Researchers develop 'in vivo' RNA-based gene editing model for blood disorders

In a step forward in the development of genetic medicines, researchers at Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania have developed a proof-of-concept model for delivering gene editing tools to treat blood disorders, allowing for the modification of diseased blood cells directly within the body. If translated into the clinic, this approach could expand access and reduce the cost of gene therapies for blood disorders, many of which currently require patients receive chemotherapy and a stem cell transplant. The findings were published today in the journal Science.

"Right now, if you want to treat hematologic diseases like sickle cell disease and beta thalassemia with gene therapy, patients must receive conditioning treatments like chemotherapy to make space for the new, corrected blood cells, which is both expensive and comes with risks," said co-senior author Stefano Rivella, PhD, Kwame Ohene-Frempong Chair on Sickle Cell Anemia and Professor of Pediatrics at Children's Hospital of Philadelphia. "In our paper, we have shown that it is possible to replace diseased blood cells with corrected ones directly within the body in a 'one-and-done' therapy, eliminating the need for myeloablative conditioning treatments and streamlining the delivery of these potentially life-changing treatments. This is a big step forward in how we think about treating genetic diseases and could expand the access of gene therapies to patients who need them most."

"Targeted delivery of mRNA-encoded therapeutics to specific tissues and cell types will have an immense impact on the way diseases will be treated with nucleic acids in the future," said senior author Hamideh Parhiz, PharmD, PhD, a research assistant professor of Infectious Diseases at Penn. "In our study, we are providing a cell-specific targeted lipid nanoparticle encapsulating mRNA therapeutics/editors as a platform technology that can be used for in vivo cellular reprogramming in many diseases in need of a precisely targeted gene therapy modality. Here, we combined the targeted platform with advances in mRNA therapeutics and RNA-based genomic editing tools to provide a new way of controlling hematopoietic stem cell fate and correcting genetic defects. A targeted mRNA-encoded genomic editing methodology could lead to controlled expression, high editing efficacy, and potentially safer in vivo genomic modification compared to currently available technologies."

Hematopoietic stem cells (HSCs) reside in the bone marrow, where they divide throughout life to produce all cells within the blood and immune system. In patients with non-malignant hematopoietic disorders like sickle cell disease and immunodeficiency disorders, these blood cells don't function correctly because they carry a genetic mutation.

For these patients, there are currently two avenues for potentially curative treatments, both of which involve a bone marrow transplant: a stem cell transplant with HSCs from a healthy donor, or gene therapy in which the patient's own HSCs are modified outside of the body and transplanted back in (often referred to as ex vivo gene therapy). The former approach comes with the risk of graft versus host disease, given that the HSCs come from a donor, and both processes involve a conditioning regimen of chemotherapy or radiation to eliminate the patient's diseased HSCs and prepare them to receive the new cells. These conditioning procedures come with significant toxic side effects, underscoring the need to investigate less-toxic approaches.

One option that would eliminate the need for the above methods would be in vivo gene editing, in which gene editing tools are infused directly into the patient, allowing HSCs to be edited and corrected without the need for conditioning regimens.

To validate this approach, a research team led by Laura Breda, PhD, and Michael P. Triebwasser, MD, PhD at CHOP (presently at the University of Michigan), Tyler E. Papp, BS at Penn, and Drew Weissman, MD, PhD, the Roberts Family Professor in Vaccine Research, the director of the Penn Institute for RNA Innovation, and a pioneer of mRNA-vaccine research, used liquid nanoparticle (LNP) to deliver mRNA gene editing tools. LNP are highly effective at packaging and delivering mRNA to cells and became widely utilized in 2020, due to the LNP-mRNA platform for two leading COVID-19 vaccines.

However, in the case of the COVID-19 vaccines, the LNP-mRNA construct did not target specific cells or organs within the body. Given that the researchers wanted to target HSCs specifically, they decorated the surface of their experimental LNPs with antibodies that would recognize CD117, a receptor on the surface of HSCs. They then pursued three approaches to test the efficacy of their CD117/LNP formulation.

First, the researchers tested CD117/LNP encapsulating reporter mRNA to show successful in vivo mRNA expression and gene editing.

Next, the researchers investigated whether this approach could be used as a therapy for hematologic disease. They tested CD117/LNP encapsulating mRNA encoding a cas9 gene editor targeting the mutation that causes sickle cell disease. This type of gene editing converts the disease-causing hemoglobin mutation into a non-disease-causing variant. Testing their construct on cells from donors with sickle cell disease, the researchers showed that CD117/LNP facilitated efficient base editing in vitro, leading to a corresponding increase in functional hemoglobin of up to 91.7%. They also demonstrated a nearly complete absence of sickled cells, the crescent-shaped blood cells that cause the symptoms of the disease.

Finally, the researchers explored whether LNPs could be used for in vivo conditioning, which would allow bone marrow to be depleted without chemotherapy or radiation. To do so, they used CD117/LNP encapsulating mRNA for PUMA, a protein that promotes cell death. In a series of in vitro, ex vivo, and in vivo experiments, the researchers showed that in vivo targeting with CD117/LNP-PUMA effectively depleted HSC, allowing for successful infusion and uptake of new bone marrow cells, a process known as engraftment, without need of chemotherapy or radiation. The engraftment rates observed in animal models were consistent with those reported to be sufficient for the cure of severe combined immunodeficiency (SCID) using healthy donor bone marrow cells, suggesting this technique could be used for severe immunodeficiences.

"These findings may potentially transform gene therapy, not only by allowing cell-type specific gene modification in vivowith minimal risk, which could allow for previously impossibly manipulations of blood stem cell physiology but also by providing a platform that, if properly tuned, can correct many different monogenic disorders," said Dr. Breda, a research assistant professor with the Division of Hematology at Children's Hospital of Philadelphia. "Such novel delivery systems may help translate the promise of decades of concerted genetic and biomedical research to ablate a wide array of human diseases."

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New study reveals why HIV remains in human tissue even after antiretroviral therapy

Thanks to antiretroviral therapy, HIV infection is no longer the life sentence it once was. But despite the effectiveness of drugs to manage and treat the virus, it can never be fully eliminated from the human body, lingering in some cells deep in different human tissues where it goes unnoticed by the immune system.

Now, new research by University of Alberta immunologist Shokrollah Elahi reveals a possible answer to the mystery of why infected people can't get rid of HIV altogether.

Elahi and his team found that in HIV patients, killer T cells -- a type of white blood cells responsible for identifying and destroying cells infected with viruses -- have very little to none of a protein called CD73.

Because CD73 is responsible for migration and cell movement into the tissue, the lack of the protein compromises the ability of killer T cells to find and eliminate HIV-infected cells, explained Elahi.

"This mechanism explains one potential reason for why HIV stays in human tissues forever," he said, adding that the research also shows the complexity of HIV infection.

"This provides us the opportunity to come up with potential new treatments that would help killer T cells migrate better to gain access to the infected cells in different tissues."

After identifying the role of CD73 -- a three-year project -- Elahi turned his focus to understanding potential causes for the drastic reduction. He found it is partly due to the chronic inflammation that is common among people living with HIV.

"Following extensive studies, we discovered that chronic inflammation results in increased levels of a type of RNA found in cells and in blood, called microRNAs," he explained. "These are very small types of RNA that can bind to messenger RNAs to block them from making CD73 protein. We found this was causing the CD73 gene to be suppressed."

The team's discovery also helps explain why people with HIV have a lower risk of developing multiple sclerosis, Elahi noted.

"Our findings suggest that reduced or eliminated CD73 can be beneficial in HIV-infected individuals to protect them against MS. Therefore, targeting CD73 could be a novel potential therapeutic marker for MS patients."

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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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Researchers develop structural blueprint of nanoparticles to target white blood cells responsible for acute lung inflammation

The COVID-19 pandemic highlighted the devastating impact of acute lung inflammation (ALI), which is part of the acute respiratory distress syndrome (ARDS) that is the dominant cause of death in COVID-19. A potential new route to the diagnosis and treatment of ARDS comes from studying how neutrophils -- the white blood cells responsible for detecting and eliminating harmful particles in the body -- differentiate what materials to uptake by the material's surface structure, and favor uptake of particles that exhibit "protein clumping," according to new research from the Perelman School of Medicine at the University of Pennsylvania. The findings are published in Nature Nanotechnology.

Researchers investigated how neutrophils are able to differentiate between bacteria to be destroyed and other compounds in the bloodstream, such as cholesterol particles. They tested a library consisting of 23 different protein-based nanoparticles in mice with ALI which revealed a set of "rules" that predict uptake by neutrophils. Neutrophils don't take up symmetrical, rigid particles, such as viruses, but they do take up particles that exhibited "protein clumping," which the researchers call nanoparticles with agglutinated protein (NAPs).

"We want to utilize the existing function of neutrophils that identifies and eliminates invaders to inform how to design a 'Trojan horse' nanoparticle that overactive neutrophils will intake and deliver treatment to alleviate ALI and ARDS," said study lead author Jacob Myerson, PhD, a postdoctoral research fellow in the Department of Systems Pharmacology and Translational Therapeutics. "In order to build this 'Trojan horse' delivery system, though, we had to determine how neutrophils identify which particles in the blood to take up."

ALI and ARDS are life-threatening forms of respiratory failure with high morbidity and mortality rates. Prior to COVID-19, there were 190,000 annual cases of ARDS in the U.S. and 75,000 deaths, with the ARDS being caused by pneumonia, sepsis, and trauma. However, COVID has increased ARDS cases into the millions. When ALI or ARDS occurs, the lung's air sacs recruit neutrophils to the lungs in order to eliminate circulating microbes. This process causes neutrophils to release compounds that further aggravate lung injury and damage the air sacs, so patients develop low blood oxygen levels. Unfortunately, despite the severity of ALI/ARDS, there is no effective drug to control it, and treatment currently focuses on supporting patients while the lungs naturally, but slowly, heal.

To address ARDS and other medical problems, researchers at Penn and elsewhere have been using nanoparticles to concentrate drugs in injured or diseased organs. Such nanoparticles are also being used for gene therapy and immunotherapy.

The researchers note that while the development of viable therapies for ALI/ARDS using nanoparticles to deliver treatments via neutrophils are a long way off, this research represents a significant step in understanding the condition and function of the immune system.

"Now that we have determined that neutrophils patrol for nanoparticles with agglutinated protein, our next step is to understand how and why other microbes, like viruses, which are rigid and symmetrical, evolved to evade neutrophils," said senior author Jacob Brenner, MD, PhD, an associate professor of Pulmonary Medicine in the Division of Pulmonary, Allergy, and Critical Care. "With this knowledge, we can continue to utilize this unique combination of material science and engineering, to create disease-specific therapies that target more advanced and complicated pathologies."

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For stem cells, bigger doesn’t mean better

MIT biologists have answered an important biological question: Why do cells control their size?

Cells of the same type are strikingly uniform in size, while cell size differs between different cell types. This raises the question of whether cell size is important for cellular physiology.

The new study suggests that cellular enlargement drives a decline in function of stem cells. The researchers found that blood stem cells, which are among the smallest cells in the body, lose their ability to perform their normal function -- replenishing the body's blood cells -- as they grow larger. However, when the cells were restored to their usual size, they behaved normally again.

The researchers also found that blood stem cells tend to enlarge as they age. Their study shows that this enlargement contributes to stem cell decline during aging.

"We have discovered cellular enlargement as a new aging factor in vivo, and now we can explore if we can treat cellular enlargement to delay aging and aging-related diseases," says Jette Lengefeld, a former MIT postdoc, who is now a principal investigator at the University of Helsinki.

Lengefeld is the lead author of the study, which appears today in Science Advances. The late Angelika Amon, an MIT professor of biology and member of the Koch Institute for Integrative Cancer Research, is the senior author of the study.

Outsized effects

It has been known since the 1960s that human cells grown in a lab dish enlarge as they become senescent -- a nondividing cellular state

that is associated with aging. Every time a cell divides, it can encounter DNA damage. When this happens, division is halted to repair the damage. During each of these delays, the cell grows slightly larger. Many scientists believed that this enlargement was simply a side effect of aging, but the Amon lab began to investigate the possibility that large cell size drives age-related losses of function.

Lengefeld studied the effects of size on stem cells -- specifically, blood stem cells, which give rise to the blood cells of our body throughout life. To study how size affects these stem cells, the researchers damaged their DNA, leading to an increase in their size. They then compared these enlarged cells to other cells that also experienced DNA damage but were prevented from increasing in size using a drug called rapamycin.

After the treatment, the researchers measured the functionality of these two groups of stem cells by injecting them into mice that had their own blood stem cells eliminated. This allowed the researchers to determine whether the transplanted stem cells were able to repopulate the mouse's blood cells.

They found that the DNA-damaged and enlarged stem cells were unable to produce new blood cells. However, the DNA-damaged stem cells that were kept small were still able to produce new blood cells.

In another experiment, the researchers used a genetic mutation to reduce the size of naturally occurring large stem cells that they found in older mice. They showed that if they induced those large stem cells to become small again, the cells regained their regenerative potential and behaved like younger stem cells.

"This is striking evidence supporting the model that size is important for functionality of stem cells," Lengefeld says. "When we damage the stem cells' DNA but keep them small during the damage, they retain their functionality. And if we reduce the size of large stem cells, we can restore their function."

Keeping cells small

When the researchers treated mice with rapamycin, beginning at a young age, they were able to prevent blood stem cells from enlarging as the mice got older. Blood stem cells from those mice remained small and were able to build blood cells like young stem cells even in mice 3 years of age -- an old age for a mouse.

Rapamycin, a drug that can inhibit cell growth, is now used to treat some cancers and to prevent organ transplant rejection, and has raised interest for its ability to extend lifespan in mice and other organisms. It may be useful in slowing down the enlargement of stem cells and therefore could have beneficial effects in humans, Lengefeld says.

"If we find drugs that are specific in making large blood stem cells smaller again, we can test whether this improves the health of people who suffer from problems with their blood system -- like anemia and a reduced immune system -- or maybe even help people with leukemia," she says.

The researchers also demonstrated the importance of size in another type of stem cells -- intestinal stem cells. They found that larger stem cells were less able to generate intestinal organoids, which mimic the structure of the intestinal lining.

"That suggested that this relationship between cell size and function is conserved in stem cells, and that cellular size is a marker of stem cell function," Lengefeld says.

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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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Natural immunity to malaria provides clues to potential therapies

WEHI researchers have identified how natural human antibodies can block malaria parasites from entering red blood cells, potentially indicating how new protective therapies could be developed against this globally significant disease.

The research provides greater insight into how antibodies block the entry of Plasmodium vivax malaria parasites into young red blood cells called reticulocytes. It builds on an earlier discovery that the P. vivax latches onto the transferrin receptor 1 (TfR1) to enter cells.

The research, led by Associate Professor Wai-Hong Tham and PhD student Li-Jin Chan from WEHI, alongside Professor Christopher King from Case Western University, US, was published in Nature Communications.

At a glance
 

• By examining antibodies from people with a history of malaria infection, researchers observed that naturally occurring antibodies can block Plasmodium vivax from latching onto transferrin receptor 1 on reticulocytes.
• One way the antibodies work is by preventing parasite proteins from getting close enough to the cell to allow parasite entry.
• The discovery opens up new avenues for developing antibody-based therapies for malaria.
   
• Shedding light on pathogen-blocking antibodies
   
• Plasmodium vivax is the most widespread malaria parasite in the world, and the predominant cause of malaria in the vast majority of countries outside Africa. It is also the main parasite responsible for recurrent malaria infections.

The malaria parasite is a complex single-celled organism, with diverse proteins that help it to invade red blood cells, reproduce and spread. Adhesins on the surface of the parasite are key-like proteins that 'unlock' cells, allowing the parasite to enter.

Previous research studies in Papua New Guinea, Thailand and Brazil showed antibodies against P. vivax adhesins were correlated with protection against infection and disease, Associate Professor Tham said.

"We wanted to understand how these human antibodies in natural infection block the parasite from getting in. By extracting and examining antibodies from people who have had P. vivax infections, we identified the different ways human antibodies against P. vivax work. One of these ways, is by stopping the parasite adhesins from getting too close to the reticulocyte membrane, denying the parasite entry," she said.

This discovery opens the door to potentially preventing not only P. vivax malaria, but also P. falciparum malaria, another significant cause of deaths globally.

"Although this was a vivax study, we believe the implications are that a broadly neutralising antibody could be created to target both P. vivax and P. falciparum malaria infections," Associate Professor Tham said.

Improving detection of relapsing malaria

WEHI Professor Ivo Mueller said beyond understanding how antibodies can block infection, there was also a crucial need to understand the development of immunity and how this could be used to detect P. vivax infections in endemic populations.

"We are currently using this information to develop diagnostic tests that will be used in the field to identify and treat people with hidden vivax infection in their livers and spleens. This is a key step towards eliminating malaria, by preventing silently infected people reinfecting their communities," he said.

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New role for white blood cells in the developing brain

Whether white blood cells can be found in the brain has been controversial, and their role there a complete mystery. In a study published in Cell, an international team of scientists led by Professor Adrian Liston (Babraham Institute, UK & VIB-KU Leuven, Belgium) describe a population of specialised brain-resident immune cells discovered in the mouse and human brain, and show that the presence of white blood cells is essential for normal brain development in mice.

Like a highly fortified headquarters, our brain enjoys special protection from what is circulating in the rest of our body through the blood-brain barrier. This highly selective border makes sure that passage from the blood to the brain is tightly regulated.

The blood-brain barrier also separates the brain from our body's immune system, which is why it has its own resident immune cells, called microglia, which trigger inflammation and tissue repair. Microglia arrive in the brain during embryonic development, and later on, the population becomes self-renewing.

Yet, white blood cells -- which are part of our immune system -- have been found to play a role in different brain diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease or stroke. Whether or not white blood cells can be found in healthy brains as well, and what they might be doing there, has been subject of intense debate. An interdisciplinary team of scientists led by Prof. Adrian Liston (Babraham Institute and VIB-KU Leuven) set out to find the answers.

White blood cells in the brain

"A misconception about white blood cells comes from their name," explains Dr Oliver Burton (Babraham Institute). "These 'immune cells' are not just present in the blood. They are constantly circulating around our body and enter all of our organs, including -- as it turns out -- the brain. We are only just starting to discover what white blood cells do when they leave the blood. This research indicates that they act as a go-between, transferring information from the rest of the body to the brain environment"

The team quantified and characterised a small but distinct population of brain-resident T helper cells present in mouse and human brain tissue. T cells are a specific type of white blood cells specialized for scanning cell surfaces for evidence of infection and triggering an appropriate immune response. New technologies allowed the researchers to study the cells in great detail, including the processes by which circulating T cells entered the brain and began to develop the features of brain-resident T cells.

Dr Carlos Roca (Babraham Institute): "Science is becoming increasingly multidisciplinary. Here, we didn't just bring in expertise from immunology, neuroscience and microbiology, but also from computer science and applied mathematics. New approaches for data analysis allow us to reach a much deeper level of understanding of the biology of the white blood cells we found in the brain."

An evolutionary role

When T helper cells are absent from the brain, the scientists found that the resident immune cells -- microglia -- in the mouse brain remained suspended between a fetal and adult developmental state. Observationally, mice lacking brain T cells showed multiple changes in their behavior. The analysis points to an important role for brain-resident T cells in brain development. If T cells participate in normal brain development in mice, could the same be true in humans?

"In mice, the wave of entry of immune cells at birth triggers a switch in brain development," says Liston. "Humans have a much longer gestation than mice though, and we don't know about the timing of immune cell entry into the brain. Does this occur before birth? Is it delayed until after birth? Did a change in timing of entry contribute to the evolution of enhanced cognitive capacity in humans?"

The findings open up a whole new range of questions about how the brain and our immune system interact. "It has been really exciting to work on this project. We are learning so much about how our immune system can alter our brain, and how our brain modifies our immune system. The two are far more interconnected than we previously thought," says Dr Emanuela Pasciuto (VIB-KU Leuven).

The study also brings in a connection with the gut microbiome, says Liston: "There are now multiple links between the bacteria in our gut and different neurological conditions, but without any convincing explanations for what connects them. We show that white blood cells are modified by gut bacteria, and then take that information with them into the brain. This could be the route by which our gut microbiome influences the brain."

Read more at Science Daily

Synthetic red blood cells mimic natural ones, and have new abilities

Illustration of red blood cells

Scientists have tried to develop synthetic red blood cells that mimic the favorable properties of natural ones, such as flexibility, oxygen transport and long circulation times. But so far, most artificial red blood cells have had one or a few, but not all, key features of the natural versions. Now, researchers reporting in ACS Nano have made synthetic red blood cells that have all of the cells' natural abilities, plus a few new ones.

Red blood cells (RBCs) take up oxygen from the lungs and deliver it to the body's tissues. These disk-shaped cells contain millions of molecules of hemoglobin -- an iron-containing protein that binds oxygen. RBCs are highly flexible, which allows them to squeeze through tiny capillaries and then bounce back to their former shape. The cells also contain proteins on their surface that allow them to circulate through blood vessels for a long time without being gobbled up by immune cells. Wei Zhu, C. Jeffrey Brinker and colleagues wanted to make artificial RBCs that had similar properties to natural ones, but that could also perform new jobs such as therapeutic drug delivery, magnetic targeting and toxin detection.

The researchers made the synthetic cells by first coating donated human RBCs with a thin layer of silica. They layered positively and negatively charged polymers over the silica-RBCs, and then etched away the silica, producing flexible replicas. Finally, the team coated the surface of the replicas with natural RBC membranes. The artificial cells were similar in size, shape, charge and surface proteins to natural cells, and they could squeeze through model capillaries without losing their shape. In mice, the synthetic RBCs lasted for more than 48 hours, with no observable toxicity. The researchers loaded the artificial cells with either hemoglobin, an anticancer drug, a toxin sensor or magnetic nanoparticles to demonstrate that they could carry cargoes. The team also showed that the new RBCs could act as decoys for a bacterial toxin. Future studies will explore the potential of the artificial cells in medical applications, such as cancer therapy and toxin biosensing, the researchers say.

The authors acknowledge funding from the Air Force Office of Scientific Research, the Laboratory Directed Research & Development Program at Sandia National Laboratories, the Department of Energy Office of Science, the National Institutes of Health and the National Natural Science Foundation of China.

From Science Daily