Tuesday, February 19, 2013
I would like to apologize for the lack of updates these past few weeks: I've been busy at work drafting/gathering my research results for publication, taking a science writing course through Johns Hopkins, and preparing for the wedding (April 6th!)- in other words, it's been hectic. I haven't forgotten about you, readers, and I am going to make every effort to update more frequently in the future. Thanks for your patience!
Wednesday, February 6, 2013
In the previous entry I wrote about cancer cell metastasis, and researchers’ attempt to understand the mechanics behind cancer cell migration. Understanding why and how cancer cells metastasize can be approached from several angles, however, and just as important as determining the ‘how’ is figuring out the ‘why’. If less than 1% of cancer cells have the ability to metastasize, what makes these cells so different from their peers?
|An invasive cancer cell makes its way into a pore. Image credit: Cornell University Chronicle Online|
Previously, researchers have addressed this question by identifying molecular signatures of metastatic cancer cells. To do this, scientists can compare which genes are turned ‘on’ or ‘off’ within a cell using RNA expression as a readout for gene activity. When a gene is active, the DNA sequence of that gene is translated into RNA, a close relative of DNA. While genomic DNA remains esconced within the nucleus of the cell, RNA is often shuttled outside of the nucleus and throughout the cell. Some RNA sequences contain the instructions for making a protein, and they are read by the cell’s protein production machinery to direct the formation of a new protein.
Another class of RNA, appropriately referred to as ‘noncoding RNA’, does not code for a new protein. But don’t be fooled: just because they don’t encode a protein doesn’t mean that they aren’t equally important. Noncoding RNAs carry out a number of different tasks within the cell, and are essentially to regulating the myriad processes occurring within the cell.
Certain noncoding RNAs have been identified as molecular markers of cancer cells, as their activity correlates with cancer progression. MALAT1 is one such example: it has been linked to various types of lung cancer, and usually serves as a predictor for a cell’s ability to metastasize. Increased levels of MALAT1 usually means bad news for lung cancer patients: the more MALAT1 cancer cells express, the more likely it is that they will metastasize and disease progression will subsequently take a turn for the worse. MALAT1 promotes metastasis by regulating genes involved in cell motility; however, until now it has not been clear how this regulation occurs.
The first possibility was that MALAT1 encouraged alternate splicing of RNA transcripts. When RNA is translated from DNA, the original sequence usually does not remain intact. Instead, it is cut, or ‘spliced’, and pasted back together in various combinations. Different combinations may produce different RNA transcripts and subsequently proteins with very different functions. It has also been hypothesized that MALAT1 may activate metastasis by turning on cell motility genes.
In a paper recently published in Cancer Research, a team of scientists led by Sven Diedrichs reported finding the latter hypothesis to be true: that MALAT1 induced the activation of genes associated with metastasis, and suppressed genes inhibiting metastasis. They found no support for the alternative splicing hypothesis.
They obtained these results by inserting sequences into the MALAT1 genome region marking MALAT1 transcripts for degradation, effectively eliminating all MALAT1 RNA from the cell. The effects of loss of MALAT1 in lung cancer cell cultures were compared to cells in which MALAT1 had not been lost. The variation between alternative splicing forms in both was insignificant, but the activity of several genes associated with metastasis was inversely correlated in the ‘normal’ and knockout cells. The ability of MALAT1 knockout cells to invade surrounding tissue was also significantly reduced when compared to cells retaining MALAT1.
To determine the effect of loss of MALAT1 in vivo, or in a living organism, the researchers then injected cancer cells with and without MALAT1 into mice. The cells with intact MALAT1 formed a greater number of tumors in the lungs of the injected mice than the cells without it, indicating that the metastatic ability of the tumors which developed from MALAT1 knockout cells was impaired.
Finally, the researchers wondered whether it would be possible to therapeutically suppress MALAT1 and, in doing so, inhibit cancer cell metastasis. They collaborated with
pharmaceuticals to create strands of RNA which complemented MALAT1 RNA, and
routinely injected these strands into mice which had also been injected with
human cancer cells. They anticipated that the complementary RNA would bind and
effectively silence MALAT1 transcripts in the cell. After five weeks they found
that the mice which had been given this treatment had fewer and smaller tumor
nodules when compared to mice that had not received the same treatment. These
results confirmed their initial findings, and are a promising platform for
Wednesday, January 23, 2013
One of the hallmarks of cancerous cells is their ability to uncontrollably divide and proliferate. As a result, cancer cells are notoriously hungry: the constant growth and DNA replication that takes place during their dividing frenzy requires a considerable amount of energy. They are greedy, hijacking the bodies own nutrients and resources to support their own proliferation. As a tumor increases in size and density, however, nutrients and sugar become scarce. As a result, several cancerous cells may break away from the tumor in search of greener pastures in a process known as metastasis. As they make their way to remote areas of the body, these cells must first travel through the capsule surrounding the tumor and other tissue. It takes a considerable effort to break through layer upon layer of tissue, and the strain can be too much for any one cell.
And they're off! In this video breast cancer cells (the same line used in the study, incidentally) are on the move. Cancer cells can move as quickly as 200 um/hour. Source: danielirima, YouTube user (link: http://www.youtube.com/watch?v=FPLbs-bV1L4)
A team of researchers led by Robert Austin, a professor of physics at
, found that
cancer cells typically travel in a group with one cell acting as the trailblazer. The authors of the study analyzed the activity of two
different breast cancer cell lines: the first line was selected for its
metastatic properties, and the second formed tumors but did not metastasize. To
encourage the cancerous cells to travel the researchers placed them in a
chamber over a layer of collagen, a tough, fibrous structural protein. The
collagen concentration used in the study was an approximation of the density of
normal breast tissue. They then formed a glucose gradient: the concentration of
glucose was lowest on the collagen layer where the cancerous cells were
deposited, gradually increasing towards the bottom of the chamber. Glucose is a
sugar which is easily converted into energy, and readily available glucose is a powerful incentive for
ravenous cancer cells that need to satisfy their increased energy requirement. Princeton
Austin and his team found that the nonmetastatic cells refused to budge regardless of glucose levels, but the higher concentration of glucose was sufficient to entice the metastatic cells to break through the collagen layer and travel to the lower glucose rich environment. The researchers filmed the cells’ movement through the chamber and observed that individual cancerous cells took turns blazing a trail for the rest of the group. As the leading cell displaced surrounding tissue, the rest of the group followed in its wake. Approximately 70 hours later another cell would take the lead. The same cell which initially led the invaders then fell back into the middle of the group, taking a well deserved break.
|Scanning electron micrograph of a cancer cell migrating through the pore of a filter. Image credit: Science Photo Library|
Although it has been estimated that less than 1% of cancerous cells have the ability to metastasize, metastasis of cancerous cells accounts for almost 90% of cancer deaths. Understanding the metastatic process, therefore, may be a valuable tool in developing therapies which prevent the spread of cancerous cells and improve cancer patients’ prognoses.
Friday, January 18, 2013
Nobody likes a cheater, but from humans to bacteria almost every community has their share of freeloaders.
Cooperation is essential for the survival of many organisms, but there are always those who are willing to reap the benefits of a community and use up collective resources without ever making their own contribution. According to a recent study published in the journal Evolution, golden algae (Prymnesium Parvum) are no exception.
|Live culture of Prymnesium Parvum. Image credit: Unviersity of Liverpool Harmful Plankton Project|
Prymnesium Parvum are found worldwide in extensive blooms blanketing the surface of marine and inland waters. Golden algae blooms produce toxic substances meant to kill off other algal species, but these same substances can be highly destructive as they are also toxic many fish species. When present at high enough concentrations, these toxins have been known to decimate nearby fish populations. It has been estimated that golden algae blooms in 33 reservoirs in
alone have killed almost 30 million fish, causing tens of millions of dollars
in revenue to be lost.
For a single cell, toxin production is largely useless as the toxic substances would drift away before reaching concentrations high enough to be lethal. For this reason it is beneficial for the algal cells to band together: many cells producing the toxins all at once permit toxin levels to accumulate to sufficiently high levels. The toxin produced by one cell would exert most of its protective effect on neighboring cells, but those same neighboring cells ensure that cell is covered.
In a study published in the journal Evolution, researchers at the
finding freeloaders in golden algae populations. These cells grow faster than
their peers because they never actually produce any toxins. Instead, the
resources that would normally be used in toxin production are redirected to
ensuring their own propagation. University
As hard times fall upon the algae, however, the toxic cells adopt a new approach. Normally, when nutrients are abundant the toxic cells use photosynthesis to generate energy. As nutrients become scarce, however, toxic cells stop growing and begin attacking other cells. They swim up to their prey using their flagella and latch on, and in some cases a struggle ensues. Other cells may join in the melee, surrounding the victim and producing more toxin before consuming their victim.
|Toxic golden algae attacking and devouring a green alga. Image credit: William Driscoll, PhysOrg|
Roving packs of carnivorous cells may seem like quite a departure from our perception of mild-mannered algae. The ‘cheaters’ never adopt this behavior, however; they just keep on growing. One would expect that because cheaters have an advantage when conditions are favorable they would eventually take over the population, but the authors of the study believe that because the cheaters are unresponsive to changing environmental conditions this doesn’t happen.
Next, scientists in the laboratory of Jeremiah Hackett at the
have set out to
determine the difference between toxic and non-toxic cells. They have found
that stress-related genes are regulated differently between the two types of
cell. Ultimately they hope that their work will lead to the identification of
ways in which the behavior of golden algae cells can be exploited to restrict
the growth of golden algae blooms, and that finding the golden algae's 'Achilles heel' may ultimately reduce the threat this species poses to their local ecosystems. University of
Monday, January 14, 2013
|Image credit: freedigitalphotos.net|
Medications typically prescribed for the treatment of Parkinson’s disease are eliciting an unexpected side effect in many Parkinson’s patients, but the risk to the patient, it seems, is minimal. Some doctors, like Rivka Inzelberg at
Sackler Faculty of Medicine, have begun to embrace the strange new phenomenon
for its therapeutic potential. Tel
Parkinson’s disease is a neurodegenerative disease in which neurons in the area of the brain that regulates movement are destroyed. As the disease progresses, even the simplest movements are hard to initiate and even harder to continue. Fine motor control is challenging, making activities like eating and writing difficult. After beginning a course of treatment for the disease, however, many Parkinson’s patients seem to be finding their muse. Parkinson’s experts are reporting that their patients are suddenly drawing, sculpting, painting, writing, and more.
Inzelberg first noticed the phenomenon around the holidays, when patients would bring small gifts, often chocolates and other small tokens, to the clinic where she worked to show their appreciation. Over time, Inzelberg noticed an emerging trend- instead of the usual holiday gifts, a surprising number of patients brought in artwork they had created themselves.
Inzelberg realized this most likely wasn’t a coincidence and began to seek out the ‘common thread’ among all of the newly inspired artists, combing through case studies from around the world and her own patients’ histories. It seemed that this wasn’t the first time this had happened, and that the same phenomenon had caught the eye of doctors and researchers treating Parkinson’s patients worldwide. What all of these patients had in common, she found, was that they were all being treated with drugs that increase dopamine activity in the brain.
Dopamine is a neurotransmitter, one of the small molecules which travel in the space between neurons to relay messages from one nerve cell to the next. Dopamine is particularly important in the part of the brain which regulates movement. When nerve cells in this area are destroyed, it can cause a loss of muscle function as dying neurons impede neural ‘communication’ in this area.
Some of the medications prescribed for the treatment of Parkinson’s disease attempt to make up for this deficit by supplying a drug which can be converted into dopamine in the brain, or by supplying a drug which activated the receptors that normally ‘receive’ the message from dopamine, even when the message itself is absent. The Parkinson’s patients were all being prescribed one of the two types of drugs described above.
Inzelberg speculates that dopamine’s alternate activity in the brain’s ‘reward system’ pathway is behind the observed creative bursts in Parkinson’s patients. Our brain’s built-in reward system is responsible for the feeling of satisfaction and pleasure we get after we accomplish something. Rewarding activities are reinforced by the burst of dopamine which accompanies them, which can be a powerful motivator.
Therapies which affect dopamine pathways in the brain sometimes result in a loss of impulse control, in extreme cases leading to addiction or obsessive behavior. It has been suggested that this lowering of inhibitions may push artistically inclined patients to free their latent creativity, and that lowered inhibitions and increased arousal may facilitate the creative process.
The link between dopamine and creativity has not been fleshed out, but misregulation of dopamine levels in the brain has been linked to several diseases, including schizophrenia. Inzelberg cites Vincent van Gogh as an example: it is believed that rising levels of dopamine in van Gogh’s brain resulted in his psychotic episodes, and that much of his creativity was drawn from those episodes.
‘Increased creativity’ may be the most beneficial side effect of these medications, as it has added therapeutic potential. Inzelberg believes that when Parkinson’s patients begin pursuing artistic endeavors it has a positive effect on them both psychologically and physiologically. Many patients report being happier when they are being creative, and sometimes their motor symptoms show improvement, especially when actively engaged in drawing, painting, sculpting, or other artistic endeavors which require fine motor control.
Does this mean that it is only a matter of time before these drugs are touted as “creative pills”? Let’s hope it doesn’t get that far. Still, it is fascinating to see the effect something as physical as brain chemistry can have on something as transcendental as art and creativity.
Friday, January 11, 2013
When my younger brother began taking piano lessons, my mother attempted to learn alongside him. Several months later, she could only ever play all twelve bars of ‘Little White Pony’ fluently, while my brother had moved on to more advanced pieces.
“It’s easier to learn when you’re young,” she explained dismissively. She eventually gave up trying to learn because, she said, at her age it would take much longer.
Was her logic flawed? Very- my mother has never been played any instrument before, is not particularly musical (sorry, Mom), and only practiced for about 15 minutes a week. Many believe, however, that there may be a kernel of truth in the claim that children learn quicker than adults- or at the very least, that they learn differently. Now, a new study suggests that there may be a physiological basis for this discrepancy.
As explained in a recent blog entry, repeated activation of a neuron is like weight training- with every ‘rep’, or activation of a neural circuit, the connection between the two neurons grows stronger. The next time the same circuit is activated, the neurons are more responsive to one another. This process and the changes which accompany it at the level of the synapse, the space between two neurons, are known as long term potentiation (LTP). LTP is important for memory and learning, which are both regulated in a part of the brain called the hippocampus. Long term depression (LTD) counters the effects of LTP by making a synapse weaker, eventually culminating in the removal of that synapse once it has been sufficiently crippled.
|Artistic rendering of a neuron. Image credit: 123rf.com|
Once again, let’s revisit the importance of NMDA receptors and their role in LTP and LTD. NMDA receptors appear to be essential for establishing LTP- without them, LTP fails to occur. They aren’t as essential for maintaining the effects of LTP, but that’s a different story.
NMDA receptors are composed of four subunits: two NR1 subunits and two NR2 subunits, NR2A or NR2B. The ratio of NR2A and NR2B subunits among neurons in the brain is dynamic, with NR2B being the more prevalent subunit until puberty hits, when the ratio begins favoring NR2A. NR2B subunits allow the neurons to ‘talk’ a moment longer by keeping the calcium (Ca2+) channel in the receptor open longer, creating stronger synapses. This characteristic of NR2B and its prevalence in younger brains, it has been hypothesized, may contribute to children’s superior ability to learn and create new memories.
Dr. Joe Tsien and his colleagues at the Medical College of Georgia at
decided to test whether the ratio of NR2 subunits correlates with the changes in
learning and memory which occur with age. Previously, Tsien found that
increasing levels of NR2B in the brains of mice made them ‘smarter’ and faster
learners due to an enhanced ability for LTP. In a paper recently published in
the journal Scientific Reports, Tsien and his team describe a study in which the opposite
conditions were tested. Tsien and his team studied mice with adult ratios of
NR2 subunits. They created transgenic mice with an increased ratio of NR2A in
their forebrain, which included the hippocampus, to analyze the effect the
altered ratio had on cognition in mice. The transgenic mice had normal
short-term memory but their long-term memory was impaired. Georgia
The researchers had predicted that decreased LTP may be the cause of the long-term memory impairment in the mice, but they found that this process was unaffected. Surprisingly, they found that long-term depression (LTD) which leads to weakening of the synapse was disrupted. Our ability to learn and form long-term memories, it seems, is not only dependent on having strong synapses, but also being able to silence ‘noise’ from weaker synapses.
Most neurons are associated with thousands of synapses, and so there needs to be some way to refine the barrage of incoming information. When our synapses are overloaded with information, it is difficult to pick out the signal from the noise and so our learning and memory function is impaired. Imagine standing in an auditorium full of people and trying to hear a friend who has an important message for you at the opposite end of the room. If everyone is yelling all at once, it would be impossible to hear what they are saying; if the crowd is silent, or speaking barely above a whisper, you will be able to hear your friend much clearer. If a high ratio of NR2B in the brain is equivalent to giving your friend a megaphone, having a high ratio of NR2A subunits turns up the volume of the crowd.
Our brains are formed from billions of neurons which are in constant communication with one another; at this moment they are reading these words, storing away the knowledge (hopefully) obtained in this post, and- assuming you are still breathing- directing the many ‘housekeeping’ activities our bodies are carrying out every second of every day. The human brain is truly a masterpiece of organized complexity. It is fitting, then, that Tsien and his team coined the term ‘sculpting’ to describe the way in which the brain takes in and assimilates new information. Active synapses are strengthened, existing synapses are weakened, old synapses are cleared away- our minds are our masterpieces.
Tuesday, January 8, 2013
|Image credit: iStockphoto/Sebastian Kaulitzki (obtained from Science Daily)|
Whether we realize it or not, the masses of tiny microbes which call our bodies 'home' are a large part of our lives. It is easy to forget about our microscopic companions- we can't see or feel them, after all- and so it isn't until they start acting up that they make their presence known. For this reason, bacteria have historically gotten a bad rap. Often vilified for their pathogenic qualities, the general public takes great care to prevent contamination through the widespread use of antibiotic soaps and hand sanitizers. It would be impossible to get rid of all of the microscopic critters we carry, however, and chances are you wouldn't want to, anyway. Bacteria are an essential part of our everyday lives- they help us to digest our food, synthesize certain vitamins, and, in some cases, interact with our immune systems and protect us against disease.
Microbes have been established as such a vital and intimately associated part of of lives that we now have a word for the population of bacteria we are at this moment sheltering in our bodies, that humble abode- the microbiome. Microbiome refers to the collection of microbes housed in and on our bodies, almost 100 trillion bacteria per person.