Forgetting Is Actively Regulated

In order to function properly, the human brain requires the ability not only to store but also to forget: Through memory loss, unnecessary information is deleted and the nervous system retains its plasticity. A disruption of this process can lead to serious mental disorders. Basel scientists have now discovered a molecular mechanism that actively regulates the process of forgetting. The renowned scientific journal “Cell” has published their results.

The human brain is build in such a way, that only necessary information is stored permanently - the rest is forgotten over time. However, so far it was not clear if this process was active or passive. Scientists from the transfaculty research platform Molecular and Cognitive Neurosciences (MCN) at the University of Basel have now found a molecule that actively regulates memory loss. The so-called musashi protein is responsible for the structure and function of the synaptic connections of the brain, the place where information is communicated from one neuron to the next.

Using olfactory conditioning, the researchers Attila Stetak and Nils Hadziselimovic first studied the learning abilities of genetically modified ringworms (C. elegans) that were lacking the musashi protein. The experiments showed that the worms exhibited the same learning skills as unmodified animals. However, with extended duration of the experiment, the scientists discovered that the mutants were able to remember the new information much better. In other words: The genetically modified worms lacking the musashi protein were less forgetful.

Forgetting is no coincidence
Further experiments showed that the protein inhibits the synthesis of molecules responsible for the stabilization of synaptic connections. This stabilization seems to play an important role in the process of learning and forgetting. The researchers identified two parallel mechanisms: One the one hand, the protein adducin stimulates the growth of synapses and therefore also helps to retain memory; on the other hand, the musashi protein actively inhibits the stabilization of these synapses and thus facilitates memory loss. Therefore, it is the balance between these two proteins that is crucial for the retention of memories.

Forgetting is thus not a passive but rather an active process and a disruption of this process may result in serious mental disorders. The musashi protein also has interesting implications for the development of drugs trying to prevent abnormal memory loss that occurs in diseases such as Alzheimer’s. Further studies on the therapeutic possibilities of this discovery will be done.

Ode to a nematode

In the pantheon of animal models upon which basic scientific research relies, no species stands taller (metaphorically speaking) than Caenorhabditis elegans, a tiny worm (just one millimeter in length) that is broadly used to study fundamental molecular, cellular and developmental  processes in animals.

Nobel laureate Sidney Brenner was among the first to promote the nematode’s utility as a model organism in the early 1960s for a variety of reasons: It is simple. Its entire neural system consists of exactly 302 neurons. It’s easy and cheap to grow in large numbers – and you can freeze the worms, and then thaw them out for later use. And it’s transparent, making it all the easier to peer at the worm’s internal workings. 

C. elegans was the first organism to have its genome completely sequenced in 1998. An adult hermaphrodite worm contains 20,470 protein-coding genes, only slightly less than the estimated total for a human being.

In recent years, scientists have begun creating systemic catalogs of how these genes function and interact, not just in C. elegans but in other model organisms as well. Some of this research is being done by researchers Karen Oegema, PhD, a professor of cellular and molecular medicine and head of the Laboratory of Mitotic Mechanisms in the Ludwig Institute for Cancer Research at UC San Diego and her colleague, Rebecca Green, PhD.

Rather than studying individual cells, Oegema, Green and co-workers look at the effect of gene inhibitions in the structure of a complex tissue. Sometimes, it results in an eye-popping picture. The image above reveals the architecture of C. elegans’ reproductive tissue – its gonads. Red fluorescent markers highlight cell boundaries; green markers indicate DNA.

Could Maple Syrup Help Protect Against Development of ALS?

Catherine Aaron and Gabrielle Beaudry were 17 when they knocked on the door of the laboratory of Alex Parker, a neuroscience researcher at the University of Montreal Hospital Research Centre (CRCHUM). While students at Collège Jean-de-Brébeuf in Montreal, they were looking for a mentor for an after-school research project. Two and half years later, the results of this scientific adventure were published today in the Journal of Agricultural and Food Chemistry.

“We wanted to test the effect of a natural product on a neurodegenerative disease such as Alzheimer’s. Professor Parker had already discovered that sugar prevents the occurrence of amyotrophic lateral sclerosis (ALS) in an animal model of the disease, the C. elegans worm. That’s how we got the idea of maple syrup, a natural sugar produced in Quebec,” said Beaudry.

Supervised by PhD student Martine Therrien and Alex Parker, Aaron and Beaudry added maple syrup to the diet of these barely 1 mm-long nematodes. “We just gave them a supplement of maple syrup at various concentrations and compared with a control group that had a normal diet,” said Aaron. “After twelve days, we counted under the microscope the worms that were moving and those that were paralyzed. The worms that had consumed the highest dose of syrup were much less likely to be paralyzed.”

New clue to how lithium works in the brain

Since the 1970s, U.S. doctors have prescribed lithium to treat patients with bipolar disorder. While the drug has a good success rate, scientists are still unsure exactly how it achieves its beneficial effects.

MIT biologists have now discovered a possible explanation for how lithium works. In a study of worms, the researchers identified a key protein that is inhibited by lithium, making the worms less active.

While these behavioral effects in worms can’t be translated directly to humans, the results suggest a possible mechanism for lithium’s effects on the brain, which the researchers believe is worth exploring further.

“How lithium acts on the brain has been this great mystery of psychopharmacology,” says Joshua Meisel, an MIT postdoc and lead author of the study. “There are hypotheses, but nothing’s been proven.”

Dennis Kim, an associate professor of biology, is the senior author of the paper, which appears in the July 7 issue of Current Biology.

Mysterious effects

Lithium’s ability to act as a tranquilizer for people suffering from mania and bipolar disorder was discovered in 1949 by the Australian psychiatrist John Cade, but the drug was not approved by the U.S. Food and Drug Administration until 1970.

Lithium interacts with many proteins and other molecules in the brain, so it has been difficult for scientists to determine which of these interactions produce mood stabilization. Some of the hypothesized targets are an enzyme that produces inositol, a simple sugar involved in cell signaling, and an enzyme called GSK3, which inactivates other proteins. However, no studies have conclusively linked these targets to lithium’s effects on bipolar patients.

The MIT team did not set out to study lithium but fell upon it while exploring interactions between Caenorhabditis elegans and its microbial environment. This worm has a simple nervous system consisting of 302 neurons, most of which occur in pairs.

In a paper published in 2014, Meisel and Kim discovered that a pair of neurons known as ASJ neurons are necessary for the worm’s avoidance of harmful bacteria. Previous studies from other labs had shown that the ASJ neurons are also required for reawakening from a starvation-induced hibernation state. This reactivation, known as the dauer exit, occurs when food becomes more plentiful.

As a follow-up to that study, the researchers performed a genetic screen in which they looked for mutated genes that disrupt ASJ neurons. To their surprise, one of the genes implicated by this screen was one that codes for a protein called BPNT1, which was already known to be inhibited by lithium.

BPNT1 is a protein that removes phosphate groups from a compound known as PAP, a process that is critical to maintaining normal cell function.

When the researchers knocked out the gene for BPNT1, they found that the ASJ neurons entered a dormant state and the worms could no longer execute either avoidance behavior or the dauer exit. They also found the same behavioral effects in worms treated with lithium.

John York, a professor of biochemistry at Vanderbilt University School of Medicine, says the findings are intriguing.

“This is an important step in showing a neural function for BPNT-1. It’s the first study to show in a multicellular system that the BPNT-1 protein might be the target for lithium’s action,” says York, who was not involved in the research.

New hypothesis

The findings suggest that lithium treatment silences activity in neurons that rely on BPNT1, which Meisel and Kim found intriguing because many human brain cells also depend on this protein. In humans, PAP, which BPNT1 degrades, is usually found in neurons that secrete dopamine, epinephrine, or norepinephrine, which are all neurotransmitters that stimulate brain activity.

“We think that it’s perfectly reasonable to add BPNT1 onto the list of hypotheses for how lithium is affecting the brain,” Meisel says. “Silencing dopaminergic neurons I would think would make you less manic because of how dopamine affects the brain.”

While Kim’s lab focuses on worms, the researchers hope that other labs will test the new hypothesis in other animals.

“Establishing that this happens in C. elegans, by no means does it prove how lithium works in humans, but it provides a very solid experimental foundation for exploring a hypothesis that lithium might have therapeutic effects in specific neurons through inhibition of BPNT1,” Kim says. “We hope that other groups that work on mammalian systems may be interested to explore this question further.”

I Programmer:

Take the connectome of a worm and transplant it as software in a Lego Mindstorms EV3 robot - what happens next?

It is a deep and long standing philosophical question: Are we just the sum of our neural networks? Of course, if you work in AI you take the answer mostly for granted, but until someone builds a human brain and switches it on we really don’t have a concrete example of the principle in action.

The nematode worm Caenorhabditis elegans (C. elegans) is tiny and only has 302 neurons. These have been completely mapped and the OpenWorm project is working to build a complete simulation of the worm in software. One of the founders of the OpenWorm project, Timothy Busbice, has taken the connectome and implemented an object oriented neuron program.

The model is accurate in its connections and makes use of UDP packets to fire neurons. If two neurons have three synaptic connections then when the first neuron fires a UDP packet is sent to the second neuron with the payload “3”. The neurons are addressed by IP and port number. The system uses an integrate and fire algorithm. Each neuron sums the weights and fires if it exceeds a threshold. The accumulator is zeroed if no message arrives in a 200ms window or if the neuron fires. This is similar to what happens in the real neural network, but not exact.

The software works with sensors and effectors provided by a simple LEGO robot. The sensors are sampled every 100ms. For example, the sonar sensor on the robot is wired as the worm’s nose. If anything comes within 20cm of the “nose” then UDP packets are sent to the sensory neurons in the network.

The same idea is applied to the 95 motor neurons but these are mapped from the two rows of muscles on the left and right to the left and right motors on the robot. The motor signals are accumulated and applied to control the speed of each motor. The motor neurons can be excitatory or inhibitory and positive and negative weights are used.

And the result?

It is claimed that the robot behaved in ways that are similar to observed C. elegans. Stimulation of the nose stopped forward motion. Touching the anterior and posterior touch sensors made the robot move forward and back accordingly. Stimulating the food sensor made the robot move forward.

The key point is that there was no programming or learning involved to create the behaviors. The connectome of the worm was mapped and implemented as a software system and the behaviors emerge.
The conectome may only consist of 302 neurons but it is self-stimulating and it is difficult to understand how it works - but it does.

Currently the connectome model is being transferred to a Raspberry Pi and a self-contained Pi robot is being constructed. It is suggested that it might have practical application as some sort of mobile sensor - exploring its environment and reporting back results. Given its limited range of behaviors, it seems unlikely to be of practical value, but given more neurons this might change.

Is the robot a C. elegans in a different body or is it something quite new? 

Is it alive?


EDIT: Wow tumblr, thanks for eating my whole description.

My C. elegans recently outgrew his little vial, so these are some pictures of me transferring my fat happy baby into a bigger container. c:
He’s actually a lot more docile and confident than I expected, and he was totally cool with being handled. EATS LIKE A MONSTER AND DOESN’T AFRAID OF ANYTHING. So I think after another moult or two I’ll start handling him once a week for a few minutes to get him more accustomed to it, and see how he does. He might make a better “hand” tarantula than I anticipated!
He’s grown so much, too. I seriously can’t get over it. I’ve only had him for less than 5 months, and he was under 0.25" when I got him. I’M SO PROUD.

(Image caption: Against a background of nematode worms, this graphic depicts the stressed mitochondria (lower right, blue and red) accumulating lipid droplets (red balls) in the interior or cytosol of the cell. The molecular structure of the two key lipid components in the newly discovered signaling pathway are ceramide (right) and cardiolipin (upper left). The background image shows a picture of the nematode C. elegans with clumps of the Huntington’s aggregates (bright green because they’re tagged with green fluorescent protein) in the body wall muscle cells. Credit: Hyun-eui Kim and Sarah Uhlein Tronnes)

Can some types of fat protect us from brain disease?

An intriguing finding in nematode worms suggests that having a little bit of extra fat may help reduce the risk of developing some neurodegenerative diseases, such as Huntington’s, Parkinson’s and Alzheimer’s diseases.

What these illnesses have in common is that they’re caused by abnormal proteins that accummulate in or between brain cells to form plaques, producing damage that causes mental decline and early death.

Huntington’s disease, for example, is caused by aggregating proteins inside brain neurons that ultimately lead to motor dysfunction, personality changes, depression and dementia, usually progressing rapidly after onset in people’s 40s.

These protein aggregates – called Huntington’s aggregates – have been linked to problems with the repair system that nerve cells rely on to fix proteins that fold incorrectly: the cell’s so-called protein folding response. Misfolded proteins can make other proteins fold incorrectly, creating a chain reaction of misfolded proteins that form clumps that the cell can’t deal with.

When University of California, Berkeley, researchers perturbed the powerhouses of the cell, the mitochondria, in a strain of the nematode C. elegans that mimics Huntington’s disease, they saw their worms grow fat. They traced the effect to increased production of a specific type of lipid that, surprisingly, prevented the formation of aggregate proteins. The fat, they found, was required to turn on genes that protected the animals and cells from Huntington’s disease, revealing a new pathway that could be harnessed to treat the disease.

The same proved true in human cell lines cultured in a dish.

“We found that the worms and human cells were almost completely protected from the Huntington’s aggregates when we turned on this response,” said Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research in UC Berkeley’s Department of Molecular and Cell Biology and a Howard Hughes Medical Institute investigator.

They subsequently treated worms and human cells with Huntington’s disease with drugs that prevented the cell from sweeping up and storing the lipid, called ceramide, and saw the same protective effect.

“If we could manipulate this lipid pathway, we could go after Huntington’s disease, because in our studies the drugs were really beneficial,” he said. “This is poised to take to the next level.”

Dillin has already begun experiments in mice with Huntington’s disease to see if the drugs result in a better outcome. He published his latest findings online Sept. 8 in the journal Cell.

How Huntington’s disease causes wasting

In an accompanying paper in the same issue of Cell, Dillin also reports that stressing neurons in the brain makes them release a hormone, serotonin, that sends alert messages throughout the body that the brain cells are under attack, setting off a similar stress response in cells far from the brain. In diseases like Huntington’s, mental decline is also associated with peripheral metabolic defects and muscle decline.

“The serotonin release dramatically changes the metabolic output of peripheral cells and the sources they use for fuel, so we think it is instituting a large-scale metabolic rewiring, maybe to protect the neurons in the brain,” he said. “If you begin to shut down the periphery and stop using the limited resources it utilizes, then more of those resources can be shifted to brain metabolic activity. This might be a very clever way to try to save the brain by having the body waste away.”

While Dillin discovered the ability of mitochondria to communicate between different cells and tissues several years ago, the new study pinpoints serotonin as a primary driver of this metabolic response, he said.

Dillin noted that drugs that lower levels of serotonin have long been used to treat depression and other psychiatric manifestations of neurodegenerative diseases, but the new findings suggest these medications may have more widespread use in age-related disease than was previously thought. These findings have broad implications not only for the potential treatment of neurodegenerative disorders, but for further understanding the impact of neurological disease on metabolism and stress responses throughout the body.

Mitochondria key to brain degeneration

Both discoveries came from studies of mitochondria, the powerhouses of the cell that burn nutrients for energy but also play a key role in signaling, cell death and growth. Over the past several years, increasing evidence has associated mitochondrial dysfunctions with aging and age-onset protein misfolding diseases such as Alzheimer’s, Parkinson’s and Huntington’s.

Dillin is particularly interested in Huntington’s disease, which is inherited and strikes people in their 40s and 50s, inevitably leading to a wasting death. The genetic cause is well-known – expansion of a part of a gene that produces a protein with too many added glutamine amino acids. How this glutamine-rich protein leads to symptoms is only graduatlly being revealed.

While investigating mitochondria in nematodes genetically engineered to have Huntington’s disease, Dillin and his colleagues discovered that the abnormal proteins actually aggregate on the mitochondria, and that this ramps up the protein folding response within the cell, flooding both the mitochrondria and the cell interior with nearly 100 types of so-called heat shock proteins to try to fix the misfolded proteins. The heat-shock proteins act as mitochondrial chaperones to assist in the import and folding of mitochondrial proteins synthesized outside of mitochondria.

The researchers were surprised to find that knockdown of one specific mitochondrial chaperone, mtHSP70, elicited a unique stress response mediated by fat accumulation, resulting in improved protein folding in the interior or cytosol of the cell. Drugs that activate this novel stress response pathway, which they call the mitochondrial-to-cytosolic stress response, protected both nematodes and cultured human cells with Huntington´s disease from protein-folding damage.

“Maybe there is a way to use one drug to alter the mitochondrial signal and another drug to alter the communciation signal from the brain,” he said. “You would never see these two effects if you were studying protein folding in a tissue culture dish, because you don’t have the whole organism, C. elegans, in which you can look at the signals being communicated.”

In this image, courtesy of Arshad Desai, a one-cell C. elegans embryo is shown undergoing mitosis. Microtubules are depicted red, chromosomes in blue, centromeres in green.

Add, subtract, divide equals life

Centromeres are regions of DNA and proteins on each chromosome that both link together sister chromatids and ensure accurate chromosome segregation and distribution during cell division or mitosis. When centromeres don’t work right, the result can be catastrophic. Indeed, aberrant division and chromosomal instability are hallmarks of cancer cells, especially the most aggressive types.
Yet despite their existential importance – “Chromosome segregation is the key event of cell division and fundamental to understanding life,” said Arshad Desai, PhD, professor of Cellular and Molecular Medicine at UC San Diego – centromeres remain imperfectly understood more than a century after German biologist Walther Flemming first described them.
In a letter published today in the advance online edition of the journal Nature,  Desai, who is also an investigator at the Ludwig Institute for Cancer Research at UC San Diego, and colleagues fill in some critical details, describing the germline transcription process that defines centromeres in Caenorhabditis elegans, a nematode whose similar molecular  mechanisms make it a model for human biology.

“How does a chromosomal region know it is a centromere and how is that information maintained. That’s the topic of our paper,” said Desai.
The work goes beyond simply advancing basic scientific understanding. Current cancer drugs like taxol and vinca alkaloids work by perturbing cell division. The problem is that these drugs can be toxic in non-dividing cells, such as neurons. A better understanding of how centromeres form and function could lead to more finely tuned or different ways for perturbing cell division.
Perhaps more significantly, said Desai, understanding centromeres will help in designing artificial chromosomes. “We currently rely on viruses for stable delivery of genetic information,” Desai said. “But this has the disadvantage that viruses integrate at random into genomes, which can negatively impact the patient.”
An artificial chromosome, with all of the genetic information tucked into the appropriate places, would preclude the need for viral vectors. And, said Desai, “the major limitation to designing true artificial chromosomes is our lack of understanding of centromeres.”

Healthy or sick? Tiny cell bubbles may hold the answer 

Rutgers scientists have uncovered biological pathways in the roundworm that provide insight into how tiny bubbles released by cells can have beneficial health effects, like promoting tissue repair, or may play a diabolical role and carry disease signals for cancer or neurodegenerative diseases like Alzheimer’s.

In a new study, published in Current Biology, Rutgers scientists isolated and profiled cells releasing these sub-micron sized bubbles, known as extracellular vesicles (EVs) in adult C. elegans and identified 335 genes that provide significant information about the biology of EVs and their relationship to human diseases.

“These EV’s are exciting but scary because we don’t know what the mechanisms are that decide what is packaged inside them.” said Maureen Barr, lead author and a professor in the Department of Genetics in Rutgers’ School of Arts and Sciences.  "It’s like getting a letter in the mail and you don’t know whether it’s a letter saying that you won the lottery or a letter containing anthrax.“

Photo: Quadell (Wikimedia Commons)

Illuminating neuron activity in 3-D

Researchers at MIT and the University of Vienna have created an imaging system that reveals neural activity throughout the brains of living animals. This technique, the first that can generate 3-D movies of entire brains at the millisecond timescale, could help scientists discover how neuronal networks process sensory information and generate behavior.

The team used the new system to simultaneously image the activity of every neuron in the worm Caenorhabditis elegans, as well as the entire brain of a zebrafish larva, offering a more complete picture of nervous system activity than has been previously possible.

“Looking at the activity of just one neuron in the brain doesn’t tell you how that information is being computed; for that, you need to know what upstream neurons are doing. And to understand what the activity of a given neuron means, you have to be able to see what downstream neurons are doing,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT and one of the leaders of the research team. “In short, if you want to understand how information is being integrated from sensation all the way to action, you have to see the entire brain.”

The new approach, described May 18 in Nature Methods, could also help neuroscientists learn more about the biological basis of brain disorders. “We don’t really know, for any brain disorder, the exact set of cells involved,” Boyden says. “The ability to survey activity throughout a nervous system may help pinpoint the cells or networks that are involved with a brain disorder, leading to new ideas for therapies.”

Boyden’s team developed the brain-mapping method with researchers in the lab of Alipasha Vaziri of the University of Vienna and the Research Institute of Molecular Pathology in Vienna. The paper’s lead authors are Young-Gyu Yoon, a graduate student at MIT, and Robert Prevedel, a postdoc at the University of Vienna.

High-speed 3-D imaging

Neurons encode information — sensory data, motor plans, emotional states, and thoughts — using electrical impulses called action potentials, which provoke calcium ions to stream into each cell as it fires. By engineering fluorescent proteins to glow when they bind calcium, scientists can visualize this electrical firing of neurons. However, until now there has been no way to image this neural activity over a large volume, in three dimensions, and at high speed.

Scanning the brain with a laser beam can produce 3-D images of neural activity, but it takes a long time to capture an image because each point must be scanned individually. The MIT team wanted to achieve similar 3-D imaging but accelerate the process so they could see neuronal firing, which takes only milliseconds, as it occurs.

The new method is based on a widely used technology known as light-field imaging, which creates 3-D images by measuring the angles of incoming rays of light. Ramesh Raskar, an associate professor of media arts and sciences at MIT and an author of this paper, has worked extensively on developing this type of 3-D imaging. Microscopes that perform light-field imaging have been developed previously by multiple groups. In the new paper, the MIT and Austrian researchers optimized the light-field microscope, and applied it, for the first time, to imaging neural activity.

With this kind of microscope, the light emitted by the sample being imaged is sent through an array of lenses that refracts the light in different directions. Each point of the sample generates about 400 different points of light, which can then be recombined using a computer algorithm to recreate the 3-D structure.

“If you have one light-emitting molecule in your sample, rather than just refocusing it into a single point on the camera the way regular microscopes do, these tiny lenses will project its light onto many points. From that, you can infer the three-dimensional position of where the molecule was,” says Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research.

Prevedel built the microscope, and Yoon devised the computational strategies that reconstruct the 3-D images.

Aravinthan Samuel, a professor of physics at Harvard University, says this approach seems to be an “extremely promising” way to speed up 3-D imaging of living, moving animals, and to correlate their neuronal activity with their behavior. “What’s very impressive about it is that it is such an elegantly simple implementation,” says Samuel, who was not part of the research team. “I could imagine many labs adopting this.”

Neurons in action

The researchers used this technique to image neural activity in the worm C. elegans, the only organism for which the entire neural wiring diagram is known. This 1-millimeter worm has 302 neurons, each of which the researchers imaged as the worm performed natural behaviors, such as crawling. They also observed the neuronal response to sensory stimuli, such as smells.

The downside to light field microscopy, Boyden says, is that the resolution is not as good as that of techniques that slowly scan a sample. The current resolution is high enough to see activity of individual neurons, but the researchers are now working on improving it so the microscope could also be used to image parts of neurons, such as the long dendrites that branch out from neurons’ main bodies. They also hope to speed up the computing process, which currently takes a few minutes to analyze one second of imaging data.

The researchers also plan to combine this technique with optogenetics, which enables neuronal firing to be controlled by shining light on cells engineered to express light-sensitive proteins. By stimulating a neuron with light and observing the results elsewhere in the brain, scientists could determine which neurons are participating in particular tasks.

Enlightened science

Ablation in medicine means to remove tissue by various means, such as cutting, chipping or vaporizing, to eliminate a threat to health. Cellular ablation is a more particular endeavor: Cells are selectively destroyed to better understand their lineage and function.
Researchers have some clever tools to do this. A laser, for example, can focus upon a single cell in Caenorhabditis elegans, a tiny worm and proven model organism. Or genetically coded reagents, such as enzymes or cytotoxic molecules, can be introduced into targeted cells to induce apoptosis or programmed cell death. 

The problem with the latter approach, which has been used in organisms other than C. elegans, is that chemical reagents may accumulate in tissues other than the targeted cells, causing non-specific toxicity. In other words, healthy cells near the target can also die.

In a paper published online this week in the Proceedings of the National Academy of Sciences, Yishi Jin, PhD, a professor in the division of biological sciences and Howard Hughes Medical Institute investigator, and Roger Tsien, PhD, professor of pharmacology, chemistry and biochemistry Howard Hughes Medical Institute investigator, and Nobel laureate describe, with colleagues,  using a tiny, light-activated molecule to effectively kill single neurons in a nematode without any apparent collateral effect.

The molecule is called a mini-singlet oxygen generator or miniSOG. It’s a radically re-engineered light-absorbing protein from the cress plant Arabidopsis thaliana that, when exposed to blue light, produces abundant quantities of singlet oxygen.  The researchers in Jin’s lab targeted the expression of miniSOG to mitochondria, and observed that the expressing cells die quickly upon blue light illumination, without affecting neighboring tissues.

“We believe that singlet oxygen generated by miniSOG (genetically introduced into the mitochondria of the targeted neuron) destroys the integrity of the mitochondria, which releases toxic molecules that lead to the death of the cell,” said Jin. “The dead neuron is then cleared away by nearby cells, most likely through phagocytosis.”

While the findings may be a boon to basic research, Tsien said they are unlikely to have direct value for developing human treatments because the method requires gene therapy, which is not yet practical enough.

“Plus it needs blue light, which doesn’t penetrate very far through organisms as thick as ourselves. However, we are separately working on synthetic injectable molecules (not minSOG) that would home in on cancer cells and kill them with red or near-infrared light, which penetrate mammalian tissues much better than blue light. But even red or near-infrared would mostly have to be applied by endoscopes or during surgery.“

A comedy act at a C. elegans conference, to which my genetics professor was a witness. (Guys. They have comedy routines at C. elegans conferences) :
  • Researcher 1: You know those Australian sheepskin boots? UGG boots?
  • Researcher 2: Oh yeah! Tryptophan boots!
  • Researcher 1: Well...why don't they make UGA boots?
  • Researcher 2: Why, that would be nonsense!