Scientists Want to Align Your Internal Clock Because Timing Is Everything


internal clock

In life, timing is everything.

Your body’s internal clock — the circadian rhythm — regulates an enormous variety of processes: when you sleep and wake, when you’re hungry, when you’re most productive. Given its palpable effect on so much of our lives, it’s not surprising that it has an enormous impact on our health as well. Researchers have linked circadian health to the risk of diabetes, cardiovascular disease, and neurodegeneration. It’s also known that the timing of meals and medicines can influence how they’re metabolized.

The ability to measure one’s internal clock is vital to improving health and personalizing medicine. It could be used to predict who is at risk for disease and track recovery from injuries. It can also be used to time the delivery of chemotherapy and blood pressure and other drugs so that they have the optimum effect at lower doses, minimizing the risk of side effects.

However, reading one’s internal clock precisely enough remains a major challenge in sleep and circadian health. The current approach requires taking hourly samples of blood melatonin — the hormone that controls sleep — during day and night, which is expensive and extremely burdensome for the patient. This makes it impossible to incorporate into routine clinical evaluations.

My colleagues and I wanted to obtain precise measurements of internal time without the need for burdensome serial sampling. I’m a computational biologist with a passion for using mathematical and computational algorithms to make sense of complex data. My collaborators, Phyllis Zee and Ravi Allada, are world-renowned experts in sleep medicine and circadian biology. Working together, we designed a simple blood test to read a person’s internal clock.

Listening to the Music of Cells

The circadian rhythm is present in every single cell of your body, guided by the central clock that resides in the suprachiasmatic nucleus region of the brain. Like the secondary clocks in an old factory, these so-called “peripheral” clocks are synchronized to the master clock in your brain, but also tick forward on their owneven in petri dishes!

Your cells keep time through a network of core clock genes that interact in a feedback loop: When one gene turns on, its activity causes another molecule to turn it back down, and this competition results in an ebb and flow of gene activation within a 24-hour cycle. These genes in turn regulate the activity of other genes, which also oscillate over the course of the day. This mechanism of periodic gene activation orchestrates biological processes across cells and tissues, allowing them to take place in synchrony at specific times of day.

The circadian rhythm orchestrates many biological processes, including digestion, immune function, and blood pressure, all of which rise and fall at specific times of the day. Misregulation of the circadian rhythm can have adverse effects on metabolism, cognitive function, and cardiovascular health.
The circadian rhythm orchestrates many biological processes, including digestion, immune function, and blood pressure, all of which rise and fall at specific times of the day. Misregulation of the circadian rhythm can have adverse effects on metabolism, cognitive function, and cardiovascular health.

The discovery of the core clock genes is so fundamental to our understanding of how biological functions are orchestrated that it was recognized by the Nobel Committee last year. Jeffrey C. Hall, Michael Rosbash, and Michael W. Young together won the 2017 Nobel Prize in Physiology or Medicine “for their discoveries of molecular mechanisms controlling the circadian rhythm.” Other researchers have noted that as many as 40 percent of all other genes respond to the circadian rhythm, changing their activity over the course of the day as well.

This gave us an idea: Perhaps we could use the activity levels of a set of genes in the blood to deduce a person’s internal time — the time your body thinks it is, regardless of what the clock on the wall says. Many of us have had the experience of feeling “out of sync” with our environments — of feeling like it’s 5:00 a.m. even though our alarm insists it’s already 7:00 a.m. That can be a result of our activities being out of sync with our internal clock — the clock on the wall isn’t always a good indication of what time it is for you personally. Knowing what a profound impact one’s internal clock can have on biology and health, we were inspired to try to gauge gene activity to measure the precise internal time in an individual’s body. We developed TimeSignature: a sophisticated computational algorithm that could measure a person’s internal clock from gene expression using two simple blood draws.

Designing a Robust Test

To achieve our goals, TimeSignature had to be easy (measuring a minimal number of genes in just a couple blood draws), highly accurate, and — most importantly — robust. That is, it should provide just as accurate a measure of your intrinsic physiological time regardless of whether you’d gotten a good night’s sleep, recently returned from an overseas vacation, or were up all night with a new baby. And it needed to work not just in our labs but in labs across the country and around the world.

A mismatch between our internal time and our daily activities may raise the risk of disease.
A mismatch between our internal time and our daily activities may raise the risk of disease.

To develop the gene signature biomarker, we collected tens of thousands of measurements every two hours from a group of healthy adult volunteers. These measurements indicated how active each gene was in the blood of each person during the course of the day. We also used published data from three other studies that had collected similar measurements. We then developed a new machine learning algorithm, called TimeSignature, that could computationally search through this data to pull out a small set of biomarkers that would reveal the time of day. A set of 41 genes was identified as being the best markers.

Surprisingly, not all the TimeSignature genes are part of the known “core clock” circuit — many of them are genes for other biological functions, such as your immune system, that are driven by the clock to fluctuate over the day. This underscores how important circadian control is — its effect on other biological processes is so strong that we can use those processes to monitor the clock!

Using data from a small subset of the patients from one of the public studies, we trained the TimeSignature machine to predict the time of day based on the activity of those 41 genes. (Data from the other patients was kept separate for testing our method.) Based on the training data, TimeSignature was able to “learn” how different patterns of gene activity correlate with different times of day. Having learned those patterns, TimeSignature can then analyze the activity of these genes in combination to work out the time that your body thinks it is. For example, although it might be 7 a.m. outside, the gene activity in your blood might correspond to the 5 a.m. pattern, indicating that it’s still 5 a.m. in your body.

Many genes peak in activity at different times of day. This set of 41 genes, each shown as a different color, shows a robust wave of circadian expression. By monitoring the level of each gene relative to the others, the TimeSignature algorithm learns to ‘read’ your body’s internal clock.
Many genes peak in activity at different times of day. This set of 41 genes, each shown as a different color, shows a robust wave of circadian expression. By monitoring the level of each gene relative to the others, the TimeSignature algorithm learns to ‘read’ your body’s internal clock. 

We then tested our TimeSignature algorithm by applying it to the remaining data, and demonstrated that it was highly accurate: We were able to deduce a person’s internal time to within 1.5 hours. We also demonstrated our algorithm works on data collected in different labs around the world, suggesting it could be easily adopted. We were also able to demonstrate that our TimeSignature test could detect a person’s intrinsic circadian rhythm with high accuracy, even if they were sleep-deprived or jet-lagged.

Harmonizing Health With TimeSignature

By making circadian rhythms easy to measure, TimeSignature opens up a wide range of possibilities for integrating time into personalized medicine. Although the importance of circadian rhythms to health has been noted, we have really only scratched the surface when it comes to understanding how they work. With TimeSignature, researchers can now easily include highly accurate measures of internal time in their studies, incorporating this vital measurement using just two simple blood draws. TimeSignature enables scientists to investigate how the physiological clock impacts the risk of various diseases, the efficacy of new drugs, the best times to study or exercise, and more.

Of course, there’s still a lot of work to be done. While we know that circadian misalignment is a risk factor for disease, we don’t yet know how much misalignment is bad for you. TimeSignature enables further research to quantify the precise relationships between circadian rhythms and disease. By comparing the TimeSignatures of people with and without disease, we can investigate how a disrupted clock correlates with disease and predict who is at risk.

Down the road, we envision that TimeSignature will make its way into your doctor’s office, where your circadian health could be monitored just as quickly, easily, and accurately as a cholesterol test. Many drugs, for example, have optimal times for dosing, but the best time for you to take your blood pressure medicine or chemotherapy may differ from somebody else.

Previously, there was no clinically feasible way to measure this, but TimeSignature makes it possible for your doctor to do a simple blood test, analyze the activity of 41 genes, and recommend the time that would give you the most effective benefits. We also know that circadian misalignment — when your body’s clock is out of sync with the external time — is a treatable risk factor for cognitive decline; with TimeSignature, we could predict who is at risk, and potentially intervene to align their clocks.

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Sharks love jazz but are stumped by classical, say scientists


A study at Macquarie University in Sydney found that sharks could recognise jazz – if there was food on offer

A Port Jackson shark, the kind used in the jazz study.
Fluke Ellington … a Port Jackson shark, the kind used in the jazz study.

Researchers at Sydney’s Macquarie University have discovered that sharks can recognise jazz music.

In a paper published in Animal Cognition, the researchers, led by Catarina Vila Pouca, trained juvenile Port Jackson sharks to swim over to where jazz was playing, to receive food. It has been thought that sharks have learned to associate the sound of a boat engine with food, because food is often thrown from tourist boats to attract sharks to cage-diving expeditions – the study shows that they can learn these associations quickly.

The test was made more complex with the addition of classical music – this confused the sharks, who couldn’t differentiate between jazz and classical. “It was obvious that the sharks knew that they had to do something when the classical music was played, but they couldn’t figure out that they had to go to a different location,” said researcher Culum Brown. “The task is harder than it sounds, because the sharks had to learn that different locations were associated with a particular genre of music, which was then paired with a food reward. Perhaps with more training, they would have figured it out.”

Vila Pouca added: “Sharks are generally underestimated when it comes to learning abilities – most people see them as mindless, instinctive animals. However, they have really big brains and are obviously much smarter than we give them credit for.” She said that the evidence would hopefully prompt more conservation work.

 

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Birds Can See Earth’s Magnetic Fields, And We Finally Know How That’s Possible


The mystery behind how birds navigate might finally be solved: it’s not the iron in their beaks providing a magnetic compass, but a newly discovered protein in their eyes that lets them “see” Earth’s magnetic fields.

main article image

These findings come courtesy of two new papers – one studying robins, the other zebra finches.

The fancy eye protein is called Cry4, and it’s part of a class of proteins called cryptochromes – photoreceptors sensitive to blue light, found in both plants and animals. These proteins play a role in regulating circadian rhythms.

There’s also been evidence in recent years that, in birds, the cryptochromes in their eyes are responsible for their ability to orient themselves by detecting magnetic fields, a sense called magnetoreception.

We know that birds can only sense magnetic fields if certain wavelengths of light are available – specifically, studies have shown that avian magnetoreception seems dependent on blue light.

This seems to confirm that the mechanism is a visual one, based in the cryptochromes, which may be able to detect the fields because of quantum coherence.

To find more clues on these cryptochromes, two teams of biologists set to work. Researchers from Lund University in Sweden studied zebra finches, and researchers from the Carl von Ossietzky University Oldenburg in Germany studied European robins.

The Lund team measured gene expression of three cryptochromes, Cry1, Cry2 and Cry4, in the brains, muscles and eyes of zebra finches. Their hypothesis was that the cryptochromes associated with magnetoreception should maintain constant reception over the circadian day.

They found that, as expected for circadian clock genes, Cry1 and Cry2 fluctuated daily – but Cry4 expressed at constant levels, making it the most likely candidate for magnetoreception.

This finding was supported by the robin study, which found the same thing.

“We also found that Cry1a, Cry1b, and Cry2 mRNA display robust circadian oscillation patterns, whereas Cry4 shows only a weak circadian oscillation,” the researchers wrote.

But they made a couple of other interesting findings, too. The first is that Cry4 is clustered in a region of the retina that receives a lot of light – which makes sense for light-dependent magnetoreception.

The other is that European robins have increased Cry4 expression during the migratory season, compared to non-migratory chickens.

Both sets of researchers caution that more research is needed before Cry4 can be declared the protein responsible for magnetoreception.

The evidence is strong, but it’s not definitive, and both Cry1 and Cry2 have also been implicated in magnetoreception, the former in garden warblers and the latter in fruit flies.

Observing birds with non-functioning Cry4 could help confirm the role it seems to play, while other studies will be needed to figure Cry1’s role.

bird visionThis is how a bird might see magnetic fields. (Theoretical and Computational Biophysics/UofI)

So what does a bird actually see? Well, we can’t ever know what the world looks like through another species’ eyes, but we can take a very strong guess.

According to researchers at the Theoretical and Computational Biophysics group at the University of Illinois at Urbana-Champaign, whose researcher Klaus Schulten first predicted magnetoreceptive cryptochromes in 1978, they could provide a magnetic field “filter” over the bird’s field of view – like in the picture above.

The zebra finch study was published in the Journal of the Royal Society Interface, and the robin study was published in Current Biology.

Butterflies of the Soul


New study sheds light on the developmental origins of interneurons

Drawing of the cells of the chick cerebellum by Santiago Ramón y Cajal, from “Estructura de los centros nerviosos de las aves,” Madrid, circa 1905.

Modern neuroscience, for all its complexity, can trace its roots directly to a series of pen-and-paper sketches rendered by Nobel laureate Santiago Ramón y Cajal in the late 19th and early 20th centuries.

His observations and drawings exposed the previously hidden composition of the brain, revealing neuronal cell bodies and delicate projections that connect individual neurons together into intricate networks.

As he explored the nervous systems of various organisms under his microscope, a natural question arose: What makes a human brain different from the brain of any other species?

At least part of the answer, Ramón y Cajal hypothesized, lay in a specific class of neuron—one found in a dazzling variety of shapes and patterns of connectivity, and present in higher proportions in the human brain than in the brains of other species. He dubbed them the “butterflies of the soul.”

Known as interneurons, these cells play critical roles in transmitting information between sensory and motor neurons, and, when defective, have been linked to diseases such as schizophrenia, autism and intellectual disability.

Despite more than a century of study, however, it remains unclear why interneurons are so diverse and what specific functions the different subtypes carry out.

Now, in a study published in the March 22 issue of Nature, researchers from Harvard Medical School, New York Genome Center, New York University and the Broad Institute of MIT and Harvard have detailed for the first time how interneurons emerge and diversify in the brain.

Using single-cell analysis—a technology that allows scientists to track cellular behavior one cell at a time—the team traced the lineage of interneurons from their earliest precursor states to their mature forms in mice. The researchers identified key genetic programs that determine the fate of developing interneurons, as well as when these programs are switched on or off.

The findings serve as a guide for efforts to shed light on interneuron function and may help inform new treatment strategies for disorders involving their dysfunction, the authors said.

“We knew more than 100 years ago that this huge diversity of morphologically interesting cells existed in the brain, but their specific individual roles in brain function are still largely unclear,” said co-senior author Gordon Fishell, HMS professor of neurobiology and a faculty member at the Stanley Center for Psychiatric Research at the Broad.

“Our study provides a road map for understanding how and when distinct interneuron subtypes develop, giving us unprecedented insight into the biology of these cells,” he said. “We can now investigate interneuron properties as they emerge, unlock how these important cells function and perhaps even intervene when they fail to develop correctly in neuropsychiatric disease.”

A hippocampal interneuron. Image: Biosciences Imaging Gp, Soton, Wellcome Trust via Creative CommonsA hippocampal interneuron. Image: Biosciences Imaging Gp, Soton, Wellcome Trust via Creative Commons

Origins and Fates

In collaboration with co-senior author Rahul Satija, core faculty member of the New York Genome Center, Fishell and colleagues analyzed brain regions in developing mice known to contain precursor cells that give rise to interneurons.

Using Drop-seq, a single-cell sequencing technique created by researchers at HMS and the Broad, the team profiled gene expression in thousands of individual cells at multiple time points.

This approach overcomes a major limitation in past research, which could analyze only the average activity of mixtures of many different cells.

In the current study, the team found that the precursor state of all interneurons had similar gene expression patterns despite originating in three separate brain regions and giving rise to 14 or more interneuron subtypes alone—a number still under debate as researchers learn more about these cells.

“Mature interneuron subtypes exhibit incredible diversity. Their morphology and patterns of connectivity and activity are so different from each other, but our results show that the first steps in their maturation are remarkably similar,” said Satija, who is also an assistant professor of biology at New York University.

“They share a common developmental trajectory at the earliest stages, but the seeds of what will cause them to diverge later—a handful of genes—are present from the beginning,” Satija said.

As they profiled cells at later stages in development, the team observed the initial emergence of four interneuron “cardinal” classes, which give rise to distinct fates. Cells were committed to these fates even in the early embryo. By developing a novel computational strategy to link precursors with adult subtypes, the researchers identified individual genes that were switched on and off when cells began to diversify.

For example, they found that the gene Mef2c—mutations of which are linked to Alzheimer’s disease, schizophrenia and neurodevelopmental disorders in humans—is an early embryonic marker for a specific interneuron subtype known as Pvalb neurons. When they deleted Mef2c in animal models, Pvalb neurons failed to develop.

These early genes likely orchestrate the execution of subsequent genetic subroutines, such as ones that guide interneuron subtypes as they migrate to different locations in the brain and ones that help form unique connection patterns with other neural cell types, the authors said.

The identification of these genes and their temporal activity now provide researchers with specific targets to investigate the precise functions of interneurons, as well as how neurons diversify in general, according to the authors.

“One of the goals of this project was to address an incredibly fascinating developmental biology question, which is how individual progenitor cells decide between different neuronal fates,” Satija said. “In addition to these early markers of interneuron divergence, we found numerous additional genes that increase in expression, many dramatically, at later time points.”

The association of some of these genes with neuropsychiatric diseases promises to provide a better understanding of these disorders and the development of therapeutic strategies to treat them, a particularly important notion given the paucity of new treatments, the authors said.

Over the past 50 years, there have been no fundamentally new classes of neuropsychiatric drugs, only newer versions of old drugs, the researchers pointed out.

“Our repertoire is no better than it was in the 1970s,” Fishell said.

“Neuropsychiatric diseases likely reflect the dysfunction of very specific cell types. Our study puts forward a clear picture of what cells to look at as we work to shed light on the mechanisms that underlie these disorders,” Fishell said. “What we will find remains to be seen, but we have new, strong hypotheses that we can now test.”

A Chink in Bacteria’s Armor


Scientists unravel the structure of common bacterial wall-building protein, setting stage for new antibacterial therapies

https://player.vimeo.com/video/262243190

Building the bacterial wall: The blue balls are wall-making proteins. The yellow represents a newly synthesized bacterial cell wall. The green color represents “scaffolding” proteins. Video: Janet Iwasa for Harvard Medical School

The wall that surrounds bacteria to shield them from external assaults has long been a tantalizing target for drug therapies. Indeed, some of modern medicine’s most reliable antibiotics disarm harmful bacteria by disrupting the proteins that build their protective armor.

For decades, scientists knew of only one wall-making protein family. Then, in 2016, a team of Harvard Medical School scientists discovered that a previously unsuspected family of proteins that regulate cell division and cell shape had a secret skill: building bacterial walls.

Now, in another scientific first described March 28 in Nature, members of the same research team have revealed the molecular building blocks—and a structural weak spot—of a key member of that family.

“Our latest findings reveal the molecular structure of RodA and identify targetable spots where new antibacterial drugs could bind and subvert its work,” said study senior investigator Andrew Kruse, associate professor of biological chemistry and molecular pharmacology at Harvard Medical School.

The newly profiled protein, RodA, belongs to a family collectively known as SEDS proteins, present in nearly all bacteria. SEDS” near-ubiquity renders these proteins ideal targets for the development of broad-spectrum antibiotics to disrupt their structure and function, effectively neutralizing a range of harmful bacteria.

A weak link

In their earlier work, the scientists showed that RodA builds the cellular wall by knitting together large sugar molecules with clusters of amino acids. Once constructed, the wall encircles the bacterium, keeping it structurally intact, while repelling toxins, drugs and viruses.

The latest findings, however, go a step further and pinpoint a potential weak link in the protein’s makeup.

Specifically, the protein’s molecular profile reveals structural features reminiscent of other proteins whose architecture Kruse has disassembled. Among them, the cell receptors for the neurotransmitters acetylcholine and adrenaline, which are successfully targeted by medications that boost or stem the levels of these nerve-signaling chemicals to treat a range of conditions, including cardiac and respiratory diseases.

One particular feature caught the scientists’ attention—a pocket-like cavity facing the outer surface of the protein. The size and shape of the cavity, along with the fact that it is accessible from the outside, make it a particularly appealing drug target, the researchers said.

“What makes us excited is that this protein has a fairly discrete pocket that looks like it could be easily and effectively targeted with a drug that binds to it and interferes with the protein’s ability to do its job,” said study co-senior author David Rudner, professor of microbiology and immunobiology at Harvard Medical School.

In a set of experiments, researchers altered the structure of RodA in two bacterial species—the textbook representatives of the two broad classes that make up most of disease-causing bacteria. One of them was Escherichia coli, which belongs to a class of organisms with a double-cell membrane known as gram-negative bacteria, so named due to a reaction to staining test used in microbiology. The other bacterium was Bacillus subtilis, a single-membrane organism that belongs to so-called gram-positive bacteria.

When researchers induced even mild alterations to the structure of RodA’s cavity, the protein lost its ability to perform its work. E. coli and B. subtilis cells with disrupted RodA structure rapidly enlarged and became misshapen, eventually bursting and leaking their contents.

“A chemical compound—an inhibitor—that binds to this pocket would interfere with the protein’s ability to synthesize and maintain the bacterial wall,” Rudner said. “That would, in essence, crack the wall, weaken the cell and set off a cascade that eventually causes it to die.”

Additionally, because the protein is highly conserved across all bacterial species, the discovery of an inhibiting compound means that, at least in theory, a drug could work against many kinds of harmful bacteria.

“This highlights the beauty of super-basic scientific discovery,” said co-investigator Thomas Bernhardt, professor of microbiology and immunobiology at Harvard Medical School. “You get to the most fundamental level of things that are found across all species, and when something works in one of them, chances are it will work across the board.”

Solving for X

To determine RodA’s structure, scientists used a visualization technique known as X-ray crystallography, which reveals the molecular architecture of protein crystals based on a pattern of scattered X-ray beams. The technique requires two variables—the intensity of scattered X-rays and a so-called “phase angle,” a property related to the configuration of the atoms in a protein. The latter is measured indirectly, typically by using a closely related protein as a substitute to calculate the variable.

In this case, however, the team had on its hands a never-before-described protein with no known molecular siblings.

“In most cases you can use a related structure and bootstrap to a solution,” Kruse said. “In this case, we couldn’t do that. We had to predict what RodA looked like without any prior information about it.”

They needed a new way to solve for X.

In a creative twist, researchers turned to evolution and predictive analytics. Working with Debora Marks, assistant professor of systems biology at Harvard Medical School, they constructed a virtual model of the RodA’s folding pattern by analyzing the sequences of its closest evolutionary cousins.

The success of this “roundabout” approach, researchers said, circumvents a significant hurdle in field of structural biology and can open the doors toward defining the structures of many more newly discovered proteins.

“These insights underscore the importance of creative crosspollination among scientists from multiple disciplines and departments,” said study first author Megan Sjodt, a research fellow in biological chemistry and molecular pharmacology at Harvard Medical School. “We believe our results set the stage for subsequent work toward the discovery and optimization of new classes of antibiotics.”

Get Ready for Same-Sex Reproduction


When artificial sperm and eggs become a reality, the sex of your baby-making partner won’t matter.

Renata Moreira’s 1-year-old daughter is just beginning to talk. She calls Renata “Mommy,” her other mother, Lori, Renata’s ex-wife and co-parent, “Mama,” and the man who donated the sperm that gave her life, “Duncle,” short for donor uncle. The couple’s sperm donor is Renata’s younger brother.

“I frankly never contemplated having kids because I didn’t have any role models,” Moreira begins as she tells her daughter’s origin story. But when she met Lori at a bar in New York in 2013, the gay marriage movement was in full swing. When the couple decided to marry, they saw many of their friends starting families because of the new legal protections that marriage offered LGBTQ families, and they too began thinking about their options.

 
The cluster on the right is a colony of iPS cells. Each one of them could become a sperm or egg cell under the right conditions, which scientists are trying to uncover.

After months of research and thinking about the values that were most important to their family, they decided that a genetic connection to their kid was a high priority. “It wasn’t that we didn’t believe in adoption,” says Moreira, who is executive director of Our Family Coalition, a nonprofit that works to advance equity for LGBTQ families. “But the idea was that we wanted a child that was related to our ancestors and the genetic code that carries.”

Moreira is Brazilian, of indigenous and Portuguese ancestry, and Lori is Italian. Given that they both wanted to carry on their genetic heritage, they asked Renata’s brother to donate his sperm, to be matched with Lori’s eggs. The family’s fertility doctor used in-vitro fertilization to conceive an embryo in a dish and implanted it into Moreira’s uterus, making her into her daughter’s “gestational carrier.”

Even as the social stigma around gay parenting lessens — the Williams Institute at UCLA estimates that as many as six million Americans have a lesbian, gay, bisexual or transgender parent — LGBTQ families that want a biological connection to their children have a lot to think about. A same-sex couple who make a baby must work through an arduous puzzle of personal values, technologies, and intermediary fertility doctors, egg and sperm donors, or surrogates.

But that could change dramatically before long. A developing technology known as IVG, short for in-vitro gametogenesis, could make it possible for same-sex couples to conceive a baby out of their own genetic material and no one else’s. They’d do this by having cells in their own bodies turned into sperm or egg cells.

The science of IVG has been underway for the last 20 years. But it really took off with research that would later win a Nobel Prize for a Japanese scientist named Shinya Yamanaka. In 2006, he found a way to turn any cell in the human body, even easy-to-harvest ones like skin and blood cells, into cells known as induced pluripotent stem cells (iPS cells), which can be reprogrammed to become any cell in the body. Until that breakthrough, scientists working in regenerative medicine had to use more limited — and controversial — stem cells derived from frozen human embryos.

There is a small international group of scientists racing to reprogram human iPS cells into sperm and egg cells.

In 2016, researchers at Kyoto University in Japan announced that they had turned cells from a mouse’s tail into iPS cells and then made those into eggs that went on to gestate into pups. There are a lot of steps that still need to be perfected before this process of creating sex cells, also known as gametes, could work in humans.

If it does work, the first application likely would be in reversing infertility: men would have new sperm made and women would have new eggs made from other cells in their bodies. But a more mind-bending trick is also possible: that cells from a man could be turned into egg cells and cells from a woman could be turned into sperm cells. And that would be an even bigger leap in reproductive medicine than in-vitro fertilization. It would alter our concept of family in ways we are only beginning to imagine.

Today same-sex couples have to involve other people’s genetic material in making a baby. Artificial gametes could let them procreate with their own. (Illustration by Aart-Jan Venema)

Sex cells!

There is now a small international group of scientists racing to recreate the mouse formula and reprogram human iPS cells into sperm and egg cells.

One of the key players is Amander Clark, a stem cell biologist at UCLA. On a Friday afternoon, she walks me through her open lab area and introduces Di Chen, a postdoctoral fellow from China who’s working on creating artificial gametes. We enter a small room with a microscope, a refrigerator incubator, and a biosafety cabinet where students work with iPS cells. Chen invites me to peer down the microscope and shows off a colony of fresh iPS cells. They look like a large amoeba.

Getting cells like these to become viable eggs or sperm requires six major steps, Clark says. All of them have been accomplished in a mouse, but doing it in a human will be no easy feat. (In 2016, scientists reported that they had turned human skin cells into sperm cells, a development that Clark calls “interesting — but no one has repeated it yet.”) And no one has yet made an artificial human egg.

Clark’s group and other labs are essentially stuck on step three. After the steps in which a cell from the body is turned into an iPS cell, the third step is to coax it into an early precursor of a germ cell. For the work in mice, one Japanese researcher, Katsuhiko Hayashi, combined a precursor cell with cells from embryonic ovaries — ovaries at the very beginning of development — which were taken from a different mouse at day 12 in its gestation. This eventually formed an artificial ovary that produced a cell that underwent sex-specific differentiation (step four) and meiosis (step five), and became a gamete (step six).

Di Chen and Amander Clark in the lab. (Photo by Reed Hutchinson/UCLA Broad Stem Cell Research Center)

Other researchers, Azim Surani at Cambridge and Jacob Hanna at the Weizmann Institute of Science in Israel, have gotten to step three with both human embryonic stem cells and iPS cells, turning them into precursors that can give rise to either eggs or sperm. Surani’s former student Mitinori Saitou, now at Kyoto University, also accomplished this feat.

It’s an impressive achievement: they’ve made something that normally begins to develop around day 17 of gestation in a human embryo. But the next step, growing these precursor cells into mature eggs and sperm, is “a very, very huge challenge,” Surani says. It will require scientists to recreate a process that takes almost a year in natural human development. And in humans they can’t take the shortcut used in mice, taking embryonic ovary cells from a different mouse.

At UCLA, Clark refers to the next three steps needed to get to a human artificial gamete as “the maturation bottleneck.”

Those amoeba-like iPS cells that Chen showed me are sitting in a dish that he lifts off the microscope and carries to the biosafety cabinet. There he separates the cells into a new dish, and adds a liquid with proteins and other ingredients to help the cells grow. He puts the cells into an incubator for one day; then he’ll collect the cells again and add more ingredients. After around four days, the cells ideally will have grown into a ball that is around the size of a grain of sand, visible to the naked eye. This ball contains the precursors to a gamete. Clark’s lab and other international teams are studying it to understand its properties, with the hope that it will offer clues to getting all the way to step six — an artificial human gamete.

“I do think we’re less than 10 years away from making research-grade gametes,” she says. Commercializing the technology would take longer, and no one can really predict how much so — or what it would possibly cost.

Some of these iPS cells have been coaxed to become early precursors to a gamete. The next steps will be much harder. (Courtesy of UCLA Broad Stem Cell Research Center)

Even then, same-sex reproduction will face one more biological hurdle: scientists would need to somehow make a cell derived from a woman, who has two X chromosomes, into a sperm cell with one X and one Y chromosome, and do the reverse, turning an XY male cell into an XX female egg cell. Whether both steps are feasible has been debated for at least a decade. Ten years ago, the Hinxton Group, an international consortium on stem cells, ethics, and law, predicted that making sperm from female cells would be “difficult, or even impossible.” But gene editing and various cellular-engineering technologies might be increasing the likelihood of a workaround. In 2015, two British researchers reported that women could “in theory have offspring together” by injecting genetic material from one partner into an egg from the other. With this method, the children would all be girls, “as there would be no Y chromosomes involved.”

Yet another possibility: a single woman might even be able to reproduce by herself in a human version of parthenogenesis, which means “virgin birth.” It could be the feminist version of the goddess Athena springing from Zeus’s head.

The genderqueer nuclear family

The question remains whether society will want this technology — and how often LGBTQ families will choose to use it. Current advanced reproductive technologies are already diversifying the ways we reproduce and opening reproduction to groups who previously may not have had access to it. This is expanding the concept of family beyond the traditional Ozzie and Harriet hetero-nuclear family. Many people who are single parents by choice now include their gamete donors as members. Many LGBTQ families are collaborations of friends and relatives who become egg and sperm donors and help raise the kids.

So it’s understandable that social and legal observers are already thinking about the potential consequences of artificial gametes for the shape of families. If the technology means that lesbian couples wouldn’t need a sperm donor, and gay male couples wouldn’t need a donor egg, it could, among other things, make it “easier for the intended parents to preserve the integrity and privacy of the family unit,” Sonia Suter, a law professor at George Washington University, wrote in the Journal of Law and Biosciences.

A single woman might be able to reproduce by herself, the feminist version of Athena springing from Zeus’s head.

Ironically, however, the technology also could create something rather conventional — a biological nuclear family, albeit one that looks more like Ozzie and Ozzie. “Collaborative reproduction has paved the way for radical new definitions of family, which really helped to lead the movement for marriage equality,” says Radhika Rao, a law professor at UC Hastings law school. “Instead of challenging hetero-normative values, IVG could end up perpetuating them.”

That’s why Renata Moreira isn’t sure she would have chosen it. “It might take away from this great opportunity to challenge and expand the notion of what family looks like,” she says.

But new reproductive technologies are invented to expand our choices more than to limit them, as egg freezing and IVF allow women to pause and even extend their biological clocks. In the coming decades, IVG could let us bend biology to bring together the genetic codes, as Moreira puts it, of people who otherwise can’t. This would increase the freedom to shape our families to meet our personal values and desires, and push human evolution in an altogether new direction.

Light pollution is altering plant and animal behaviour


Light pollution can be problematic for animals like the Cory’s shearwater. Image credit – Airam Rodríguez (Estación Biológica de Doñana CSIC), licensed under CC BY 4.0

You could call it fatal attraction. Drawn by artificial lights in our brightening night-time world, animals find their lives in peril.

Fledgling birds disorientated by lights can collide with human structures on the ground and then get hit by cars, or become more vulnerable to predation, starvation or dehydration. Or newly hatched turtles may set out in the opposite direction to the sea, exposing themselves to similar dangers.

And our skies are getting brighter. A recent study found that our planet’s artificially lit outdoor area grew by about 2% each year between 2012 and 2016, while already lit areas brightened at the same rate.

‘Global growth in lighting at that kind of level is quite profound,’ said Kevin Gaston, a professor of biodiversity and conservation at the University of Exeter, UK. ‘We know that lighting is getting steadily worse.’

Researchers say one big problem has been a lack of awareness about light pollution. That is growing, but in the meantime, certain factors are potentially heightening its impact.

For example, white light-emitting diodes (LEDs) have been swiftly replacing traditional outdoor lighting such as yellow sodium street lights because of their higher energy efficiency. But because they emit light across a broad part of the visible spectrum, LEDs can affect a wider range of photosensitive cells in different organisms.

‘The negative consequences of light pollution are as unknown by the population as those of smoking in the 80s.’

Professor Oscar Corcho, Universidad Politécnica de Madrid, Spain

In a project called ECOLIGHTS FOR SEABIRDS, which ran from 2014 to the end of 2016, researchers found that the threat to fledgling shearwaters of being grounded on Phillip Island in south-eastern Australia was higher from broader-spectra metal halide and LED lights than from sodium lights. This suggests that using certain types of lights in different areas could be used to limit the effects on these birds.

Grounded

Separate studies on the Spanish island of Tenerife found that half of the Cory’s shearwater fledglings grounded around lights were within 3 kilometres of their nest sites and tended to be from inland colonies.

Dr Airam Rodríguez, a postdoctoral researcher at Doñana Biological Station in Seville, Spain, who worked on the project, said that knowing such information makes it easier to do things such as arrange safe corridors between breeding colonies and the ocean.

Many effects of light pollution on such seabirds have been poorly understood before, because of factors such as their breeding in remote locations and the fact they need to be tracked at night. Advances in technology are helping though, with the team using miniature GPS trackers and nocturnal high-resolution satellite imagery to follow the birds’ routes.

Dr Rodríguez said his team is now using GPS to look in more detail at what happens to birds rescued after being grounded by lights during their first days out on the ocean. He would also like to look more into the physiology of their eyes to find out which wavelengths the birds are more sensitive to.

Another little-known facet has been how much artificial lighting affects whole communities of organisms rather than just individual species, but recent research shows the effects can be significant.

As part of a project called ECOLIGHT, which finished last year, researchers set up 54 outdoor experimental environments, known as mesocosms, at the University of Exeter. These took the form of mesh-covered containers that held different combinations of plants, invertebrates and types of lighting, or were unlit. From this, they discovered that lighting seemed to suppress the flowering of the trefoil Lotus pedunculatus, and, in turn, the pea aphid population that feeds on them.

The team found similar effects in an experiment with bean plants and aphids.

Container-based experiments at the University of Exeter showed that lighting seemed to suppress the flowering of pea and bean plants and affected the aphid population that feeds on them. Image credit - James Duffy

Container-based experiments at the University of Exeter showed that lighting seemed to suppress the flowering of pea and bean plants and affected the aphid population that feeds on them. Image credit – James Duffy

Pervasive

Prof. Gaston, who was principal investigator on ECOLIGHT and also used field experiments to investigate the impact of light pollution, said: ‘This leads to the conclusion that lighting is having pretty pervasive ecological impacts. The effects are exceedingly widespread and are shaping the way that communities are structured – which was something that people hadn’t observed before.’

He also pointed to other research showing that bud burst in trees can happen a week earlier in the brightest compared with the darkest areas. ‘When we’ve discovered these kinds of things for climate change and they’ve shifted by about a week, we’ve said that’s profoundly worrying,’ he said.

His team is now looking more into the impacts of different intensities and colours of lights to build a more detailed picture.

In addition, they are scouring through images of Earth photographed by astronauts on the International Space Station so they can map how the colours of lights are changing as cities introduce more white LEDs.

Prof. Gaston explained that satellites are effectively colour-blind to the shift to white light, so using the pictures that astronauts take is a good way to track this, with about half a million pictures taken at night between 2003 and 2015.

This work complements the Cities at Night project, a citizen science initiative that gets help from volunteers to classify, locate and georeference these pictures.

A composite image of the Earth at night shows changes in light intensity between 2012 and 2016 including, for example, rapid electrification in India. Image credit - NASA's Goddard Space Flight Center

A composite image of the Earth at night shows changes in light intensity between 2012 and 2016 including, for example, rapid electrification in India. Image credit – NASA’s Goddard Space Flight Center

Also involved in Cities at Night is the STARS4ALL project, coordinated by Oscar Corcho, a professor at the Universidad Politécnica de Madrid in Spain, which acts as a platform to raise awareness of the issues involved in light pollution and inspire further research and better planning in lighting programmes. It seeks to engage people through methods such as games, broadcasting of astronomical events and a citizen-sensor network of low-cost photometers for people to measure light pollution in their area.

‘The negative consequences of light pollution are as unknown by the population as those of smoking in the (19)80s,’ said Prof. Corcho. ‘It’s still a very difficult problem to understand. Light pollution does not have the same immediate effects over animals as other forms of pollution.’

Regulation

Prof. Corcho said that one of STARS4ALL’s main aims this year is to run a petition on its website to ask for more overarching regulation to avoid light pollution at an EU level. STARS4ALL will collect signatures from citizens and hopes to present the petition in Brussels by the end of the year.

He says the good news is that there are easy fixes. ‘There are good technology options. For instance, there are types of lamps that could be used that are both respectful to the environment in terms of light pollution and at the same time as energy-efficient as white LEDs.’ He cites PC amber LEDs, for example.

If we move to solve these issues, there might well be an added bonus for us all. ‘As an indirect result… our recommendations for public lighting may result in having more populated places where we can see more and more stars in our sky,’ said Prof. Corcho.

Bee Colonies Draw an Uncanny Parallel to the Neurons of the Brain


The human brain follows certain laws, which govern how the complex organ reacts to stimuli and makes decisions. In a new study, scientists argue that super-organisms like honeybees follow the same laws: Like neurons in the brain, they argue, the different bees in a colony coordinate their responses to external stimuli according to strict rules. This discovery suggests, for the first time, that psychological and physical laws don’t just operate in human brains but drive other natural behaviors as well.

In the study, released Tuesday in Scientific Reports, researchers from the University of Sheffield and the Italian National Research Council observe bees to better understand the basic principles that guide these laws. If bees follow the same laws as neurons, then observing them can lead to a better understanding of the human brain. Studying bee colonies, they figure, is simpler than watching the neurons of a brain while a human makes a decision.

“This study is exciting because it suggests that honeybee colonies adhere to the same laws as the brain when making collective decisions,” co-author Andreagiovannia Reina, Ph.D. explained in a statement released Tuesday. “This study also supports the view of bee colonies as being similar to complete organisms or better still, super-organisms, composed of a large number of fully developed and autonomous individuals that interact with each other to bring forth a collective response.”

bees
Bees operate as a super-organism. 

Most biologists refer to honeybees as super-organisms, wherein the individuals comprising a hive are comparable to the cells that make up a single organism. Working together through structured, cooperative behavior bolsters the hive’s chance for survival. The ability to make decisions collectively has previously been compared to the way a brain’s different parts are involved in cognitive deliberation, but here, the scientists take the analysis a step further by observing how bees make the difficult decision of choosing a nest location for the entire group.

In the spring, colonies of European bees go through a mix-up: Part of the swarm leaves to find the best possible nesting location, while the other half stays behind to protect the queen. After exploring, scout bees return to the hive to recruit other scouts to check out the site, delivering “stop signals.” When the honeybees reach a collective agreement for the same option, the colony moves.

Bee hive
Hives are chosen via collective decision making. 

This process became the basis of the researchers’ theoretical model, which led the researchers to determine that the bee colony acts as a single super-organism that then coordinates a response to an external stimulus. They conclude, in the statement accompanying the paper, that “the way in which bees ‘speak’ with each other and make decisions is comparable to the way the many individual neurons in the human brain interact with each other.”

Just as individual neurons in the brain don’t obey psychophysical laws themselves but do so as part of the whole brain, single bees sometimes fire off different signals than the other bees. But regardless, the super-organism still obeys the rules — just like the brain.

And, just like bees, the human brain is known to follow certain rules. Pieron’s Law, for example, states that the brain makes decisions more quickly when the options to choose from are all of high quality. Hick’s Law, meanwhile, shows that the brain makes decisions more slowly when the number of options increases; with their model, the scientists determined that decision-making among bees follows similar guidelines. The colony chooses the location of their new hive more quickly when it has high-quality nest-site options and does so more slowly when the site options are limited.

Then, there’s Weber’s Law, which states that the brain selects the best option when there is a “minimum difference between the qualities of the options.” Like the brain, bee colonies were shown to do the same.

“With this view in mind, parallels between bees in a colony and neurons n a brain can be traced,” says Reina, “helping us to understand and identify the general mechanisms underlying psychophysics laws, which may ultimately lead to a better understanding of the human brain.”

Weird New Theory Presents Unexpected Reason Huge Mammals Live in the Sea


Fifty million years ago, whales were four-footed, tailed land mammals about the size of wolves. Over the next 12 million years, these terrestrial whales evolved into fully aquatic animals, complete with oceanic adaptations like flippers and flukes. Today, all of the Earth’s largest mammals live in the sea, including blue whales, considered the biggest animal to have ever existed. For a long time, scientists believed these ocean mammals grew to their modern sizes because the ocean provided them with immense space and the ability to float, but a new study presents an entirely different line of reasoning.

According to a study published Monday in the Proceedings of the National Academy of Sciences, mammal growth is actually more constrained in water than on land. Size in the ocean is bound by hard limits, the scientists from Stanford and Louisiana Universities Marine Consortium explain: Mammals that are too small struggle to retain heat in the cold water, and those that are too large must capture enough food to live.

“Many people have viewed going into the water as more freeing for mammals, but what we’re seeing is that it’s actually more constraining,” co-author and Stanford geological sciences professor Jonathan Payne, Ph.D., explained in a statement released Monday. “It’s not that water allows you to be a big mammal, it’s that you have to be a big mammal in water — you don’t have any other options.”

marine mammals, ocean life
A marine mammal, the blue whale, is the largest creature in the ocean.

Payne and his team compiled data sets of the body masses for 3,859 living species and 2,999 fossil mammal species, paying attention to when the mammals turned aquatic and when they became their modern size. They determined a pattern: Once the land mammals became aquatic, they evolved very quickly to their new size until they reached a plateau and stalled growth.

The researchers’ reason that being large means being in charge is because larger mammals are better at retaining heat in water that’s lower than their body temperature. Metabolism, however, increases with size more than the animal’s actual ability to gather food, which puts a limit on how big they can get.

Baleen whales, for example, can be so huge because they spend less energy on feeding. Their mouth contains a filter-feeder system, which means that when a baleen whale opens its mouth, it scoops up water, then pushes it out through its bristle-like baleen. While the water is filtered away, the krill captured in the water remains as a meal. This method allows them to grow larger than mammals that use teeth to munch and capture prey, like orcas.

“The sperm whale seems to be the largest you can get without a new adaptation,” lead author and Stanford Ph.D. candidate Will Gearty explained in a statement. “The only way to get as big as a baleen whale is to completely change how you’re eating.”

Sperm Whale - Kaikorua - New ZealandFJ0A3401
Sperm whales are thought to represent an upper size limit for swimming mammals; anything bigger requires additional adaptations.

What sizes comes down to, the researchers contend, are the basic principles of physics and chemistry. Living in water imposes selective pressures on metabolic rates and size — to be a big boy of the sea you need to live a pretty chill existence so that you don’t waste any precious energy not maintaining your largeness.

There’s one exception, though. The only aquatic mammals that didn’t rapidly evolve to be huge once they entered the sea are the much more manageable-sized sea otters. The scientists theorize that’s because these water-loving mammals took to the ocean relatively recently and, per the study’s accompanying statement, “many otter species still live much of their lives on land.”

sea otter
Sea otters don’t really follow the marine mammal size pattern.

Octopus And Squid Evolution Is Officially Weirder Than We Could Have Ever Imagined


Just when we thought octopuses couldn’t be any weirder, it turns out that they and their cephalopod brethren evolve differently from nearly every other organism on the planet.

In a surprising twist, in April last year scientists discovered that octopuses, along with some squid and cuttlefish species, routinely edit their RNA (ribonucleic acid) sequences to adapt to their environment.

main article image

This is weird because that’s really not how adaptations usually happen in multicellular animals. When an organism changes in some fundamental way, it typically starts with a genetic mutation – a change to the DNA.

Those genetic changes are then translated into action by DNA’s molecular sidekick, RNA. You can think of DNA instructions as a recipe, while RNA is the chef that orchestrates the cooking in the kitchen of each cell, producing necessary proteins that keep the whole organism going.

But RNA doesn’t just blindly execute instructions – occasionally it improvises with some of the ingredients, changing which proteins are produced in the cell in a rare process called RNA editing.

When such an edit happens, it can change how the proteins work, allowing the organism to fine-tune its genetic information without actually undergoing any genetic mutations. But most organisms don’t really bother with this method, as it’s messy and causes problems more often that solving them.

“The consensus among folks who study such things is Mother Nature gave RNA editing a try, found it wanting, and largely abandoned it,” Anna Vlasits reported for Wired.

But it looks like cephalopods didn’t get the memo.

In 2015, researchers discovered that the common squid has edited more than 60 percent of RNA in its nervous system. Those edits essentially changed its brain physiology, presumably to adapt to various temperature conditions in the ocean.

The team returned in 2017 with an even more startling finding – at least two species of octopus and one cuttlefish do the same thing on a regular basis. To draw evolutionary comparisons, they also looked at a nautilus and a gastropod slug, and found their RNA-editing prowess to be lacking.

“This shows that high levels of RNA editing is not generally a molluscan thing; it’s an invention of the coleoid cephalopods,” said co-lead researcher, Joshua Rosenthal of the US Marine Biological Laboratory.

The researchers analysed hundreds of thousands of RNA recording sites in these animals, who belong to the coleoid subclass of cephalopods. They found that clever RNA editing was especially common in the coleoid nervous system.

“I wonder if it has to do with their extremely developed brains,” geneticist Kazuko Nishikura from the US Wistar Institute, who wasn’t involved in the study, told Ed Yong at The Atlantic.

It’s true that coleoid cephalopods are exceptionally intelligent. There are countless riveting octopus escape artist stories out there, not to mention evidence of tool use, and that one eight-armed guy at a New Zealand aquarium who learned to photograph people. (Yes, really.)

So it’s certainly a compelling hypothesis that octopus smarts might come from their unconventionally high reliance on RNA edits to keep the brain going.

“There is something fundamentally different going on in these cephalopods,” said Rosenthal.

But it’s not just that these animals are adept at fixing up their RNA as needed – the team found that this ability came with a distinct evolutionary tradeoff, which sets them apart from the rest of the animal world.

In terms of run-of-the-mill genomic evolution (the one that uses genetic mutations, as mentioned above), coleoids have been evolving really, really slowly. The researchers claimed that this has been a necessary sacrifice – if you find a mechanism that helps you survive, just keep using it.

“The conclusion here is that in order to maintain this flexibility to edit RNA, the coleoids have had to give up the ability to evolve in the surrounding regions – a lot,” said Rosenthal.

As the next step, the team will be developing genetic models of cephalopods so they can trace how and when this RNA editing kicks in.

“It could be something as simple as temperature changes or as complicated as experience, a form of memory,” said Rosenthal.

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