Many of the fundamental features of life don't necessarily have to be the way they are. Chance plays a major role in evolution, and there are always alternate paths that were never explored, simply because whatever evolved previously happened to be good enough. One instance of this idea is the genetic code, which converts the information carried by our DNA into the specific sequence of amino acids that form proteins. There are scores of potential amino acids, many of which can form spontaneously, but most life uses a genetic code that relies on just 20 of them.

Over the past couple of decades, scientists have shown that it doesn't have to be that way. If you supply bacteria with the right enzyme and an alternative amino acid, they can use it. But bacteria won't use the enzyme and amino acid very efficiently, as all the existing genetic code slots are already in use.

In a new work, researchers have managed to edit bacteria's genetic code to free up a few new slots. They then filled those slots with unnatural amino acids, allowing the bacteria to produce proteins that would never be found in nature. One side effect of the reprogramming? No viruses could replicate in the modified bacteria.

Lost in translation

The genetic code handles translation, during which the information encoded in DNA is made into a functional protein. Key to this process is a group of small RNA molecules called transfer RNAs (or tRNAs). Transfer RNAs have a small, three-base segment that can be matched through base pairing, with information carried by DNA. RNAs can also be chemically linked to a specific amino acid in a process catalyzed by particular enzymes.

That combination—three specific bases paired with a particular amino acid—is the key to translation, i.e., to matching the bases of DNA with a specific amino acid.

A three-base code and four possible bases (A, T, C, and G) yield 64 possible three-base combinations, called codons. Three of those codons signal for translation to be stopped when the end of the protein-coding sequence is reached. That leaves 61 codons for only 20 amino acids. As a result, some amino acids are encoded by two, four, or even six different codons.

That redundancy in the code is what the research team—based in Cambridge, UK—targeted. A few years ago, the researchers edited the entire E. coli genome so that some of the redundant codons were freed up. The research team edited all instances of one of the three stop codons into one of the others so that there were no longer any instances of it in the entire genome. Instead of being used for something, the codon was freed up to be redefined.

The researchers did similar experiments with the codons for the amino acid serine. Instead of leaving six codons that say "serine," the team edited the total down to just four by changing every instance of the two they targeted to a different serine codon.

(That may sound simple, but even a small genome like E. coli's has thousands of each of these codons scattered through millions of base pairs. Editing the genetic code is an impressive technical achievement on its own.)

Tolerating change

While the bacteria didn't use the three edited codons, they still could. All the pieces needed to use the codons—the transfer RNAs, the enzymes that attach amino acids to them, etc.—were still present. For reasons that aren't entirely clear, the modified bacteria weren't especially healthy and grew at a slower pace than their unedited source.

For their follow-up work, the researchers evolved the strain to tolerate the modified genetic code better. They exposed the bacteria to mutagens and then grew lots of samples using an automated system that identified when a sample was growing well and kept supplying the sample with fresh food. (Fast-growing bacteria turn whatever they're grown in cloudy, allowing them to be identified.) After a couple of rounds of mutation, near-normal growth was restored.

At that point, the researchers went back and deleted the genes for the transfer RNAs and enzymes that allowed their three edited codons to work. With those changes made, it wasn't that the codons were no longer being used—they could no longer be used.

Again, this issue slowed down the growth of the bacteria, although it's not clear why—either some of the deleted genes have other functions or there were codon instances the researchers missed in editing. Regardless, they mutated the bacteria again and selected a strain in which much of the growth had been restored. By the time everything was done, the scientists had a strain that grew about half as well as a normal E. coli. They also had three completely unused codons.

(As an aside, the team also obtained a genome sequence of this final strain to see what mutations had occurred during this process. Although numerous differences were identified, none were obviously associated with the ability to grow with a modified genetic code. The lab has undoubtedly since assigned a few grad students to figure out that conundrum.)

New code, who dis?

To confirm that the three unused codons were nonfunctional, the researchers infected them with viruses. The proteins encoded by these viruses normally include the unused codons, so this method provides a test of whether the codons' use was truly eliminated.

The bacteria passed the test. No viruses could grow in the codons, even when a mixture of five different viruses were thrown in the culture at the same time. It was clear that in this strain, these codons simply could not be used.

That's what the researchers wanted in the first place (it's fair to say they didn't set out to make virus-resistant bacteria). Now they could start using the three codons for amino acids that aren't naturally used by life on Earth.

The researchers supplied the bacteria with some non-native amino acids, along with the genes for a transfer RNA to attach the amino acids to and an enzyme that would do the attaching. They then started inserting the gene for a nonbacterial protein that could only be translated by using the codons they had redefined and confirmed that the protein was made and that it incorporated these non-natural amino acids. The team even made a version that incorporated three different artificial amino acids, showing that they truly had expanded the genetic code.

The researchers were also able to make strains that used a different set of three artificial amino acids. So it's possible to make a large collection of strains, each specialized to use a different set of artificial amino acids.

Interesting polymer chemistry

The authors didn't go on to demonstrate anything practical, but there are plenty of potential uses for the research. Artificial amino acids can potentially catalyze reactions that aren't possible or efficient with the normal set of 20. And we don't have to necessarily design an enzyme that incorporates the new amino acids; instead, we can simply try to evolve the function in strains with an expanded genetic code.

There's also the possibility for some interesting polymer chemistry. In the chemical reactions that form most polymers, we typically use only a single type of subunit to build the polymer, since you can't control what links with what. But proteins let you build a polymer chain with complete control of the order of each subunit because you can specify the order of amino acids. With an expanded genetic code, we can potentially get molecule-level control over the construction of polymers.

Science, 2021. DOI: 10.1126/science.abg3029  (About DOIs).

Sharks have been swimming and hunting in the world's oceans for 450 million years, and though their numbers have recently declined because of human activity, they're still with us. But the world once had many more, and many more varieties of, the large marine predators compared to today. In fact, new research published in Science suggests that 19 million years ago, the vast majority of sharks and shark species died off. We don't understand why or how this large extinction event occurred.

“Sharks have... weathered a large number of mass extinctions. And this extinction event is probably the biggest one they've ever seen. Something big must have happened,” Elizabeth Sibert, one of the authors of the paper, told Ars.

Sibert is a Hutchinson postdoctoral fellow at the Yale Institute for Biospheric Sciences, and she was a junior fellow in the Harvard Society of Fellows for the initial phases of this research back in 2017.

Back then, the team analyzed ancient sediment core samples, one from the South Pacific and one from the North. The International Ocean Discovery Program collected these samples in 1983 and 1992, but the material they contain dates back hundreds of millions of years. Each centimeter down on the cores represents a few 100,000 years back in time.

Embedded in the sample were 1,381 tiny shark scale, or denticle, fossils. The team looked at the raw number of scales and the different types of scales that appeared in the different layers of sediment. "Dermal denticles offer an incredible window into the past of these ancient and elusive marine predators and thus the state of ocean ecosystems through time,” Leah Rubin, another author on the paper, told Ars.

Sharp decline in sharks

Prior to 19 million years ago, the researchers found a wealth of shark biodiversity and abundance. But after that point, they saw a stark decrease in the number of scale fossils and fewer varieties of them. In all, there was a 90 percent decrease in terms of raw population and a 70 percent decrease in species diversity. Sharks never really recovered to the dizzying highs of pre-history.

Though the sediment cores are from the Pacific, Sibert suspects that the team's findings could hold true for other parts of the deep. According to Sibert, some core samples from the Atlantic Ocean show an abundance of shark life 30 million years ago. There are also more recent samples, from only a few million years ago, that similarly show a decline—but so far, there are no Atlantic samples from the timeframe of the extinction event.

Whatever led to the shark-pocalypse is still unknown. The oxygen and carbon isotopes—which are used to reconstruct what the temperatures and carbon cycles were like in the past—don't show anything amiss. In fact, they were so normal that researchers haven't spent much time studying 19 million years ago. However, Sibert noted that with more research and more sediment samples, the mystery is quite likely to be solved.

“One of the challenges with this particular bit of research is 'what happened to the sharks at this time and why was there this massive die-off?' The answer is 'we really don't know right now,'” she said, adding that the team hopes to look into how the die-off impacted other oceanic species.

We’re gonna need a bigger data set

According to Seth Finnegan, associate professor at the University of California, Berkeley's department of Integrative Biology, the paper's findings are intriguing, but they rely on only two samples. He noted that it is also possible that the large shark die-off only happened in the Northern and Southern Pacific. But that's probably not the case, as something affecting one part of the ocean will usually affect others, he said.

All the same, Finnegan noted that to get a clearer picture of what happened 19 million years ago, more samples from other parts of the ocean, and places closer to shore, would be helpful. “There are multiple levels of uncertainty here, but it's a very interesting and striking pattern. It's not subtle,” he told Ars.

It's too early to say how this research fits into our understanding of history, Finnegan said. But the study shows that sharks have been around for a long time and have seen some pretty staggering biodiversity swings. Future research into the impacts that this shark die-off had on other creatures could also outline the importance of shark conservation today. According to Finnegan, sharks are an essential part of their ecosystems, and having large swaths of them kick the bucket could produce impacts that we don't yet fully understand.

“They tend to be very important apex predators in a lot of ecosystems, very important in regulating ecosystem structures,” he said.

Among well-studied species, stumbling onto a large extinction event is quite rare, Finnegan said. However, considering fossilized shark denticles have not been thoroughly studied relative to other fossils, it's perhaps not that surprising to come across a previously undiscovered die-off.

There could be other extinction events throughout history that scientists simply haven't discovered yet, Sibert told Ars. Even today, researchers might come across some other ancient surprises. For example, her team began the work looking for background information on fish and sharks around 80 million years in the past—instead, they came across a doomsday event for the ocean predators.

“To me, that's something that's really fascinating and really exciting. If you go looking, there are probably all sorts of things we don't know about the Earth and its history.”

Science, 2021. DOI:  10.1126/science.aaz3549

NASA announced Wednesday that it will send, not one, but two spacecraft to Venus this decade as part of its efforts to ramp up exploration of the closest planet to Earth.

The decision was hailed by scientists who study Venus and have felt neglected by a space agency decidedly more interested in Mars. NASA has not sent a robotic spacecraft to Venus since the launch of the Magellan orbiter in 1989. Launched by space shuttle Atlantis, Magellan made a controlled entry into the Venusian atmosphere in 1994 after collecting reams of data that have tantalized scientists ever since.

"The Venus community is absolutely elated and excited and wants to just get to work and see this happen," said Venus researcher Ellen Stofan, the Smithsonian Under Secretary for Science and Research, in an interview. "We all are so hungry for data, for moving the science forward. A lot of us worked in this field since Magellan. We've had these really fundamental science questions for so long."

The missions, named DAVINCI+ and VERITAS, have a cost cap of $500 million apiece and were selected as part of NASA's "Discovery" program. Two other finalists in the competition, an Io Volcano Observer and a mission to Neptune's icy moon Triton, will be eligible for future awards.

NASA scientists said the two Venus missions were selected on their merits, scoring highest on the agency's assessments. Although both are going to Venus, each mission is different from the other and will provide complementary data.

The DAVINCI+ mission will be the first NASA probe to sample the Venusian atmosphere since 1978. The space agency said DAVINCI+ will study how the atmosphere formed and evolved as well as determine whether the planet ever had an ocean. It will also carry a "descent sphere" that will plunge through the planet’s thick atmosphere, making precise measurements of noble gases and other elements to understand why Venus' atmosphere is a runaway hothouse compared the Earth's. This sphere will return the first high-resolution pictures of the unique geological features on Venus known as "tesserae," which may be comparable to Earth's continents.

VERITAS, by contrast, will map Venus' surface to determine the planet's geologic history and understand why it developed so differently than Earth. Orbiting Venus with a synthetic aperture radar, the probe will chart surface elevations over nearly the entire planet to create 3D reconstructions of topography and confirm whether processes such as plate tectonics and volcanism are still active on Venus. VERITAS also will map infrared emissions from Venus' surface to map its rock types.

Stofan said the overriding goal of these missions will be to assess how Venus and Earth came to follow such divergent paths in their evolution. Both are of similar size, and while Venus is closer to the Sun, that does not account for the differences in the hellish conditions on the surface of Venus—especially in terms of atmospheric pressure and temperature—compared to Earth.

"If we really understood how Venus and Earth became so different, we would be a lot closer to understanding how common or rare Earths are," Stofan said. This research would greatly inform scientists who are studying Earth-like worlds in the "habitable zone" around other stars, she added.

Both missions are slated to launch during the 2028 to 2030 timeframe, NASA said.

Over its history, NASA has sent many more probes to Mars than Venus. This is because Mars, although it is significantly smaller than Earth, has some common characteristics, including a thin atmosphere and ice at its poles, and imagining humans walking on Mars one day is not farfetched. Venus, not so much.

The disparity in expenditures is striking. According to Casey Dreier of The Planetary Society, through 2020, NASA has spent $3.7 billion (adjusted for inflation) on its Venus missions, compared to $28.5 billion on Mars missions and related programs, out of a total of $96.9 billion for its Planetary Science program.

The James Webb Space Telescope won't launch as scheduled on Halloween this year—which is definitely a trick rather than a treat for the space community. However, the delay may only be a few weeks.

Last summer, NASA and the European Space Agency (ESA) set an October 31, 2021, launch date for the $10 billion telescope. The instrument, which is the largest science observatory ever placed into space, will launch on a European Ariane 5 rocket from a spaceport in French Guiana. Now, however, three considerations have pushed the launch into November or possibly early December.

During a press briefing with reporters on Tuesday, the telescope's director for launch services, Beatriz Romero, said that there are a "combination of different factors" to consider when setting a new launch date. These factors include shipment of the telescope, the readiness of the Ariane 5 rocket, and the readiness of the spaceport in South America as well. Romero said she did not expect to identify a new launch date until later this summer or early fall.

NASA plans to ship the telescope to the launch site by boat late this summer. (NASA is keeping precise plans vague due to concerns about piracy at sea. Seriously.) The space agency's chief of science, Thomas Zurbuchen, said Tuesday that "we don't have a lot of reserve" left in the schedule to prepare for shipment. However, he added that NASA and Webb's primary contractor, Northrop Grumman, are close to folding up the telescope and putting it into a shipping container. He said that this should happen toward the "end of August."

The launch campaign, which begins when the telescope arrives in French Guiana, requires 55 days. Asked whether this means that Webb will not launch until mid-November at the earliest, Zurbuchen said this assessment was correct.

The rocket is also not ready. The Ariane 5 booster, a venerable rocket in service for more than 25 years, has been grounded since August 2020 due to a payload fairing issue. However, officials with Arianespace, which manages launch for the Ariane 5, said the fairing issue's cause has been diagnosed and addressed with a redesign. Two Ariane 5 launches are scheduled before Webb's launch to ensure that the fairing issue has been fixed. (Those launches are scheduled for July and August, but delays are possible.)

Finally, there are concerns about the spaceport itself, where operations have been limited by COVID-19. Vaccines are not yet widely available in French Guiana, and officials have said that if virus activity worsens, it could further slow operations.

While it is not pleasant to hear about further delays to launching the James Webb Space Telescope, it is nonetheless clear that NASA is finally bringing this project closer to space. Webb's launch has been delayed for more than a decade by technical problems and by the need for extensive testing. Some of this is understandable, however. Launching and deploying Webb successfully would be a masterful feat—unfurling it in deep space requires 50 major deployments and 178 major release mechanisms. All of these must work, or the instrument will fail.

So if NASA needs just a little more time to get Webb into space, and if ESA needs a little more time to ensure the safety of its ride, these are perhaps not such bad precautions to take.

As part of last week's federal budget rollout, a process during which the White House proposes funding levels for fiscal year 2022, the US Air Force released its "justification book" to compare its current request to past budget data. The 462-page book contains a lot of information about how the Air Force spends its approximately $200 billion budget.

For those tracking the development of SpaceX's ambitious Starship vehicle, there is an interesting tidbit tucked away on page 305, under the heading of "Rocket Cargo" (see .pdf). The Air Force plans to invest $47.9 million into this project in the coming fiscal year, which begins October 1.

"The Department of the Air Force seeks to leverage the current multi-billion dollar commercial investment to develop the largest rockets ever, and with full reusability to develop and test the capability to leverage a commercial rocket to deliver AF cargo anywhere on the Earth in less than one hour, with a 100-ton capacity," the document states.

Although this does not refer to Starship by name, this is the only vehicle under development in the world with this kind of capability. The Air Force does not intend to invest directly into the vehicle's development, the document says. However, it proposes to fund science and technology needed to interface with the Starship vehicle so that the Air Force might leverage its capabilities.

Clearly, some Air Force officials are intrigued by the possibility of launching 100 tons of cargo from the United States and having the ability to land it anywhere in the world about an hour later.

Accordingly, the Air Force science and technology investments will include "novel loadmaster designs to quickly load/unload a rocket, rapid launch capabilities from unusual sites, characterization of potential landing surfaces and approaches to rapidly improve those surfaces, adversary detectability, new novel trajectories, and an S&T investigation of the potential ability to air drop a payload after reentry," the document states.

The Air Force is spending $9.7 million on these activities in the current fiscal year but seeks to increase that total for the coming year as it moves into the test phase of the program. The funds will have to be approved by Congress as part of its budget deliberation process this summer and fall.

This clearly is an important contract for SpaceX, as the US Department of Defense has near-limitless budgets and could become an important customer of Starship. This fully reusable vehicle, currently undergoing tests in South Texas, theoretically has both the capability to fly to the Moon or Mars, as well as suborbital point-to-point flights on Earth. If it is successful, it would offer the US military logistical capabilities that no other force on the planet could match.

SpaceX already launches spy and communications satellites for the US military. However, in moving into logistics and the potential movement of munitions, the company may be treading on an ethical line with some space enthusiasts. It would also further embolden the claims of some international critics, such as Russian space leader Dmitry Rogozin, who has suggested (without evidence) that SpaceX aims to launch nuclear weapons into space.

Lo Friesen reaches for a plastic bag the size of a pillowcase filled with dark green plant matter. “Here we have some more material for our edibles clients,” she says. “Just giant bags of weed."

Behind her, something is making a soft, regular chirping noise, like a little bird. Friesen turns and gestures at a silver contraption made of pipes and cylinders. “These are our machines,” she says. “This is where the material goes in.”

Friesen is a cannabis extractor in Seattle. Her company, Heylo Cannabis, is part of a whole ecosystem of suppliers, processors and distributors that has sprouted up since Washington state legalized marijuana in 2012. In this food chain, Friesen is somewhere between the plant growers and the retailers that sell to consumers. With the help of the chirping machines, her team separates and distills the various compounds found in the raw cannabis plant—the essence of weed. The result is a kind of oily, maple syrup–colored liquid that gently sloshes in glass flasks and jars in her lab.

Some of that oil is for vaping. But a hefty portion of Friesen’s extract will go into chocolates, mints, gummy candies and even beverages—consumables that are broadly referred to as cannabis edibles.

This shopping aisle’s worth of pickings—from sweets such as brownies and gummies to savory treats such as beef jerky and mac and cheese—have become big business. Recreational cannabis is currently legal in 16 states and Washington, DC, and several more are considering legalization. The global market for edibles—spurred in part by people being both housebound and lung-health wary during the pandemic—was nearly $3 billion in 2020; it’s predicted to top $11.5 billion by 2025. Major brands including Molson Coors and Carl’s Jr. are staking claims in the edibles landscape.

Many people still prefer inhaling cannabis—edibles make up roughly 11 percent of the cannabis market—but a growing number are eating their greens, so to speak. Edibles are more lung-friendly than smoking and more discreet—they don’t generate stinky secondhand smoke and can be consumed both in and out of the home. And edibles can be a vehicle for a more sustained high.

But therein lies a problem for both product makers and consumers. The potency, duration and timing of an edible experience can’t always be counted on. They are notoriously variable in their effects.

Two edibles, both with the same quantity of THC (tetrahydrocannabinol, the main intoxicating ingredient in cannabis), can feel very different to a consumer. One may have milquetoast results, while the other hits like a truck and lasts for hours.

And it’s very difficult to investigate exactly what’s behind that variability, both on the product side and the consumer side. The federal government still lists cannabis as a Schedule 1 drug, a classification that severely restricts access to the plant and its compounds for research purposes.

“In more than half of the United States right now, these products are available for retail purchase and millions of people are taking them,” says Ryan Vandrey, a psychiatrist at Johns Hopkins School of Medicine who has studied the effects of cannabis edibles in the body. And yet, he says, there are still many fundamental things about edibles that we don’t understand, leaving gaps in the knowledge needed to make rules to protect consumers.

Nonetheless, chemistry and nutrition science do offer clues to how edibles are absorbed by the body and how that might influence their effects. The aim is to design precision products to provide finely tailored experiences while protecting consumers—despite the uncertainty baked into edibles by the diversity of ingredients and quirks of human physiology.

The trip in

The cannabis plant contains hundreds of compounds that interact with the human body. Most well-studied—and arguably most important—are the cannabinoids, which include both the psychoactive THC and cannabidiol (CBD). These chemicals mimic ones made in the brain and other organs and can have diverse effects—from appetite stimulation to pain relief to altering mood and more.

When smoked, the path cannabinoids travel is relatively straightforward—they are inhaled into the lungs and pass into the bloodstream. Via this route, data suggest, blood levels of THC peak within about 10 minutes of exposure, and then dive, returning to baseline within three to six hours.

But cannabinoids that are eaten take a longer, more circuitous route to the bloodstream. The little research available suggests that the effects of many edibles peak two to three hours after consumption and may persist for as long as six to 20 hours. If this initial delay is unexpected, it may prompt people to dose again and end up with a far more intense experience than desired. For some, it prompts a visit to the emergency room.

Even if the delayed onset is anticipated, there’s still a lot of variation in the timing and potency of the effect, thanks in part to the food—whether brownie or beverage—that delivers the cannabinoids.

“From a consumer perspective, if I’m a cannabis user and I go to a dispensary and the product says it’s got 10 milligrams of THC in it, and then there’s another product that says 10 milligrams—and another product, it says 10 milligrams—my assumption is that, well, they’ll all be the same,” Vandrey says.

But not necessarily. If one product is a vitamin-like capsule, another’s a buttery brownie and the third is a drink, the different fats in the vitamin capsule versus the brownie can skew how quickly and how much the body absorbs. And the drink? Vandrey says compounds in drinks will sometimes separate out of the solution and get stuck to the lid or glass.

“So even though 10 milligrams may have gone into the bottle, only three might come out. And the high-fat–containing brownie’s going to have three times the absorption than the capsule.” So three products all labeled as containing 10 milligrams can produce a huge range of effects.

Some of those differing effects result from basic chemistry. Cannabinoids are hydrophobic—meaning they don’t dissolve in water. But they do in fats and oils. That’s why the home chef’s classic recipe for pot brownies calls for slowly and patiently cooking the cannabis with butter to leach out the compounds from the herb. Once dissolved in butter or oil, cannabinoids can be absorbed during digestion much more easily.

Skip this buttery step and just throw the raw plant matter into the batter and you’ll probably get a batch with no kick. The cannabinoids will either be absorbed so slowly that you don’t notice, digested by the bacteria that live in the gut, or end up flushed down the toilet.

A key step in the dissolving process is the formation of little bubbles of fat or oil called micelles. During digestion, the body makes soaplike chemicals called surfactants that break down large blobs of fat or oil, creating smaller micelles that can be taken up by cells lining the gut.

The size, quantity and chemical structure of these micelles may be important factors in when cannabinoids hit the rest of the body, dictating in part the timing, potency and duration of their effects.

Most edible fats and oils are made of chainlike molecules called triglycerides, which can be saturated (often solid at room temperature, like butter) or unsaturated (typically liquid at room temperature, as with many vegetable oils). The amount of saturation and length of triglyceride molecules can affect the shape and properties of the micelles that form in the gut.

Carotenoids—fat-soluble molecules such as beta-carotene—are more absorbable in the body when packaged in micelles with oils containing long triglycerides, like sunflower oil, research suggests. Coconut oil, on the other hand, has shorter triglycerides and yields smaller micelles. Such small micelles may not be able to carry larger molecules, like cannabinoids, to the gut wall at all, says David Julian McClements, a food nanotechnologist at the University of Massachusetts Amherst.

“Say you had a cannabinoid. It’s like an elephant and you want to get it transported somewhere,” says McClements, who wrote about cannabinoid delivery in the 2020 Annual Review of Food Science and Technology. “You couldn’t get it into a MINI Cooper. But if you put the elephant into a big truck, then you could carry it around somewhere.”

So using sunflower oil instead of coconut oil in a pot brownie could, theoretically, increase how much and how soon the effects kick in. That information could inform both consumer expectations and product-maker recommendations.

A 2020 study in rats, for example, investigated delivering cannabinoids via different formulations of tiny, oil-based globules. The globules formulated from cocoa butter (long-chain molecules and mostly saturated) were more available for absorption than those delivered via a medium-chain fat called tricaprin.

But the data aren’t clear-cut. The same study compared drug delivery in globules based on the long-chain, mostly unsaturated sesame oil with a medium-chain oil derived from saturated coconut and palm kernel. The two formulations basically performed the same, the researchers reported in International Journal of Pharmaceutics.

Various factors influence the effects of cannabis beverages as well. These drinks are emulsions—blends of two liquids that don’t like to mix, akin to a balsamic vinaigrette dressing—so surfactants are added to stabilize things and slow separation. Adding surfactants, such as the milk protein casein, into a recipe could potentially accelerate micelle formation and promote uptake in the gut. Surfactants added to a THC-rich emulsion sped up pain relief in mice, for example.

Variable outcomes

The perplexing complexity of edibles science may actually present an opportunity for designing specific outcomes: a fast-acting edible to stimulate appetite, for example, or an extended-release one for pain management. But such efforts are hindered by the lack of regulations and quality control standards at the federal level. Currently, there’s a patchwork of different rules and methods developed by various labs, associations and states.

“It’s very clear that we need some sort of standard,” says Friesen, the extracts processor.

Such regulations exist for pharmaceutical cannabinoids. The drug Epidiolex, for example, contains the cannabinoid CBD and was approved by the US Food and Drug Administration in 2018 for epilepsy. Its CBD is always delivered via a sesame oil carrier that should keep the effective dose consistent, and the product is regularly analyzed and monitored, says Tyler Gaston, a neurologist at the University of Alabama at Birmingham who has studied the use of cannabinoids for treatment-resistant epilepsy.

But with artisanal products, lack of regulation leads to uncertainty, Gaston says.

Regulations and monitoring could also protect consumers from erroneous claims. The labeling for THC and CBD content on commercial products is often inaccurate, research by Vandrey and colleagues has shown.

The Schedule 1 status of cannabis continues to pose obstacles for researchers who would like to better understand the nuances of edibles physiology. Approval to work with cannabis can mean a long and arduous series of review processes, including multiple applications to the FDA, the Drug Enforcement Administration and state agencies. There are also burdensome protocols, such as requiring vaults or safes for storage and on-site security inspections of the lab by the DEA.

What’s more, funding for the research and supplies of the plant itself have historically been very limited. For years, researchers have had to purchase cannabis for research through a specific agency, the National Institute on Drug Abuse, which typically offered only a handful of products and potencies.

This situation may be changing. In December 2020, the DEA finalized regulations that would increase the number of approved marijuana growers and the variety of products available to researchers. And federal bills to deschedule the drug have been proposed, though not passed. If legislation changes things, then researchers could really dive in and investigate the complexity in people and animals, says McClements. “Then we can ask, you know, what is the difference between coconut oil and palm oil or fish oil?”

Researchers have a good idea about such differences from previous work with vitamins and nutraceuticals, he says, “but I think we need to confirm it, because every system’s a little bit different.”

For now, much of edibles science remains shrouded. So many consumers, especially those new to edibles, can’t predict how strong or how delayed the effects may be, which can lead to people inadvertently taking too much. It also means people who might benefit from edibles might be missing out, says Friesen.

She’s seen one bad experience turn people away from what might be a promising way to help manage their anxiety or pain. Was it an ingredient that caused that? Can we make it better? Perhaps one day we will know.

Types of edibles

Baked goods: This includes brownies, cakes and cookies. The cannabinoids are usually dissolved in a fat or oil, like butter or shortening. Baked goods have fairly complex structures and a lot of ingredients compared with other edibles, so probably are slower-acting, though this may vary considerably from product to product or person to person.

Chocolates: In a finished product, the cannabinoids are probably primarily in the cocoa butter in the chocolate—a good vehicle for absorption, some data suggest.

Gummies: Traditionally made from gelatin, pectin or carrageenan, candy gummies naturally contain sugars and flavors, but usually don’t contain fat. To incorporate cannabinoids, oil droplets or other particles need to be mixed in.

Tinctures: Not a traditional edible, these liquid formulations are taken by mouth, though they’re held under the tongue instead of swallowed. In this case the cannabinoids are dissolved in alcohol and diffuse directly into the bloodstream through the mucous membranes of the mouth, making them much more fast-acting.

James Gaines is a freelance science journalist living in Seattle. He also contains a great variety of ingredients.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.

To most people, giraffes are merely adorable, long-necked animals that rank near the top of a zoo visit or a photo-safari bucket list. But to a cardiovascular physiologist, there’s even more to love. Giraffes, it turns out, have solved a problem that kills millions of people every year: high blood pressure. Their solutions, only partly understood by scientists so far, involve pressurized organs, altered heart rhythms, blood storage—and the biological equivalent of support stockings.

Giraffes have sky-high blood pressure because of their sky-high heads that, in adults, rise about six meters (almost 20 feet) above the ground—a long, long way for a heart to pump blood against gravity. To have a blood pressure of 110/70 at the brain—about normal for a large mammal—giraffes need a blood pressure at the heart of about 220/180. It doesn’t faze the giraffes, but a pressure like that would cause all sorts of problems for people, from heart failure to kidney failure to swollen ankles and legs.

In people, chronic high blood pressure causes a thickening of the heart muscles. The left ventricle of the heart becomes stiffer and less able to fill again after each stroke, leading to a disease known as diastolic heart failure, characterized by fatigue, shortness of breath and reduced ability to exercise. This type of heart failure is responsible for nearly half of the 6.2 million heart failure cases in the US today.

When cardiologist and evolutionary biologist Barbara Natterson-Horowitz of Harvard and UCLA examined giraffes’ hearts, she and her student found that the giraffes’ left ventricles did get thicker but without the stiffening, or fibrosis, that would occur in people. The researchers also found that giraffes have mutations in five genes related to fibrosis. In keeping with that find, other researchers who examined the giraffe genome in 2016 found several giraffe-specific gene variants related to cardiovascular development and maintenance of blood pressure and circulation. And in March 2021, another research group reported giraffe-specific variants in genes involved in fibrosis.

And the giraffe has another trick to avoid heart failure: The electrical rhythm of its heart differs from that of other mammals so that the ventricular-filling phase of the heartbeat is extended, Natterson-Horowitz found. (Neither of her studies has been published yet.) This allows the heart to pump more blood with each stroke, allowing a giraffe to run hard despite its thicker heart muscle. “All you have to do is look at a picture of a fleeing giraffe,” Natterson-Horowitz says, “and you realize that the giraffe has solved the problem.”

Natterson-Horowitz is now turning her attention to another problem that giraffes seem to have solved: high blood pressure during pregnancy, a condition known as pr-eeclampsia. In people, this can lead to severe complications that include liver damage, kidney failure, and detachment of the placenta. Yet giraffes seem to fare just fine. Natterson-Horowitz and her team are hoping to study the placentas of pregnant giraffes to see if they have unique adaptations that allow this.

People who suffer from hypertension are also prone to annoying swelling in their legs and ankles because the high pressure forces water out of blood vessels and into the tissue. But you only have to look at the slender legs of a giraffe to know that they’ve solved that problem, too. “Why don’t we see giraffes with swollen legs? How are they protected against the enormous pressure down there?” asks Christian Aalkjær, a cardiovascular physiologist at Aarhus University in Denmark who wrote about giraffes’ adaptations to high blood pressure in the 2021 Annual Review of Physiology.

In part, at least, giraffes minimize swelling with the same trick that nurses use on their patients: support stockings. In people, these are tight, elastic leggings that compress the leg tissues and prevent fluid from accumulating. Giraffes accomplish the same thing with a tight wrapping of dense connective tissue. Aalkjær’s team tested the effect of this by injecting a small amount of saline solution beneath the wrapping into the legs of four giraffes that had been anesthetized for other reasons. Successful injection required much more pressure in the lower leg than a comparable injection in the neck, the team found, indicating that the wrapping helped resist leakage.

Giraffes also have thick-walled arteries near their knees that might act as flow restrictors, Aalkjær and others have found. This could lower the blood pressure in the lower legs, much as a kink in a garden hose causes water pressure to drop beyond the kink. It remains unclear, however, whether giraffes open and close the arteries to regulate lower-leg pressure as needed. “It would be fun to imagine that when the giraffe is standing still out there, it’s closing off that sphincter just beneath the knee,” says Aalkjær. “But we don’t know.”

Aalkjær has one more question about these remarkable animals. When a giraffe raises its head after bending down for a drink, blood pressure to the brain should drop precipitately—a more severe version of the dizziness that many people experience when they stand up suddenly. Why don’t giraffes faint?

At least part of the answer seems to be that giraffes can buffer these sudden changes in blood pressure. In anesthetized giraffes whose heads could be raised and lowered with ropes and pulleys, Aalkjær has found that blood pools in the big veins of the neck when the head is down. This stores more than a liter of blood, temporarily reducing the amount of blood returning to the heart. With less blood available, the heart generates less pressure with each beat while the head’s down. As the head is raised again, the stored blood rushes suddenly back to the heart, which responds with a vigorous, high-pressure stroke that helps pump blood up to the brain.

It’s not yet clear whether this is what happens in awake, freely moving animals, though Aalkjær’s team has recently recorded blood pressure and flow from sensors implanted in free-moving giraffes, and he hopes to have an answer soon.

So, can we learn medical lessons from giraffes? None of the insights have yet yielded a specific clinical therapy. But that doesn’t mean they won’t, says Natterson-Horowitz. Even though some of the adaptations are probably not relevant for hypertension in humans, they may help biomedical scientists think about the problem in new ways and find novel approaches to this far-too-common disease.

Bob Holmes is a science writer based in Edmonton, Canada.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.