In a serendipitous discovery, scientists at The Scripps Research Institute (TSRI) have found a way to turn bone marrow stem cells directly into brain cells.
Current techniques for turning patients’ marrow cells into cells of some other desired type are relatively cumbersome, risky and effectively confined to the lab dish. The new finding points to the possibility of simpler and safer techniques. Cell therapies derived from patients’ own cells are widely expected to be useful in treating spinal cord injuries, strokes and other conditions throughout the body, with little or no risk of immune rejection.
“These results highlight the potential of antibodies as versatile manipulators of cellular functions,” said Richard A. Lerner, the Lita Annenberg Hazen Professor of Immunochemistry and institute professor in the Department of Cell and Molecular Biology at TSRI, and principal investigator for the new study. “This is a far cry from the way antibodies used to be thought of—as molecules that were selected simply for binding and not function.”
The researchers discovered the method, reported in the online Early Edition of the Proceedings of the National Academy of Sciences the week of April 22, 2013, while looking for lab-grown antibodies that can activate a growth-stimulating receptor on marrow cells. One antibody turned out to activate the receptor in a way that induces marrow stem cells—which normally develop into white blood cells—to become neural progenitor cells, a type of almost-mature brain cell.
Natural antibodies are large, Y-shaped proteins produced by immune cells. Collectively, they are diverse enough to recognize about 100 billion distinct shapes on viruses, bacteria and other targets. Since the 1980s, molecular biologists have known how to produce antibodies in cell cultures in the laboratory. That has allowed them to start using this vast, target-gripping toolkit to make scientific probes, as well as diagnostics and therapies for cancer, arthritis, transplant rejection, viral infections and other diseases.
In the late 1980s, Lerner and his TSRI colleagues helped invent the first techniques for generating large “libraries” of distinct antibodies and swiftly determining which of these could bind to a desired target. The anti-inflammatory antibody Humira®, now one of the world’s top-selling drugs, was discovered with the benefit of this technology.
Last year, in a study spearheaded by TSRI Research Associate Hongkai Zhang, Lerner’s laboratory devised a new antibody-discovery technique—in which antibodies are produced in mammalian cells along with receptors or other target molecules of interest. The technique enables researchers to determine rapidly not just which antibodies in a library bind to a given receptor, for example, but also which ones activate the receptor and thereby alter cell function.
Lab Dish in a Cell
For the new study, Lerner laboratory Research Associate Jia Xie and colleagues modified the new technique so that antibody proteins produced in a given cell are physically anchored to the cell’s outer membrane, near its target receptors. “Confining an antibody’s activity to the cell in which it is produced effectively allows us to use larger antibody libraries and to screen these antibodies more quickly for a specific activity,” said Xie. With the improved technique, scientists can sift through a library of tens of millions of antibodies in a few days.
In an early test, Xie used the new method to screen for antibodies that could activate the GCSF receptor, a growth-factor receptor found on bone marrow cells and other cell types. GCSF-mimicking drugs were among the first biotech bestsellers because of their ability to stimulate white blood cell growth—which counteracts the marrow-suppressing side effect of cancer chemotherapy.
The team soon isolated one antibody type or “clone” that could activate the GCSF receptor and stimulate growth in test cells. The researchers then tested an unanchored, soluble version of this antibody on cultures of bone marrow stem cells from human volunteers. Whereas the GCSF protein, as expected, stimulated such stem cells to proliferate and start maturing towards adult white blood cells, the GCSF-mimicking antibody had a markedly different effect.
“The cells proliferated, but also started becoming long and thin and attaching to the bottom of the dish,” remembered Xie.
To Lerner, the cells were reminiscent of neural progenitor cells—which further tests for neural cell markers confirmed they were.
A New Direction
Changing cells of marrow lineage into cells of neural lineage—a direct identity switch termed “transdifferentiation”—just by activating a single receptor is a noteworthy achievement. Scientists do have methods for turning marrow stem cells into other adult cell types, but these methods typically require a radical and risky deprogramming of marrow cells to an embryonic-like stem-cell state, followed by a complex series of molecular nudges toward a given adult cell fate. Relatively few laboratories have reported direct transdifferentiation techniques.
“As far as I know, no one has ever achieved transdifferentiation by using a single protein—a protein that potentially could be used as a therapeutic,” said Lerner.
Current cell-therapy methods typically assume that a patient’s cells will be harvested, then reprogrammed and multiplied in a lab dish before being re-introduced into the patient. In principle, according to Lerner, an antibody such as the one they have discovered could be injected directly into the bloodstream of a sick patient. From the bloodstream it would find its way to the marrow, and, for example, convert some marrow stem cells into neural progenitor cells. “Those neural progenitors would infiltrate the brain, find areas of damage and help repair them,” he said.
While the researchers still aren’t sure why the new antibody has such an odd effect on the GCSF receptor, they suspect it binds the receptor for longer than the natural GCSF protein can achieve, and this lengthier interaction alters the receptor’s signaling pattern. Drug-development researchers are increasingly recognizing that subtle differences in the way a cell-surface receptor is bound and activated can result in very different biological effects. That adds complexity to their task, but in principle expands the scope of what they can achieve. “If you can use the same receptor in different ways, then the potential of the genome is bigger,” said Lerner.
19 April 2013
A healthy blood supply is essential to our lives. But before a single drop of blood can flow, cells lining a developing vessel (endothelial cells, pictured here in green with their nuclei stained blue) need to reach out to the surrounding tissue for support. This tiny feat of structural engineering is vital, but difficult to investigate inside the human body. Instead, these endothelial cells have been grown inside a man-made microenvironment – a ‘home-from-home’ recreation of a tissue’s natural chemicals and cells, constructed in a dish. Suitably comfortable, these cells behave as they would in a developing blood vessel, migrating towards deep-tissue cells (bunched-up on the right) that offer firm anchorage and support. Understanding the early stages of vessel formation, known as angiogenesis, might allow pre-emptive treatment of problems during foetal development, but also – as life’s processes often don’t discriminate – to stop new blood vessels developing towards hungry cancers.
Written by John Ankers
Bursts of Brain Activity May Protect Against Alzheimer’s Disease
Evidence indicates that the accumulation of amyloid-beta proteins, which form the plaques found in the brains of Alzheimer’s patients, is critical for the development of Alzheimer’s disease, which impacts 5.4 million Americans. And not just the quantity, but also the quality of amyloid-beta peptides is crucial for Alzheimer’s initiation. The disease is triggered by an imbalance in two different amyloid species — in Alzheimer’s patients, there is a reduction in a relative level of healthy amyloid-beta 40 compared to 42.
Now Dr. Inna Slutsky of Tel Aviv University’s Sackler Faculty of Medicineand the Sagol School of Neuroscience, with postdoctoral fellow Dr. Iftach Dolev and PhD student Hilla Fogel, have uncovered two main features of the brain circuits that impact this crucial balance. The researchers have found that patterns of electrical pulses (called “spikes”) in the form of high-frequency bursts and the filtering properties of synapses are crucial to the regulation of the amyloid-beta 40/42 ratio. Synapses that transfer information in spike bursts improve the amyloid-beta 40/42 ratio.
This represents a major advance in understanding that brain circuits regulate composition of amyloid-beta proteins, showing that the disease is not just driven by genetic mutations, but by physiological mechanisms as well. Their findings were recently reported in the journal Nature Neuroscience.
Tipping the balance
High-frequency bursts in the brain are critical for brain plasticity, information processing, and memory encoding. To check the connection between spike patterns and the regulation of amyloid-beta 40/42 ratio, Dr. Dolev applied electrical pulses to the hippocampus, a brain region involved in learning and memory.
When increasing the rate of single pulses at low frequencies in rat hippocampal slices, levels of both amyloid-beta 42 and 40 grew, but the 40/42 ratio remained the same. However, when the same number of pulses was distributed in high-frequency bursts, researchers discovered an increased amyloid-beta 40 production. In addition, the researchers found that only synapses optimized to transfer encoded by bursts contributed towards tipping the balance in favor of amyloid-beta 40. Further investigations conducted by Fogel revealed that the connection between spiking patterns and the type of amyloid-beta produced could revolve around a protein called presenilin. “We hypothesize that changes in the temporal patterns of spikes in the hippocampus may trigger structural changes in the presenilin, leading to early memory impairments in people with sporadic Alzheimer’s,” explains Dr. Slutsky.
Behind the bursts
According to Dr. Slutsky, different kinds of environmental changes and experiences — including sensory and emotional experience — can modify the properties of synapses and change the spiking patterns in the brain. Previous research has suggested that a stimulant-rich environment could be a contributing factor in preventing the development of Alzheimer’s disease, much as crossword and similar puzzles appear to stimulate the brain and delay the onset of Alzheimer’s. In the recent study, the researchers discovered that changes in sensory experiences also regulate synaptic properties — leading to an increase in amyloid-beta 40.
In the next stage, Dr. Slutsky and her team are aiming to manipulate activity patterns in the specific hippocampal pathways of Alzheimer’s models to test if it can prevent the initiation of cognitive impairment. The ability to monitor dynamics of synaptic activity in humans would be a step forward early diagnosis of sporadic Alzheimer’s.
Frog-like robot will help surgeons
Researchers at the University of Leeds are using the feet of tree frogs as a model for a tiny robot designed to crawl inside patients’ bodies during keyhole surgery.
The tiny device is one of a growing stable of bio-inspired robots being built in the University’s School of Mechanical Engineering and featured on the BBC’s The One Show last night.
It is designed to move across the internal abdominal wall of a patient, allowing surgeons to see what they are doing on a real-time video feed.
The tree frog’s feet provide a solution to the critical problem of getting the device to hold onto wet, slippery tissue when it is vertical or upside down. Although it is relatively easy to find ways of sticking to or gripping tissue, the patterns on the frog’s feet offer a way to hold and release a grip without harming the patient.
Biological transistor enables computing within living cells
When Charles Babbage prototyped the first computing machine in the 19th century, he imagined using mechanical gears and latches to control information. ENIAC, the first modern computer developed in the 1940s, used vacuum tubes and electricity. Today, computers use transistors made from highly engineered semiconducting materials to carry out their logical operations.
And now a team of Stanford University bioengineers has taken computing beyond mechanics and electronics into the living realm of biology. In a paper to be published March 28 in Science, the team details a biological transistor made from genetic material — DNA and RNA — in place of gears or electrons. The team calls its biological transistor the “transcriptor.”
“Transcriptors are the key component behind amplifying genetic logic — akin to the transistor and electronics,” said Jerome Bonnet, PhD, a postdoctoral scholar in bioengineering and the paper’s lead author.
The creation of the transcriptor allows engineers to compute inside living cells to record, for instance, when cells have been exposed to certain external stimuli or environmental factors, or even to turn on and off cell reproduction as needed.
“Biological computers can be used to study and reprogram living systems, monitor environments and improve cellular therapeutics,” said Drew Endy, PhD, assistant professor of bioengineering and the paper’s senior author.
The biological computer
In electronics, a transistor controls the flow of electrons along a circuit. Similarly, in biologics, a transcriptor controls the flow of a specific protein, RNA polymerase, as it travels along a strand of DNA.
“We have repurposed a group of natural proteins, called integrases, to realize digital control over the flow of RNA polymerase along DNA, which in turn allowed us to engineer amplifying genetic logic,” said Endy.
Using transcriptors, the team has created what are known in electrical engineering as logic gates that can derive true-false answers to virtually any biochemical question that might be posed within a cell.
They refer to their transcriptor-based logic gates as “Boolean Integrase Logic,” or “BIL gates” for short.
Transcriptor-based gates alone do not constitute a computer, but they are the third and final component of a biological computer that could operate within individual living cells.
Despite their outward differences, all modern computers, from ENIAC to Apple, share three basic functions: storing, transmitting and performing logical operations on information.
Last year, Endy and his team made news in delivering the other two core components of a fully functional genetic computer. The first was a type of rewritable digital data storage within DNA. They also developed a mechanism for transmitting genetic information from cell to cell, a sort of biological Internet.
It all adds up to creating a computer inside a living cell.
Digital logic is often referred to as “Boolean logic,” after George Boole, the mathematician who proposed the system in 1854. Today, Boolean logic typically takes the form of 1s and 0s within a computer. Answer true, gate open; answer false, gate closed. Open. Closed. On. Off. 1. 0. It’s that basic. But it turns out that with just these simple tools and ways of thinking you can accomplish quite a lot.
“AND” and “OR” are just two of the most basic Boolean logic gates. An “AND” gate, for instance, is “true” when both of its inputs are true — when “a” and “b” are true. An “OR” gate, on the other hand, is true when either or both of its inputs are true.
In a biological setting, the possibilities for logic are as limitless as in electronics, Bonnet explained. “You could test whether a given cell had been exposed to any number of external stimuli — the presence of glucose and caffeine, for instance. BIL gates would allow you to make that determination and to store that information so you could easily identify those which had been exposed and which had not,” he said.
By the same token, you could tell the cell to start or stop reproducing if certain factors were present. And, by coupling BIL gates with the team’s biological Internet, it is possible to communicate genetic information from cell to cell to orchestrate the behavior of a group of cells.
“The potential applications are limited only by the imagination of the researcher,” said co-author Monica Ortiz, a PhD candidate in bioengineering who demonstrated autonomous cell-to-cell communication of DNA encoding various BIL gates.
Building a transcriptor
To create transcriptors and logic gates, the team used carefully calibrated combinations of enzymes — the integrases mentioned earlier — that control the flow of RNA polymerase along strands of DNA. If this were electronics, DNA is the wire and RNA polymerase is the electron.
“The choice of enzymes is important,” Bonnet said. “We have been careful to select enzymes that function in bacteria, fungi, plants and animals, so that bio-computers can be engineered within a variety of organisms.”
On the technical side, the transcriptor achieves a key similarity between the biological transistor and its semiconducting cousin: signal amplification.
With transcriptors, a very small change in the expression of an integrase can create a very large change in the expression of any two other genes.
To understand the importance of amplification, consider that the transistor was first conceived as a way to replace expensive, inefficient and unreliable vacuum tubes in the amplification of telephone signals for transcontinental phone calls. Electrical signals traveling along wires get weaker the farther they travel, but if you put an amplifier every so often along the way, you can relay the signal across a great distance. The same would hold in biological systems as signals get transmitted among a group of cells.
“It is a concept similar to transistor radios,” said Pakpoom Subsoontorn, a PhD candidate in bioengineering and co-author of the study who developed theoretical models to predict the behavior of BIL gates. “Relatively weak radio waves traveling through the air can get amplified into sound.”
To bring the age of the biological computer to a much speedier reality, Endy and his team have contributed all of BIL gates to the public domain so that others can immediately harness and improve upon the tools.
“Most of biotechnology has not yet been imagined, let alone made true. By freely sharing important basic tools everyone can work better together,” Bonnet said.
Science fiction? Science reality.
Higgs Boson Positively Identified! (Probably)
by Adrian Cho
Eight months ago, physicists working with the world’s biggest atom smasher—Europe’s Large Hadron Collider (LHC)—created a sensation when they reported that they had discovered a particle that appeared to be the long-sought Higgs boson, the last missing piece in their standard model of particles and forces. Today, those researchers reported that the particle does indeed have the basic predicted properties of the standard model Higgs boson, clinching the identification.
“It sure does look like the standard model Higgs boson, you bet,” says Sally Dawson, a theorist at Brookhaven National Laboratory in Upton, New York, who was not involved with the measurements.
It’s a big step, at least semantically. Ever since the new particle was reported last July, officials at the home of the LHC—the European particle physics laboratory, CERN, near Geneva, Switzerland—have taken great care to describe the new thing as a “Higgs-like particle.” Now, a CERN press release calls the particle “a Higgs boson.” “That’s a big deal for the community,” Dawson says.
To make the positive identification, researchers relied not on dental records, but on observations of how the Higgs boson decays into combinations of other, more familiar particles. Key characteristics of the Higgs include its spin and its parity, a symmetry property. They can be determined by looking at correlations in the particle directions when, for example, a Higgs boson decays into two particles called Z bosons, each of which then decays into two particles called muons…
(read more: Science NOW) (images: CERN/ATLAS Project)
Electronic chips self-heal after laser blast
It might sound like the stuff of science fiction, but a team of engineers at the California Institute of Technology (Caltech), for the first time ever, has developed just such self-healing integrated chips.
The team demonstrated this self-healing capability in tiny power amplifiers. The amplifiers are so small that 76 of the chips—including everything they need to self-heal—could fit on a single penny.
In perhaps the most dramatic of their experiments, the team destroyed various parts of their chips by zapping them multiple times with a high-power laser, and then observed as the chips automatically developed a work-around in less than a second.“It was incredible the first time the system kicked in and healed itself. It felt like we were witnessing the next step in the evolution of integrated circuits,” says Ali Hajimiri, professor of electrical engineering. “We had literally just blasted half the amplifier and vaporized many of its components, such as transistors, and it was able to recover to nearly its ideal performance.
The team’s results appear in the March issue of IEEE Transactions on Microwave Theory and Techniques.
Side Note: A few days ago I highlighted an article from WiredScience that delved into the idea, and even serious plans of humans undergoing a 501 day trip to Mars in the year 2018 and I recall many of you thought it was downright madness, a near impossibility due to our technological restraints. But is it really that crazy of an idea at this point in space exploration’s progression considering what has already been achieved? While the mission doesn’t necessarily send humans into Mars but close to its orbit much the same way astronauts like Chris Hadfield navigate close to Earth’s orbit in the International Space Station, it still provides a trove of data and experience much needed in our later attempts to actually try and colonize Mars. This follow up explains the mission a little more and gets into its possibility and chances of success.
This bold undertaking is planned by the Inspiration Mars Foundation, a non-profit company founded by millionaire and space tourist Dennis Tito that was officially unveiled on Feb. 27 after early details leaked. Though the spacecraft would not land humans on Mars or even put them in orbit, it would bring people within a few hundred kilometers of the Martian surface — roughly the same distance between the International Space Station and Earth — and represent a major milestone in human spaceflight. If successful, the mission would go down in history as the first time a private company accomplished something government agencies were unable to do in space.
The mission is extremely ambitious, well beyond anything previously accomplished by the private sector and it faces plenty of obstacles. The company has an aggressive schedule to keep if it wants to hit its 2018 mark and needs to make sure the necessary technology is developed and well-tested. Despite its deep-pocketed backer, the mission has nowhere near the funding it needs to launch and will require raising greater sums than have ever been done for a private space endeavor. Its designers also need to figure out exactly how to keep the crew healthy, both physically and psychologically, for the 501-day duration of the flight as they face dangers from radiation, bone and muscle loss, fatigue, and depression. Mission designers will have to ensure they can get the crew safely to the ground when the capsule returns to Earth at a screaming 30,000 mph.
Yet despite these hurdles, of all the bold announcements from private spaceflight companies in recent years, this one seems the most achievable.
“The reason this entire thing is possible is because it’s actually a very simple mission,” said Jane Poynter, president of the Paragon Space Development Corporation, which makes life-support systems and has partnered with Inspiration Mars. “We’re not trying to land, we’re going to fly by and we’re using extant technologies that NASA and the space industry have been developing for years.”
Inspiration Mars isn’t looking to sell a product in an unknown market, like the asteroid-mining Planetary Resources or the national-moon-ferrying Golden Spike Company, and doesn’t have incredibly aspirational aims, like the planet-colonizing Mars One. It hopes to undertake a straightforward mission that could spur innovation, inspire young scientists and engineers, and move human spaceflight forward.
“You have to have a reasonable degree of skepticism and realism,” said Taber MacCallum, who co-founded Paragon with Poynter (and is also her husband). “We might run into some insurmountable obstacle 18 months in. But with proper engineering, support, and a good mess of luck, we could see this done.”
Now all they have to do is actually fly to Mars.
Scientists believe a little girl born with HIV has been cured of the infection.
She’s the first child and only the second person in the world known to have been cured since the virus touched off a global pandemic nearly 32 years ago.
Doctors aren’t releasing the child’s name, but we know she was born in Mississippi and is now 2 ½ years old – and healthy. Scientists presented details of the case on Sunday at a scientific conference in Atlanta.
The case has big implications. While fewer than 130 such children are born each year in the U.S., an estimated 330,000 children around the world get infected with HIV at or around birth every year, most of them in sub-Saharan Africa.
Until now, such children have been considered permanently infected. Specialists thought they needed lifelong antiviral drugs to prevent HIV from destroying their immune system and killing them of AIDS.
The Mississippi child’s surprising cure came about from happenstance – and the quick thinking of a University of Mississippi pediatric infectious disease specialist named Hannah Gay.
Microscopy image of HIV infecting an immune cell from the NIAID Flickr stream.
This is amazing, I hope that A.) the science community doesn’t downplay studies or observations such as this one and B.) that these observations are implemented and used wisely.
As I understand it, it’s more “functional” than “actual,” and the infant’s age is a huge contributor to the treatment’s success since it’s just a load of aggressive antiretrovirals (Brown is the only person i can think of off the top of my head who could have been said to be cured). Still, this is exciting.