It helps to be flexible: disordered proteins in biological stress response

Imagine you are working on a project with a large group of people, all with different personalities and responsibilities. Your group was just informed that something important to the progress of the project went terribly wrong. Some people in the group start to panic, which causes other people to panic. There is no defined leader for this group project but you tend to take the lead during stressful times, so you quickly step up to the plate. You know that to get this project back on track, you first need to calm everyone down so that they can refocus on the tasks at hand.

Now try to imagine that instead of people, you and your group are large molecules composed of long chains of amino acids, a.k.a. proteins, and the group project is maintaining the life of your cell.

Much like a dollar bill must undergo many intricate folds to become an origami elephant, chains of amino acids must go through several steps to form a well-folded protein. Top image created by Chris Pielak

Proteins make up many important biological structures (such as hair, nails, and connective tissues) and carry out most chemical reactions in cells (such as converting food into energy or light into sight). For a long time it was thought  that proteins only function once they have “folded” into a highly-ordered shape, similar to how a flat sheet of paper folds into a smile-inducing origami elephant. The unique shape of a protein is dictated by chemical interactions between the amino acids that make up the protein as well as interactions between the protein and water. When drastic changes take place in the environment of the protein (i.e. during cellular stresses such as extreme heat, dehydration, or acidification), these important interactions are disrupted, which can cause proteins that are usually well-folded to temporarily unfold and become inactive. If such a protein remains unfolded for too long, temporary inactivity can become permanent as the protein becomes tangled up with other unfolded proteins in a process known as irreversible aggregation. Under extremely stressful conditions, a significant portion of the proteins in a cell can unfold and irreversibly aggregate, ultimately leading to cell death. So let’s keep all our proteins nicely folded, shall we?

Not so fast! In the past twenty years, the idea that a protein must be folded to function has been challenged by an up-and-coming group of proteins known as intrinsically disordered proteins (IDPs). As the name suggests, IDPs are defined by a distinct lack of a stable, well-folded structure, much like a single strand of spaghetti in a pot of water.

This cat knows spaghetti makes you feel better when you’re stressed out.

Interestingly, organisms across all domains of life have been shown to use IDPs to deal with environmental stresses. Many of these stress-response IDPs are “conditionally disordered”, meaning they can transition into or out of a more ordered state in response to an environmental cue. Given that IDPs are used to being in an unfolded-like state, it kind of makes sense that they can “survive” many of the environmental stresses that typically well-folded proteins can’t. But besides persisting through stressful times, how do IDPs help cells survive extreme environmental stresses? One emerging hypothesis is that stress-response IDPs work by morphing into a shape that can stick to partially unfolded proteins before irreversible aggregation can occur, thus making it possible for stress-sensitive proteins to refold after the stress goes away. In support of this idea, recent studies showed that the bacterial acid-sensing protein HdeA becomes disordered in acidic conditions, and it is in this disordered state that it can stick to partially unfolded proteins and prevent aggregation. Similar modes of action have been proposed for IDPs involved in heat- and dehydration-response as well.

So, just like you in the hypothetical scenario described at the beginning of this post, some IDPs keep the group project (the life of the cell) on track by pulling aside the easily stressed out group members (highly-ordered, stress-sensitive proteins) and calming them down a bit so that once the stress has subsided, everyone in the group can refold and get back to work.

Peer edited by Giehae Choi.

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A Southwest Turn

Hurricanes are well-known for how unpredictable their paths can be. As wild as they can get, we can usually count on two things for storms that live primarily in the ocean in the Northern hemisphere: their general hook shape, and sharp bends.

source: https://en.wikipedia.org/wiki/File:2018_Atlantic_hurricane_season_summary_map.png

2018 Atlantic Hurricane Season

As has been frequently reported in the news, Florence took a particularly strange turn when it headed southwest. To see how that came about, we can look at the Cauchy momentum equation, one of the Navier Stokes equations that are central to fluid dynamics:

The Cauchy momentum equation

The equation itself can take on several forms, depending on the usefulness for the particular application. For our purposes, however, the above is sufficient since we have the relevant terms. In determining the path for Florence, two out of three of the terms on the right side of the equal sign are important.

The first is the Coriolis force, usually lumped in with other forces. This is the force most famous for causing the spiral pattern of the storms, but, at the largest scale, is also why we have the trade winds and westerlies. This gives us the hook.

The second term is the change in pressure over space. The negative sign simply means that air and liquid prefer to move from areas of high pressure to areas of low pressure. If the pressure is high enough, as it was over New England and the Maritimes during Florence’s landfall, the path can acquire a sharp bend.

Put these two competing terms together, and we get Florence’s odd path.

map source: https://www.flickr.com/photos/internetarchivebookimages/19794489843/

Pressure field during Florence’s landfall.

Peer edited by Gabby Budziewski.

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Improving Science Literacy: How to Read Scientific Papers

 

Science literacy is the ability to read English words in a new language – the language of science.  You might measure science literacy by being conversant in various fields. Each sub-field in science has its own language.  For example, being literate in cancer biology does not mean you are literate in neuroscience (I am highly literate in only one of these). Luckily, many terms in one field of science help us understand other areas of research.  It’s all about your focus:

Resolution vs. Field of View in Biology

Here’s an analogy from one of the most commonly used tools in biology:  microscopy. Scientists use microscopes to image tissues, cells, or even pieces of cells.  The smallest distance that the microscope can image, or resolve, is called the resolution.  In science, it’s often very helpful to look at things under a high-resolution microscope, which  lets us see super small structures.

Left: a high resolution capture lets us see structural detail, while Right: A low res, large field of view lets us see the big picture.

 For example, a super high-resolution technique, electron microscopy, helps us see the structure of mitochondria, the “powerhouse of the cell,” quite easily.

But how do we know mitochondria are the powerhouse of the cell?  Just because we can see something as small as a mitochondria under a microscope doesn’t mean we know what it is or does,  nor does it help us understand how the cell works – a “missing the forest through the trees” kind of problem. To understand how one piece fits into the bigger puzzle, we have to first zoom out to see the whole cell.  This expands the field of view. Having a large field of view helps us understand complex systems like cell biology, the brain, or even species within an ecosystem.

Review Articles vs. Primary Literature vs. Textbooks

Google and Wikipedia are your friends.  Most scientific papers will drop key terms without much explanation.  It’s okay if you have no clue what those words mean – a quick search will fix that!  Building your own key terms glossary for science helps you get a handle on something as large as an entire field of research.

Review articles summarize the recent key findings for a question within a particular research field.  These articles are particularly useful if you need a basic understanding of something with a large field of view. Once you understand the basics of the system, you can delve deeper. Make sure to choose an article that is fairly recent if you’re reading anything life-sciences related.

Primary literature is science straight from the horse’s mouth. In other words, the same lab that performs the research and experiments writes about them in great detail.  This gives the highest resolution, but a limited field of view. Scientists have only so many hours in the day, and only so many dollars of funding. Neuroscientists would love to ask endless questions about the brain, for example, but alas, we are few and mortal. As such, primary literature is typically narrow and targeted, but delivers a cutting edge understanding of the science within.  Most people go to Pubmed to find these articles.

Textbooks are a great resource for the highly curious, but are dense, expensive, and hard to get if you can’t access a library or they are in high demand.  They also take far longer to write, publish, and print than a review article or primary research publication, meaning the information printed could be obsolete by the time you read it.

Finding research articles can often be the hardest part of all of this.  Some tips for finding scientific papers:

  1. If you attend a research institution, your library probably has access to most journals.
  2. Researchers are allowed to share their publications to those who request them: I recommend ResearchGate for contacting them on this subject, but you can always reach out to them directly (Many labs and scientists are on Twitter!)
  3. Google Scholar is your next best bet, or simply searching [Article title] + .pdf using your search engine.
  4. For finding new articles of interest and organizing old ones, I recommend Meta, Mendeley, or Endnote.  For health-related questions, Examine.com has a great database on various nutritional supplements.

*All images sourced from Pixabay.com, and modified by Connor Wander.

Peer edited by Justine Grabiec.

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Leaves Are Falling From the Trees

When the days suddenly seem shorter and the nights are colder, you know fall has arrived. You especially know it’s here when the leaves gain a reddish hue and soon after fall from the trees by the truckload. In fact, the name ‘fall’ has been used in America since the 17th century, shortened from the English phrase “leaves falling from the trees.” Fall technically begins with the autumnal equinox in late September, when the hours of daylight and night are the same. At this point, perennial trees, or trees that grow year after year, have two tasks: 1) to stop growing leaves and instead prepare flower buds for next spring, and 2) to protect those buds from winter’s cold. First, we must ask how trees sense changes in daylight in the first place?

Hybrid aspen trees (which are most often used in plant science to study genetics and growth regulation) have light and color detectors that respond to levels of light. One response is the activation of a protein called CONSTANS, which controls growth genes but gets broken down in the absence of light. In that regard, as the days grow shorter and there is more darkness, CONSTANS becomes less stable and leaf growth slows. The slowing of leaf growth marks the beginning of a process when the plant uses much of its remaining energy to form a bud, or an immature flower. This bud will bloom the following spring, but it needs protection from the cold and often dry climate brought on by winter. In addition to the bud, a multi-layered and extremely hardy outer shell is formed to protect the bud from the cold and drying out. The process of forming a bud is highly variable between plant species, but typically lasts 6-10 weeks. After the bud and its protective shell have formed, almost all plants in the Northern hemisphere enter the ‘dormancy’ phase to survive the winter.

Created by Clare Gyorke

Transition into Dormancy

To protect against drying out and cold temperatures, it is important that a bud receives no growth signals during dormancy. As buds are formed in trees, a plant hormone called abscisic acid, or ABA, encourages the production of callose, a starchy sugar that blocks signaling between plant cells. During dormancy, ABA maintains callose production, but becomes less effective as daylight hours increase. Even after ABA loses its effect (when we reach a certain amount of daylight hours), buds are still protected by callose, which is broken down slowly by prolonged low temperatures. Callose protects the plant by preventing it from growing during random hot spells in January and February, when there are more daylight hours, but temperatures will likely drop again. When there have been enough hours of cold (~30-55 °F), all callose will be broken down and the bud will slowly start receiving signals to grow. The accumulation of growth signals and the right temperature (usually above 60°F) will tell the tree to open its buds and start growing. One potential problem with this system is that if a frost comes after the buds have opened, they might become damaged from the cold and won’t produce flowers or fruit. However, as temperatures warm and the days get longer, the risk of frost decreases.

The spring equinox will mark the shift into longer days, and often coincides with trees exiting dormancy with an explosion of growth by the buds they formed in the previous the fall. These buds will rapidly cover the tree with beautiful green leaves, highlighting the beginning of the transition to the long, languid days of summer.

Peer Edited by Keean Braceros.

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A Scientist’s View of Animal Research

One of the most controversial aspects of biomedical research is the use of animals to benefit humans. Scientists use animals to test new treatments for human diseases and to understand human biology. Many groups have protested the use of animals for research. The most well-known and influential of these groups has been People for the Ethical Treatment of Animals (PETA). These groups have successfully raised concerns about using animals for research, and they have brought about changes such as closing down some research labs and decreasing the number of airlines that will transport animals destined for research. People perceive the benefits and detriments of these actions differently depending on whether they support or condemn animal use in research.

I am not writing this article from an entirely unbiased position because I work with animals to understand basic human biology and to discover treatments for human diseases. Since many articles about the negative aspects of animal research have been published, I intend to provide a more positive perspective on animal research from a scientist’s point of view.

The goal of using animals for research is to save human lives and improve human health.  Scientists do not use animals because it is fun, and they do not use animals when there are better alternatives (e.g. using humans, cell culture, or computer models). Scientists use animals for research because animal research can provide information to eliminate human diseases, improve health, and ultimately save human lives. Animal research has saved millions of human lives and has improved the health of billions more. Animals have played an important role in discovering cures for deadly diseases such as polio, smallpox, and hepatitis C. Animal research has also discovered treatments for Type 1 diabetes, malaria, cystic fibrosis, and thousands of other diseases.

Animal research improves animal health and finds cures for animal diseases. Animals contract many of the same diseases as humans do, such as heart failure and diabetes. Research in animals has saved the lives of millions of pets by providing vaccines, pacemakers, artificial joints, and chemotherapy for pets. Animal research has also improved our understanding of endangered species so that we can prevent their extinction.

Research in humans has limitations that can be overcome by using animals. Scientists and animal activists may ask why we cannot conduct all research in humans so that we can avoid the ethical dilemma of animal research. First, many studies are conducted in humans (over 100,000 people participate in clinical trials every year, and this number does not include the thousands more people involved studies that are not considered clinical trials). However, many studies are not feasible to perform  in humans. For example, studies involving diets or food components require subjects to be very compliant (follow the diet exactly) so that scientists can definitively answer their research questions (such as whether a vitamin or mineral is necessary for health). However, people are not usually very compliant with their diets, leading to confusing data and sometimes wrong answers to research questions. In animal studies, diets can be carefully controlled, which ensures that the data obtained is accurate. This allows scientists to answer very specific research questions about diet effects. Using animals for research also optimizes research funds by ensuring that research does not need to be repeated due to non-compliant human research subjects. Furthermore, research in humans is substantially more expensive than animal research, due to compensation for the research subjects and extra costs of research monitoring. Finally, humans have much longer lifespans than most animals, meaning that a single study could require 1-50X longer to complete in humans than in animals. This both raises research costs and increases the time required to make scientific discoveries.

Scientists prioritize animal health and minimize animal pain. When alternative methods of study, such as those in humans, are not an option, scientists use animals. Scientists undergo substantial training so that they know how to conduct research with animals in an ethical manner. Furthermore, before any animal research takes place, scientists must get approval for their planned study from the Institutional Animal Care and Use Committee (IACUC). This committee  includes at least one veterinarian, who ensures that the animals in the study are healthy and well. The committee also includes at least one person from the community who is not associated with the research institution. This ensures that animals used in experiments receive the maximum amount of care without interfering with the experiment. Every scientist must consider 3 words before they start working with animals: Replacement, Reduction, and Refinement. First, can the scientist replace animals with some other model? (For example, cells isolated from humans or animals or computer models). Second, can the scientist reduce the number of animals so that as few as possible are harmed? And third, can the scientist refine their experiments so that animals suffer as little as possible? All three questions must be addressed before research can begin.

While scientists may enjoy working with animals, they do not like causing pain for animals. Researchers ensure that the animals in their care are healthy and well for the research study. Many scientists are animal activists and whole-heartedly care for the animals they work with.

Science has a small impact on animals in comparison to animals harmed by other factors. Scientists in the United States used 12-27 million animals in 2010. Although this sounds like a large

A monument to the laboratory mouse in Novosibirsk, Russia

number, 99% of these animals are rats, mice, birds, or fish.  People in the U.S. consume more than 340 chickens for every 1 animal that is studied in a research facility. Furthermore, for every animal involved in research, another 14 animals are killed on roads.

Scientists and those who benefit from the science appreciate what animal research has accomplished. Scientists appreciate all that animals have done to benefit scientific advances and human health. A town in Russia raised enough money to erect a statue to pay tribute to all of the sacrifices that animals, namely the laboratory mouse, have paid to save human lives (see picture). This statue reflects the attitudes that scientists have for their laboratory animals, and it thanks them for what they have done to save millions of human lives.

Peer-reviewed by Caitlyn Molloy and Elise Hickman.

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What an 1.5°C increase can bring

Did you find the past few years’ climate peculiar, with extremely high temperature or intense rainfall days occurring more often? Have you ever heard of shrinking ice sheets or seen this famous photo of polar bear clinging to an iceberg? What about the massive bleaching of coral reefs? Unfortunately, you’ve spotted evidence of climate change

Temperature trends by NASA

Human-induced global warming has resulted in a 1°C increase in global mean surface temperature in 2017 when compared to the period prior to the spur of large-scale industrial activities (1850-1900, here-on referred to as pre-industrial levels). Further, the temperature increase can reach 1.5°C (2.7°F) above pre-industrial levels as early as 2030 and as late as 2052, a recent report released by Intergovernmental Panel on Climate Change (IPCC) says. We are already noticing some inconveniences previously noted at the 1°C above pre-industrial levels, but the extra 0.5°C warming on top of that is projected to amplify risks for all inhabitants on Earth.

The report by IPCC explains that many regions will be impacted with the global warming of 1.5°C above pre-industrial levels, with high temperature days, heavy precipitation, and intense droughts occurring more often. Such changes will impact our lives in the foreseeable future, not only by causing the disturbances we notice nowadays, but by increasing food insecurity, water stress, risk of vector-borne disease (e.g., malaria, flu), and heat-related deaths. Many ecosystems and the biodiversity within are at risk too; some species will face extinction and some will lose their habitats due sea-level rise, sea-ice loss in the Antarctic, coral bleaching, shifts in biomes.

So what is being done in the global scale to address the issues that come with climate change? The first global effort to fight climate change, the Paris Agreement, was initiated in Paris 2015 by the IPCC. 195 participating countries have agreed to focus their efforts on limiting the global temperature rise to not more than 2°C above pre-industrial level. Long-term climate change adaptation goals were established through the Paris Agreement, which will be met by participating countries through nationally determined contributions. Each countries are requested to outline and communicate country-level efforts to reduce greenhouse gas emissions and adapt to climate change (nationally determined contributions). To facilitate reduction in greenhouse emissions through nationally determined contributions, Talanoa Dialogue was launched in January 2018 and the next meeting will take place in December 2018. More recently in October 2018, the special report by IPCC was released in South Korea, assessing the global warming of 1.5°C above pre-industrial levels.

This special report by IPCC includes the impact of 1.5°C above pre-industrial levels and assessments on mitigation and adaptation strategies. To halt global warming, the amount of CO2 emitted into the atmosphere must equal the amount that is removed from the atmosphere (net zero). The report warns that such net zero CO2 emissions must be reached around 2050 to limit global warming to 1.5°C above pre-industrial levels. Good news is that we could slow the progression of climate change using currently available means, by changing our (individual and industrial) behaviors to reducing energy consumption and switch to more energy-efficient fuel options. Additionally, energy consumers can implement carbon capture options; energy providers must switch from coal-based to renewable energy sources, agricultural sector can shift to producing non-CO2 emitting crops and limit expansion into carbon rich ecosystems such as tropical forests. Luckily, some of these strategies are already underway in many countries, but the report warns us that more drastic measures need to be implemented in order to keep the temperature rise below 1.5°C. Given that the U.S, the world’s second largest greenhouse gas emitter, has announced to withdraw from the Paris Agreement, it is of particular importance to continue to increase awareness. It is critical to actively tackle adaptation and mitigation strategies to response to climate change across the nation.

Want to learn more and get involved? Visit the website for IPCC to read recent reports and activities to help reduce climate change. Follow their SNS to be up-to-date on global effort to fight climate change (facebook, twitter, instagram, or linkedin)!

Peer edited by Eliza Thulson.  

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Superior Syntheses: Sustainable Routes to Life-Saving Drugs

While HIV treatment has come a long way over the past few decades, there is still a discrepancy between total number of HIV patients and those with access to life-saving antiretroviral therapies (ART). The inability to access medications is often directly linked to the cost of the medication, demonstrating the need for ways to make these medicines cheaper. In October 2018, Dr. B. Frank Gupton and Dr. Tyler McQuade of Virginia Commonwealth University were awarded a 2018 Green Chemistry Challenge Award for their innovative work on the affordable synthesis of nevirapine, an essential component of some HIV combination drug therapies.

https://www.flickr.com/photos/blyth/1074446532

Neviripine, a component of some HIV therapies.

For the past 22 years, the American Chemical Society (ACS) in partnership with the U.S. Environmental Protection Agency (EPA), has awarded scientists who have contributed to the development of processes that protect public health and the environment. Awardees have made significant contributions in reducing hazards linked to designing, manufacturing, and using chemicals. As of 2018, the prize-winning technologies have eliminated 826 million pounds of dangerous chemicals and solvents, enough to fill a train 47 miles long. The nominated technologies are judged on the level of science and innovation, the benefits to human health and the environment, and the impact of the discovery.

https://www.flickr.com/photos/37873897@N06/8277000022

Green Chemistry protects public health and the environment.

Gupton and McQuade were awarded the Green Chemistry Challenge Award for the development of a sustainable and efficient synthesis of nevirapine. The chemists argue that oftentimes, the process to produce a drug remains consistent over time, and is not improved to reflect new innovations and technologies in the field of chemistry, which could make syntheses easier, cheaper, and more environmentally friendly. Synthesizing a drug molecule is not unlike building a Lego tower; the tower starts with a single Lego and bricks are added one-by-one until it resembles a building. Researchers start with a simple chemical and add “chemical blocks” one-by-one until it is the desired drug molecule.  Gupton and McQuade demonstrated that by employing state-of-the-art chemical methods, they can significantly decrease the cost to synthesize nevirapine.

https://www.flickr.com/photos/billward/5818794375

Producing pharmaceutical molecules is like building a Lego house.

Before this discovery, there were two known routes toward the synthesis of nevirapine. Researchers used projections to determine which steps were the costliest. With this knowledge, they were able to improve the expensive step of the synthesis by developing a new reaction that used cheap reagents (“chemical blocks”) and proceeded in high yield. A chemical yield is the amount of product obtained relative to the amount of material used. The higher the yield, the more efficient the reaction. Reactions may have a poor yield because of alternative reactions that result in impurities, or unexpected, undesired products (byproducts). Pharmaceutical companies often quantify chemical efficiency by using the Process Mass Intensity (PMI), which is the mass of all materials used to produce 1 kg of product. Solvent, the medium in which the reaction takes place, is a big contributor to PMI because it is a material that is necessary for the reaction, but not incorporated into the final product. Gupton and McQuade were able to decrease the amount of solvent used because they streamlined reactions that reduced impurities, allowing them to recycle and reuse solvent. These improvements reduced the PMI to 11 relative to the industry standard PMI of 46.

https://commons.wikimedia.org/wiki/File:Nevirapine.svg

Molecular structure of nevirapine 

In addition to their synthesis of nevirapine, Gupton and McQuade also developed a series of core principles to improve drug access and affordability for all medications. The general principles include implementation of novel and innovative chemical technologies, a decrease in the total number of synthetic steps and solvent changes, and use of cheap starting materials. Oftentimes, the pharmaceutical industry focuses on starting with very complex molecules in order to decrease the number of steps needed to reach the target molecule. Interestingly/unfortunately, starting with complex “chemical blocks” is often the most expensive part of  producing a medication. By starting with simpler chemicals, they believe production costs can be significantly decreased. Virginia Commonwealth University recently established the Medicines for All Institute in collaboration with the Bill & Melinda Gates foundation, and Gupton and McQuade hope that by employing the process development principles, they will be able to more efficiently and affordably synthesize many life-saving medications.

Peer edited by Dominika Trzilova and Connor Wander.

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Understanding Sea Turtle Navigation with Laser-based Imaging

https://www.maxpixel.net/Sea-Turtle-Is-Animals-2547084If you’ve ever been lost in an unfamiliar city or tried to walk around in the dark, then you may have found yourself wishing you had the eyes of a cat or the echolocation abilities of a bat. But have you ever wished for the navigation abilities of a sea turtle? While many animals are known for their superb sensory perception which make them better navigators than humans, it may surprise you to hear that sea turtles are among the elite navigators of the animal kingdom. Sea turtles are able to cross entire ocean basins (covering distances of thousands of miles) surrounded by seemingly featureless, dark water in order to return years later to their original nesting grounds. This behavior is as perplexing as it is impressive: while we know that sea turtle navigation has something to do with sensing Earth’s magnetic field, the mechanism which enables them to sense and interpret magnetic fields has not yet been identified.

To compare, humans have five senses. Each of these senses is linked to some kind of receptor which converts the environmental stimulus into a signal which our brains can interpret as either an image, a sound, a taste, a texture or a smell. For example, our eyes contain photoreceptors which convert light into electrical signals that travel to our brains and are interpreted as images. Sea turtles have another sense: they are able to sense magnetic fields. This means they must have some magnetic receptor which converts the magnetic field into a signal which is interpreted by the animal’s brain. However, scientists don’t know what these magnetic receptors are or where they are located within the body of a sea turtle. This is a crucial step on the path to understanding the impressive navigation abilities of sea turtles.

Working in collaboration with biologists who study sea turtle navigation, my research project is to design and build a special imaging system which is able to locate these magnetic receptors in sea turtles. This project can be broken down into three parts: design the imaging system, develop a method for detecting magnetic particles, then build and test the hardware.

Designing an Imaging System

You may wonder why it’s so hard to find these magnetic receptors if we know they must exist. It’s difficult because these magnetic receptors are extremely tiny, thought to be smaller than the size of a single cell, and they may be located anywhere inside the body of the sea turtle. The smallest species of sea turtle is roughly the same size and weight as a Labrador, with some species being several times larger, making the search for a cell-sized particle challenging. For an imaging system to detect these magnetic receptors, we need the following conditions:

  1. High resolution- Because these receptors may be very small, we need high resolution to locate where they reside within the tissue.
  2. High magnetic sensitivity- If we want to detect very small magnetic particles, then our system has to be very sensitive to small amounts of magnetic material.
  3. Fast- Because we have to search through large volumes of tissue, we need a fast imaging system to do this in a reasonable amount of time.
  4. Non-destructive- Many existing imaging methods require the addition of dyes and other contrast agents which irreversibly alter the tissue. We would like to avoid this because sea turtles are endangered and finding dead sea turtle tissue to image can be challenging.

So why can’t we use an imaging system that already exists? Although there are several imaging systems which are able to detect magnetic particles, none of them meet all four of our requirements. For example, magnetic resonance imaging (MRI) is very sensitive to magnetic material, but the resolution is not high enough for our aim. A microscope has really good resolution, but it can only image a very small section of tissue at one time, so the overall imaging speed is slow.

In order to meet all four imaging system requirements, we use a relatively new optical imaging system called Optical Coherence Tomography (OCT). OCT is very similar to an ultrasound, the same technology used to produce fetal sonograms.  Rather than using sound waves to form an image as in ultrasound, OCT uses light waves from a laser to create an image. By using light instead of sound, we shrink the scale of the imaging down so that our resolution is much better than that of MRI or ultrasound. By its nature, OCT is also non-destructive.

OCT works by illuminating the sample we want to image with light waves. When the light hits the sample, it can either pass through the sample or it can bounce away (we call this scattering). OCT captures the light that is scattered back in the direction from which it came. We record this light on a camera along with light that was reflected from a stationary mirror in a process called interferometry. By comparing the light reflected from the mirror and the light back-scattered from the sample, we can tell how far the light travelled after it was scattered from the sample. This allows us to create 2D images of the sample.

Developing a Method for Magnetic Particle Detection

To get the desired magnetic sensitivity, I designed and built an electromagnet which can produce a sufficiently high magnetic force. We place this magnet over the tissue we want to image. By applying a current with a sinusoidally varying amplitude to the electromagnet, we create a magnetic field with a sinusoidally varying amplitude. This variation in the magnetic field strength causes the magnetic force felt by a magnetic particle to vary sinusoidally as well. Therefore, any tiny magnetic receptors in the sea turtle tissue we are imaging will oscillate up and down in sync with the applied magnetic force. As the magnetic particles oscillate up and down, they will cause the surrounding tissue to deform. This deformation causes a measurable change in the back-scattered light. We record a series of images while applying the oscillating magnetic force. We can then compare consecutive frames to identify any pixels whose intensity is varying in sync with the applied magnetic force and by doing so, locate the magnetic receptors (see Fig. 2). An OCT system combined with this method of magnetic particle detection is called magnetomotive OCT.

https://users.physics.unc.edu/~aold/MethodsMMimaging.htm

Fig. 2 Schematic Diagram showing that when the magnetic receptors (black spheres) feel the oscillating magnetic force, they oscillate up and down creating a measurable change in the light reflected from the surrounding tissue.

Testing the Magnetomotive OCT System

After designing and building the magnetomotive OCT system, we first had to test the system to ensure it met our requirements for  resolution, speed, and magnetic sensitivity. We measured the resolution by imaging small, highly scattering particles and confirmed that we achieved our desired resolution. To test the imaging speed, we imaged human bronchial epithelial cells. These are the cells lining our airways which contain cilia and secrete mucus. The mucus layer acts like a shield preventing the bacteria we breathe in from entering our bloodstream. The cilia beat to propel the mucus (containing all those trapped bacteria) out of our airways and are a vital component of a healthy immune system. Therefore, the ability to image living, beating cilia is helpful to doctors who study respiratory diseases such as Cystic Fibrosis. Our collaborators in the Cystic Fibrosis Center at UNC provided us with a sample of these cells, and we were able to image the beating cilia. This was a very exciting result. Not only did we confirm that our OCT system has a fast imaging speed, but we also discovered that this novel imaging system may be useful for helping to diagnose and research respiratory diseases.

Future Research: Turtles and Beyond

Our imaging speed experiment using epithelial cells demonstrates a vital point in the scientific process: often, by setting out to answer one question, you may open avenues of investigation you had never considered. We demonstrated with this experiment that our OCT system has the best combination of high resolution and high-speed of any OCT system to date. We will next measure the magnetic sensitivity of our system by imaging tissue phantoms, silicone-based samples which mimic the light-scattering properties of biological tissue, containing increasingly small concentrations of magnetic particles. Once we are sure that our system has the desired magnetic sensitivity, we can begin imaging animal tissue. If we are able to locate the magnetic receptors, it would be a huge breakthrough in the study of sea turtle navigation. If we are able to find these receptors, biologists can study them to understand exactly how they are used to sense magnetic fields and how the turtles use that information to navigate. Building this novel imaging system is just one step toward finally understanding sea turtle navigation. In addition, we have also discovered that our technology may have other uses, as our preliminary work with the cilia suggest. We will continue toward our goal of detecting magnetic receptors in sea turtle tissue while also investigating the system’s applications in respiratory disease research.

Peer edited by Allison Lacko and Laetitia Meyrueix.

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Nobel in Chemistry for an Evolutionary Revolution

https://phys.org/news/2017-10-nobel-chemistry-prize-major-award.html

The Nobel Prize awarded to Dr. Arnold, Dr. Smith, and Dr. Winters

Evolution, the process of gradual changes to genetic information in each generation over millions of years, proposed by Charles Darwin in the 19th century is being revolutionized by modern science. Unexpectedly, the revolution is driven not by evolutionary biologists or ecologists, but rather centered around the methodologies of chemists and enzymologists.

Accumulation of mutations is a slow and random process. However, scientists were able to harness the power of evolution to identify and select for specific mutations that improve the ability of molecules of interest. This year’s Nobel Prize in Chemistry was awarded to Dr. Frances Arnold “for the directed evolution of enzymes” and to Dr. George Smith and Dr. Gregory Winters “for the phage display of peptides and antibodies.”

Dr. Arnold was able to develop a methodology to enhance enzyme activity and give existing enzymes new functionality, a feat that was realized in unprecedented amount of time. She was able to accomplish this by simply using error prone PCR to cause mutations in enzymes and then selecting one with favorable ability compared to the many enzymes produced. Repeating the cycles hundreds of times enhancing the functionality of the enzyme each time, allowed her to develop P450 with novel function.

Dr. Smith was also able to apply the concepts of evolution by using bacteriophages, viruses that normally infect bacteria. Dr. Smith developed the process of phage display, a means to study protein-protein interactions by encoding genetic information into bacteriophages. By using E. coli cells infected with bacteriophages and then infecting with another virus, Dr. Smith was able to encode genetic information of a protein on to the viral coat of bacteriophages. This allowed the new protein to be displayed on the viral coat and able to be recognized with an antibody.

Dr. Winters then incorporated the antibody gene rather than a specific protein into the viral coat. This allowed him to scavenge for antibodies with a specific binding site via interactions with different antigens. Using a similar method to Dr. Arnold, he caused mutations in the antibody, and selected for the antibody with highest affinity to the antigen. The results were highly efficient antibodies and a mechanism that is used to produce 11 out the 15 most-sold drugs on the planet.

Peer edited by Rachel Battaglia.

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Science Behind the Dance – Autobiography by Wayne McGregor

Auto-Bio-Graphy = Self-Life-Writing or how your body and life look as told through choreography.  This is what Wayne McGregor imagined as he began working on Autobiography with the McGregor Company Dancers.  The Science Writing and Communication club (SWAC) and Carolina Performing Arts recently sat down with the dancers to discuss how science and dance intersect.

SWAC learned that McGregor has been collaborating with scientists for many years regarding different facets of dance.  For example, his dancers have worked with Professor David Kirsh at the University of California, San Diego, where he studied creative cognition with the dancers and how dance content is created and remembered between dancers and choreographer.

Photo by Andrej Uspenski

Company Wayne McGregor dancers perform Autobiography. Photo by Andrej Uspenski.

When McGregor began working on Autobiography, inspired by having his DNA sequenced, he gave his dancers ideas, or what they call tasks, to demonstrate different concepts with their bodies through dance.  For example, at the beginning of creating Autobiography, the dancers were paired into groups of 4 and given the letters A,T,G, or C.  He then asked them to create choreography together.  Then McGregor and the dancers visited The Wellcome Sanger Institute in Cambridge UK, a world leader in genome research, and learned what the letters A,T,G,C meant biologically as the building blocks of DNA. After visiting the sequencing facility, McGregor asked the dancers to repeat their choreography tasks.  During our conversation, the dancers said that with their new understanding of DNA biology, the choreography tasks took on a new meaning.

The dance Autobiography is broken down into 23 different choreographed segments that are assigned an order randomly by an algorithm to mimic the randomness of DNA recombination.  This aspect of the choreography is complicated for the dancers, who don’t know the order of the segments until a couple days before the performance.  This meant that sometimes they would be dancing for long periods of time, whereas other times their performances would be broken up into smaller segments throughout the night.  Sometimes the dance segments flow into the next piece of choreography seamlessly, and sometimes they end quite abruptly.  In our conversation, the dancers said they envisioned this re-ordering and occasional abrupt stopping as being very similar to the chaos of life.

An interesting moment from our conversation evolved as both dancers and scientists alike realized that we both strive to achieve communication through our bodies.  It is easy to imagine how dancers do this, but not as easy to imagine how scientists communicate with body movement.  As scientists, we realized that we attempt to communicate concepts visually through use of our bodies, whether it be through gesturing with our hands to emphasize points during a presentation, or through mimicking with our bodies what we believe is happening, invisible to us, inside a cell during DNA damage, repair, or replication.  Another moment in our conversation where science connected easily to dance was when the scientists and dancers discussed how both published scientific findings and performed choreography are both put into the ether for others to interpret using their personal lenses.  We all interpret data differently based on our own experiences, and as scientists and as dancers we hope that people find use in our work and can apply it to their own lives.

Peer edited by Adrienne Cox.

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