To scientists' delight, the incredible appendage from 99 million years ago is covered in feathers.
The tail of a 99-million-year-old dinosaur, including bones, soft tissue, and even feathers, has been found preserved in amber, according to a report published today in the journal Current Biology.
While individual dinosaur-era feathers have been found in amber, and evidence for feathered dinosaurs is captured in fossil impressions, this is the first time that scientists are able to clearly associate well-preserved feathers with a dinosaur, and in turn gain a better understanding of the evolution and structure of dinosaur feathers.
How did life start on planet Earth? I mentioned recently that single-celled life emerged about four billion years ago. But the first single cells didn't pop into existence. Even the simplest organisms on our planet are incredibly well-organized: they have specialized substructures called organelles, and separate parts of the cell are enclosed in membranes to keep them separate.
Most origin-of-life work concludes that life got its start from relatively basic molecules that could produce more of themselves, long before the complex parts of modern cells learned to work in tandem. One of the ideas about how this started is called the RNA World Hypothesis.
Emphasis on the hypothesis here; there are a lot of unexplained holes in this idea, and it is not universally accepted. On the other hand, we’ll probably never have substantial evidence to support or refute origin-of-life hypotheses. Instead, such theories are evaluated primarily on their plausibility. Does this make sense as a way that life could have emerged?
Recall the central dogma of molecular biology. Information stored in DNA (replicated by proteins) is transcribed into RNA (also by proteins) and translated into proteins (by RNA). The system is interlocking; none of these molecule types can reproduce themselves. They are interdependent.
The RNA World hypothesis suggests that all of these roles were once played exclusively by RNA. It may have kickstarted life as information storage, messenger molecule, and molecular catalyst, all at once.
We already know that RNA can have enzyme-like activity - the ribosome, which translates RNA into protein, is universal. And in the RNA World hypothesis, RNA doesn't need to perform complex tasks like protein enzymes do in modern cells. They just need to be able to replicate other RNAs.
Self-replication has never been demonstrated in an RNA enzyme, also known as a ribozyme. However, research this year described an artificial ribozyme that was capable of replicating other RNAs. The ribozyme’s own genome is too long and complex for it to handle at this point, but the scientists are hoping to improve it in the future. If they are able to develop a ribozyme that can replicate its own genome, it will be significant boost to the plausibility of the RNA World as a possible origin of life.
Such an RNA would encode information, like modern DNA. A single strand of it would fold into a ribozyme, while a complementary strand would simply encode the ribozyme for future replication. And it would have the catalytic function of modern enzymes required to reproduce its own population in the future.
(To be clear, a “self-replicating” molecule doesn't have to unwind and replicate itself - it has to be able to replicate nearby molecules with similar characteristics. The population is what is described as self-replicating.)
Generally in the RNA world hypothesis, the ribosome evolves next; RNA develops the ability to shape other molecules (proteins) into useful catalysts. The ribosome's modern status as a protein-enhanced ribozyme is the strongest surviving evidence for the RNA world hypothesis; it would be considered one of the few surviving RNA enzymes. Although there are a handful of other ribozymes in modern cells, they almost exclusively interact with other RNA or DNA molecules in their tasks. (Being able to recognize RNA and DNA sequences is the single major advantage that ribozymes have over their protein counterparts, which have a much larger chemical alphabet to work with.)
The shift to DNA as an information storage strategy is less complicated to explain. The differences between DNA and RNA are very small:
Image from Penn State.
In the DNA/RNA backbone, the loss of a single oxygen atom makes the deoxyribose of DNA a more stable storage molecule. Oxygen is a relatively reactive atom; the bottom-left oxygen is the connective atom that links successive nucleotides together, but the bottom-right oxygen (OH) in RNA is free for other molecules to react with it. This is dangerous when you need your genome to be reliably stable!
The four-letter alphabets of DNA vs RNA also have one letter difference in thymine (T) versus uracil (U), but looking at the image above you can see these molecules are also very similar. Changing from RNA to DNA requires adding only one methyl (CH3) group on the top right corner of the hexagon. There are several possible reasons that this change may have come about, generally following the same pattern of increasing stability.
Of course, the RNA World Hypothesis faces challenges of its own. It considers the first life as RNA-based, but RNA itself is a fairly complex molecule, consisting of four monomer types which each have three distinct parts (ribose, phosphate, and base).
Image from Science Prof Online.
RNA polymers naturally base pair with complementary sequences, giving them an advantage on being simple to self-replicate, but how those polymers came to exist in the first place is its own challenge to unravel!
Artist and scientist Jill Pelto hopes to inspire people to take action by imbuing her dreamy paintings with hard scientific data and field research.
I posted an article, and some images, several months ago of Jill Pelto’s art. But this article has some new art. It’s worth a repeat. Here’s some of her art. Link into the article to read her story.
Little side note to give this post some context. Over the weekend, I participated in a climate change research seminar and field work studying joshua trees and piñon pines in Joshua Tree National Park. Dr. Cameron Barrows, who is one of the lead researchers on the effects on climate change in the desert environment, was doing his usual lecture, showing us data and charts and graphs. But he inserted a poem into his presentation, written by a woman from England who did some citizen-scientist work in Joshua Tree National Park earlier this year. She came into the research perceiving the desert to be a horrible, desolate place with no life. She left with a 180 degree turn, and wrote a poem about what she then realized a desert to be, as a place full of life. Dr. Barrows told us, completely correctly, that art can add a gloss to science that we all need to appreciate the science.
‘Landscape of Change’ was painted using data about sea level rise, glacier volume decline, increasing global temperatures and the rise in fossil fuel usage. (Photo: Jill Pelto)
‘Habitat Degradation: Arctic Melt’ depicts Arctic sea ice data from 1980 to present. (Photo: Jillian Pelto)
‘Habitat Degradation: Deforestation’ depicts the plight of tigers using data showing the decline in rainforest area from 1970 to 2010. (Photo: Jillian Pelto)
‘Increasing Forest Fire Activity’ uses global temperature rise information to illustrate how harsh drought conditions affect forested regions. (Photo: Jillian Pelto)
‘Salmon Population Decline’ draws population data from the Coho salmon of the North Pacific. (Photo: Jillian Pelto)
'Decrease in Glacier Mass Balance’ uses data from a group of North Cascade, WA glaciers from 1980-2014. (Photo: Jillian Pelto)
'Habitat Degradation: Ocean Acidification’ depicts the decreasing pH (meaning increasing acidity) in oceans from 1998 to 2012. (Photo: Jillian Pelto)
I talked a little bit about the ribosome in this post, where I describe its basic role in protein synthesis. To tackle this paper we need a little more background in what a ribosome actually looks like.
Image from University of California, Santa Cruz.
This giant squiggle is a bacterial ribosome. In this representation we can see the two main subunits of the ribosome, cleverly named the small and large subunits. THe small subunit is blue and the large subunit is grey. This is the RNA that makes up the majority of the ribosome's mass as well as its catalytic center. (The light purple RNA on the upper right is colored differently because it's part of a different RNA strand, but it still belongs to the large subunit.)
Decorating the RNA in pink and purple - the part that looks like springy confetti - are ribosomal proteins, which are essential for the ribosome to function but not particularly important for understanding how it works.
The two subunits of the ribosome associate with each other only after the small subunit has found a gene to translate - the messenger RNA depicted above in orange. The small subunit has to pick this message out of many options, and its choice is vital to the balance of gene expression
In this paper, scientists engineered ribosomes where the two subunits are attached to each other, instead of floating separately through the cell until they meet to translate a messenger RNA. I'm geeking out already, but if you're not, read on.
How do you attach the ribosomal subunits together in the first place? The ends of the RNAs aren't necessarily arranged near each other once they're folded; if you just fused the genes together the way we did to make GST fusion proteins, you could end up with one subunit suck to the wrong side of the other like an unfortunate wart - or it may not fold properly at all. Instead, the writers use a technique called circular permutation to place one gene in the middle of the other, like Russian nesting dolls.
In circular permutation, researchers linked the two ends of the large subunit RNA together, forming a circular gene with a small linker, and then cut it again in a different place. So if the gene originally looked like this:
ABCD
It might now look like any of these:
BCDA CDAB DABC
Is this terrible for the cell? Of course. But the whole point of studying biology is to torture bacteria.*
*source needed
Researchers tried 91 ways to combine the two subunits and put the gene for each one in a different bacterial strain, replacing the natural ribosome. Of those strains, 22 survived, demonstrating that they had the capability to synthesize protein like ribosomes are supposed to.
Here's Figure 1 of the paper.
Phew, that’s a lot of squiggles!
Panel A shows us how circular permutation works. They connected the two natural ends of the gene and cut new ends, resulting in the blue gene on the left labeled CP23S (CP for circularly permuted). The former ends of the gene are now in the middle, with the purple connector linking them.
In panel B, we're looking at a flattened map of the large subunit, showing the most important places where the RNA folds back and bonds to itself. Each new cut they tried is marked; red ones died, while green ones survived. The original ends with the linker are also shown, in the middle marked “Linked WT 5′ and 3′”.
In panel C, we see these cuts mapped onto the 3D ribosome.
Each cut forms two new "ends" to the RNA; in the mutants that survive, those portions of the 3D structure are formed even if the RNA isn't a single linked chain. In panel C above, a blue arrow points to H101 on the 3D structure - H for Helix. That helix is cut in the mutant CP2861, and you can see the cut site on the 2D diagram, on the bottom and just slightly right of middle.
Also noted in panel C is h44 of the small subunit. (H still means helix - as far as I can tell, it's not capitalized to remind you it belongs to the small subunit.) h44 is suspiciously close to H101. The plan is to cut h44, generating two new free ends, and connect them to the two free ends already created at H101.
Here's Figure 2 of the paper, where they explain how they combined the ribosomal RNA genes.
In panel A, the "normal" genes are on the left, compared to the nesting-doll genes on the right. 16S is the RNA that forms the small subunit and 23S is the RNA that forms the large; 5S is that tiny extra RNA on the large subunit that I told you isn't very important here.
In panel B, you get a look at how this is going to work with an actual RNA. When this gene is being transcribed from the DNA, it will start at one end of the yellow 16S RNA, marked 5', follow it along to the h44-H101 linker, transcribe the entire circularly permuted 23S RNA (including its original ends, now linked), get back to the other side of the h44-H101 linker, and finish up the 16S RNA when it reaches the end marked 3′. The 5S RNA gets transcribed separately as normal.
Then in panel C, we see the linker in place on a folded ribosome. On the left is a view that is probably becoming familiar; on the right, they've opened the two subunits like a book so you can get a better look at the parts they're changing.
Panel D is just them proving that the cells make only the tethered ribosomes - that they’re not cheating by making normal ribosomes too. If anyone is interested in a detailed breakdown I'll write one in a separate post, but suffice to say it's pretty convincing.
The problem with the linkers is, they have to be short enough to make sure the subunits stay monogamous, but long enough to let them move and perform their function. I'm picturing this like a pac-man sort of situation, with the two halves floating around chomping on other parts of the cell, but it's hard to say for sure.
To solve this problem, the writers took advantage of biology the same way they did before: they made linkers of different lengths, put them all in different bacteria, and tested which colonies grew the fastest. (Fast growth is a sign of fast protein synthesis, indicating the ribosome works well.) These cells were still pretty slow-growing, though. Nature is pretty efficient and it doesn't usually like when you mess with it. So they grew these cells for 100 generations and then selected the fastest-growing strains, and then for good measure, sequenced their genomes to see which mutants sped them up.
One of the major implications of this work is how it could help us engineer ribosomes for new tasks. Previously, scientists have been able to create modified small subunits that choose their messenger RNAs differently than most ribosomes. These modified subunits can perform specific tasks, but they have to coexist in cells which also have normal ribosomes to keep them healthy and growing. And since the subunits are separate, the mutant and natural small subunits share the same pool of large subunits; you can't make a mutant large subunit that only works with your mutant small subunit. This is especially problematic because the large subunit contains the ribosome's catalytic center, which is a big target for engineering the ribosome for new tasks, such as making new synthetic kinds of protein.
With a tethered ribosome, you can mutate either subunit and guarantee that it will function with its correct mutated counterpart. You can also exclusively purify your mutant ribosomes from cells that have been making them, but living mostly off of their normal ribosomes. There's a lot of potential here, basically.
Among possible modifications to these ribosomes is antibiotic resistance. Antibiotics often target ribosomes because bacterial ribosomes are different enough from plant and animal ones that we can attack the bacteria without hurting ourselves. The resistance mutations can fall in either subunit of the ribosome, so by tethering them, you can create ribosomes resistant to multiple types of antibiotics. I described one way that antibiotic resistance can be scientifically useful in this post. And don't worry - the resistances that are used in science are well-established ones to antibiotics not very prevalent in medicine. We're not creating superbugs here.
In another example, the writers evolved their tethered ribosome to handle RNA that is challenging for normal ribosomes. They did this with strategies that should look familiar by now: they introduced mutations in a bunch of ribosomes and tested to see which ones did best with the challenging RNA.
The reason this could never be done before is that the mutations they introduced are in the catalytic center of the ribosome - the part that actually links amino acids together to build proteins. Such mutations kill bacteria. Even if you introduce a mutated large subunit along with a normal one in bacteria, the mutant ones still use up some of the cell's small ribosomal subunits, crippling it beyond viability. With the tethered ribosome, however, the mutant can work alongside normal ribosomes without impeding their function, since it only interacts with its own small subunit.
I should clarify that tethered ribosomes are still a lot slower than natural ones - like I said, Nature is efficient - but we're not engineering speed here. We're engineering the ability to deal with difficult RNAs.
And how do we figure out which mutated ribosomes are good at translating the challenging sequences? With biologists' favorite gene, lacZ. LacZ is part of E. coli's lactose-digesting system, but more importantly than that, it's blue.
The scientists put the challenging RNA sequence right before lacZ in a gene. If that strain of bacteria has an ribosome mutant that's good at handling the difficult sequence, it will get through the challenge, transcribe lacZ, and the colony will turn blue.
Image from here.
Blue colonies have ribosome mutants that can handle the difficult RNA sequence, while white colonies have mutants that could not. It's clear now why it's so important to perform cloning; since each of these small dots is descended from a single cell, it is genetically uniform. We don't have to worry about whether it's only blue because SOME mutants can translate the challenge sequence, because they all have the same mutant.
The researchers can then pick each blue colony and sequence its genome.
So now we have these wacky ribosomes, and we've demonstrated several things about them. First, we've demonstrated that it's possible for cells to survive with tethered ribosomes. They're quite slow growing and they would never be competitive with common strains of E. coli “in the wild," but they're viable. Second, by growing cells with both normal life-sustaining ribosomes and mutated tethered ribosomes, you can develop two distinct populations of translation machinery which select different genes to express, including by mutations that kill cells when introduced into their life-support ribosomes.
(Those mutations are called "dominant lethal" because the presence of the mutation is lethal even if it is accompanied by an unmutated gene. Dominant lethal mutations are especially common in systems that have exchanging subunits, since even one mutated subunit breaks the whole complex.)
The paper describes the advance thusly: "This finding made possible an evolvable gene expression system in the cell in which an entire specialized ribosome is dedicated to the translation of a defined genetic template." (Quote shortened for clarity.)
This is also significant because we can now examine the effects of lethal ribosomal mutations, which are otherwise impossible to grow in cells.
Following their study, the authors conclude that the beetle must have inhabited the sparsely-vegetated sand and gravel banks of a meltwater-fed stream that was once part of an outwash plain at the head of a fjord in the Transantarctic Mountains.
Fossilised forewings from two individuals, discovered on the Beardmore Glacier, revealed the first ground beetle known from the southernmost continent. It is also the second beetle for the Antarctic insect fauna with living descendants. The new species, which for now is also the sole representative of a new genus, is to be commonly known as Ball’s Antarctic Tundra Beetle. Scientists Dr Allan Ashworth, North Dakota State University, and Dr Terry Erwin, Smithsonian Institution, published their findings in the open access journal ZooKeys.
The insect fauna in Antarctica is so poor that today it consists of only three species of flightless midges, with one of them having been probably introduced from the subantarctic island of South Georgia. The absence of biodiversity is considered to be a result of lack of moisture, vegetation and low temperatures.
Following their study, the authors conclude that the beetle must have inhabited the sparsely-vegetated sand and gravel banks of a meltwater-fed stream that was once part of an outwash plain at the head of a fjord in the Transantarctic Mountains. Plants associated with the extinct beetle include southern beech, buttercup, moss mats, and cushion plants, all typical for a tundra ecosystem. The species may or may not have been able to fly.
The closest modern relatives to the extinct species live in South America, the Falkland Islands, South Georgia, Tasmania and Australia. Tracking the ancient lineage of this group of beetles, known as the carabid beetle tribe Trechini, confirms that they were once widely distributed in Gondwana, the supercontinent that used to unite what today we recognise as Antarctica, South America, Africa, Madagascar, Australia, the Arabian Peninsula and the Indian Subcontinent. Ball’s Antarctic Tundra Beetle is also an evidence that even after Gondwana broke apart, the tundra ecosystem persevered in Antarctica for millions of years.
“The conflicting signals both in anatomical attributes and biogeography, and in ecological setting as well, leave open the question of relationships, thus giving us no alternative but to flag the species represented by fossil evidence through erection of new genus status, hence drawing attention to it and the need for further paleontological studies in Antarctica,” speak of their discovery the authors.
The new Ball’s Antarctic Tundra Beetle is scientifically identified as Antarctotrechus balli, where the genus name (Antarctotrechus) refers to its being related to the tribe Trechini, and the species name (balli) honours distinct expert of ground beetles Dr. George E. Ball, who celebrated his 90th birthday on 26th September, 2016.
A Short List of Features of the Universe Without Which You Would Not Be Alive
Earth's Liquid Core
If you take a physics class on Electricity and Magnetism, you'll learn that electrically charged particles are affected by magnetic fields. (You’ll also have to contort your fingers in silly ways if you want to figure out how.) The sun emits ions and electrons in solar wind and during solar flares, but these particles are deflected by the Earth's magnetic field.
But where does the magnetic field come from? It turns out electrically charged particles also generate magnetic fields when they're in motion. The motion of iron atoms in our liquid core produce the Earth's magnetic field, and it's maintained by a process called a dynamo, which is a great name but a complicated concept. In short, it's a feedback loop that causes the magnetic field to maintain itself.
So why do you need it to survive? Well besides the fact that solar radiation would kill you relatively quickly, it would also strip away our atmosphere, leaving us nothing to breathe and allowing all the water on Earth to boil away in the absence of vapor pressure. (We think that’s what happened to Mars’ atmosphere.) So!
Speaking of water...
The Density of Ice
You know how ice floats in water? You know how that's incredibly weird? Almost all other compounds get more dense as they freeze. This is a really unique property of water, and it also allows life on Earth to exist.
Because cold water is denser than warm water, it sinks - as you'll know if you've ever been swimming in a lake with a sunshine-warmed surface and toe-chilling depths. In the ocean, where it's cold and deep enough to approach freezing temperatures, water’s density decreases as it solidifies, and the frozen water rises toward the surface. That brings cold water upward to get warm again and causes thermal cycling in our oceans.
Without that - if frozen water sank like almost all other frozen liquids do - the oceans would freeze through from the bottom up. Most likely the sun would melt a small layer of water on the surface each day, which would refreeze during the night. Life as we know it could never have developed - though it would be interesting to consider the other kinds of life that might have existed, depending on geothermal vents or perhaps even adapting to the daily freeze-thaw cycle.
Why is frozen water so unusual? Because of water's unique hydrogen-bonding structure.
The First Green Bacteria
Ancient single-celled Earthlings created the first massive global extinction by expelling poisonous gas into the atmosphere. That poisonous waste? Oxygen.
Over two and a half billion years ago, cells called cyanobacteria lived on a wet and well-lit but oxygen-free Earth - the atmosphere was almost all nitrogen. Over the next few million or billion years of photosynthesis, oxygen, a poisonous and volatile waste product, was released into the atmosphere. Eventually, oxygen levels were too great to be absorbed by the ocean or burn away in reactions with other volatile compounds. The oxygen concentration in the atmosphere reached a critical level where it became toxic to most bacteria living on earth. The following mass extinction, and the permanently changed atmosphere it left behind, opened up room for aerobic (oxygen-using) life to emerge on Earth.
Sudan is the last of his kind on Earth. He just looks like a rhino. But as his keeper will quickly inform you, he is one of just three northern white rhinos remaining on the planet. The other two, a mother-daughter pair named Najin and Fatu, are unable to bear young. In addition to being …
In honor of #WorldWildlifeConservationDay, did you know there are just three northern white rhinos remaining on the planet?
Researchers formulated a game plan for saving the northern white rhino, which they outlined in a paper published in Zoo Biology.
The approach is two-pronged. The first part entails the creation a test tube baby rhino. Doing this requires figuring out how to safely harvest egg cells from Najin and Fatu. Hildebrant is currently devising such a method by carefully practicing on southern white rhinos kept in zoos in Europe. Dilly-dallying on this task is not an option, given that Fatu and Najin are currently the only depositories of eggs left on the planet. As Vigne put it, “If they die, their eggs die with them.”
As for sperm, Sudan faces no pressure to produce. The Genome Resource Bank in Berlin contains sperm that Hildebrandt and his colleagues collected from four other northern white rhino males. Given that Sudan is Najin and Fatu’s father and grandfather, respectively, his sperm, even if it was viable, risks the problems associated with inbreeding.
Assuming the researchers can successfully unite egg and sperm in a petri dish, the embryo would then be transplanted into the womb of a young, healthy southern white rhino surrogate mother in Kenya. While the procedure is nothing new for cows, pigs and other livestock, it has never been tried in a rhino.
...
While Hildebrandt and Galli work on the problem of egg collection, in vitro fertilization and implantation, another research team is focusing on solving a separate issue: how to introduce more diversity into the northern white rhino’s gene pool. Even if Najin and Fatu’s eggs are successfully harvested, fertilized and implanted into southern white rhinos, basing an entire species’ recovery on a single mother-daughter pair would provide too narrow a window of genetic variation for creating a healthy population.
The genetic jackpot may reside on yet another continent. In the 1980s, The San Diego Zoo began banking tissue samples from various individuals in its frozen zoo, the world’s largest and most diverse collection of frozen animal samples. The samples include tissue from 12 northern white rhinos, representing eight unrelated individuals.
“We believe there’s enough genetic diversity in the cells we’ve preserved that they could reconstitute a breeding population,” says Oliver Ryder, the San Diego Zoo’s director of genetics.
Tapping into that diversity depends on harnessing the most recent breakthrough technologies in stem cell biology. In 2012, Shinya Yamanaka won the Nobel Prize in Physiology for the discovery that changing the activity of only four genes can imbue a cell with the ability to become any other type of cell in the body. Induced pluripotent stem cells, as they are known, are usually discussed in terms of human health and fertility, but they could also have a conservation application. Indeed, in 2011, a team led by Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute, successfully created induced pluripotent stem cells from Fatu’s skin cells.
...
Much remains untested and unproven, including whether induced pluripotent stem cells from northern white rhinos can be turned into viable eggs and sperm. But as Loring says, “There’s no point in being pessimistic about it. It’ll either be easy or hard or really hard.”
Synthesizing a pharmaceutical is an impressive high school project, but the feat won’t change anything about the soaring cost of generic drugs in the United States.
In a series of tweets, [Martin] Shkreli argued that this analysis was misleading. His main objections with the claim were that this research proved it was possible to manufacture the drug for “$2 a dose,” suggesting that that didn’t involve lab equipment or fees [or] the paid salaries of knowledgeable PhDs and laboratory technicians...
In terms of claims that the drug — based on the students’ project — could be sold for $2.00, Shkreli makes valid objections. The project (while not a full time effort) lasted roughly a year, and had the input of multiple PhD scientists, all of whom would need to be paid for their work were it not an outreach program. At many points along the way, the manufacture of pyrimethamine required repeated trial and error tests conducted by laboratory technicians.
The main hurdle, as illuminated by these discussions, was to find a way to get from their starting chemical (2,4-chlorophenyl acetonitrile) to pyramine without exposing the students to significantly dangerous chemicals or conditions. The scientists in this group did a lot of work upfront to brainstorm and test the process in an effort to identify a viable pathway.
Further, as Shkreli points out, the cost of making a batch of a drug and the cost of bringing a drug to market are very different things. If, for argument’s sake, the students wanted to get their generic version approved in the USA, they would have to subject it to a relatively shorter FDA drug trial called a Abbreviated New Drug Application which, while much less expensive, can still make it unprofitable to bring less commonly used generics to market. That was the the case with Daraprim, and it was the reason Turing Pharmaceuticals was able to hike the price without fear of being undercut.
...
No matter how much help the students had with the design and execution of this project, it is nevertheless an impressive achievement, as it is promoting discussions about the economic and regulatory environment that allow drugs that are (demonstrably) capable of being produced at a low price to be sold with such a high markup.
As a scientific development, however, the project will do nothing to destroy Turing Pharmaceuticals’ ability to set the price of Daraprim in the United States.
Hi everyone! Thanks for following me this month. If you missed my introductory post, I'm writing this blog as my 2016 NaNoWriMo (National Novel Writing Month) project - which I'm happy to report I just won!
There are still quite a few posts in my drafts that I'm going to clean up and queue, so the fruits of my November labor will continue to be posted here for a few days or weeks. I haven't decided what to do with this blog after that. I learned a lot of interesting new things from doing this, and revisited my enthusiasm for things I already knew. I'm going to take a little time off to recover from the marathon of writing 50,000 words in 30 days, and then... I guess I'll experiment a little.
If there's anything you've seen this month that you particularly liked, or if you have new requests for the potential future, feel free to drop me a line. You're a small audience out there but I welcome your feedback!
How does a neuroscientist activate specific brain cells for their experiment?
Electrodes can send electrical signals in certain brain regions - but on the scale of neurons, electrodes are huge. Instead, scientists shine a light on the brain.
How does that make a difference? It's a modern marvel of genetic engineering, and it starts with channelrhodopsin proteins. Channelrhodopsins are light-sensitive ion channels found in single-celled algae. The protein is embedded in the algae's cell membrane, forming a tunnel across it that can be opened or closed. Channelrhodopisns open in response to blue light, allowing positive sodium ions to flow across the membrane into the cell. This serves as a signal to the algae to help it move in the direction of blue light so it can maximize photosynthesis.
"A few years [after this discovery, scientists recognized the potential of the archaeal protein halo- rhodopsin, which triggers influx of negatively-charged chlorine ions in response to yellow light." In other words, this related protein does the opposite of channelrhodopsin: it allows negatively charged ions to flow across the membrane, into the cell, in response to yellow light.
These two complementary channels are especially exciting in light of the fact that electrical currents in neurons are created by electrically charged ions flowing across the cell membrane. An influx of positive ions through channelrhodopsin could turn “on” neural firing, while an influx of negative ions through halorhodopsin could turn the signal back “off”. And all you need to produce the signal is different colors of light.
While simple in principle, the approach raises several challenges. First of all, the light-sensitive channels in question are found in single-celled organisms. In contrast, neural ion channels are finely tuned to work in conjunction with thousands of surrounding cells.
Second, scientists needed methods to introduce the channels only to the cells they were interested in influencing. And they needed to do it while the brains those cells were a part of were still alive and functioning in an animal.
And finally, shining light directly onto a living brain is no trivial task.
Convincing microbial proteins to influence neuron signaling proved less complex than anticipated, though. Neurons "fire" their electrical signals by chain reactions. If channelrhodopsin starts that chain reaction, the neuron obliges by opening positive ion channels of its own. Only three years after channelrhodopsin was described in scientific literature, this paper was published detailing how it could be used to create light-sensitive neurons.
To get the genes for these channel proteins into the neuron, scientists usually use a virus delivery system. After all, viruses are experts at introducing foreign DNA to living cells. Generally the viruses are designed only to express the genes for their protein cargo in certain cells. For example, the signal to transcribe the rhodopsin gene may only be recognized in specific neurons.
Thus, the protein is expressed exclusively in a small subset of neurons. This is the "genetics" part of optogenetics.
The optics comes in with the light source. Typically, a small optical fiber is implanted into the brain of a live mouse.
Image from ScienceLife, in a cool article about using optogenetic techniques on unmodified cells.
After recovering from surgery, the mice are able to move about freely, letting researchers examine the effect of neural activation on their behavior, in contrast to the rather limited scope of immobilized brain scanning.
The fiberoptic cable works on the principle of total internal reflection. When light hits an interface, it is refracted at an angle that depends on the materials it passes through.
Image from Highlights.
Here, the light is refracted differently passing from air to glass than it is passing from water to glass.
Depending on the two materials forming the interface and the angle the light comes from, it can be "refracted" so strongly that it actually travels back into the first material - that is, it is reflected.
In a fiberoptic cable, light enters in a straight line. (Light always travels in straight lines.) When the cable curves, the light hits the side of the cable and is reflected - not backwards, but at an angle that allows it to continue moving forward through the cable.
Image from HowStuffWorks.
In this way, you can treat the cable almost like a pipe carrying the light the same way a pipe might carry water. It enters one end and follows all the twists and turns to come out the other. Because of this, the cables can be flexible, allowing the mice they are attached to free range of motion without requiring that their brains be exposed for light treatment.
With this combination of techniques, scientists have (1) discovered on and off switches for neurons, (2) successfully installed those switches in some neurons and not in others, and (3) engineered control of those switches in mouse brains in a way that is relatively noninvasive to their behavior. Cool!
Neurons, the cells of your brain and nervous system, have three main parts: the cell body, the axon, and the dendrites.
Image from Penn State.
The cell body is the largest part of the cell. Generally the dendrites receive signals from the surrounding neurons, while the axon sends signals to other cells. When the signal reaches the axon terminal (or the terminal bulb in the image above), it gets passed to other neurons in the network.
Some of the largest biological cells in the world are neurons, including the largest ones in your body; neurons at the base of your spine have axons that extend all the way into your feet. The giant squid has neurons with axons many meters long and up to a millimeter thick; these comparatively large cells were key to the first studies on neural function.
What makes up neural signals? Neurons operate on both chemical and electrical signaling mechanisms. Let's address the electrical signaling first.
When we think of electricity, we usually imagine electrons moving in a current. But more generally, an electrical current consists of any motion of charged particles. In cells, ions like sodium (Na+), potassium (K+), and chlorine (Cl-) make up this electrical landscape. (Remember the sodium potassium pump?) Neurons are covered in channels that control whether these ions can pass through the cell membrane at any given time, and they work hard to keep potassium mostly in the cell, and sodium and chlorine mostly out of the cell.
Because the ions are separated this way, neurons have a negative electric charge across their cell membranes, called the membrane potential. What's important with neuron electrics is not the number of ions are inside or outside, but the relative levels between the inside and outside. So the negative membrane potential means that there are more negative ions inside the cell, or more positive ions outside the cell.
(You may notice that the inside is more negative despite the fact that the negative chlorine ions mostly stay on the outside. This is because the positive potassium ions inside the cell are balanced by negatively charged proteins, which cannot cross the membrane.)
The membrane potential represents the fact that the ions are not at equilibrium when they are stuck on either side of the membrane. Because they are so concentrated on each side, if the channels were to suddenly open, ions would rush through until equilibrium was reached.
But the channels don't open all at once. When a neuron receives a signal from a neighbor, it opens a few of its sodium channels in response, and sodium begins to rush into the cell. An increase in the membrane potential, caused by more positively-charged ions entering the cell, triggers other fast-opening sodium channels to open, the sodium rushes in even faster, and the membrane potential spikes. This is called an action potential.
GIF from Neuroscience For Kids.
The influx of sodium ions travels down the cell axon - incoming sodium ions triggering other nearby sodium channels to open. But potassium channels are triggered by the sodium influx too: they're just slower to open. A few milliseconds after the first sodium channels opened, potassium channels begin to let potassium ions flow out of the cell, dropping the membrane potential just as rapidly as it spiked. The sodium channels close when the membrane potential drops, letting the potassium flow return the cell back to its "resting" membrane potential.
In actuality, the potential drops a little lower than its resting level, then slowly raises back up as the cell equalizes itself. The sodium-potassium pump works to put potassium back into the cell and sodium back out of it. For a period of time, the neuron is unable to fire another action potential until it's ready again: this is called the refractory period.
Image from Neuroscience for Kids.
What does all that electrical signaling do, anyway? At the axon terminal, the sudden increase in membrane potential causes bags full of neurotransmitter to fuse with the membrane, releasing their cargo out into the space between neurons called a synapse. The type and amount of neurotransmitter released can depend on the type of neuron, the frequency of the signal, or countless other factors. The neurotransmitter, which is a small chemical, floats across the synapse until it binds to receptors on surrounding dendrites, where it causes sodium channels to open up in those neurons.
I've described a simple-case outline; chlorine ions, calcium ions (Ca++), and many other factors can induce more interesting behavior in neurons such as multiple spiking in response to a signal, or desensitization to a signal received too many times.
This entire process happens in milliseconds and spreads across large regions of your brain - it's happening right now to let you read these words. Thinking is just chemistry! And that's pretty cool.
Scientists tend to use shorthand that describes evolution as having a will. We talk about what evolution wants and likes, what it makes and what it leaves by the wayside.
It's useful to think this way, and it's often a fair description of the patterns that emerge when we study evolution. But it's vital to remember that we are anthropomorphizing. Evolution isn't a force; it's an emergent phenomenon.
Imagine that you have the history of the universe spread out before you. You're curious about what kinds of molecules are most common throughout time. Overwhelmingly first is hydrogen: it's both the simplest and most abundant atom in the universe. Larger and larger atoms have to be forged in the hearts of stars, so they are less common. And even less common than that are complex molecules.
Let's zoom in and look at only the history of the Earth. Here, water molecules are pretty common. Molecules are more common when they are relatively stable, because they last longer, and easy to make, because they’re more likely to show up in the first place.
But uniquely (as far as we know), on Earth, the easiest molecules to make are the ones that can make copies of themselves.
It's possible for a particular unique arrangement of atoms to come about completely by accident. But in most cases, that unique arrangement would only appear once. For a random molecule to show up repeatedly across Earth's history, an astonishing number of unlikely coincidences have to occur.
But for a molecule that can copy itself, that coincidence only has to happen once. Once a self-replicating molecule has appeared for the first time, it can continue to propagate, and it’s more likely to show up over and over again throughout history. And over billions of years, that first, vital coincidence is bound to happen eventually.
Evolution is a description of this reality. When an arrangement of atoms, from the human-shaped to the amoeba-shaped, can guarantee its own reproduction, the probability of similar atomic arrangements in the future increases. Survival of the fittest.
What's really remarkable here is that the universe is less than fourteen billion years old, but single-celled life on Earth came about over four billion years ago. This planet has been host to molecules replicating themselves for almost 30% of the history of the universe!
You are so fundamentally unlikely, and yet statistically possible because your molecules tend to arrange other molecules into a similar shape. We're glad to have you.
You once consisted of a single cell, too small to see without a microscope. Your entire body is descended from that single cell: your blood cells, skin cells, liver cells, and neural cells, all cousins. That first cell had the ability to produce each of these cell types and more, but as that cell divided and multiplied into an embryo, each subsequent generation of cells grew more specialized and the number of roles it could eventually perform narrowed.
Cells that have the capacity to mature into multiple different cell types are called stem cells. The ones I described above are embryonic stem cells, but adults have stem cells in their bodies too. The most famous of these are the hematopoetic stem cells, which mature into different kinds of blood cells (white blood cells, red blood cells, platelets, and others.) Other active stem cells reside in your digestive tract and hair follicles.
(This is essentially why some chemotherapies cause nausea and hair loss. Fighting cancer means preventing rapidly-dividing cells from growing into tumors, but it often impacts other rapidly-growing cell types as well.)
You may have noticed a major difference between these embryonic and adult stem cell types. While the first cells of an embryo go on to eventually form every cell in a human body, the adult stem cells are already relatively specialized. One kind of adult stem cell forms blood cells, another kind forms skin cells, and so on.
This difference is pluripotency. A pluripotent stem cell has the ability to form every cell that makes up the human body. Adult stem cells, on the other hand, are multipotent: they can form many different types of cells, but not all.
(The first few cells of a zygote are actually totipotent: they can form not only all the cells in a human body, but also all the cells to make up a placenta.)
Pluripotent stem cells are of significant biological interest; scientific dreams of growing new organs and stalling neurodegenerative damage rely on their availability. But they have been the focus of significant ethical controversy. Pluripotent stem cells are naturally only found in embryos, and that's where they came from for early stem cell research.
Human embryonic stem cells are derived from embryos discarded by in vitro fertilization clinics, which often fertilize multiple eggs to increase their chances of success, but only advance pregnancy with one. No embryo has ever been created for stem cell research, and all embryos used for scientific research would have died regardless of their research use. Still, the ethical ramifications remain murky and controversial.
Enter induced pluripotent stem cells.
"In 2006, researchers at Kyoto University in Japan identified conditions that would allow specialized adult cells to be genetically "reprogrammed" to assume a stem cell-like state.
Through research on embryonic stem cells (though often using nonhuman embryos), the scientists found genes responsible for making embryonic stem cells pluripotent. Since then, other research has been able to replicate this finding without the use certain genes that promote tumors.
(This is a constant challenge of working with stem cells. Cancer cells are no longer bound by normal rules about when to multiply, often because they have turned on genes from embryonic development that direct cells to grow and divide. Overlap between embryonic development and tumor development exists in the very definitions of those processes.)
Because of this research, it is now possible to take skin cell samples from an adult and create embryonic-like stem cells from them.
It's important to note that an embryo cannot be created this way, so don't get too excited about the future of cloning - the cells aren't totipotent, meaning they cannot develop into a placenta, and thus cannot support embryo growth. However, by influencing their environments regulating their development, they can be induced to grow into a variety of different cell types.
Sidestepping the ethical dilemma of embryonic stem cells is a major advantage to induced pluripotency, but it isn't the only one. When stem cells are created from an adult patient, they are guaranteed to be a genetic and immunological match. Although directing such cells to develop into complex structures (i.e. growing new organs) remains unrealistic, it is possible to grow new cells to replenish failing populations, and the first disease treatments using induced pluripotent stem cells are beginning clinical trials.
It should be noted that as of 2016, no such treatments have cleared trials, so any clinic claiming to be using stem cell treatments is either making use of dangerously unregulated science or, more likely, lying. The only approved medical uses for stem cells are grafting stem cell tissue from a donor, as in a bone marrow transplant.
Current efforts using induced pluripotent stem cells are developing treatments for a variety of diseases: from macular degeneration, to regrow damaged rods and cones in the eye; to multiple sclerosis and other autoimmune disorders, to "reboot" immune systems; to Parkinson's disease, to introduce new dopamine-producing neurons to supplement failing ones.
Thanks to induced pluripotency, it is now possible to grow a petri dish full of neurons out of a skin sample. But if scientists have their way, that won’t be the coolest thing to come out of this technology by a long shot.
Thousands of years of human breeding transformed wild species into the domesticated varieties we enjoy every year. Most of these foods were originally found in the Americas. Some of my favorite details:
The original domesticated carrots were purple. Carrots were bred to be orange by Dutch farmers in the 17th century, and then used as a political symbol of the ruling family - the House of Orange.
The ancestors of pumpkins were mainly eaten by mastodons and giant sloths - they were too bitter for smaller animals to stomach.
Turkeys were bred to have white plumage so their skin would be more uniform in color.
