Nanoparticles reprogram immune cells to fight cancer

Dr. Matthias Stephan has a bold vision. He imagines a future where patients with leukemia could be treated as early as the day they are diagnosed with cellular immunotherapy that’s available in their neighborhood clinic and is as simple to administer as today’s chemotherapy, but without the harsh side effects. The key to that scientific leap? Nanoparticles, tiny technology that’s able to carry tumor-targeting genes directly to immune cells still within the body and program them to destroy cancer. In a proof-of-principle study published Monday in Nature Nanotechnology, Stephan and other researchers at Fred Hutchinson Cancer Research Center showed that nanoparticle-programmed immune cells, known as T cells, can clear or slow the progression of leukemia in a preclinical model.

nanoparticles reprogram genes

“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Stephan, the study’s senior author. Although his method for programming T cells is still several steps away from the clinic, Stephan envisions a future in which biodegradable nanoparticles could transform cell-based immunotherapies — whether for cancer or infectious disease — into an easily administered, off-the-shelf treatment that’s available anywhere.

Stephan imagines that in the future, nanoparticle-based immunotherapy could be “something that is available right away and can hopefully out-compete chemotherapies. That’s my excitement.”


‘Protective’ DNA strands are shorter in adults who had more infections as infants

New research indicates that people who had more infections as babies harbor a key marker of cellular aging as young adults: the protective stretches of DNA which “cap” the ends of their chromosomes are shorter than in adults who were healthier as infants.

TELOMERESThe 46 chromosomes of the human genome, with telomeres highlighted in white

These are important and surprising findings because — generally speaking — shorter chromosome ‘caps’ are associated with a higher burden of disease later in life,” said lead author Dan Eisenberg, an assistant professor of anthropology at the University of Washington.

The ‘caps’ Eisenberg and his co-authors measured are called telomeres. These are long stretches of DNA at the ends of our chromosomes, which protect our genes from damage or improper regulation. One Nobel Prize-winning scientist who studies telomeres has compared them to aglets — the plastic or metal sheath covering ends of shoelaces. When aglets wear down, the shoelace is exposed to fraying and degradation from environmental forces.

Like aglets, telomeres don’t last forever. In most of our cells, telomeres get shorter each time that cell divides. And when they get too short, the cell either quits dividing or dies.

That makes telomere length particularly important for the cells of our immune system, especially the white blood cells circulating in our bloodstream. When activated against a pathogen, white blood cells undergo rapid rounds of cell division to raise a defensive force against the infectious invader. But if telomeres in white blood cells are already too short, the body may struggle to mount an effective immune response.

Many studies — in laboratory animals and humans — have associated shorter telomeres with poor health outcomes, especially in adults,” said Eisenberg. But few studies have addressed whether or not events early in a person’s life might affect telomere length. To get at this question, Eisenberg turned to the Cebu Longitudinal Health and Nutrition Survey, which has tracked the health of over 3,000 infants born in 1983-1984 in Cebu City in the Philippines. Researchers collected detailed data every two months from mothers on the health and feeding habits of their babies up through age two. Mothers reported how often their babies had diarrhea — a sign of infection — as well as how often they breastfed their babies. As these babies grew up, scientists collected additional health data during follow-up surveys over the next 20 years. In 2005, 1,776 of these offspring donated a blood sample. By then, they were 21- or 22-year-old young adults.

Eisenberg measured telomere length in cells from those blood samples. He then combined the data on adult telomere length with information about their health and feeding habits as babies. He found that babies with higher reported cases of diarrhea at 6 to 12 months also had the shortest telomeres as adults.

The findings have been published in the American Journal of Human Biology.


Buildings That Grow Their Own Foundations

Could buildings one day grow their own foundations? This British architect thinks so. He says that within a decade his research team will create bacteria that interacts with the soil, strengthening buildings above and rendering concrete-filled trenches obsolete.

buildings-that-grow-their-own-foundationsCLICK ON THE IMAGE TO ENJOY THE VIDEO

Dr  Martyn Dade-Robertson, Reader in Design  Computation, Newcastle University, explains: “What we want to do is design a type of bacteria that would detect the mechanical changes in that soil, essentially synthesise materials so they would make materials in response. So they’re strengthening the soils where those loads are. The first part of that has been to identify pressure sensing genes, so genes in the bacteria that will respond to relatively low levels of pressure – and we can use that as a switch, effectively to turn on a process of material synthesis in the bacteria.”

His research team has identified dozens of genes in E. Coli bacteria, modifying them to create a ‘gene circuit‘.  This enables bacteria to respond to its environment and produce ‘biocement‘. Research is at an early stage, although self-healing material is already used in some concrete. Here the concept is being taken much further. Dr  Martyn Dade-Robertson adds: “We want to make the ground respond to the loads that are placed on it. The idea is that as you load the ground you get these pressures within this material and you get the ground essentially intelligently responding to those pressures by reinforcing itself, so you could construct large-scale civil engineering projects without digging those foundation trenches, by essentially seeding the ground with these microscopic bacteria.”

The team’s new computer aided design application is already predicting where underground bacteria may produce materials. If a grant application succeeds, they hope to have created and tested large-scale responsive material within three years.


The Gene That Causes Grey Hair Is Now Identified

No matter who you are; for most of us grey hair is an inevitable part of getting older. But what if you could switch off the gene that causes it? For the first time, scientists have identified a gene called IRF4 as the culprit behind grey hair. DNA samples from over 6,000 volunteers were collected in Latin America; chosen for the diverse ancestry of its inhabitants. And it turns out if you have your roots in Europe, grey hair is much more likely.


This genetic variant of IRF4 has two forms; one form is present world-wide and the other form is present only in Europeans. And we saw that this particular European specific form gives you almost double the chance of hair greying,” says Dr Kaustubh Adhikari from University College London (UCL), department of cell and developmental biology.

The gene IRF4 helps regulate melanin in the body, which determines – among other things – hair colour. Age and environmental factors will, of course, influence how quickly IRF4 triggers hair greying. But the researchers say their discovery could lead to a treatment that could stop it in its tracks.

Switching off a gene is of course feasible, the issue is whether it will have the desired effect and whether it’s the right thing to do… But in terms of trying to develop a therapy to delay or prevent hair greying, that is something that is potentially feasible; yes“, comments Professor Andres Ruiz-Linares, UCL (department of BioSciences).

Scientists think that a simple cosmetic treatment for switching off the grey gene would take many more years of research. But for those keen to banish the grey forever, your prayers might one day be answered.

The study has been published in the journal  Nature Communications.


Red Light To Attack Viruses

Light is helping Rice University scientists control both the infectivity of viruses and gene delivery to the nuclei of target cells. The researchers have developed a method to use two shades of red to control the level and spatial distribution of gene expression in cells via an engineered virus.

Although viruses have evolved to deliver genes into host cells, they still face difficulties getting their payloads from the cytoplasm into a cell’s nucleus, where gene expression occurs. The Rice labs of bioengineers Junghae Suh and Jeffrey Tabor have successfully found a way to overcome this critical hurdle. The result from labs at Rice’s BioScience Research Collaborative combines Suh’s interest in designing viruses to deliver genes to target cells with Tabor’s skills in optogenetics, in which light-responsive proteins can be used to control biological behavior. They built custom adeno-associated virus (AAV) vectors by incorporating proteins that naturally come together when exposed to red light (650-nanometer wavelengths) and break apart when exposed to far red (750-nanometer wavelengths). These naturally light-responsive proteins help the viral capsids – the hard shells that contain genetic payloadsenter the host cell nuclei.

red light against virusesViruses in general are relatively efficient at delivering genes into cells, but they still experience great limiting barriers,” she said. “If you add these viruses to cells, most of them seem to hang out outside of the nucleus, and only a small fraction make their way inside, which is the goal,” said Junghae Suh.

The team drew upon the Tabor lab’s expertise in optogenetics to increase the AAVs’ efficiency. “Jeff works with many different types of light-responsive proteins. The particular pair we decided upon was first identified in plants. Light is really nice because you can apply it externally and you can control many aspects: at what areas the light is exposed, the duration of exposure, the intensity of the light and, of course, its wavelength,” she added.


Robot Mother Builds Its Own Children

Researchers led by the University of Cambridge have built a mother robot that can independently build its own children and test which one does best; and then use the results to inform the design of the next generation, so that preferential traits are passed down from one generation to the next. Without any human intervention or computer simulation beyond the initial command to build a robot capable of movement, the mother created children constructed of between one and five plastic cubes with a small motor inside. In each of five separate experiments, the mother designed, built and tested generations of ten children, using the information gathered from one generation to inform the design of the next.

mother robot

Natural selection is basically reproduction, assessment, reproduction, assessment and so on,” said lead researcher Dr Fumiya Iida of Cambridge’s Department of Engineering, who worked in collaboration with researchers at ETH Zurich. “That’s essentially what this robot is doing – we can actually watch the improvement and diversification of the species.” For each robot child, there is a unique ‘genome’ made up of a combination of between one and five different genes, which contains all of the information about the child’s shape, construction and motor commands. As in nature, evolution in robots takes place through ‘mutation’, where components of one gene are modified or single genes are added or deleted, and ‘crossover’, where a new genome is formed by merging genes from two individuals.
The results, reported in the open access journal PLOS One, found that preferential traits were passed down through generations, so that the ‘fittest’ individuals in the last generation performed a set task twice as quickly as the fittest individuals in the first generation.


How To Cure Genetic Deafness

In this lab at Boston Children’s Hospital a cure for genetic deafness is taking shape. Lead researcher Jeff Holt says that if all goes as planned, children of the future who lose their ability to hear due to genetic mutation will never go deaf. Holt and his fellow researchers are attacking the problem at its source – they’re using engineered viruses to repair damaged genes that make up parts of the inner ear.


Our strategy was to take a viral vector, remove the viral genes so that it doesn’t make anyone sick and to replace those with the correct DNA sequence for TMC1” says Holt.

TMC1 is a gene critical to hearing. It’s responsible for encoding proteins that convert sound into electrical signals that the brain can process. To test their treatment protocol, Holt and his team used two types of deaf mice that model the dominant and recessive genetic mutations of TMC1 in humans. They delivered their engineered virus to the inner ears of the mice.

We found that we can restore function in both cases for recessive and dominant forms of TMC1 mutations“,  explains Holt. While genetic testing and brain activity showed that their treatment worked, the researchers still needed to find out if the deaf mice could actually hear.

We can’t really ask a mouse if they are able to hear but we can play a loud sudden sound and a normal mouse will jump in response to that, a deaf mouse does not move at all but after our gene therapy treatment the deaf mice began to jump“, he adds. There is at least 70 different mutations that cause one in one thousand people do go deaf in adolescence. Holt  says this gene therapy platform could potentially lead to treatment for all of them – ensuring that in the future no child ever loses their ability to hear.


Remote-Controlled Cyborg Beetles

Hard-wiring beetles for radio-controlled flight turns out to be a fitting way to learn more about their biology. Cyborg insect research led by engineers at UC Berkeley and Singapore’s Nanyang Technological University (NTU) is enabling new revelations about a muscle used by beetles for finely graded turns.

Research video showing remote-controlled steering of a giant flower beetle flying untethered. By strapping nanocomputers and wireless radios onto the backs of giant flower beetles and recording neuromuscular data as the bugs flew untethered, scientists determined that a muscle known for controlling the folding of wings was also critical to steering. The researchers then used that information to improve the precision of the beetles’ remote-controlled turns.

This study, published in the journal Current Biology, showcases the potential of wireless sensors in biological research. Research in this field could also lead to applications such as tools to aid search-and-rescue operations in areas too dangerous for humans.
cyborg beetle
What things would you have to strip out in terms of genes or in terms neurosystems to be left with a chassis that is effectively a flyable chassis. Why is an insect not a flying robot, because it has stuff in there that you would like to knock out and then get yourself a chassis“, says Michele Maharbiz, an associate professor in UC Berkeley’s Department of Electrical Engineering and Computer Sciences and the study’s principal investigator.. A chassis like you would find in a car. But while cars were designed with the sole purpose of driving, evolution has hardwired beetles for multiple functions, like mating and eating. All of these need to taken into account when developing a remote controlled beetle. The researchers have made much progress over the years. They have proven they can control the beetles with stimulation to both the brain and muscles. Maharbiz thinks a combination of both techniques will probably be needed to create an ideal cyborg beetle. “At a short term practical level I think that we could stand to build controlled flyers at very small scales this way, in other words using the best of electronics and the best of the natural world,“, adds Maharbiz.

RadioGenetics Remotely Control Cells, Genes

It’s the most basic of ways to find out what something does, whether it’s an unmarked circuit breaker or an unidentified geneflip its switch and see what happens. New remote-control technology may offer biologists a powerful way to do this with cells and genes. A team at Rockefeller University and Rensselaer Polytechnic Institute is developing a system that would make it possible to remotely control biological targets in living animals — rapidly, without wires, implants or drugs.
The team describes in the journal Nature Medicine, how it succeeded using electromagnetic waves to turn on insulin production to lower blood sugar in diabetic mice. Their system couples a natural iron storage particle, ferritin, to activate an ion channel called TRPV1 such that when the metal particle is exposed to a radio wave or magnetic field it opens the channel, leading to the activation of an insulin producing gene. Together, the two proteins act as a nano-machine that can be used to trigger gene expression in cells.

Tied together: Researchers experimented with different configurations for their remote control system, and they found the best relies on an iron nanoparticle (blue), which is tethered by a protein (green) to an ion channel (red). Above, all three appear within cell membranes.

The method allows one to wirelessly control the expression of genes in a living animal and could potentially be used for conditions like hemophilia to control the production of a missing protein. Two key attributes are that the system is genetically encoded and can activate cells remotely and quickly,” says Jeffrey Friedman, Marilyn M. Simpson Professor head of the Laboratory of Molecular Genetics at Rockefeller. “We are now exploring whether the method can also be used to control neural activity as a means for noninvasively modulating the activity of neural circuits.” Friedman and his Rensselaer colleague Jonathan S. Dordick were co-senior researchers on the project.


RNA Silences Genes, Treats Cancer

RNA interference (RNAi), a technique that can turn off specific genes inside living cells, holds great potential for treating many diseases caused by malfunctioning genes. RNA, a nanoparticle, transfers information from DNA to protein-forming system of the cell. However, it has been difficult for scientists to find safe and effective ways to deliver gene-blocking RNA to the correct targets.
Up to this point, researchers have gotten the best results with RNAi targeted to diseases of the liver, in part because it is a natural destination for nanoparticles. But now, in a study appearing in the May 11 issue of Nature Nanotechnology, an MIT-led team reports achieving the most potent RNAi gene silencing to date in nonliver tissues.
Using nanoparticles designed and screened for endothelial delivery of short strands of RNA called siRNA, the researchers were able to target RNAi to endothelial cells, which form the linings of most organs. This raises the possibility of using RNAi to treat many types of disease, including cancer and cardiovascular disease, the researchers say.

MIT engineers designed RNA-carrying nanoparticles (red) that can be taken up
There’s been a growing amount of excitement about delivery to the liver in particular, but in order to achieve the broad potential of RNAi therapeutics, it’s important that we be able to reach other parts of the body as well,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and one of the paper’s senior authors.
The paper’s other senior author is Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute. Lead authors are MIT graduate student James Dahlman and Carmen Barnes of Alnylam Pharmaceuticals.


Viruses Designed To Destroy Breast Cancer Cells

Rice University scientists have designed a tunable virus that works like a safe deposit box. It takes two keys to open it and release its therapeutic cargo. The Rice lab of bioengineer Junghae Suh has developed an adeno-associated virus (AAV) that unlocks only in the presence of two selected proteases, enzymes that cut up other proteins for disposal. Because certain proteases are elevated at tumor sites, the viruses can be designed to target and destroy the cancer cells.

We were looking for other types of biomarkers beyond cellular receptors present at disease sites,” Suh said. “In breast cancer, for example, it’s known the tumor cells oversecrete extracellular proteases, but perhaps more important are the infiltrating immune cells that migrate into the tumor microenvironment and start dumping out a whole bunch of proteases as well.
“So that’s what we’re going after to do targeted delivery. Our basic idea is to create viruses that, in the locked configuration, can’t do anything. They’re inert,
” she said. When programmed AAVs encounter the right protease keys at sites of disease, “these viruses unlock, bind to the cells and deliver payloads that will either kill the cells for cancer therapy or deliver genes that can fix them for other disease applications.”
The work appears online this week in the American Chemical Society journal ACS Nano.

Lipid Nanoparticles Ideal For Delivering Drugs

A research team from the Faculty of Pharmacy of the Basque Public University(UPV/EHU) – Spain – is using nanotechnology to develop new formulations that can be applied to drugs and gene therapy. Specifically, they are using nanoparticles to design systems for delivering genes and drugs; this helps to get the genes and drugs to the point of action so that they can produce the desired effect. The scientists have shown that lipid nanoparticles are ideal for acting as vectors in gene therapy. Gene therapy is a highly promising alternative for diseases that so far have no effective treatment. It consists of delivering a nucleic acid, for example, a therapeutic gene, to modulate the expression of a protein that is found to be altered in a specific disease, thus reversing the biological disorder.
lipid nanoparticle
“Using lipid nanoparticles conducts to new formulations to deliver drugs that are not particularly soluble or which are difficult to absorb”, Dr Rodriguez explained. “40% of the new pharmacologically active molecules are reckoned to be insoluble or not very soluble in water; that prevents many of these potentially active molecules from ever reaching the clinic because of the problems involved in developing a safe, effective formulation.” explains Dr Alicia Rodriguez.