Glassfrogs achieve transparency by packing red blood cells into mirror-coated liver

New research shows that glassfrogs -- known for their highly transparent undersides and muscles -- perform their "disappearing acts" by stowing away nearly all of their red blood cells into their uniquely reflective livers. The study, led by scientists at the American Museum of Natural History and Duke University, is being published Friday in the journal Science. The work could lead to new avenues of research tied to blood clots, which the frogs somehow avoid while packing and unpacking about 90 percent of their red blood cells into their livers on a daily basis.

"There are more than 150 species of known glassfrogs in the world, and yet we're really just starting to learn about some of the really incredible ways they interact with their environment," said co-lead author Jesse Delia, a Gerstner postdoctoral fellow in the Museum's Department of Herpetology.

Glassfrogs, which live in the American tropics, are nocturnal amphibians that spend their days sleeping upside down on translucent leaves that match the color of their backs -- a common camouflage tactic. Their tummies, however, show something surprising: translucent skin and muscle that allows their bones and organs to be visible, giving the glassfrog its common name. Recent research has proposed that this adaptation masks the frogs' outlines on their leafy perches, making them harder for predators to spot.

Transparency is a common form of camouflage among animals that live in water, but it's rare on land. In vertebrates, attaining transparency is difficult because their circulatory system is full of red blood cells that interact with light. Studies have shown that ice fish and larval eels achieve transparency by not producing hemoglobin and red blood cells. But glassfrogs use an alternative strategy, according to the findings of the new study.

"Glassfrogs overcome this challenge by essentially hiding red blood cells from view," said Carlos Taboada, the study's co-lead author from Duke University. "They almost pause their respiratory system during the day, even at high temperatures."

At Duke, the researchers used a technique called photoacoustic imaging, which uses light to induce sound-wave propagation from red blood cells. This allows researchers to map the location of the cells within sleeping frogs without restraint, contrast agents, sacrifice, or surgical manipulation -- particularly important to this study because glassfrog transparency is disrupted by activity, stress, anesthesia, and death.

The researchers focused on one particular species of glassfrog, Hyalinobatrachium fleischmanni. They found that resting glassfrogs increase transparency two- to threefold by removing nearly 90 percent of their red blood cells from circulation and packing them within their liver, which contains reflective guanine crystals. Whenever the frogs need to become active again, they bring the red blood cells back into the blood, which gives the frogs the ability to move around -- at which point, light absorption from these cells breaks transparency.

In most vertebrates, aggregating red blood cells can lead to potentially dangerous blood clots in veins and arteries. But glassfrogs don't experience clotting, which raises a set of significant questions for biological and medical researchers.

"This is the first of a series of studies documenting the physiology of vertebrate transparency, and it will hopefully stimulate biomedical work to translate these frogs' extreme physiology into novel targets for human health and medicine," Delia said.

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Being in space destroys more red blood cells

A world-first study has revealed how space travel can cause lower red blood cell counts, known as space anemia. Analysis of 14 astronauts showed their bodies destroyed 54 percent more red blood cells in space than they normally would on Earth, according to a study published in Nature Medicine.

"Space anemia has consistently been reported when astronauts returned to Earth since the first space missions, but we didn't know why," said lead author Dr. Guy Trudel, a rehabilitation physician and researcher at The Ottawa Hospital and professor at the University of Ottawa. "Our study shows that upon arriving in space, more red blood cells are destroyed, and this continues for the entire duration of the astronaut's mission."

Before this study, space anemia was thought to be a quick adaptation to fluids shifting into the astronaut's upper body when they first arrived in space. Astronauts lose 10 percent of the liquid in their blood vessels this way. It was thought astronauts rapidly destroyed 10 percent of their red blood cells to restore the balance, and that red blood cell control was back to normal after 10 days in space.

Instead, Dr. Trudel's team found that the red blood cell destruction was a primary effect of being in space, not just caused by fluid shifts. They demonstrated this by directly measuring red blood cell destruction in 14 astronauts during their six-month space missions.

On Earth, our bodies create and destroy 2 million red blood cells every second. The researchers found that astronauts were destroying 54 percent more red blood cells during the six months they were in space, or 3 million every second. These results were the same for both female and male astronauts.

Dr. Trudel's team made this discovery thanks to techniques and methods they developed to accurately measure red blood cell destruction. These methods were then adapted to collect samples aboard the International Space Station. At Dr. Trudel's lab at the University of Ottawa, they were able to precisely measure the tiny amounts of carbon monoxide in the breath samples from astronauts. One molecule of carbon monoxide is produced every time one molecule of heme, the deep-red pigment in red blood cells, is destroyed.

While the team didn't measure red blood cell production directly, they assume the astronauts generated extra red blood cells to compensate for the cells they destroyed. Otherwise, the astronauts would end up with severe anemia, and would have had major health problems in space.

"Thankfully, having fewer red blood cells in space isn't a problem when your body is weightless," said Dr. Trudel. "But when landing on Earth and potentially on other planets or moons, anemia affecting your energy, endurance, and strength can threaten mission objectives. The effects of anemia are only felt once you land, and must deal with gravity again."

In this study, five out of 13 astronauts were clinically anemic when they landed -- one of the 14 astronauts did not have blood drawn on landing. The researchers saw that space-related anemia was reversible, with red blood cells levels progressively returning to normal three to four months after returning to Earth.

Interestingly, the team repeated the same measurements one year after astronauts returned to Earth, and found that red blood cell destruction was still 30 percent above preflight levels. These results suggest that structural changes may have happened to the astronaut while they were in space that changed red blood cell control for up to a year after long-duration space missions.

The discovery that space travel increases red blood cell destruction has several implications. First, it supports screening astronauts or space tourists for existing blood or health conditions that are affected by anemia. Second, a recent study by Dr. Trudel's team found that the longer the space mission, the worse the anemia, which could impact long missions to the Moon and Mars. Third, increased red blood cell production will require an adapted diet for astronauts. And finally, it's unclear how long the body can maintain this higher rate of destruction and production of red blood cells.

These findings could also be applied to life on Earth. As a rehabilitation physician, most of Dr. Trudel's patients are anemic after being very ill for a long time with limited mobility, and anemia hinders their ability to exercise and recover. Bedrest has been shown to cause anemia, but how it does this is unknown. Dr. Trudel thinks the mechanism may be like space anemia. His team will investigate this hypothesis during future bedrest studies done on Earth.

"If we can find out exactly what's causing this anemia, then there is a potential to treat it or prevent it, both for astronauts and for patients here on Earth," said Dr. Trudel.

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New model points to solution to global blood shortage

Blood transfusions save lives, yet the precious fluid is in desperately short supply, not just in the U.S. but around the globe. But what if transfusions don't always require blood?

A new mathematical model of the body's interacting physiological and biochemical processes -- including blood vessel expansion, blood thickening and flow-rate changes in response to the transfusion of red blood cells -- shows that patients with anemia, or blood with low oxygen levels, can be effectively treated with transfusions of blood substitutes that are more readily available.

The research, co-authored by scientists at Stanford University and the University of California, San Diego (UCSD), was published on Oct. 14 in the Journal of Applied Physiology.

Using a different fluid could also eliminate a harmful consequence of blood transfusion: Blood use has been observed to lower lifespan by 6 percent per unit transfused per decade because of its adverse side effects.

"Instead of real blood, we can use a substitute that can lower the costs and eliminate blood transfusion's negative effects," said lead study author Weiyu Li, a PhD student in energy resources engineering at Stanford's School of Earth, Energy & Environmental Sciences (Stanford Earth).

Transfusion is a common procedure for transferring blood components directly to anemic patients' circulation. Red blood cells are uniquely equipped to perform the function of carrying oxygen, which is why they are used for transfusions for patients experiencing anemia. But the process of obtaining, storing and delivering the correct, sanitary blood type for each patient is also intensive and costly. Moreover, the supply of blood that is available falls far short of the demand: The global deficit across all countries without enough supply totals about 100 million units of blood per year.

"You could deliver more goods, in this case, oxygen, with less -- that's actually the basic idea of sustainability," said senior study author Daniel Tartakovsky, a professor of energy resources engineering at Stanford Earth. "It's all about how to do more with less."

Transfusion of red blood cells is done to improve the likelihood that oxygen vital to organ and tissue function will be delivered. However, the process also thickens the blood, and that increased viscosity can be a problem, according to the research. The new model shows that during transfusion, some patients' blood vessels do not dilate and, since their blood has been thickened by additional red blood cells, it is more viscous and does not circulate as easily to deliver oxygen. For these patients, treating anemia with a 2-unit transfusion -- currently, the most frequently used transfusion quantity -- would reduce blood flow, regardless of the state of anemia, according to the model.

However, for many people, transfusion causes blood vessels to dilate, thereby increasing circulation and delivering more oxygen to the body. The findings reveal the advantage of anemic patients whose blood vessels dilate during transfusion. The model suggests that either abstaining from transfusion or transfusing alternative fluids known as plasma expanders, which prompt blood vessels to dilate, may be a more effective way to increase oxygen delivery. Plasma expanders consist of solutions of high-molecular-weight starch dissolved in normal saline; they have been in use in transfusion medicine for several decades and have proven to be effective in experimental studies.

"At present, blood transfusion is determined by addressing the wrong target, namely restoring oxygen-carrying capacity," said co-author Marcos Intaglietta, a professor and founder of the bioengineering discipline at UCSD. "But the logical target of a blood transfusion is restoring oxygen-delivery capacity."

Projections of the team's results show that safe and low-cost blood substitutes can decrease the overall cost of blood transfusion by 10 times, while significantly lowering the negative aspects of the process. Their model of the body's circulatory processes was derived from previously published experiments on how mammals react to transfusion.

"Our mathematical model identifies natural physiological processes that explain the conclusion of multiple observational studies: People can get the benefit of blood transfusion without using blood," Tartakovsky said. "But nothing really comes out of modeling alone -- it has to be grounded in observations, investigational studies and experience."

The co-authors hope their findings will lead to clinical trials that test the capacity for non-blood alternatives to increase oxygen delivery. To date, there have not been consistent results from rigorous medical trials that support the notion that small amounts of blood are more effective than just adding human plasma, according to the study authors.

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