SciThreads

Unravelling the tapestry of nature Be curious...ask questions!

[cancerbiophd]

can i rant about something that i feel like is super important yet extremely understated? ok here goes:

heath care givers, scientists, and other health advocates oftentimes overlook the obstacle that poverty has on cancer prevention. i’m not talking about treatment, which we all know can absolutely devastate a family’s finances. i’m talking about the “simple” and “easy” day-to-day lifestyle actions that can dramatically decrease one’s risk of certain cancers, and how they can be hard to achieve when money is tight. 

take sunscreen for example. sun protection is the #1 best way to decrease one’s risk of skin cancer, the most commonly diagnosed type of cancer. but sunscreen can be a luxury when that ~$6/bottle needs to be spent on food, or saved up penny by penny for utilities or rent. and take into consideration that many low-wage jobs are spent outdoors, like farm workers. 

diet and exercise–other great ways to lower the risk of certain cancers (and other diseases). but the ratio of fast-food places to grocery stores with fresh produce can be extremely skewed in poorer neighborhoods. and then think about how much $5 can buy in terms of fresh vegetables and fruits (and then other ingredients to cook them with, along with the utilities to keep them fresh/cooked well) vs items from the dollar menu at mcdonalds. i see so many ads calling for the “mediterranean diet” to prevent cancer, and i always think… ok that’s pricey. fish is pricey. also if i was someone who worked a labor-intensive job, and only had $3 to spend on lunch, would i go for a low-calorie salad, or a high-calorie high-protein burger? 

and trying to jog through unsafe streets, without access to nearby and well-maintained parks? not easy. 

and then there’s cancer prevention routines at the clinic–like mammograms and pap smears and visits to the dermatologist to get a mole checked out. covered by insurance or not, these procedures involve having that time off from work/other responsibilities, and having the transportation to get to the clinic. again, very real obstacles for those who can’t afford them. 

none of what i’m saying here is new, nor is it isolated to just cancer prevention. talk to anyone experiencing or has experienced poverty about these concerns and they’ll say “well duh”. but the thing is that we–the people advocating for these “simple” cancer/other disease prevention strategies–are not listening to them and making the necessary changes to society. all i hear from scientists and doctors is “prevention is key!!!” and yes, that’s true, but i want to yell back “well what are you doing to address the societal and financial barriers to that!! your fancy DNA test to detect cancer early is neato and all but can everyone afford it!!!” 

and i get it. sometimes we as scientists and doctors can’t really have control over this (money has to come from somewhere, and we all have mouths to feed). but as a society, a community of people who can care for others, there are things we can do: raise minimum wage. have better employee benefits like more personal time off (to go to clinics). expand public transportation. have affordable universal healthcare. aliquot more government spending on scientific research to offset costs. promote neighborhood gardens, parks, better infrastructure (without gentrification). end the cycle of poverty and crime by means other than prison (like reaching out and understanding mental health needs, improving public education, etc). basically make the fundamental changes to society so the downstream effect is that people can realistically afford positive impacts to their health. 

bottomline: we can’t hope to prevent or cure cancer–or any other disease–until we address affordability and accessibility. a new diagnostic test is sweet and all, but it does absolutely nothing if it can’t actually help people. 

[cancerbiophd]

hi! i sent u tht ask abt my mom having cancer, n i have a (rly dumb) question. i know shes on epoch-r, and i read about that, but im just. confused about how chemo in general works? ive tried looking it up but everywhere i looked says "chemo attacks cancer cells" and doesn't explain further.

hi hi hi!!! 

that’s totally not a dumb question. i’ve always been confused too, especially since there are so many cancer treatment terms and honestly it gets really confusing sometimes (like holy cow are cancer drug names awful to pronounce?)

historically, the term “chemotherapy” used to mean just any chemical compound (aka a drug) that can be used to treat a disease, such as antibacterial chemotherapy. and then the nomenclature slowly became known as just any drug that’s used to attack and kill cancer cells. this was way before anything like “targeted therapy” or “immunotherapy” was discovered, so you can look at chemotherapy being the grandfather or umbrella term for cancer-killing agents. 

chemotherapy is also used to describe a treatment that’s given systemically–as in it goes everywhere in the body, usually through intravenous (IV) injections. therefore it’s pretty darn useful to, for example, treat cancers that have metastasized to different organs. (that’s not the exclusive use of chemo tho; patients with primary tumors that haven’t metastasized can still use chemo). this is in comparison to radiation therapy, which uses radiation to blast a very very specific area of the body where the tumor is. 

the majority of the time, chemotherapy is a group of drugs that kill cancer cells because they attack their more-or-less unique characteristic of being crazy fast cell dividers. these drugs will often go after the mitosis machinery, and cause so much chaos that the cells have no choice but to undergo apoptosis, or a type of programmed cell death. 

however, chemo can’t really tell the different between a cancer cell and a healthy normal cell; it just so happens to be more effective at killing cells that divide quickly. so that’s why chemo regimens aren’t given over a really long period of time (treatment usually only lasts days), and why patients can experience side effects such as immunosuppression and gastrointestinal issues, as the immune cells and the cells lining our intestines are also fast dividers. they’re civilian casualties, so to say :(

certain chemos tend to work better with certain cancers, which is why there are specific chemo regimens. chemos are oftentimes given as a batch rather than individually. for example, EPOCH-R is a combo of drugs that work as a team to attack different aspects of the NHL cells, and can achieve much better results than if any of them went on a solo mission. here’s a breakdown of what each drug does:

Rituximab: this is an antibody that can bind specifically to B-cells, which in NHL have gone rogue and replication-happy. B-cells have a very specific protein on their surface, CD20, and rituximab gloms on like velcro. This causes natural killer cells and macrophages to recognize the B-cells as “foreign” and attack them. It also causes the complement system to be activated by the B-cells, which also furthers destruction of the cell. The downside of rituximab is it doesn’t discriminate between cancerous B-cells and normal B-cells though. 

Etoposide: these dudes inhibit the topoisomerase, which is an enzyme that helps unwind DNA during cell replication. when DNA unwinds, the downstream strands tend to get tangled and bent (think of unwinding one of those old-school phone cords–the part of the cord you’re not straightening gets super stressed and coils in on itself). Cells don’t like that, so they tell topoisomerase to go in and form small harmless nicks in the DNA to help relax it, and then when the DNA is unwound, it seals back the nick again. That last step is pretty crucial; without that action, DNA will just be floating around in fragments and the cell can’t function and will undergo apoptosis. so by inhibiting topoisomerase, etoposide is able to kill the cell. like most chemos tho, it can’t distinguish between cancer cells and non-cancer cells, but because cancer cells replicate so much faster than normal cells, and thus rely on topoisomerase so much more frequently, etoposide should be more effective in killing the cancer cells. 

Prednisolone: i don’t think the exact mechanism of how prednisolone kills cancer cells is well known. it’s used generally in low doses to dampen the immune system during allergic reactions, but with a high dose during chemo, it specifically causes immune cells (like NHL cells) to undergo apoptosis. 

Oncovin: aka vincristine (which imo is a much prettier name). this drug binds to a protein called tubulin. tubulin is required during mitosis, or cell division, to form microtubules–think of tubulin as like the fibers of a rope. microtubules form the mitotic spindles which separates the two daughter cells during cell division, so without tubulin, the cells can’t separate, things go haywire, and the cells undergo apoptosis. again, this drug isn’t specific to cancer cells, but relies on the faster rate of cell division in cancer cells to “spare” as many normal cells as possible. 

Cyclophosphamide: this drug has a metabolite that’s formed in NHL cells that’s able to form crosslinks in the DNA, rendering it almost impossible for the cell to create RNA (and protein), or to replicate. without these functions, the cell undergoes apoptosis. 

Hydroxydaunorubicin: aka doxorubicin. this drug is able to interacalate DNA, which means it’s able to get all nice and snug inside the DNA strand, and now the cell can’t synthesize RNA or proteins, or replicate (much like the effect of crosslinking of DNA). it’s akin to getting a rock in your shoe, and the presence of the rock causes you to cease all normal function and undergo apoptosis. that’s one deadly rock. it can also prevent topoisomerase from sealing DNA nicks (much like etoposide).

I hope that was a bit helpful! i maaayyy have delved into more detail than what you were looking for, but it’s all just really fascinating stuff…and i hope it gives you something to launch off of if you’re curious to learn more (and also feel free to ask me any questions you may have!)

good luck to your mom! i’m still rooting for her <3

[scithreads]

MAGIC mitochondria garbage disposals

Almost everybody is familiar with the role of mitochondria play in extracting the energy from nutrients, and some people are even aware that mitochondria release proteins (cytochrome C) involved in the process of orderly cell death (apoptosis).

Some researchers at Johns Hopkins University have discovered another useful service mitochondria provide: they act as garbage disposals to eliminate misfolded proteins. This particular round of experiments focused on aggregated proteins that occur after yeast cells experience the sudden shock from being overheated. Apparently the clumped proteins are attracted to the surface of the mitochondria, where other proteins help them unwind and slither through the TOM and TIM membrane pores to the inner part of the mitochondria (the matrix).

Once the unraveled proteins are inside the mitochondria, another protein called Pim1 goes to work. This enzyme is a protease, meaning that it chops up proteins into amino acid building blocks which can be reused by the cell.

Although the main series of experiments were in yeast, they observed a similar process taking place in human cells. This discovery could prove helpful in understanding and treating a whole range of illnesses resulting from protein aggregates (such as Alzheimer’s disease).

Oh, and the MAGIC? Apparently, the best part of writing a biology paper is that you get to name the stuff you discover. The Johns Hopkins researchers called this garbage-disposal mechanism “mitochondria as guardian in cytosol”, or MAGIC. (And yes, they even managed to get this name published in Nature...)

References

Sort and destroy, Agnieska Chacinska, Nature 3/16/2017

Cytosolic proteostasis through importing of misfolded proteins into mitochondria, Linhao Ruan et al, Nature 3/16/2017

Image Credit: Louisa Howard, Public Domain

[scithreads]

Cancer: luck of the draw?

An interesting paper published last week in Science has been making the rounds, most often with a headline indicating that two-thirds of cancer mutations are random chance. After reading the actual paper, I think the author’s evidence generally supports that conclusion, but there are some very important points to keep in mind that often get missed in common reporting.

Mutations are common

Most people don’t realize just how common mutations are, even in the absence of environmental factors like smoking, chemical exposure, or diet. Although there is extensive proofreading and DNA repair machinery in human cells, about 1 out of every billion base pairs gets copied incorrectly to the next generation. Since the human genome contains 3 billion base pairs, this means that there are about three mistakes every time a cell divides.

Most mutations are harmless

A lot of the human genome is not critical, which is a good thing. Considering that the body has about 37 trillion cells, those copying errors really begin to add up. Many of the errors show up in unimportant stretches of DNA, and even when they do show up in critical areas, the change may not make any difference. (For example, there are four ways to say “alanine” in genetic code, GCU, GCC, GCA, and GCG. Change the last C to an A, and it makes no difference to the cell.)

Not all harmful mutations cause cancer

While it is true that cancer results from mutation or other damage to the genome, just because one of your cells is mutated in a critical place doesn’t mean you’re going to grow a tumor. There are numerous non-cancerous options. For example:

The mutation could be in a gene that’s not active in that cell type

The mutated gene is critical for continued cell life, so the damaged cell simply dies and is recycled by the immune system

The damage to the gene simply makes the cell less efficient, but since your body contains so many other cells, you don’t really notice

Cancers typically require many mutations

One mutation is almost never enough to kick a cell in to “cancer mode”. The machinery of the cell has many built-in safeguards, and the immune system is constantly patrolling for cells that have gone off the rails and have started to do their own thing. 

Think of it this way: pretend you are behind the wheel of a car, driving down the highway, and the gas pedal gets stuck. To make matters worse, about a half-mile down the road is a railroad crossing, and a train is passing through. There are several things you can try to stop the car--slam on the brakes, shift into neutral, or turn off the key. If all that didn’t work--the shifter broke off and the key was stuck too, you could make a last-ditch effort to save yourself by, well, driving into the ditch. The single failure of the gas pedal alone doesn’t spell certain doom.

Cancer works in a similar fashion. The kinds of mutations that lead to cancer usually either act as a stuck gas pedal, encouraging the cells to rapidly divide, or like a defective brake or broken shifter, preventing the cells from slowing down the rate of division. Only when a cell has the gas pedal stuck to the floor and no brakes or shifter does it really become a problem. (Of course, once that happens, things go downhill pretty quickly, because cells that divide too quickly don’t put much effort into proofreading and repair, and the genome gets pretty well shredded, making things a lot worse.)

Environment still matters -- a lot

Let’s assume, like the authors of this paper did, that three gas-or-brake functions need to be disrupted in order for a tumor to take hold. Even if two-thirds of mutations are just random copying errors, that other one-third has to come from somewhere: either you inherited the mistake from your parents, or you were exposed to an environmental factor that caused the final necessary mutation. Some cancers are driven far more by environmental factors: 18 out of 20 lung adenocarcinoma tumors and 8 out of 20 pancreatic cancers have at least one mutation caused by environmental damage (like smoking or diet). Getting too much sun is bad too: 86% of the mutations in melanoma are caused by environmental factors.

The take-home message

Cancer sucks. A lot of the causes are due to chance, so if you or a loved one is diagnosed with a tumor, in a lot of cases, you just drew the short straw. This means that even when you live a healthy lifestyle, you still need to talk with your doctor to make sure you get the appropriate screenings for your age and gender. Since cancer has a lot of randomness to it, one of the best weapons for fighting it is early detection.

But don’t let the randomness keep you from trying to avoid unhealthy behaviors. In the car example, the brakes, shifter, and key aren’t likely to all break at once if you visit the mechanic occasionally. In the same way, if you avoid things that can cause genetic damage, it is a lot less likely that your cells will end up with a stuck gas pedal and no brakes, heading for a speeding train.

A note for the more advanced

If you have a deeper understanding of cell biology and/or statistics and have access, the supplemental info on this paper is really worth at least glancing at. In particular, some of the tables (S5, S6) give some good information on the percentage of mutations resulting from environmental, heredity, and random factors in various tumors.

References and further reading:

Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention, Cristian Tomasetti, Lu Li, Bert Vogelstein, Science, 3/24/2017.

Image credit: Wikimedia user !KryzsiekBu!, Creative Commons BY-SA 4.0

[scithreads]

Q&A: NASA’s science head says investment in earth science is a ‘no-brainer'

Thomas Zurbuchen on risk, trust, and the potential of small satellites

I particularly like Zurbuchen’s attitude:

“Trust is important. You can't just go walk up and scream at people, like, "I tell you what's true or what's real!" Even if you're right! That's not the way to do it. Because listen to it from their point of view: "Wow, that's an arrogant prick. Just because he has this tremendous education doesn't mean that I'm stupid." Right?

The way to make progress is to learn with a little bit of empathy—listening to others: “What do you care about?””

Especially given the current political climate, we’re going to get a lot further listening to people’s concerns instead of acting superior or just trying to shout them down. Everyone has reasons for the positions they hold, and unless we understand those reasons, division will continue to derail progress.

[smilesandvials]

Tuesday, at an discussion round-table type event, one of our students from Iran told us he had a friend back in Iran who wanted to come to the United States for graduate school. She was published. She was good. She had one problem. He advisor refused to write a letter of recommendation because he felt that if she came here, she might stop wearing her hijab.

And he told us this and I think everybody’s heart broke. 

And he felt like if he asked somebody what to do, or told us, that it would feel like an endorsement for her to study here. It isn’t. It’s sharing a problem.

And a professor told him to tell her to contact our dean. To tell the schools she is applying to, us included, what the dilemma was. We were sure that we could help – we have deans, we have experts, we have people who know how to make an application shine even when one part is missing.

And then I woke up today and saw the visa ban.

And I felt crushed. I know this doesn’t hurt me personally. I don’t know her. I’m not her. But we were so hopeful and so sure that we could do something, anything, just something to help out somebody who wanted so badly to do science and one racist executive order shattered that.

And now, well, the United States is missing out on her ideas. Her writings. Her ability to do good science. It is our loss. 

[adventuresinchemistry]

I really do believe that at least part of the problem of people distrusting science has to do with how we as scientists portray ourselves.

We have actively created a system where we derive authority from being seen as better/smarter/more competent than everyone else and then when people ask why they should trust us we respond with a very condescending version of ‘because SCIENCE IS FACT’ or something along those lines.

Like, consider how that would feel from the outside? Here are a small group of people who you have never met/interacted with who sequester themselves in impenetrable ~elite institutions that you can’t access and don’t feel party to who then tell you that what they say is fact because they’re smarter and better educated than you. And if you ever try to question them (no matter how reasonable your objections may be/seem to you) they condescendingly pat you on the head and say something like ‘don’t worry we know better. you can’t possibly understand what we do.’

Why the hell would you trust them? 

No one likes being told that they’re not smart enough to understand something, and no one likes feeling excluded from something they’ve essentially been asked to accept sight unseen. 

I don’t really have a solution to this, except some vague notion about working harder to portray scientists as people working a job, rather than geniuses who are above it all. 

And like trying harder to understand where people are coming from when they question science. And remembering that being better educated than most doesn’t make us smarter than most. It just makes us better trained in certain types of thinking.

I just think we need to keep in mind what we are asking of people. Which is to put a whole hell of a lot of faith in us.

[scithreads]

We don’t have the right to ask for blind trust just because “we know better.” We really should know better than anyone that claims require evidence. But it’s becoming more and more clear that this problem of trust needs to be solved, or we are eventually going to lose our place in the public discourse.

The complexity of the body of scientific knowledge is partly to blame. Most basic scientific findings are based on decades of research by highly trained individuals. How do you distill all of that knowledge and present the important points to help someone understand that our positions are valid, based on a solid logical foundation? This is something I struggle with every time I sit down to write a blog post.

Without an engaged audience, I don’t see how we can accomplish this. The mental work required to see how the stones fit into the wall of knowledge is not insignificant, and people need some incentive to put in the time and thought. 

I’m not sure I have a real solution either, other than respecting where others come from, and not making people feel inferior for not seeing the scientific light that seems to us to be so obvious nobody could miss it. Without respect, we have already lost.

[scithreads]

Why we need to stand up for science...

There is no denying that we have entered a new era. The last week has brought a whirlwind of concerning announcements, statements, and revelations with wide-ranging consequence. To be honest, it’s hard to know exactly where to focus, with so much at stake in so many areas.

Personally, the seeming attack on science has affected me deeply. So many of the positive things in our world society are dependent on the advances in science and technology, based on following the evidence and rejecting what doesn’t hold water.

I was reminded the other day what can happen when science is pushed to the side by powerful people for whom its message is inconvenient. In Stalin’s Soviet Union, a biologist named Trofim Lysenko rejected Mendelian genetics in favor of his pseudoscientific principles for increasing agricultural yields. For example, he believed that acquired characteristics could be passed on to offspring, and hoped to use those principles to develop crops that could better withstand the harsh Russian climate. 

He introduced new processes and ideas so quickly, there wasn’t time for legitimate biologists to conduct experiments to counter his false viewpoints. Following a period of famine during the 1930s, he managed to convince leaders to put him in charge of agricultural affairs. Once there, he put down legitimate geneticists and biologists, gaining Stalin’s attention and favor by painting them as enemies of Marxism. 

By 1948, traditional genetics was officially banned in favor of Lysenkoism. Over 3,000 mainstream biologists who failed to get on board were fired, imprisoned, or even executed. Not until the mid-1960s did the Soviet Union manage to shake off Lysenko’s radical pseudoscience and resume legitimate evidence-based progress in biology.

I understand the political conditions in the US are nowhere near the same as Stalinist Russia. Our system of checks and balances is far more robust, not only in the structure of our government, but in the wide availability of information. Journalists, at least the good ones, try to hold our leaders accountable with some degree of success. Thankfully, there’s no sign they are going to let up anytime soon. Beyond that, myriad social media platforms allow us to organize as scientists and present clear, accurate information directly to the public.

I’ve always been an optimist, so I’m hopeful we can pull this one off. With one voice, we need to let our leaders know that we won’t stand for the suppression of evidence-based science. Even if your science isn’t on the endangered list today, that doesn’t mean you are safe in the future. When leaders get in the habit of inventing “science” to fit desired policy, rather than the other way around, we’re all in trouble--not just in the US, but throughout the world.

[sagansense]

[neilarmstrong]

We’ve arranged a global civilization in which most crucial elements profoundly depend on science and technology. We’ve also arranged things so that almost no one understands science and technology. This is a prescription for disaster. We might get away with it for a while, but sooner or later this combustible mixture of ignorance and power is going to blow up in our faces.

Carl Sagan (The Demon Haunted World: Science as a Candle In the Dark)

[smilesandvials]

Science communications has to change.

It does. It’s important that we change now. We should have done it before. 

And I don’t know what changes need to be made but I do feel like science communications and outreach has a few really glaring problems.

1. We mostly talk to children. That’s fine. They are the future. But they aren’t the now and when we don’t get their parents engaged to, we’re asking them to clean up a mess when they’re old enough. And when I say children, I really mean children. I don’t know the last time I was at an outreach event that focused on high schoolers or was made for a high school audience. 

2. We’re mostly talking to people who will already be fairly well educated. That’s fine to. But we’re missing people who either have little interest in actively investing in education and people who don’t have access to it. We’re mostly getting contact with people who are already in school. 

3. We are talking to people who already agree. We are preaching to the choir. That makes sense – they are who shows up. I don’t know how to talk to people who already think I’m wrong or a waste of tax payer dollars but I would love to find out. Negin Farsad might have some tips, though.

4. We exclude people. We do. We often implicitly exclude religious groups. We often implicitly exclude people who don’t have a higher education. My mother, even, was nervous about having dinner with my undergraduate advisor because, “[she doesn’t] have a doctorate, [she doesn’t] know how to talk to somebody that smart.” I don’t know how to stop that impression but I would love to. 

5. Maybe, too many of us are career scientists. That’s fantastic – we have a job we are passionate about. But…then it is a little easy to write off our excitement. I’m not always that impressed by how cool math is when a mathematician gets excited about it. But if my barista got excited about a proof – wow, that must be a really cool proof, right!?

6. We don’t always have the communication skills. This is obvious because the seminars I go to are not as exciting to me as a TEDTalk, even if the subject matters to me more. We need to hone those skills. For me, I’m hoping to take improv classes. Write more. Try different things. But we need to include professional communicators or theater departments or artists in our efforts.

I am 23. I am not a seasoned science communicator. I might not even be a seasoned communicator. I can’t find the answers to all of these but I know they are problems. 

[scithreads]

This map-like spalting pattern in this section of wood was caused by a fungus invading the tree before it was cut down by forest managers. The dark lines are the boundaries between different fungal colonies.

[scithreads]

Phage viruses use quorum sensing to decide what to do

It’s fairly well known that many bacteria use a signaling method called quorum sensing to determine how many neighbors are around. They use this information to make decisions about metabolism and growth strategies. The system is based on secreted chemicals that rise in concentration as the population of bacteria grows.

For the first time, this behavior has been observed in phage viruses, which are harmless to humans, but infect bacteria. In phages, quorum sensing is used to determine when to switch from one multiplication strategy to another. 

Phages infect bacteria by injecting their DNA through the cell wall. In the first multiplication strategy, called the lytic cycle, the DNA is transcribed and translated by the hosts cellular machinery to make more copies of itself. After many copies of the virus are produced, the bacteria ruptures, spilling all the new viruses into the surrounding environment to infect other cells.

The other multiplication strategy is called lysogeny. In lysogeny, the viral DNA is spliced into the host cell’s chromosome. Every time the bacteria divides, it replicates the viral DNA along with its own. 

During the initial invasion of a bacterial colony by a phage, the lytic cycle provides a much faster spread, allowing the virus to take over an entire bacterial colony pretty quickly. Once most of the surrounding bacteria are infected, though, the phage doesn’t get much advantage from the lytic cycle anymore, since there are few new bacteria to infect. In order to most efficiently spread its genome, it switches to lysogeny mode. Now, every doubling of the bacterial colony doubles the number of phage copies.

The new research has identified a tiny peptide (only six amino acids long) that is coded by the phage DNA. This peptide, called arbitrium, is secreted into the environment around infected bacteria. When only a handful of cells are infected, the concentration of secreted arbitrium is low. Once the infection really starts to take hold, arbitrium levels skyrocket, and start to tell the phage to start the lysogeny phase.

Just like the countless messages that fly by us every second, carried by unseen radio waves, all kinds of life are sending signals to each other all the time. It is exciting to see how viruses have joined the club of communicating organisms.

References:

Communication between viruses guides lysis–lysogeny decisions, Zohar Erez et al, Nature, 1/18/2017

Virology: Phages make a group decision, Alan R. Davidson, Nature, 1/18/2017

Image credits: Wikimedia user Suly12, Creative Commons BY-SA 3.0

[scithreads]

Cancer cells can trick ribosomes into helping them out

A lot of cancer research is focused on regulation of transcription--which genes are turned “on” or “off”. Genes that are “on” are actively being used to make messenger RNA (mRNA), which is exported from the nucleus and used by the ribosomes to make the proteins the cell needs (a process called translation). In cancers, the on-and-off pattern gets disrupted in favor of genes that promote growth and division, the delicate balance of mRNAs is upset, and the cells begin to grow uncontrollably.

Some intriguing research published this week suggests that this is far from the whole story. At least in some cancers, the tumor cells manage to find a way to trick the ribosomes into preparing more pro-cancer proteins. Accomplishing this takes a couple steps. 

First, a protein called eIF2-alpha is inhibited. eIF2-alpha is part of the complex that directs the ribosome to the right stretch of the mRNA so translation can begin. With reduced levels of available eIF2-alpha, overall production of proteins drops off. As a result, cancer cells tend to produce less of the proteins the cell needs for health.

The second steps is a bit insidious. Another protein called eIF2A (yeah, it is a similar name) takes the place of eIF2-alpha, but tends to convince the ribosome to start at slightly different sites on the mRNA. These sites, known as upstream open reading frames, or uORFs, are closer to the beginning of the mRNA strand. It just so happens that only a handful of all mRNAs seem to have these uORF sites, and guess what? Many of these mRNAs code for proteins that have been implicated in tumor growth.

These findings highlight the incredible complexity of the cell, and the difficulty in teasing out the details of regulatory pathways. Cancer researchers can’t just look at the relative levels of various mRNAs in a cell and know what’s going on with protein production. Since cancer cells can change the pattern of protein translation, scientists need to look at what proteins are actually being made in higher amounts in tumor cells. It is clear that there is still far more to the puzzle of cancers and how they are able to hijack cellular machinery.

Interesting side note: you probably learned in an intro-to-bio course that the first amino acid is always methionine, coded by the genetic letters AUG. Apparently, eIF2A is able to convince the ribosome to start at CUG, resulting in proteins that start with leucine instead. (By the way, whenever a biology instructor tells you something ALWAYS happens a certain way, they’re fibbing. There are always exceptions in this field, and to be honest, that is where most of the interesting bits are...)

References:

Translation from unconventional 5′ start sites drives tumour initiation, Ataman Sendoel et al, Nature, 1/11/2017

[bpod-bpod]

Caught Red-handed

Imagine if one blood test could help a doctor see whether cancerous cells are spreading to other organs in their patient’s body? Now, a device has been developed by engineers that could do just that: by trapping potentially metastatic cancer cells, it can help identify cells before they invade other organs. The device, a sort of lab-on-a-chip, is made up of a 76-element array (pictured left). Each element has a well, and at the bottom of each well are specific antibodies that attach to unique proteins on a cancer cell’s surface. Blood droplets from a patient’s sample are placed into the wells (right), and if cancerous cells are present, an electrical signal is created, signalling to researchers that these cells should be investigated further. This device could be used to detect a wide-range of cancer types, helping to increase a patient’s survival.

Written by Katie Panteli

Adapted from images by Farhad Khosravi and colleagues

Small Systems Laboratory,Department of Mechanical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA

Images originally published under a Creative Commons Attribution (CC BY 3.0)

Published in Nanotechnology, September 2016

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[scithreads]

After a decade of progress, Argentina’s scientists are battling a government bent on twisting public conceptions of their role, writes Alberto Kornblihtt.

The concerns raised in this article are eerily similar to some of the things I’ve been thinking about since the US election. For example, the cabinet chief, Marcos Peña, said “critical thinking has done too much damage to our country”. He continued: “Some people in Argentina think that being critical is being smart. Our government believes that being smart is being enthusiastic and optimistic.”

I can’t help but think of the parallels to what is happening in the US. Evidence and critical thinking is being downplayed, or even thrown out in favor of enthusiastic repetition of groundless viewpoints and rampant clickbait. 

We’re headed for an uphill battle in the science community to make sure evidence and reason wins out over ignorance, and it isn’t yet clear how successful we will be.

[medresearch]

New Precision Medicine Tool Helps Optimize Cancer Treatment

Columbia University Medical Center (CUMC) researchers have created a computational tool that can rapidly predict which genes are implicated in an individual’s cancer and recommend treatments. It is among the most comprehensive tools of its kind, and the first that incorporates a user-friendly web interface that requires little knowledge of bioinformatics.

The researchers found that the tool, called integrated CAncer GEnome Score (iCAGES), identified personal cancer “drivers” 77 percent of the time when presented with a pair of randomly chosen driver genes and non-driver genes, compared with about 51 percent for other computational tools.

Most cancers are caused by the accumulation of somatic (versus inherited) genetic mutations, or variants. Many of the variants involved in numerous types of cancer have been identified with genetic sequencing studies of large numbers of patients. However, this information is not always clinically useful on an individual level. Cancer “drivers” can vary from patient to patient, and there are no practical clinical tools for predicting which variants in an individual’s genome are driving his or her disease and which are present but not causing disease.

To address this shortfall, Kai Wang, PhD, associate professor of biomedical informatics and director of clinical informatics at the Institute for Genomic Medicine at CUMC, and his colleagues developed iCAGES. First, iCAGES analyzes the patient’s entire genome, comparing it to the genomic sequence of the patient’s tumor to identify possible cancer-causing variants. Next, iCAGES cross-references these variants to databases of known cancer-causing genes, using statistical analyses and machine learning techniques to prioritize the most likely driver genes. Finally, iCAGES matches the variants to FDA-approved and experimental drug therapies that specifically address those variants or genes. The entire process takes about 30 minutes. In contrast, conventional approaches require many separate steps involving human input, taking as long as several weeks.

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Funding:  The study was supported by grants from the National Institutes of Health (HG006465 and MH108728).

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