How a new quantum sensor could improve cancer treatment
The development of medical imaging and monitoring methods has profoundly impacted the diagnosis and treatment of cancer. These non-invasive techniques allow health care practitioners to look for cancer in the body and determine if treatment is working.
But current techniques have limitations; namely, tumours need to be a specific size to be visible. Being able to detect cancer cells, even before there are enough to form a tumour, is a challenge that researchers around the world are looking to solve.
The solution may lie in nanotechnology
Researchers at the University of Waterloo’s Institute for Quantum Computing (IQC) have developed a quantum sensor that is promising to outperform existing technologies in monitoring the success of cancer treatments.
Artist’s rendering of the interaction of incident single photon pulses and a tapered semiconductor nanowire array photodetector.
“A sensor needs to be very efficient at detecting light,” explains principal investigator Michael Reimer, an IQC faculty member and professor in the Faculty of Engineering. “What’s unique about our sensor is that the light can be absorbed all the way, from UV to infrared. No commercially available device exists that can do that now.”
Current sensors reflect some of the light, and depending on the material, this reflection can add up to 30 percent of the light not being absorbed.
This next-generation quantum sensor designed in Reimer’s lab is very efficient and can detect light at the fundamental limit — a single photon — and refresh for the next one within nanoseconds. Researchers created an array of tapered nanowires that turn incoming photons into electric current that can be amplified and detected.
When applied to dose monitoring in cancer treatment, this enhanced ability to detect every photon means that a health practitioner could monitor the dose being given with incredible precision — ensuring enough is administered to kill the cancer cells, but not too much that it also kills healthy cells.
Moving quantum technology beyond the lab
Reimer published his findings in Nature Nanotechnology in March and is now working on a prototype to begin testing outside of his lab. Reimer’s goal is to commercialize the sensor in the next three to five years.
“I enjoy the fundamental research, but I’m also interested in bringing my research out of the lab and into the real world and making an impact to society,” says Reimer.
He is no stranger to bringing quantum technology to the marketplace. While completing his post doctorate at the Delft University of Technology in The Netherlands, Reimer was an integral part of the startup, Single Quantum, developing highly efficient single-photon detectors based on superconducting nanowires.
Reimer’s latest sensor has a wide range of applications beyond dose monitoring for cancer treatments. The technology also has the ability to significantly improve high-speed imaging from space and long-range, high-resolution 3D images.
“A broad range of industries and research fields will benefit from a quantum sensor with these capabilities,” said Reimer. “It impacts quantum communication to quantum lidar to biological applications. Anywhere you have photon-starved situations, you would want an efficient sensor.”
He is exploring all industries and opportunities to put this technology to use.
Breakthroughs come in unexpected places
After earning his undergraduate degree in physics at the University of Waterloo, Reimer moved to Germany to play professional hockey. While taking graduate courses at the Technical University of Munich, he met a professor of nanotechnology who sparked his interest in the field.
“I played hockey and science was my hobby,” says Reimer. “Science is still my hobby, and it’s amazing that it is now my job.” Reimer went on to complete his PhD at the University of Ottawa/National Research Council of Canada, and turned his attention to quantum light sources. Reimer is an internationally renowned expert in quantum light sources and sensors. The idea for the quantum sensor came from his initial research in quantum light sources.
“To get the light out from the quantum light source, we had to come up with a way that you don’t have reflections, so we made this tapered shape. We realized that if we can get the light out that way we could also do the reverse — that’s where the idea for the sensor came from.”
Reimer will be at the Waterloo Innovation Summit on October 1, to present his latest breakthrough and its potential impact on the health care sector. And while he works to bring the sensor to market, Reimer’s lab continues to push the boundaries of quantum photonics.
From discovering the path to perfect photon entanglement to developing novel solid-state quantum devices, Reimer’s research is advancing technologies that could disrupt a multitude of industries and research fields.
Scientists from the University of Cambridge have developed a platform that uses nanoparticles known as metal-organic frameworks to deliver a promising anti-cancer agent to cells.
Research led by Dr. David Fairen-Jimenez, from the Cambridge Department of Chemical Engineering and Biotechnology, indicates metal-organic frameworks (MOFs) could present a viable platform for delivering a potent anti-cancer agent, known as siRNA, to cells.
Small interfering ribonucleic acid (siRNA), has the potential to inhibit overexpressed cancer-causing genes, and has become an increasing focus for scientists on the hunt for new cancer treatments.
Fairen-Jimenez’s group used computational simulations to find a MOF with the perfect pore size to carry an siRNA molecule, and that would breakdown once inside a cell, releasing the siRNA to its target. Their results were published today in Cell Press journal, Chem.
Some cancers can occur when specific genes inside cells cause over-production of particular proteins. One way to tackle this is to block the gene expression pathway, limiting the production of these proteins.
SiRNA molecules can do just that—binding to specific gene messenger molecules and destroying them before they can tell the cell to produce a particular protein. This process is known as ‘gene knockdown’. Scientists have begun to focus more on siRNAs as potential cancer therapies in the last decade, as they offer a versatile solution to disease treatment—all you need to know is the sequence of the gene you want to inhibit and you can make the corresponding siRNA that will break it down. Instead of designing, synthesising and testing new drugs—an incredibly costly and lengthy process—you can make a few simple changes to the siRNA molecule and treat an entirely different disease.
One of the problems with using siRNAs to treat disease is that the molecules are very unstable and are often broken down by the cell’s natural defence mechanisms before they can reach their targets. SiRNA molecules can be modified to make them more stable, but this compromises their ability to knock down the target genes. It’s also difficult to get the molecules into cells—they need to be transported by another vehicle acting as a delivery agent.
The Cambridge researchers have used a special nanoparticle to protect and deliver siRNA to cells, where they show its ability to inhibit a specific target gene.
Fairen-Jimenez leads research into advanced materials, with a particular focus on MOFs: self-assembling 3-D compounds made of metallic and organic building blocks connected together.
There are thousands of different types of MOFs that researchers can make—there are currently more than 84,000 MOF structures in the Cambridge Structural Database with 1000 new structures published each month—and their properties can be tuned for specific purposes. By changing different components of the MOF structure, researchers can create MOFs with different pore sizes, stabilities and toxicities, enabling them to design structures that can carry molecules such as siRNAs into cells without harmful side effects.
“With traditional cancer therapy if you’re designing new drugs to treat the system, these can have different behaviours, geometries, sizes, and so you’d need a MOF that is optimal for each of these individual drugs,” says Fairen-Jimenez. “But for siRNA, once you develop one MOF that is useful, you can in principle use this for a range of different siRNA sequences, treating different diseases.”
“People that have done this before have used MOFs that don’t have a porosity that’s big enough to encapsulate the siRNA, so a lot of it is likely just stuck on the outside,” says Michelle Teplensky, former Ph.D. student in Fairen-Jimenez’s group, who carried out the research. “We used a MOF that could encapsulate the siRNA and when it’s encapsulated you offer more protection. The MOF we chose is made of a zirconium based metal node and we’ve done a lot of studies that show zirconium is quite inert and it doesn’t cause any toxicity issues.”
Using a biodegradable MOF for siRNA delivery is important to avoid unwanted build-up of the structures once they’ve done their job. The MOF that Teplensky and team selected breaks down into harmless components that are easily recycled by the cell without harmful side effects. The large pore size also means the team can load a significant amount of siRNA into a single MOF molecule, keeping the dosage needed to knock down the genes very low.
“One of the benefits of using a MOF with such large pores is that we can get a much more localised, higher dose than other systems would require,” says Teplensky. “SiRNA is very powerful, you don’t need a huge amount of it to get good functionality. The dose needed is less than 5% of the porosity of the MOF.”
MOFs or other vehicles to carry small molecules into cells is that they are often stopped by the cells on the way to their target. This process is known as endosomal entrapment and is essentially a defence mechanism against unwanted components entering the cell. Fairen-Jimenez’s team added extra components to their MOF to stop them being trapped on their way into the cell, and with this, could ensure the siRNA reached its target.
The team used their system to knock down a gene that produces fluorescent proteins in the cell, so they were able to use microscopy imaging methods to measure how the fluorescence emitted by the proteins compared between cells not treated with the MOF and those that were. The group made use of in-house expertise, collaborating with super-resolution microscopy specialists Professors Clemens Kaminski and Gabi Kaminski-Schierle, who also lead research in the Department of Chemical Engineering and Biotechnology.
Using the MOF platform, the team were consistently able to prevent gene expression by 27%, a level that shows promise for using the technique to knock down cancer genes.
Fairen-Jimenez believes they will be able to increase the efficacy of the system and the next steps will be to apply the platform to genes involved in causing so-called hard-to-treat cancers.
“One of the questions we get asked a lot is ‘why do you want to use a metal-organic framework for healthcare?’, because there are metals involved that might sound harmful to the body,” says Fairen-Jimenez. “But we focus on difficult diseases such as hard-to-treat cancers for which there has been no improvement in treatment in the last 20 years. We need to have something that can offer a solution; just extra years of life will be very welcome.”
The versatility of the system will enable the team to use the same adapted MOF to deliver different siRNA sequences and target different genes. Because of its large pore size, the MOF also has the potential to deliver multiple drugs at once, opening up the option of combination therapy.
Researchers have found a way to dispatch minute fragments of palladium—a key component in motor manufacture, electronics and the oil industry—inside cancerous cells.
Tiny extracts of a precious metal used widely in industry could play a vital role in new cancer therapies.
Scientists have long known that the metal, used in catalytic converters to detoxify exhaust, could be used to aid cancer treatment but, until now, have been unable to deliver it to affected areas.
A molecular shuttle system that targets specific cancer cells has been created by a team at the University of Edinburgh and the Universidad de Zaragoza in Spain.
The new method, which exploits palladium’s ability to accelerate—or catalyse—chemical reactions, mimics the process some viruses use to cross cell membranes and spread infection.
The team has used bubble-like pouches that resemble the biological carriers known as exosomes, which can transport essential proteins and genetic material between cells. These exosomes exit and enter cells, dump their content, and influence how the cells behave.
This targeted transport system, which is also exploited by some viruses to spread infection to other cells and tissues, inspired the team to investigate their use as shuttles of therapeutics.
The researchers have now shown that this complex communication network can be hijacked. The team created exosomes derived from lung cancer cells and cells associated with glioma—a tumour that occurs in the brain and spinal cord—and loaded them with palladium catalysts.
These artificial exosomes act as Trojan horses, taking the catalysts—which work in tandem with an existing cancer drug- straight to primary tumours and metastatic cells.
Having proved the concept in laboratory tests, the researchers have now been granted a patent that gives them exclusive rights to trial palladium-based therapies in medicine.
The study was funded by the Engineering and Physical Sciences Research Council and the European Research Council. It has been published in the journal, Nature Catalysis.
Professor Asier Unciti-Broceta, from the University of Edinburgh’s CRUK Edinburgh Centre, said: “We have tricked exosomes naturally released by cancer cells into taking up a metal that will activate chemotherapy drugs just inside the cancer cells, which could leave healthy cells untouched.”
Professor Jesús Santamaría, of the Universidad de Zaragoza, said: “This has the potential to be a very exciting technology. It could allow us to target the main tumour and metastatic cells, thus reducing the side effects of chemotherapy without compromising the treatment.”
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 inNature 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 theimmune systemto 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 amouse modelbearing 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 melanomacellsfollowed. “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-vaccinecan 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—thevaccine approach—for effective treatment ofmelanoma, 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.”
Researchers at Oregon State University have developed an improved technique for using magnetic nanoclusters to kill hard-to-reach tumors.
Magnetic nanoparticles – tiny pieces of matter as small as one-billionth of a meter – have shown anti-cancer promise for tumors easily accessible by syringe, allowing the particles to be injected directly into the cancerous growth.
Once injected into the tumor, the nanoparticles are exposed to an alternating magnetic field, or AMF. This field causes the nanoparticles to reach temperatures in excess of 100 degrees Fahrenheit, which causes the cancer cells to die.
But for some cancer types such as prostate cancer, or the ovarian cancer used in the Oregon State study, direct injection is difficult. In those types of cases, a “systemic” delivery method – intravenous injection, or injection into the abdominal cavity – would be easier and more effective.
The challenge for researchers has been finding the right kind of nanoparticles – ones that, when administered systemically in clinically appropriate doses, accumulate in the tumor well enough to allow the AMF to heat cancer cells to death.
Olena Taratula and Oleh Taratula of the OSU College of Pharmacy tackled the problem by developing nanoclusters, multiatom collections of nanoparticles, with enhanced heating efficiency. The nanoclusters are hexagon-shaped iron oxide nanoparticles doped with cobalt and manganese and loaded into biodegradable nanocarriers.
Findings were published in ACS Nano.
“There had been many attempts to develop nanoparticles that could be administered systemically in safe doses and still allow for hot enough temperatures inside the tumor,” said Olena Taratula, associate professor of pharmaceutical sciences. “Our new nanoplatform is a milestone for treating difficult-to-access tumors with magnetic hyperthermia. This is a proof of concept, and the nanoclusters could potentially be optimized for even greater heating efficiency.”
The nanoclusters’ ability to reach therapeutically relevant temperatures in tumors following a single, low-dose IV injection opens the door to exploiting the full potential of magnetic hyperthermia in treating cancer, either by itself or with other therapies, she added.
“It’s already been shown that magnetic hyperthermia at moderate temperatures increases the susceptibility of cancer cells to chemotherapy, radiation and immunotherapy,” Taratula said.
The mouse model in this research involved animals receiving IV nanocluster injections after ovarian tumors had been grafted underneath their skin.
“To advance this technology, future studies need to use orthotopic animal models – models where deep-seated tumors are studied in the location they would actually occur in the body,” she said. “In addition, to minimize the heating of healthy tissue, current AMF systems need to be optimized, or new ones developed.”
The National Institutes of Health, the OSU College of Pharmacy and Najran University of Saudi Arabia supported this research.
Also collaborating were OSU electrical engineering professor Pallavi Dhagat, postdoctoral scholars Xiaoning Li and Canan Schumann of the College of Pharmacy, pharmacy graduate students Hassan Albarqi, Fahad Sabei and Abraham Moses, engineering graduate student Mikkel Hansen, and pre-pharmacy undergrads Tetiana Korzun and Leon Wong.
Researchers at Rice University, Durham (U.K.) University and North Carolina State University reported their success at activating the motors with precise two-photon excitation via near-infrared light. Unlike the ultraviolet light they first used to drive the motors, the new technique does not damage adjacent, healthy cells.
The team’s results appear in the American Chemical Society journal ACS Nano.
The research led by chemists James Tour of Rice, Robert Pal of Durham and Gufeng Wang of North Carolina may be best applied to skin, oral and gastrointestinal cancer cells that can be reached for treatment with a laser.
In a 2017 Nature paper, the same team reported the development of molecular motors enhanced with small proteins that target specific cancer cells.
Once in place and activated with light, the paddlelike motors spin up to 3 million times a second, allowing the molecules to drill through the cells’ protective membranes and killing them in minutes.
Since then, researchers have worked on a way to eliminate the use of damaging ultraviolet light. In two-photon absorption, a phenomenon predicted in 1931 and confirmed 30 years later with the advent of lasers, the motors absorb photons in two frequencies and move to a higher energy state, triggering the paddles.
A video produced in 2017 explains the basic concept of cell death via molecular motors. Video produced by Brandon Martin/Rice University.
“Multiphoton activation is not only more biocompatible but also allows deeper tissue penetration and eliminates any unwanted side effects that may arise with the previously used UV light,” Pal said.
The researchers tested their updated motors on skin, breast, cervical and prostate cancer cells in the lab. Once the motors found their targets, lasers activated them with a precision of about 200 nanometers.
In most cases, the cells were dead within three minutes, they reported. They believe the motors also drill through chromatin and other components of the diseased cells, which could help slow metastasis.
Because the motors target specific cells, Tour said work is underway to adapt them to kill antibiotic-resistant bacteria as well.
“We continue to perfect the molecular motors, aiming toward ones that will work with visible light and provide even higher efficacies of kill toward the cellular targets,” he said.
Rice postdoctoral researcher Dongdong Liu is lead author of the paper. Co-authors are Rice alumni Victor Garcia-López, Lizanne Nilewski and Amir Aliyan, visiting research scientist Richard Gunasekera, and senior research scientist Lawrence Alemany and graduate student Tao Jin of North Carolina State.
Wang is an assistant professor of chemistry at North Carolina State. Pal is an assistant professor of chemistry at Durham. Tour is the T.T. and W.F. Chao Chair in Chemistry as well as a professor of computer science and of materials science and nanoengineering at Rice.
The Royal Society, the United Kingdom’s Engineering and Physical Sciences Research Council, the Discovery Institute, the Pensmore Foundation and North Carolina State supported the research.
About Rice University
Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,962 undergraduates and 3,027 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 2 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.
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The U.S. National Cancer Institute (NCI) in Bethesda, Maryland, will halt funding next year for its long-running Centers of Cancer Nanotechnology Excellence (CCNEs), which are focused on steering advances in nanotechnology to detect and treat cancer.
The shift marks nanotechnology’s “natural transition” from an emerging field requiring dedicated support to a more mature enterprise able to compete head to head with other types of cancer research, says Piotr Grodzinski, who heads NCI’s Nanodelivery Systems and Devices Branch, which oversees the CCNEs. “This doesn’t mean NCI’s interest in nanotechnology is decreasing.”
Nevertheless, cancer nanotechnology experts see the decision as a blow. “It’s disappointing and very shortsighted given the emergence of nanotechnology and medicine,” says Chad Mirkin, who directs a CCNE at Northwestern University in Evanston, Illinois.
CCNEs have spawned dozens of clinical trials for new drugs and drug delivery devices, as well as novel technologies for diagnosing disease, he says. “Cancer research needs new ways of making new types of medicines. Nanotechnology represents a way to do that,” he says.
Nanotechnology also has a unique place in cancer research, where making advances requires multiple disciplines, including chemistry, physics, cell biology, and patient care, to design novel drugs and drug carriers that can navigate the body and seek out and destroy tumors.
“We’re talking about a different beast here,” says Michelle Bradbury, a radiologist at Memorial Sloan Kettering Cancer Center in New York City, who co-directs the Sloan Kettering-Cornell University CCNE. “The center format is perfect for that.”
NCI launched eight CCNEs in 2005 for an initial 5-year term. Nine received funding in 2010 for the project’s second phase, and six in 2015 for phase three. In total, CCNEs received about $330 million over 15 years, Grodzinski says, with an additional $70 million in funding for training and other types of nanotechnology research centers.
That, he says, represents between 10% to 20% of NCI’s funding for nanotechnology research, depending on the specific 5-year phase. NCI will continue to support nanotechnology through R01 and other grant mechanisms, Grodzinski says. But Bradbury and others are concerned that a more piecemeal funding approach might be less successful. “You might not see the integration between disciplines,” she says.
RESEARCH TRIANGLE PARK, N.C. — Army research is the first to develop computational models using a microbiology procedure that may be used to improve novel cancer treatments and treat combat wounds.
Using the technique, known as electroporation, an electrical field is applied to cells in order to increase the permeability of the cell membrane, allowing chemicals, drugs, or DNA to be introduced into the cell.
For example, electro-chemotherapy is a cutting-edge cancer treatment that uses electroporation as a means to deliver chemotherapy into cancerous cells.
The research, funded by the U.S. Army and conducted by researchers at University of California, Santa Barbara and Université de Bordeaux, France, has developed a computational approach for parallel simulations that models the complex bioelectrical interaction at the tissue scale.
Previously, most research has been conducted on individual cells, and each cell behaves according to certain rules.
“When you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” said Pouria Mistani, a researcher at UCSB. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”
This new research, published in the Journal of Computational Physics, is funded by the U.S. Combat Capabilities Development Command’s Army Research Lab, the Army’s corporate research laboratory known as ARL, through its Army Research Office.
“Mathematical research enables us to study the bioelectric effects of cells in order to develop new anti-cancer strategies,” said Dr. Joseph Myers, Army Research Office mathematical sciences division chief.
“This new research will enable more accurate and capable virtual experiments of the evolution and treatment of cells, cancerous or healthy, in response to a variety of candidate drugs.”
Researchers said a crucial element in making this possible is the development of advanced computational algorithms.
“There is quite a lot of mathematics that goes into the design of algorithms that can consider tens of thousands well-resolved cells,” said Frederic Gibou, a faculty member in the Department of Mechanical Engineering and Computer Science at UCSB.
Another potential application is accelerating combat wound healing using electric pulsation.
“It’s an exciting, but mainly unexplored area that stems from a deeper discussion at the frontier of developmental biology, namely how electricity influences morphogenesis,” — or the biological process that causes an organism to develop its shape — Gibou said. “In wound healing, the goal is to externally manipulate electric cues to guide cells to grow faster in the wounded region and accelerate the healing process.”
The common factor among these applications is their bioelectric physical nature. In recent years, it has been established that the bioelectric nature of living organisms plays a pivotal role in the development of their form and growth.
To understand bioelectric phenomena, Gibou’s group considered computer experiments on multicellular spheroids in 3-D. Spheroids are aggregates of a few tens of thousands of cells that are used in biology because of their structural and functional similarity with tumors.
“We started from the phenomenological cell-scale model that was developed in the research group of our colleague, Clair Poignard, at the Université de Bordeaux, France, with whom we have collaborated for several years,” Gibou said.
This model, which describes the evolution of transmembrane potential on an isolated cell, has been compared and validated with the response of a single cell in experiments.
“From there, we developed the first computational framework that is able to consider a cell aggregate of tens of thousands of cells and to simulate their interactions,” he said. “The end goal is to develop an effective tissue-scale theory for electroporation.”
One of the main reasons for the absence of an effective theory at the tissue scale is the lack of data, according to Gibou and Mistani. Specifically, the missing data in the case of electroporation is the time evolution of the transmembrane potential of each individual cell in a tissue environment. Experiments are not able to make those measurements, they said.
“Currently, experimental limitations prevent the development of an effective tissue-level electroporation theory,” Mistani said. “Our work has developed a computational approach that can simulate the response of individual cells in a spheroid to an electric field as well as their mutual interactions.”
Each cell behaves according to certain rules.
“But when you consider a large number of them together, the aggregate exhibits novel coherent behaviors,” Mistani said. “It is this emergent phenomenon that is crucial for developing effective theories at the tissue-scale — novel behaviors that emerge from the coupling of many individual elements.”
The effects of electroporation used in cancer treatment, for example, depend on many factors, such as the strength of the electric field, its pulse and frequency.
“This work could bring an effective theory that helps understand the tissue response to these parameters and thus optimize such treatments,” Mistani said. “Before our work, the largest existing simulations of cell aggregate electroporation only considered about one hundred cells in 3-D, or were limited to 2-D simulations. Those simulations either ignored the real 3-D nature of spheroids or considered too few cells for tissue-scale emergent behaviors to manifest.”
The researchers are currently mining this unique dataset to develop an effective tissue-scale theory of cell aggregate electroporation.
The CCDC Army Research Laboratory (ARL) is an element of the U.S. Army Combat Capabilities Development Command. As the Army’s corporate research laboratory, ARL discovers, innovates and transitions science and technology to ensure dominant strategic land power. Through collaboration across the command’s core technical competencies, CCDC leads in the discovery, development and delivery of the technology-based capabilities required to make Soldiers more effective to win our Nation’s wars and come home safely. CCDC is a major subordinate command of the U.S. Army Futures Command.
Instead of searching for a needle in a haystack, what if you were able to sweep the entire haystack to one side, leaving only the needle behind? That’s the strategy researchers in the University of Georgia College of Engineering followed in developing a new microfluidic device that separates elusive circulating tumor cells (CTCs) from a sample of whole blood.
CTCs break away from cancerous tumors and flow through the bloodstream, potentially leading to new metastatic tumors. The isolation of CTCs from the blood provides a minimally invasive alternative for basic understanding, diagnosis and prognosis of metastatic cancer. But most studies are limited by technical challenges in capturing intact and viable CTCs with minimal contamination.
“A typical sample of 7 to 10 milliliters of blood may contain only a few CTCs,” said Leidong Mao, a professor in UGA’s School of Electrical and Computer Engineering and the project’s principal investigator. “They’re hiding in whole blood with millions of white blood cells. It’s a challenge to get our hands on enough CTCs so scientists can study them and understand them.”
Leidong Mao (right) and graduate student Yang Liu stand in Mao’s lab at UGA.
Circulating tumor cells are also difficult to isolate because within a sample of a few hundred CTCs, the individual cells may present many characteristics. Some resemble skin cells while others resemble muscle cells. They can also vary greatly in size.
“People often compare finding CTCs to finding a needle in a haystack,” said Mao. “But sometimes the needle isn’t even a needle.”
To more quickly and efficiently isolate these rare cells for analysis, Mao and his team have created a new microfluidic chip that captures nearly every CTC in a sample of blood - more than 99% – a considerably higher percentage than most existing technologies.
The new device could be “transformative” in the treatment of breast cancer, according to Melissa Davis, an assistant professor of cell and developmental biology at Weill Cornell Medicine and a collaborator on the project.
“Physicians can only treat what they can detect,” Davis said. “We often can’t detect certain subtypes of CTCs, but with the iFCS device we will capture all the subtypes of CTCs and even determine which subtypes are the most informative concerning relapse and disease progression.”
Davis believes the device may ultimately allow physicians to gauge a patient’s response to specific treatments much earlier than is currently possible.
While most efforts to capture circulating tumor cells focus on identifying and isolating the few CTCs lurking in a blood sample, the iFCS takes a completely different approach by eliminating everything in the sample that’s not a circulating tumor cell.
The device, about the size of a USB drive, works by funneling blood through channels smaller in diameter than a human hair. To prepare blood for analysis, the team adds micron-sized magnetic beads to the samples. The white blood cells in the sample attach themselves to these beads. As blood flows through the device, magnets on the top and bottom of the chip draw the white blood cells and their magnetic beads down a specific channel while the circulating tumor cells continue into another channel.
The device combines three steps in one microfluidic chip, another advance over existing technologies that require separate devices for various steps in the process.
“The first step is a filter that removes large debris in the blood,” said Yang Liu, a doctoral student in UGA’s department of chemistry and the paper’s co-lead author. “The second part depletes extra magnetic beads and the majority of the white blood cells. The third part is designed to focus remaining white blood cells to the middle of channel and to push CTCs to the side walls.”
Wujun Zhao is the paper’s other lead author. Zhao, a postdoctoral scholar at Lawrence Berkeley National Laboratory, worked on the project while completing his doctorate in chemistry at UGA.
“The success of our integrated device is that it has the capability to enrich almost all CTCs regardless of their size profile or antigen expression,” said Zhao. “Our findings have the potential to provide the cancer research community with key information that may be missed by current protein-based or size-based enrichment technologies.”
The researchers say their next steps include automating the iFCS and making it more user-friendly for clinical settings. They also need to put the device through its paces in patient trials. Mao and his colleagues hope additional collaborators will join them and lend their expertise to the project.
This is Part II of MIT’s 10 Technology Breakthroughs for 2019′ Re-Posted from MIT Technology Review, with Guest Curator Bill Gates. You can Read Part I Here
Part I Into from Bill Gates: How We’ll Invent the Future
I was honored when MIT Technology Review invited me to be the first guest curator of its 10 Breakthrough Technologies. Narrowing down the list was difficult. I wanted to choose things that not only will create headlines in 2019 but captured this moment in technological history—which got me thinking about how innovation has evolved over time.
Why it matters If robots could learn to deal with the messiness of the real world, they could do many more tasks.
Key Players OpenAI
Carnegie Mellon University
University of Michigan
Availability 3-5 years
Robots are teaching themselves to handle the physical world.
For all the talk about machines taking jobs, industrial robots are still clumsy and inflexible. A robot can repeatedly pick up a component on an assembly line with amazing precision and without ever getting bored—but move the object half an inch, or replace it with something slightly different, and the machine will fumble ineptly or paw at thin air.
But while a robot can’t yet be programmed to figure out how to grasp any object just by looking at it, as people do, it can now learn to manipulate the object on its own through virtual trial and error.
One such project is Dactyl, a robot that taught itself to flip a toy building block in its fingers. Dactyl, which comes from the San Francisco nonprofit OpenAI, consists of an off-the-shelf robot hand surrounded by an array of lights and cameras. Using what’s known as reinforcement learning, neural-network software learns how to grasp and turn the block within a simulated environment before the hand tries it out for real. The software experiments, randomly at first, strengthening connections within the network over time as it gets closer to its goal.
It usually isn’t possible to transfer that type of virtual practice to the real world, because things like friction or the varied properties of different materials are so difficult to simulate. The OpenAI team got around this by adding randomness to the virtual training, giving the robot a proxy for the messiness of reality.
We’ll need further breakthroughs for robots to master the advanced dexterity needed in a real warehouse or factory. But if researchers can reliably employ this kind of learning, robots might eventually assemble our gadgets, load our dishwashers, and even help Grandma out of bed. —Will Knight
New-wave nuclear power
Advanced fusion and fission reactors are edging closer to reality.
New nuclear designs that have gained momentum in the past year are promising to make this power source safer and cheaper. Among them are generation IV fission reactors, an evolution of traditional designs; small modular reactors; and fusion reactors, a technology that has seemed eternally just out of reach. Developers of generation IV fission designs, such as Canada’s Terrestrial Energy and Washington-based TerraPower, have entered into R&D partnerships with utilities, aiming for grid supply (somewhat optimistically, maybe) by the 2020s.
Small modular reactors typically produce in the tens of megawatts of power (for comparison, a traditional nuclear reactor produces around 1,000 MW). Companies like Oregon’s NuScale say the miniaturized reactors can save money and reduce environmental and financial risks.
From sodium-cooled fission to advanced fusion, a fresh generation of projects hopes to rekindle trust in nuclear energy.
There has even been progress on fusion. Though no one expects delivery before 2030, companies like General Fusion and Commonwealth Fusion Systems, an MIT spinout, are making some headway. Many consider fusion a pipe dream, but because the reactors can’t melt down and don’t create long-lived, high-level waste, it should face much less public resistance than conventional nuclear. (Bill Gates is an investor in TerraPower and Commonwealth Fusion Systems.) —Leigh Phillips
Why it matters 15 million babies are born prematurely every year; it’s the leading cause of death for children under age five
Key player Akna Dx
Availability A test could be offered in doctor’s offices within five years
A simple blood test can predict if a pregnant woman is at risk of giving birth prematurely.
Our genetic material lives mostly inside our cells. But small amounts of “cell-free” DNA and RNA also float in our blood, often released by dying cells. In pregnant women, that cell-free material is an alphabet soup of nucleic acids from the fetus, the placenta, and the mother.
Stephen Quake, a bioengineer at Stanford, has found a way to use that to tackle one of medicine’s most intractable problems: the roughly one in 10 babies born prematurely.
Free-floating DNA and RNA can yield information that previously required invasive ways of grabbing cells, such as taking a biopsy of a tumor or puncturing a pregnant woman’s belly to perform an amniocentesis. What’s changed is that it’s now easier to detect and sequence the small amounts of cell-free genetic material in the blood. In the last few years researchers have begun developing blood tests for cancer (by spotting the telltale DNA from tumor cells) and for prenatal screening of conditions like Down syndrome.
The tests for these conditions rely on looking for genetic mutations in the DNA. RNA, on the other hand, is the molecule that regulates gene expression—how much of a protein is produced from a gene. By sequencing the free-floating RNA in the mother’s blood, Quake can spot fluctuations in the expression of seven genes that he singles out as associated with preterm birth. That lets him identify women likely to deliver too early. Once alerted, doctors can take measures to stave off an early birth and give the child a better chance of survival.
Complications from preterm birth are the leading cause of death worldwide in children under five.
The technology behind the blood test, Quake says, is quick, easy, and less than $10 a measurement. He and his collaborators have launched a startup, Akna Dx, to commercialize it. —Bonnie Rochman
Gut probe in a pill
Why it matters The device makes it easier to screen for and study gut diseases, including one that keeps millions of children in poor countries from growing properly
Key player Massachusetts General Hospital
Availability Now used in adults; testing in infants begins in 2019
A small, swallowable device captures detailed images of the gut without anesthesia, even in infants and children.
Environmental enteric dysfunction (EED) may be one of the costliest diseases you’ve never heard of. Marked by inflamed intestines that are leaky and absorb nutrients poorly, it’s widespread in poor countries and is one reason why many people there are malnourished, have developmental delays, and never reach a normal height. No one knows exactly what causes EED and how it could be prevented or treated.
Practical screening to detect it would help medical workers know when to intervene and how. Therapies are already available for infants, but diagnosing and studying illnesses in the guts of such young children often requires anesthetizing them and inserting a tube called an endoscope down the throat. It’s expensive, uncomfortable, and not practical in areas of the world where EED is prevalent.
So Guillermo Tearney, a pathologist and engineer at Massachusetts General Hospital (MGH) in Boston, is developing small devices that can be used to inspect the gut for signs of EED and even obtain tissue biopsies. Unlike endoscopes, they are simple to use at a primary care visit.
Tearney’s swallowable capsules contain miniature microscopes. They’re attached to a flexible string-like tether that provides power and light while sending images to a briefcase-like console with a monitor. This lets the health-care worker pause the capsule at points of interest and pull it out when finished, allowing it to be sterilized and reused. (Though it sounds gag-inducing, Tearney’s team has developed a technique that they say doesn’t cause discomfort.) It can also carry technologies that image the entire surface of the digestive tract at the resolution of a single cell or capture three-dimensional cross sections a couple of millimeters deep.
The technology has several applications; at MGH it’s being used to screen for Barrett’s esophagus, a precursor of esophageal cancer. For EED, Tearney’s team has developed an even smaller version for use in infants who can’t swallow a pill. It’s been tested on adolescents in Pakistan, where EED is prevalent, and infant testing is planned for 2019.
The little probe will help researchers answer questions about EED’s development—such as which cells it affects and whether bacteria are involved—and evaluate interventions and potential treatments. —Courtney Humphrie
Custom cancer vaccines
Why it matters Conventional chemotherapies take a heavy toll on healthy cells and aren’t always effective against tumors
Key players BioNTech
Availability In human testing
The treatment incites the body’s natural defenses to destroy only cancer cells by identifying mutations unique to each tumor
Scientists are on the cusp of commercializing the first personalized cancer vaccine. If it works as hoped, the vaccine, which triggers a person’s immune system to identify a tumor by its unique mutations, could effectively shut down many types of cancers.
By using the body’s natural defenses to selectively destroy only tumor cells, the vaccine, unlike conventional chemotherapies, limits damage to healthy cells. The attacking immune cells could also be vigilant in spotting any stray cancer cells after the initial treatment.
The possibility of such vaccines began to take shape in 2008, five years after the Human Genome Project was completed, when geneticists published the first sequence of a cancerous tumor cell.
Soon after, investigators began to compare the DNA of tumor cells with that of healthy cells—and other tumor cells. These studies confirmed that all cancer cells contain hundreds if not thousands of specific mutations, most of which are unique to each tumor.
A few years later, a German startup called BioNTech provided compelling evidence that a vaccine containing copies of these mutations could catalyze the body’s immune system to produce T cells primed to seek out, attack, and destroy all cancer cells harboring them.
In December 2017, BioNTech began a large test of the vaccine in cancer patients, in collaboration with the biotech giant Genentech. The ongoing trial is targeting at least 10 solid cancers and aims to enroll upwards of 560 patients at sites around the globe.
The two companies are designing new manufacturing techniques to produce thousands of personally customized vaccines cheaply and quickly. That will be tricky because creating the vaccine involves performing a biopsy on the patient’s tumor, sequencing and analyzing its DNA, and rushing that information to the production site. Once produced, the vaccine needs to be promptly delivered to the hospital; delays could be deadly. —Adam Pior
The cow-free burger
Why it matters Livestock production causes catastrophic deforestation, water pollution, and greenhouse-gas emissions
Key players Beyond Meat
Availability Plant-based now; lab-grown around 2020
Both lab-grown and plant-based alternatives approximate the taste and nutritional value of real meat without the environmental devastation.
The UN expects the world to have 9.8 billion people by 2050. And those people are getting richer. Neither trend bodes well for climate change—especially because as people escape poverty, they tend to eat more meat.
By that date, according to the predictions, humans will consume 70% more meat than they did in 2005. And it turns out that raising animals for human consumption is among the worst things we do to the environment.
Depending on the animal, producing a pound of meat protein with Western industrialized methods requires 4 to 25 times more water, 6 to 17 times more land, and 6 to 20 times more fossil fuels than producing a pound of plant protein.
The problem is that people aren’t likely to stop eating meat anytime soon. Which means lab-grown and plant-based alternatives might be the best way to limit the destruction.
Making lab-grown meat involves extracting muscle tissue from animals and growing it in bioreactors. The end product looks much like what you’d get from an animal, although researchers are still working on the taste. Researchers at Maastricht University in the Netherlands, who are working to produce lab-grown meat at scale, believe they’ll have a lab-grown burger available by next year. One drawback of lab-grown meat is that the environmental benefits are still sketchy at best—a recent World Economic Forum report says the emissions from lab-grown meat would be only around 7% less than emissions from beef production.
Meat production spews tons of greenhouse gas and uses up too much land and water. Is there an alternative that won’t make us do without?
The better environmental case can be made for plant-based meats from companies like Beyond Meat and Impossible Foods (Bill Gates is an investor in both companies), which use pea proteins, soy, wheat, potatoes, and plant oils to mimic the texture and taste of animal meat.
Beyond Meat has a new 26,000-square-foot (2,400-square-meter) plant in California and has already sold upwards of 25 million burgers from 30,000 stores and restaurants. According to an analysis by the Center for Sustainable Systems at the University of Michigan, a Beyond Meat patty would probably generate 90% less in greenhouse-gas emissions than a conventional burger made from a cow. —Markkus Rovito
Carbon dioxide catcher
Why it matters Removing CO2 from the atmosphere might be one of the last viable ways to stop catastrophic climate change
Key players Carbon Engineering
Availability 5-10 years
Practical and affordable ways to capture carbon dioxide from the air can soak up excess greenhouse-gas emissions.
Even if we slow carbon dioxide emissions, the warming effect of the greenhouse gas can persist for thousands of years. To prevent a dangerous rise in temperatures, the UN’s climate panel now concludes, the world will need to remove as much as 1 trillion tons of carbon dioxide from the atmosphere this century.
In a surprise finding last summer, Harvard climate scientist David Keith calculated that machines could, in theory, pull this off for less than $100 a ton, through an approach known as direct air capture. That’s an order of magnitude cheaper than earlier estimates that led many scientists to dismiss the technology as far too expensive—though it will still take years for costs to fall to anywhere near that level.
But once you capture the carbon, you still need to figure out what to do with it.
Carbon Engineering, the Canadian startup Keith cofounded in 2009, plans to expand its pilot plant to ramp up production of its synthetic fuels, using the captured carbon dioxide as a key ingredient. (Bill Gates is an investor in Carbon Engineering.)
Zurich-based Climeworks’s direct air capture plant in Italy will produce methane from captured carbon dioxide and hydrogen, while a second plant in Switzerland will sell carbon dioxide to the soft-drinks industry. So will Global Thermostat of New York, which finished constructing its first commercial plant in Alabama last year.
Klaus Lackner’s once wacky idea increasingly looks like an essential part of solving climate change.
Still, if it’s used in synthetic fuels or sodas, the carbon dioxide will mostly end up back in the atmosphere. The ultimate goal is to lock greenhouse gases away forever. Some could be nested within products like carbon fiber, polymers, or concrete, but far more will simply need to be buried underground, a costly job that no business model seems likely to support.
In fact, pulling CO2 out of the air is, from an engineering perspective, one of the most difficult and expensive ways of dealing with climate change. But given how slowly we’re reducing emissions, there are no good options left. —James Temple
An ECG on your wrist
Regulatory approval and technological advances are making it easier for people to continuously monitor their hearts with wearable devices.
Fitness trackers aren’t serious medical devices. An intense workout or loose band can mess with the sensors that read your pulse. But an electrocardiogram—the kind doctors use to diagnose abnormalities before they cause a stroke or heart attack— requires a visit to a clinic, and people often fail to take the test in time.
ECG-enabled smart watches, made possible by new regulations and innovations in hardware and software, offer the convenience of a wearable device with something closer to the precision of a medical one.
An Apple Watch–compatible band from Silicon Valley startup AliveCor that can detect atrial fibrillation, a frequent cause of blood clots and stroke, received clearance from the FDA in 2017. Last year, Apple released its own FDA-cleared ECG feature, embedded in the watch itself.
Making complex heart tests available at the push of a button has far-reaching consequences.
The health-device company Withings also announced plans for an ECG-equipped watch shortly after.
Current wearables still employ only a single sensor, whereas a real ECG has 12. And no wearable can yet detect a heart attack as it’s happening.
But this might change soon. Last fall, AliveCor presented preliminary results to the American Heart Association on an app and two-sensor system that can detect a certain type of heart attack. —Karen Hao
Sanitation without sewers
Why it matters 2.3 billion people lack safe sanitation, and many die as a result
Key players Duke University
University of South Florida
California Institute of Technology
Availability 1-2 years
Energy-efficient toilets can operate without a sewer system and treat waste on the spot.
About 2.3 billion people don’t have good sanitation. The lack of proper toilets encourages people to dump fecal matter into nearby ponds and streams, spreading bacteria, viruses, and parasites that can cause diarrhea and cholera. Diarrhea causes one in nine child deaths worldwide.
Now researchers are working to build a new kind of toilet that’s cheap enough for the developing world and can not only dispose of waste but treat it as well.
In 2011 Bill Gates created what was essentially the X Prize in this area—the Reinvent the Toilet Challenge. Since the contest’s launch, several teams have put prototypes in the field. All process the waste locally, so there’s no need for large amounts of water to carry it to a distant treatment plant.
Most of the prototypes are self-contained and don’t need sewers, but they look like traditional toilets housed in small buildings or storage containers. The NEWgenerator toilet, designed at the University of South Florida, filters out pollutants with an anaerobic membrane, which has pores smaller than bacteria and viruses. Another project, from Connecticut-based Biomass Controls, is a refinery the size of a shipping container; it heats the waste to produce a carbon-rich material that can, among other things, fertilize soil.
One drawback is that the toilets don’t work at every scale. The Biomass Controls product, for example, is designed primarily for tens of thousands of users per day, which makes it less well suited for smaller villages. Another system, developed at Duke University, is meant to be used only by a few nearby homes.
So the challenge now is to make these toilets cheaper and more adaptable to communities of different sizes. “It’s great to build one or two units,” says Daniel Yeh, an associate professor at the University of South Florida, who led the NEWgenerator team. “But to really have the technology impact the world, the only way to do that is mass-produce the units.” —Erin Winick
Smooth-talking AI assistants
Why it matters AI assistants can now perform conversation-based tasks like booking a restaurant reservation or coordinating a package drop-off rather than just obey simple commands
Key players Google
Availability 1-2 years
New techniques that capture semantic relationships between words are making machines better at understanding natural language.
We’re used to AI assistants—Alexa playing music in the living room, Siri setting alarms on your phone—but they haven’t really lived up to their alleged smarts. They were supposed to have simplified our lives, but they’ve barely made a dent. They recognize only a narrow range of directives and are easily tripped up by deviations.
But some recent advances are about to expand your digital assistant’s repertoire. In June 2018, researchers at OpenAI developed a technique that trains an AI on unlabeled text to avoid the expense and time of categorizing and tagging all the data manually. A few months later, a team at Google unveiled a system called BERT that learned how to predict missing words by studying millions of sentences. In a multiple-choice test, it did as well as humans at filling in gaps.
These improvements, coupled with better speech synthesis, are letting us move from giving AI assistants simple commands to having conversations with them. They’ll be able to deal with daily minutiae like taking meeting notes, finding information, or shopping online.
Some are already here. Google Duplex, the eerily human-like upgrade of Google Assistant, can pick up your calls to screen for spammers and telemarketers. It can also make calls for you to schedule restaurant reservations or salon appointments.
In China, consumers are getting used to Alibaba’s AliMe, which coordinates package deliveries over the phone and haggles about the price of goods over chat.
But while AI programs have gotten better at figuring out what you want, they still can’t understand a sentence. Lines are scripted or generated statistically, reflecting how hard it is to imbue machines with true language understanding. Once we cross that hurdle, we’ll see yet another evolution, perhaps from logistics coordinator to babysitter, teacher—or even friend? —Karen Hao