able to respond to different conditions without creating new genes.

    We don’t have any more genes that a fruit fly, yet we’re much more complex in many of our functions,” Sharp says. “The incremental expanding and contracting of these intrinsically disordered domains could explain a large part of how that evolution happens.”

    Similar condensates appear to play a variety of other roles in biological systems, offering a new way to look at how the interior of a cell is organized.

    Instead of floating through the cytoplasm and randomly bumping into other molecules, proteins involved in processes such as relaying molecular signals may transiently form droplets that help them interact with the right partners.

    “This is a very exciting turn in the field of cell biology,” Sharp says. “It is a whole new way of looking at biological systems that is richer and more meaningful.”

    Some of the MIT researchers, led by Young, have helped form a company called Dewpoint Therapeutics to develop potential treatments for a wide variety of diseases by exploiting cellular condensates.

    There is emerging evidence that cancer cells use condensates to control sets of genes that promote cancer, and condensates have also been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease.

    The research was funded by the National Science Foundation, the National Institutes of Health, and the Koch Institute Support (core) Grant from the National Cancer Institute.

    Scientists develop novel nano-vaccine for melanoma


    Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma. Credit: Wikipedia/CC BY-SA 3.0

    Researchers at Tel Aviv University have developed a novel nano-vaccine for melanoma, the most aggressive type of skin cancer. Their innovative approach has so far proven effective in preventing the development of melanoma in mouse models and in treating primary tumors and metastases that result from melanoma.

    The focus of the research is on a nanoparticle that serves as the basis for the new vaccine. The study was led by Prof. Ronit Satchi-Fainaro, chair of the Department of Physiology and Pharmacology and head of the Laboratory for Cancer Research and Nanomedicine at TAU’s Sackler Faculty of Medicine, and Prof. Helena Florindo of the University of Lisbon while on sabbatical at the Satchi-Fainaro lab at TAU; it was conducted by Dr. Anna Scomparin of Prof. Satchi-Fainaro’s TAU lab, and postdoctoral fellow Dr. João Conniot. The results were published on August 5 in Nature Nanotechnology.

    Melanoma develops in the skin cells that produce melanin or skin pigment. “The war against cancer in general, and melanoma in particular, has advanced over the years through a variety of treatment modalities, such as chemotherapy, radiation therapy and immunotherapy; but the vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” says Prof. Satchi-Fainaro. “In our study, we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma and to sensitize the  to immunotherapies.”

    The researchers harnessed tiny particles, about 170 nanometers in size, made of a biodegradable polymer. Within each particle, they “packed” two peptides—short chains of amino acids, which are expressed in melanoma cells. They then injected the nanoparticles (or “nano-vaccines”) into a  bearing melanoma.

    “The nanoparticles acted just like known vaccines for viral-borne diseases,” Prof. Satchi-Fainaro explains. “They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides—that is, the melanoma cells. This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

    The researchers then examined the effectiveness of the vaccine under three different conditions.

    First, the vaccine proved to have prophylactic effects. The vaccine was injected into healthy mice, and an injection of melanoma  followed. “The result was that the mice did not get sick, meaning that the vaccine prevented the disease,” says Prof. Satchi-Fainaro.

    Second, the nanoparticle was used to treat a primary tumor: A combination of the innovative vaccine and immunotherapy treatments was tested on melanoma model mice. The synergistic treatment significantly delayed the progression of the disease and greatly extended the lives of all treated mice.

    Finally, the researchers validated their approach on tissues taken from patients with melanoma brain metastases. This suggested that the nano- can be used to treat brain metastases as well. Mouse models with late-stage melanoma brain metastases had already been established following excision of the primary melanoma lesion, mimicking the clinical setting. Research on image-guided surgery of primary melanoma using smart probes was published last year by Prof. Satchi-Fainaro’s lab.

    “Our research opens the door to a completely new approach—the —for effective treatment of , even in the most advanced stages of the disease,” concludes Prof. Satchi-Fainaro. “We believe that our platform may also be suitable for other types of cancer and that our work is a solid foundation for the development of other cancer nano-vaccines.”

    More information: Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators, Nature Nanotechnology(2019). DOI: 10.1038/s41565-019-0512-0 , https://nature.com/articles/s41565-019-0512-0

    Journal information: Nature Nanotechnology

    Provided by Tel Aviv University

    The Nano–Bio Interactions of Nanomedicines: ENMs – Understanding the Biochemical Driving Forces and Redox Reactions


    Engineered nanomaterials (ENMs) have been developed for imaging, drug delivery, diagnosis, and clinical therapeutic purposes because of their outstanding physicochemical characteristics.

    However, the function and ultimate efficiency of nanomedicines remain unsatisfactory for clinical application, mainly because of our insufficient understanding of nanomaterial/nanomedicine–biology (nano–bio) interactions.

    The nonequilibrated, complex, and heterogeneous nature of the biological milieu inevitably influences the dynamic bioidentity of nanoformulations at each site (i.e., the interfaces at different biological fluids (biofluids), environments, or biological structures) of nano–bio interactions.

    The continuous interplay between a nanomedicine and the biological molecules and structures in the biological environments can, for example, affect cellular uptake or completely alter the designed function of the nanomedicine.

    Accordingly, the weak and strong driving forces at the nano–bio interface may elicit structural reconformation, decrease bioactivity, and induce dysfunction of the nanomaterial and/or redox reactions with biological molecules, all of which may elicit unintended and unexpected biological outcomes.

    In contrast, these driving forces also can be manipulated to mitigate the toxicity of ENMs or improve the targeting abilities of ENMs.

    Therefore, a comprehensive understanding of the underlying mechanisms of nano–bio interactions is paramount for the intelligent design of safe and effective nanomedicines.

    In this Account, we summarize our recent progress in probing the nano–bio interaction of nanomedicines, focusing on the driving force and redox reaction at the nano–bio interface, which have been recognized as the main factors that regulate the functions and toxicities of nanomedicines.

    First, we provide insight into the driving force that shapes the boundary of different nano–bio interfaces (including proteins, cell membranes, and biofluids), for instance, hydrophobic, electrostatic, hydrogen bond, molecular recognition, metal-coordinate, and stereoselective interactions that influence the different nano–bio interactions at each contact site in the biological environment.

    The physicochemical properties of both the nanoparticle and the biomolecule are varied, causing structure recombination, dysfunction, and bioactivity loss of proteins; correspondingly, the surface properties, biological functions, intracellular uptake pathways, and fate of ENMs are also influenced.

    Second, with the help of these driving forces, four kinds of redox interactions with reactive oxygen species (ROS), antioxidant, sorbate, and the prosthetic group of oxidoreductases are utilized to regulate the intracellular redox equilibrium and construct synergetic nanomedicines for combating bacteria and cancers. Three kinds of electron-transfer mechanisms are involved in designing nanomedicines, including direct electron injection, sorbate-mediated, and irradiation-induced processes.

    Finally, we discuss the factors that influence the nano–bio interactions and propose corresponding strategies to manipulate the nano–bio interactions for advancing nanomedicine design. We expect our efforts in understanding the nano–bio interaction and the future development of this field will bring nanomedicine to human use more quickly.