The Scientist: Week in Review: February 3–7

Federal stem cell regulations vary; Salmonella exploit host immune system; microglia help maintain synaptic connections; prosthesis re-creates feeling of touch

Federal agencies clash over stem cell regs

WIKIMEDIA, RYDDRAGYN 

Moving basic research discoveries into the clinic can be difficult even with regulatory considerations set aside. Researchers working with some National Institutes of Health-approved stem cells face an additional translational challenge: therapies using these cells are not be eligible for commercialization because they don’t meet Food and Drug Administration requirements. That’s according to an analysis published in Cell Stem Cell this week (February 6).

“The main concern is: How do we move this technology [to the clinic]? How do we translate it?” author Erica Jonlin, the regulatory manager at the University of Washington Institute for Stem Cell and Regenerative Medicine, told The Scientist.

Salmonella hijack host immune response

WIKIMEDIA, CDC 

By outcompeting commensal E. coli, Salmonella enterica serovar Typhimurium can exploit a standard immune response in mice to promote their own growth, scientists from the University of California, Irvine, and their colleagues reported in Immunity this week (February 6).

“[This study] takes several counterintuitive observations in the field and connects them to a coherent picture—a daring ‘Battle of the Bugs,’” said microbiologist Sebastian Winter, from the University of Texas Southwestern Medical Center in Dallas, who was not involved in the work.

Synaptic maintenance improves connections

WIKIMEDIA, GRZEGORZ WICHER

Without microglia to perform “synaptic pruning”—in which unwanted neural links are disposed of—mouse brains develop with weaker connections, leading to altered social behavior. In a Nature Neuroscience paper published this week (February 3), researchers from the European Molecular Biology Laboratory and their colleagues proposed that their findings in mice could provide clues about human brain disorders that involve altered connectivity.

“The finding of a microglial role in synaptic pruning, and ultimately the emergence of efficient distributed networks, is very interesting,” said Ralph-Axel Müller from San Diego State University, who was not involved in the work.

Feeling touch with prosthesis takes some nerve

LIFEHAND 2/PATRIZIA TOCCI

By surgically implanting electrodes into the upper-arm nerves of a man whose limb had been amputated at the forearm, researchers from École Polytechnique Fédérale de Lausanne in Switzerland and their colleagues were able to partially and temporarily restore the man’s sense of touch, and to improve his ability to operate a motorized prosthesis, according to a study published in Science Translational Medicine this week.

“For the first time, the amputee was able to modulate the force produced by him in real time according to the sensory feedback we were providing,” study coauthor Silvestro Micera told The Scientist.

Other news in life science:

First CRISPR-Tinkered Primates Born
Twin macaques are the first primates born whose genomes were edited using CRISPR technology.

New Bird Flu Threat?
Chinese officials report the first two human cases of H10N8 avian influenza, one of which is linked to the death of a 73-year-old woman.

Judges Side with FDA on Stem Cells
A US federal appeals court maintains that stem cells proliferated in a lab must be regulated as a drug.

Microbial Smog
Some 1,300 species of microbes, including some associated with allergies and lung disease, are adrift in Beijing’s thick smog.

Researchers Read Fewer Papers
A new survey shows that scientists are perusing the literature less now than they have annually for 35 years.

ORIGINAL: Week in Review 

By Tracy Vence

February 7, 2014

Stanford scientists sequence genome of human's closest invertebrate relative

ORIGINAL: Stanford
By Bjorn Carey 

August 14, 2013

Botryllus schlosseri, a small sea creature, can regenerate its entire body from its blood vessels alone. Stanford researchers hope that sequencing its genome will lead to advances in regenerative and transplant medicine for humans.

Botryllus schlosseri is humans' closest living invertebrate relative. Chris Patton

At first glance, Botryllus schlosseri has very little in common with humans. The small sea creature fuses together with others to form colonies that look like psychedelic blobs, encrusting rocks and seaweeds. It can reproduce asexually, and an entire individual can be regenerated from its blood vessels alone.

And yet, Botryllus is humans' closest living invertebrate relative. (Invertebrates lack a spinal column.) Now, a group led by Stanford scientists has sequenced its genome, making it possible to find the genetic basis for some of the animal's amazing regenerative abilities and immunity features, which potentially could be applied to human medicine.

In total, the group sequenced the animal's 580 million base pairs of DNA. (The human genome, by comparison, consists of more than 3 billion base pairs.) Though the researchers haven't studied the entire genome, they found evidence that Botryllus makes a useful invertebrate model for studying human genetics, in particular for highlighting the evolution of immunity and stem cell-mediated regeneration.

The researchers compared the Botryllus genome with several vertebrate and invertebrate genomes. Focusing on genes involved in various human diseases – affecting things such as heart and eye development, pregnancy and cancer – they found homologous genes for each in Botryllus, far more matches than in any of a dozen other invertebrates commonly used in research.

An additional investigation of blood-related genes revealed that Botryllus was probably the first invertebrate to have vasculature in the same context of the human circulatory system, with blood cells traveling through blood vessels.

For example, in looking at a set of 20 genes that encode for humans' hematopoietic stem cells – cells that can self-renew and differentiate into other types of blood cells – they found 14 that are also expressed in cells isolated from the Botryllus stem cell niche. The scientists are now investigating how these genes function in Botryllus.

"The whole body can regenerate from the vasculature alone: the heart, digestive system, sophisticated tissues," said Ayelet Voskoboynik, a scientist at Stanford's Stem Cell Institute and Hopkins Marine Station, and the lead author on the study. "And it can do this relatively fast, probably using stem cells. Now that we have the genome, we can try to understand the mechanism behind it."

The study of Botryllus' genome could also lead to advances in transplant medicine. When two genetically distinct Botryllus colonies come into contact with each other, they either fuse their blood vessels to create a single organism, or reject one another and maintain individuality. When the blood vessels between the two colonies fuse into one interconnected network, the stem cells from each partner colony begin to circulate throughout the other.

The stem cells compete and in many cases one partner's stem cells "win" – and any new or replacement tissue grown through the fused colony does so based on the "winner's" genetic code.

A similar process occurs in humans who undergo an allogeneic transplant – when a patient receives tissue or cells from a non-identical donor. For instance, if a patient receives bone marrow or a ligament graft from a donor, over time, the recipient's cells replace the donor tissue.

In some instances, particularly concerning transplants of bone marrow or hematopoietic stem cells, the recipient's body rejects the donor cells. Voskoboynik suspects that studying the genetic basis for this interaction in Botryllus could lead to improvements in human therapies.

"If we can learn what makes a highly competitive stem cell a winner, and why others are rejected, we could hope to apply that knowledge to improve the success rate of allogeneic transplantations in humans," Voskoboynik said.

An important byproduct of the research, Voskoboynik said, was that Botryllus' complicated genome required the team to develop a new sequencing technique. The method, which has been patented, yielded exceptionally long, accurate sequences of DNA.

Additionally, rather than creating an average of the genetic information encoded on each paired chromosome, as standard techniques do, the new method yielded individual results from each chromosome. That advance, Voskoboynik said, could play a critical role in studying human diseases that occur as the result of different versions of genes existing on paired chromosomes.

The study was recently published in the peer-reviewed journal eLIFE.

Media Contact
Ayelet Voskoboynik: (831) 655-6244, ayeletv@stanford.edu

Bjorn Carey, Stanford News Service: (650) 725-1944, bccarey@stanford.edu

Here’s What Happens Inside You When a Mosquito Bites

ORIGINAL: Phenomena - NatGeo
by Ed Yong

Anopheles gambiae. Credit: James D. Gathany, CDC.

The video above shows a brown needle that looks like it’s trying to bury itself among some ice-cubes. It is, in fact, the snout of a mosquito, searching for blood vessels in the flesh of a mouse.

This footage was captured by Valerie Choumet and colleagues from the Pasteur Institute in Paris, who watched through a microscope as malarial mosquitoes bit a flap of skin on an anaesthetised mouse. The resulting videos provide an unprecedented look at exactly what happens when a mosquito bites a host and drinks its blood.

For a start, look how flexible the mouthparts are! The tip can almost bend at right angles, and probes between the mouse’s cells in a truly sinister way. This allows the mosquito to search a large area without having to withdraw its mouthparts and start over.

“I was genuinely amazed to see the footage,” says James Logan from the London School of Hygiene and Tropical Medicine, who studies mosquitoes. “I had read that the mouthparts were mobile within the skin, but actually seeing it in real time was superb. What you assume to be a rigid structure, because it has to get into the skin like a needle, is actually flexible and fully controllable. The wonders of the insect body never cease to amaze me!”

From afar, a mosquito’s snout might look like a single tube, but it’s actually a complicated set of tools, encased in a sheath called the labium. You can’t see the labrum at all in the videos; it buckles when the insect bites, allowing the six mouthparts within to slide into the mouse’s skin.

Four of these—a pair of mandibles and a pair of maxillae—are thin filaments that help to pierce the skin. You can see them flaring out to the side in the video. The maxillae end in toothed blades, which grip flesh as they plunge into the host. The mosquito can then push against these to drive the other mouthparts deeper.

The large central needle in the video is actually two parallel tubes—

• the hypopharynx, which sends saliva down, and 
• the labrum, which pumps blood back up. 

When a mosquito finds a host, these mouthparts probe around for a blood vessel. They often take several attempts, and a couple of minutes, to find one. And unexpectedly, around half of the ones that Choumet tested failed to do so. While they could all bite, it seemed that many suck at sucking.
The video below shows what happens when a mosquito finally finds and pierces a blood vessel. On average, they drink for around 4 minutes and at higher magnifications, Choumet could actually see red blood cells rushing up their mouthparts. They suck so hard that the blood vessels start to collapse. Some of them rupture, spilling blood into the surrounding spaces. When that happens, the mosquito sometimes goes in for seconds, drinking directly from the blood pool that it had created.

When the mosquitoes were infected with the Plasmodium parasites that cause malaria, they spent more time probing around for blood vessels. It’s not clear why—the parasites could be controlling the insect’s nervous system or changing the activity of genes in its mouthparts. Either way, the infected mosquitoes give up much less readily in their search for blood, which presumably increases the odds that the parasites will enter a new host.

Many hours after a bite, Choumet’s team found Plasmodium in the rodents’ skin, huddled in areas that were also rife with the mosquito’s saliva. The mosquito starts salivating as soon as it probes the mouse’s skin, releasing substances that 

• prevent blood vessels from constricting, 
• stop blood from clotting, and 
• prevent inflammation. 

Sometimes, Choumet could see the saliva as small bubbles that hung around the tips of the mouthparts. And even after the mosquito stops feeding, pockets of saliva linger in the lower layers of the skin. Plasmodium parasites seem to stay in the same place—perhaps they work together with the salivary chemicals to suppress the mouse’s immune system.
The team also tested “immunised” mice, which were loaded with antibodies that recognise a mosquito’s saliva. “Some people, especially in Africa and Asia, are bitten several times every day, so we wanted to know if mosquitoes behaved differently when they bit animals that were immunised against their saliva,” says Choumet.

She found that the antibodies reacted with the insect’s saliva during a bite, forming noticeable white clumps at the tips of the probing mouthparts. This clogged up smaller blood vessels, which stopped the mosquitoes from drinking from them. But the insects got around this problem by probing around for longer, and by hitting the largest blood vessels.

Beyond the stunning videos, these discoveries are unlikely to lead to new ways of preventing or treating malaria by themselves. However, they do tell us a lot more about the event that kicks off every single malaria case—a mosquito bite. It’s a resource that other researchers will undoubtedly use. “I have submitted a grant application to investigate aspects of the interactions between mosquitoes, hosts and parasites,” says Logan. “The techniques and discoveries from this paper are very exciting to me, and will be of value to future activities of my own research group.”

Hat-tip to James Logan for alerting me to the story via Twitter, and inspiring the headline!

Reference: Choumet, Attout, Chartier, Khun, Sautereau, Robbe-Vincent, Brey, Huerre & Bain. 2012. Visualizing Non Infectious and Infectious Anopheles gambiae Blood Feedings in Naive and Saliva-Immunized Mice. PLoS ONE http://dx.doi.org/10.1371/journal.pone.0050464

Learning from a Virus: Keeping Genes Under Wraps

ORIGINAL: University of Arizona

Cytomegalovirus particles as seen through an electron microscope: While some of the protein capsules are empty, others contain tightly packaged DNA, visible as dark structures. The diameter of a human hair would cover a line of about 600 virus particles. (Photo: Farah Bughio, Felicia Goodrum)

July 30, 2013 — An international collaboration of researchers including Felicia Goodrum of the University of Arizona's immunobiology department has studied how a human herpes virus carried by the majority of the population packages its genetic information during infection.

The discoveries improve the chances of developing more targeted therapies in place of existing drugs, which do not always work or come with side effects.

Experts estimate that 60 to 90 percent of the world's population carry the human cytomegalovirus, or CMV, which is one of the eight herpes viruses that infect humans.

In healthy individuals, the virus lies dormant and does not cause overt disease. However, it poses a significant risk when contracted by unborn children -- whose immune system has not matured yet -- and individuals with compromised immune function.

CMV is the leading cause of birth defects resulting from any infectious agent. It affects one in 150 births in the US and most commonly results in hearing loss, but can also cause cognitive or physical anomalies and cerebral palsy. Once infected, the virus stays in the body for life and flares up only when the immune system is suppressed, for example in AIDS patients, transplant patients and cancer patients undergoing intensive chemotherapy.

For the study, published in the scientific journal Proceedings of the National Academy of Sciences (PNAS), Goodrum teamed up with collaborators in Germany and Israel.

The researchers investigated how a fundamental aspect of the human cell regulates the virus: the mechanism by which genetic information is packaged and stored. Understanding how the viral DNA behaves in the human host cells during dormancy and reactivation of the virus provides the basis for the development of drugs that could prevent the virus from "waking up" and causing disease.

"The human immune system is very sophisticated, and the way this virus has managed to stealthily integrate into our biology to ensure its own survival is no small feat," said Goodrum, also a member of the UA's BIO5 Institute.

"CMV is a master of human cell biology. From transcribing DNA into blueprints for proteins to the manufacturing of those proteins, from cell division to cellular metabolism, there is not a process this virus has not tweaked," Goodrum also said.

Virus factory: The top image shows uninfected, normal human cells with cell nuclei in blue and the cellular protein processing apparatus in red. In the infected cells (bottom image), the virus has produced proteins (green) that take over and reorganize the cellular processing apparatus into a virus factory. (Credit: Photo: Farah Bughio, Felicia Goodrum)

That mastery, she explained, is the reason the virus is so elusive to vaccine, and there currently is no way to eradicate it. Goodrum noted that with other herpes viruses, like Epstein-Barr or chicken pox, the infection is obvious. But that is not the case with CMV.

"From the perspective of a virus, that is the pinnacle of mastery -- to infect without ever making its presence known," Goodrum said.

"To develop more effective antiviral strategies, we must understand the biology of the virus infection and how the virus manages to persist for our lifetimes," she said. "We are trying to understand how our cellular mechanisms are being used by this virus and discover targets for drugs to control it."

Each human cell contains a thread of DNA that is about 6 feet long, stowed away in its nucleus and tightly packaged by proteins called histones. One such package of genetic material is called a chromosome.

"You can imagine histones as a spool, and the thread is DNA that wraps around the spool," Goodrum said. "This accomplishes two important objectives: first, it condenses DNA so that it can be packed into the cell nucleus and second, it provides the cell with a mechanism to regulate the activity of the genes encoded on that DNA."

The association between histones and DNA is very dynamic and acts as a key mechanism used by cells to control which genes are expressed and which are not, Goodrum explained.

For example, when DNA is wound tightly around histones, it is not accessible to enzymes specializing in making copies of genes in a process called transcription, which subsequently serve as blueprints to manufacture proteins.

"When a virus like CMV infects our cells, its DNA is packaged by histones just as if it were the cell's own DNA," Goodrum said.

"The question is, how does this happen, and does the virus have any choice in the matter? Our work maps the deposition of histones across the viral DNA chromosome and shows that the virus encodes a mechanism to reorganize these histones to favor the expression of genes from the viral chromosome."

Michael Nevels of the Institute for Medical Microbiology and Hygiene at the University of Regensburg, Germany, said: "Now that we have determined the positions of the nucleosomes, we can study how transcription is regulated, and from that others can start developing therapies."

For example, if researchers can identify molecules that play key roles in the process, they can design new drugs that target those molecules.

"Since we can't eliminate the virus, the goal is to keep it in check," said Nevels, who led the study together with Eran Segal and Einat Zalckvar of the Weizmann Institute of Science in Rehovot, Israel.

"The idea is to target the virus on the level of its DNA structure and to reduce the gene activity back to the dormancy levels," Nevels said.

One such molecular target identified in this study is a viral protein called IE1. Because it regulates the packaging and unpacking of the viral DNA, it could potentially be a target for new therapies.

Cautioning that many more steps will be necessary before this could be achieved, Nevels said that "if we could inhibit IE1, the virus genome would be packed more tightly with histones, which leaves less DNA accessible and prevents genes from becoming active."

Another strategy takes the opposite direction by deliberately awaking the virus from its dormant state so it becomes vulnerable to antiviral drugs. This could be an option for patients about to undergo an organ transplantation, which requires immune-suppressing drugs to prevent the new organ from being rejected. Suppressing the immune system allows the virus to reactivate.

"There are antivirals that target the active, replicating virus but they can't target latent virus because in that state, it's really just a piece of DNA in the cell nucleus," Goodrum said. "Before those patients enter a immunosuppressed state, you would target the viral reservoirs and force the virus out of latency."

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference: E. Zalckvar, C. Paulus, D. Tillo, A. Asbach-Nitzsche, Y. Lubling, C. Winterling, N. Strieder, K. Mucke, F. Goodrum, E. Segal, M. Nevels. Nucleosome maps of the human cytomegalovirus genome reveal a temporal switch in chromatin organization linked to a major IE protein. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1305548110

Of Bacteria, Batman, and Yosemite Sam

ORIGINAL: OxBridgeBiotech

By Robert Cooper
Monday, 24th June 2013

In the past few centuries, our understanding of bacteria has progressed from mysterious medieval vapours, to the microscopic “animalcules” of van Leeuwenhoek, to the germ theory of disease à la Pasteur, to the realizations that bacteria outnumber us within our own bodies and that good ”probiotic” bacteria actually make us healthier. Now, a new study seems to have discovered a Batman bacterium. Well, technically, the bacterium was already well-known; the discovery was to show that this prokaryotic Bruce Wayne is, in fact, Batman.

An electron micrograph of Pseudomonas aeruginosa in its
natural environment.

What are the three defining characteristics of Batman?

• First, you don’t want to mess with Batman, for he will mess you up. 
• Second, Batman is a benevolent guardian. Behave yourself, and all will be fine. 
• Third, Batman is multidimensional. He is dark, his morality complex. 

Given those defining characteristics, I submit to you, courtesy of Basler et al. [1], that the bacterial species Pseudomonas aeruginosa is, indeed, Batman.

The bacterial world is a tough one, pockmarked by chemical and biological warfare. (Anthrax, after all, is a completely natural bacterium). In this microscopic world, one of the most common weapons is the type VI secretion system (T6SS), which blasts through opponent bacterial cell walls and delivers (all-natural) biological weapon warheads. P. aeruginosa, our Batman, has stockpiles of T6SS missiles, and it also has a missile defense system to deflect the T6SS of aggressors. UN inspectors are still trying to determine how exactly this defense system works, but Basler et al. suggest it may involve super-strong cell wall armor, a kind of bullet-proof vest, in addition to antidotes for any poison that does get in. Mix P. aeruginosa with other T6SS-packing bacteria, such as Vibrio cholera or Acinetobacter baylyi, and P. aeruginosa wins, pilli down. So Batman feature one – badassness: check.

However, if you mix P. aeruginosa with well-behaving bacteria that are not firing off T6SS’s, it turns out that P. aeruginosa keeps its own T6SS holstered. Even if you disarm the normally aggressive V. cholera by mutating its T6SS genes, P. aeurginosa now leaves it well-enough alone. P. aeruginosa will mess you up, but only if you shoot first. Contrast that with V. cholera, the Yosemite Sam of the bacterial world, which shoots off its T6SS at random but without P. aeruginosa‘s deadly precision. Batman feature two – benevolence: check.


Vibrio cholera has a bit of trouble controlling its T6SS.

As for the third feature of Batman – moral ambiguity – well, remember that P. aeruginosa is known to attack humans as well, especially those with cystic fibrosis. We should also note that P. aeruginosa can be rather high-strung; every once in a while one P. aeruginosa will flash its T6SS (presumably by accident [2], but we can’t discount the possibility that it’s showing off), which can spark violent duels with its neighboring sister cells. Batman feature three: check.

So what exactly is going on here? What role does this bacterial Batman play in microbial Gotham? The study authors suggest that P. aeruginosa may play a kind of sheepdog role, protecting other bacteria within the same biofilm from aggressors. In return, the other bacteria may help break down food that P. aeruginosa couldn’t eat on its own. However, microbial ecology is a very young field, and we can really only speculate what trauma P. aeruginosa went through as an evolutionary child to create this superhero. At any rate, this discovery is yet more evidence of how complex the microscopic world really is.

On a more practical level, by understanding what makes P. aeruginosa unsheath its T6SS, we might be able to re-establish a truce when this bacterium does cause infections. Eventually, we might even figure out how to hire it as a mercenary to supplement our own immune systems. I hear Basler et al. are working on a bat signal.

References
Basler, M., Ho, B.T.&Mekalanos, J.J., 2013. Tit-for-Tat: Type VI Secretion System Counterattack during Bacterial Cell-Cell Interactions. Cell, 152(4), pp.884–894.
By “accident” we mean, of course, a stochastic process following Poisson statistics.

Fire with Fire - Ross Kauffman MD

ORIGINAL: GE Focus / Forward

"...T - cells were infected with HIV-Virus cells genetically engineered so it can not cause disease anymore, but still retain the ability to reprogram the immune system so it will now attack cancer cells..."

Who would dare to pit one fatal disease against another... inside the body of an six-year-old patient? The results will shatter all expectations.

Birth Control Pills Affect Women's Taste in Men

ORIGINAL: Scientific American

How synthetic hormones change desire in women--and their choice in a mate

By Melinda Wenner

Image: © iStockPhoto / Ceneri

This year 2.25 million Americans will get married—and a million will get divorced. Could birth control be to blame for some of these breakups? Recent research suggests that the contraceptive pill—which prevents women from ovulating by fooling their body into believing it is pregnant—could affect which types of men women desire. Going on or off the pill during a relationship, therefore, may tempt a woman away from her man.

It’s all about scent. Hidden in a man’s smell are clues about his major histocompatibility complex (MHC) genes, which play an important role in immune system surveillance. Studies suggest that females prefer the scent of males whose MHC genes differ from their own, a preference that has probably evolved because it helps offspring survive: couples with different MHC genes are less likely to be related to each other than couples with similar genes are, and their children are born with more varied MHC profiles and thus more robust immune systems.

A study published in August in the Proceedings of the Royal Society B, however, suggests that women on the pill undergo a shift in preference toward men who share similar MHC genes. The female subjects were more likely to rate these genetically similar men’s scents (via a T-shirt the men had worn for two nights) as pleasant and desirable after they went on the pill as compared with before. Although no one knows why the pill affects attraction, some scientists believe that pregnancy—or in this case, the hormonal changes that mimic pregnancy—draws women toward nurturing relatives.

Women who start or stop taking the pill, then, may be in for some relationship problems. A study published last year in Psychological Science found that women paired with MHC-similar men are less sexually satisfied and more likely to cheat on their partners than women paired with MHC-dissimilar men. So a woman on the pill, for example, might be more likely to start dating a MHC-similar man, but he could ultimately leave her less sexually satisfied. Then if she goes off the pill during the relationship, the accompanying hormonal changes will draw her even more strongly toward more MHC-dissimilar men. These immune genes may have a “powerful effect in terms of how well relationships are cemented,” says University of Liverpool psychologist Craig Roberts, co-author of the August paper.