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Lunar quarantine dropped — Science News, May 8, 1971

Spacecraft and men from Earth can contaminate space … with Earth-related material or organisms. But there is also a chance material returned from another celestial body could contain something harmful to the Earth…. Last week [NASA] announced it will [recommend] … that “further lunar missions need not be subject to quarantine” [because] … “there is no hazard to man, animal or plants” from anything brought back from the moon.

Update

The last U.S. lunar mission to come back to Earth, Apollo 17, didn’t have to quarantine upon return in 1972. But missions to the moon remained under strict protocols to prevent spacecraft from contaminating it. In 2020, NASA exempted most of the moon — minus areas of scientific interest and historic sites — from those rules (SN: 11/23/19, p. 10). For missions to other planets, though, strict anti­contamination measures still apply. NASA has called for research of possible risks as it aims to land humans on Mars in the 2030s.

High in the forest canopy, a mass of strange ferns grips a tree trunk, looking like a giant tangle of floppy, viridescent antlers. Below these fork-leaved fronds and closer into the core of the lush knot are brown, disc-shaped plants. These, too, are ferns of the very same species.

The ferns — and possibly similar plants — may form a type of complex, interdependent society previously considered limited to animals like ants and termites, researchers report online May 14 in Ecology. 

Kevin Burns, a biologist at Victoria University of Wellington in New Zealand, first became familiar with the ferns while conducting fieldwork on Lord Howe Island, an isolated island between Australia and New Zealand. He happened to take note of the local epiphytes — plants that grow upon other plants — and one species particularly caught his attention: the staghorn fern (Platycerium bifurcatum), also native to parts of mainland Australia and Indonesia.

“I realized, God, you know, they never occur alone,” says Burns, noting that some of the larger clusters of ferns were massive clumps made of hundreds of individuals. 

It was soon clear to Burns that “each one of those individuals was doing a different thing.”

He likens the fern colonies to an upside-down umbrella made of plants. Ferns with long, green, waxy “strap” fronds appeared to deflect water to the center of the aggregation, where disc-shaped, brown, spongey “nest” fronds could soak it up.

The shrubby apparatus reminded Burns of a termite mound, with a communal store of resources and the segregation of different jobs in the colony. Scientists call these types of cooperative groups, where overlapping generations live together and form castes to divide labor and reproductive roles, “eusocial.” The term has been used to describe certain insect and crustacean societies, along with two mole rat species as the only mammalian examples (SN: 10/18/04). Burns wondered if the ferns could also be eusocial.

His team’s analysis of frond fertility revealed 40 percent couldn’t reproduce, and the sterile colony members were predominantly nest fronds. This suggests a reproductive division of labor between the nest and strap frond types. Tests of the fronds’ absorbency confirmed that nest fronds sop up more water than strap fronds do. Previous research by other scientists found networks of roots running throughout the colony, which means that nest fronds have the ability to slake strap fronds’ thirst. The fronds divided labor, much like ants and termites.

The team also analyzed genetic samples from 10 colonies on Lord Howe Island and found that eight were composed of genetically identical individuals, while two contained ferns of differing genetic origins. High degrees of genetic relatedness are also seen in colonies of eusocial insects, where many sisters contribute to the survival of the nest.

Taken together, Burns thinks these traits tick many of the boxes for eusociality. That would be a “big deal,” he says.

An assumed requirement for eusocial colonial living is behavioral coordination, because it allows different individuals to work together. But ferns are plants, not animals, which so often coordinate their behaviors. Seeing eusocial living in plants “seems to indicate to me that this type of transition in the evolution of complexity doesn’t require a brain,” Burns says.

The study opens up the “opportunity to look at [epiphytes] with the lens of eusociality,” which is “really cool,” says Michelle Spicer, an ecologist at the University of Puget Sound in Washington who was not involved with this study.

Spicer points out that water and nutrient exchange is known in other epiphytic plants. Though, Burns notes that the division of labor to build communal resources “appears to be a key feature that sets staghorn [ferns] apart from other colonial plants.” 

A stressful life in the canopy — far away from the soil — may have contributed to the ferns’ evolution of eusociality by providing water and nutrient security, Burns says.

“The epiphyte lifestyle certainly facilitates group living, and group living is where all social stories start,” says Brian Whyte, an evolutionary biologist at the University of California, Berkeley also not involved with this research.

These ferns could certainly fit the definition of eusociality, Whyte says. He is particularly fascinated by how the plants form castes and colonies in the wild but remain as individual strap fronds when grown in soil as ornamental plants. This variability differs from many eusocial species, he says. 

Burns and his colleagues are currently investigating if strap fronds can become nest fronds after being transplanted to another part of the colony. Burns also wants to study another staghorn fern species in Madagascar that appears to also grow in colonies. 

Whyte sees major benefits in broadening a view of eusociality to include plants. 

“It’s so nice to be able to notice something and be like ‘wait, this is comparable to some of the coolest, most advanced societies in the living world,’” he says. Regardless of where the ferns sit on the eusociality spectrum, he notes, they still have intriguing similarities and differences to caste-forming animals. “Learning more about [these ferns] will improve our theories on why these characteristics have evolved across the diversity of life.”

Nuclear clocks could be the GOAT: Greatest of all timepieces.

If physicists can build them, nuclear clocks would be a brand-new type of clock, one that would keep time based on the physics of atoms’ hearts. Today’s most precise clocks, called atomic clocks, rely on the behavior of atoms’ electrons. But a clock based on atomic nuclei could reach 10 times the precision of those atomic clocks, researchers estimate.

Better clocks could improve technologies that depend on them, such as GPS navigation, physicist Peter Thirolf said June 3 during an online meeting of the American Physical Society Division of Atomic, Molecular and Optical Physics. But “it’s not just about timekeeping.” Unlike atoms’ electrons, atomic nuclei are subject to the strong nuclear force, which holds protons and neutrons together. “A nuclear clock sees a different part of the world,” said Thirolf, of Ludwig-Maximilians-Universität München in Germany. That means nuclear clocks could allow new tests of fundamental ideas in physics, including whether supposedly immutable numbers in physics known as fundamental constants are, in fact, constant.

Atomic clocks tally time using the energy jumps of atoms’ electrons. According to quantum physics, electrons in atoms can carry only certain amounts of energy, in specific energy levels. To bump electrons in an atom from one energy level to another, an atomic clock’s atoms must be hit with laser light of just the right frequency. That frequency — the rate of oscillation of the light’s electromagnetic waves — serves as a highly precise timekeeper.

Like the electrons in an atom, the protons and neutrons within atomic nuclei also occupy discrete energy levels. Nuclear clocks would be based on jumps between those nuclear energy levels, rather than those of electrons. Notably, nuclei are resistant to the effects of stray electric or magnetic fields that can hinder atomic clocks. As a result, nuclear clocks “would be more stable and more accurate,” says theoretical physicist Adriana Pálffy of Friedrich-Alexander-Universität Erlangen-Nürnberg in Germany.

But there’s a problem. To tally time with nuclei, scientists need to be able to set off the jump between nuclear energy levels with a laser. “Nuclear levels are not normally accessible with lasers,” said theoretical physicist Marianna Safronova of the University of Delaware in a June 2 talk at the meeting. For most nuclei, that would require light of higher energy than suitable lasers can achieve. Luckily, there’s one lone exception in all of the known nuclei, Safronova said, “a freak-of-nature thing.” A variety of thorium called thorium-229 has a pair of energy levels close enough in energy that a laser could potentially set off the jump.

Recent measurements have more precisely pinpointed the energy of that jump, a crucial step toward building a thorium nuclear clock. Thirolf and colleagues estimated the energy by measuring electrons emitted when the nucleus jumps between the two levels, as reported in Nature in 2019. And in a 2020 paper in Physical Review Letters, physicist Andreas Fleischmann and colleagues measured other energy jumps the thorium nucleus can make, subtracting them to deduce the energy of the nuclear clock jump.

The teams agree that the jump is just over 8 electron volts in energy. That energy corresponds to ultraviolet light in a range for which setting off the jump with a laser is possible, but at the edge of scientists’ capabilities.

Now that physicists know the size of the energy jump, they are aiming to trigger it with lasers. At the meeting, physicist Chuankun Zhang of the research institute JILA in Boulder, Colo., reported efforts to use a frequency comb (SN: 10/5/18) — a method of creating an array of discrete frequencies of laser light — to initiate the jump and measure its energy even better. “If it’s a success, we can directly build a nuclear-based optical clock from that,” he said at the meeting. Thirolf’s team also is working with frequency combs, aiming for a working nuclear clock within the next five years.

Meanwhile, Pálffy is looking into using what’s called an “electronic bridge.” Rather than using a laser to directly initiate an energy jump by the nucleus, the laser would first excite the electrons, which would then transfer energy to the nucleus, Pálffy reported at the meeting.

Nuclear clocks could let researchers devise new tests to determine if fundamental constants of nature vary over time. For example, some studies have suggested that the fine-structure constant, a number that sets the strength of electromagnetic interactions, could change (SN: 11/2/16). “This nuclear clock is a perfect system to search for variation of fundamental constants,” Victor Flambaum of the University of New South Wales in Sydney said at the meeting. The devices could also test a foundation of Einstein’s general theory of relativity called the equivalence principle (SN: 12/4/17). Or they could search for dark matter, elusive undetected particles that physicists believe account for most of the universe’s matter, which could tweak the ticking of the clock.

The potential of nuclear clocks is so promising that for Fleischmann, of Heidelberg University in Germany, it took just an instant to settle on tackling the quandary of how scientists could build a nuclear clock, he says. It was “from the very first second clear that this is a question that one should work on.”

Forty years ago, researchers described the mysterious cases of five gay men who had fallen ill with a pneumonia caused by the bacteria Pneumocystis carinii. Two of the five men had already died.

That type of pneumonia usually affects only individuals who are severely immunocompromised, researchers wrote in the June 5, 1981 Morbidity and Mortality Weekly Report. Scientists would soon discover that a disease that would come to be known as AIDS was devastating the men’s immune systems.

Three years later, scientists pinned the blame for AIDS on a virus dubbed HIV, or human immunodeficiency virus. Margaret Heckler, the then-U.S. Secretary of Health and Human Services, said in an April 1984 news conference that a vaccine to build protection against the virus would be ready to test within two years, holding out promise that protection was on its way.   

We’re still waiting.

Meanwhile, the HIV pandemic, which probably got its start in Congo in the 1920s, has led to devastating loss. More than 75 million people have been infected around the world as of the end of 2019. Approximately 32.7 million people have died.

That toll would undoubtedly be much higher if it weren’t for advances in antiviral treatments that can prevent infected people from dying from HIV and from transmitting the virus to others (SN: 3/4/20; SN: 11/15/19). To date, only three people have beaten an HIV infection (SN: 8/26/20). For most, it lasts a lifetime.

That long-lasting infection is just one reason why no vaccine against HIV exists yet. It’s also a tricky virus to pin down, with many variants and an uncanny ability to evade the immune system.

And money is an issue too. The lack of an effective HIV vaccine stands in stark contrast to COVID-19 vaccines that took less than a year to develop (SN: 11/9/20). For COVID-19 vaccine development, “the money poured in, which was the right thing to do,” says Susan Zolla-Pazner, an immunologist at the Icahn School of Medicine at Mount Sinai in New York City. Funding for HIV vaccine research comes in five-year installments, making it difficult to allocate the money in an efficient way to get a vaccine off the ground. Still, that funding stream has allowed for advances in HIV research, which partly enabled the rapid success of multiple COVID-19 vaccines.

The technology behind Johnson & Johnson’s COVID-19 jab, for instance, was first developed as a strategy to tackle HIV because it triggers a strong immune response (SN: 2/27/21). The shot uses a common cold virus that has been altered so that it no longer causes disease. That carrier delivers instructions to cells to make the viral proteins needed to train the immune system to recognize the invader. Johnson & Johnson’s COVID-19 vaccine uses a virus called adenovirus 26; the first HIV vaccine candidates used adenovirus 5.

Unfortunately, a clinical trial to test the HIV vaccine showed that participants who had already been naturally infected with adenovirus 5 were more likely to become infected with HIV. Researchers halted the trial. They speculated that those participants were more susceptible to HIV because they already had immunity to adenovirus 5 and that dampened HIV-protective responses from the vaccine.

The absence of a good HIV vaccine is not for lack of trying, says Mark Feinberg, a viral immunologist who is president and CEO of the International AIDS Vaccine Initiative in New York City. “The work that’s gone into HIV vaccine development has been by far the most sophisticated and creative.”

Complexities of HIV

Much of the difficulty in making a vaccine comes from the complex biology of the virus itself.

One major challenge is the immense genetic diversity among HIV viruses infecting people around the world. Much like the coronavirus, which has variants that are more transmissible or able to evade parts of the immune system (SN: 1/27/21), HIV has variants too. But “it’s a completely different world for HIV,” says Morgane Rolland, a virologist with the Military HIV Research Program at the Walter Reed Army Institute of Research in Silver Spring, Md.  

That’s because the virus makes new copies of its genetic blueprint at a dizzyingly fast rate, generating tens of thousands of new copies every day in a single person, Rolland says. Each of those new copies carries on average at least one unique mutation. Over the course of years, a single person can carry myriad variants in their body, though only a select few variants can be transmitted to others. 

The main problem these variants pose for vaccines is that some mutations are in parts of the virus that the immune system tends to attack. Such changes can essentially help the virus go incognito. Good vaccines must spark an immune response capable of handling that vast diversity to provide broad protection against infection.

What’s more, the virus deploys multiple tactics to hide from the immune system. One tactic the virus uses is to cover parts of its surface in a dense layer of sugar molecules. Many of those surfaces would be the prime targets of immune proteins called antibodies that latch onto viral particles.

The body recognizes these sugars as “self,” says Barton Haynes, an immunologist at Duke University School of Medicine’s Human Vaccine Institute. “Basically, what the virus is saying to our immune system is ‘Sure, you can make a protective immune response, go for it.’” But if the antibodies attack, they’re seen as turncoats and are eliminated. That means the body can’t fight the virus as effectively.

Perhaps the biggest hurdle, however, is the lifelong nature of the infection. Many viruses disappear from the body after the immune system fights them off. But HIV has the ability to insert its genetic blueprint into host DNA, establishing a hidden reservoir in immune cells called T cells, which normally fight infections (SN: 10/24/13). That reservoir makes the virus invisible to the immune system. Once the virus inhabits its new hideout, the immune system can’t eradicate it, nor can drug treatments.

That means “you’ve got to have protective immunity there the day, the moment of transmission,” Haynes says. “If [the immune system] doesn’t get rid of the virus within 24 hours, the virus has won.”

Most vaccines don’t generate this type of sterilizing immunity that stops the infection from ever happening in most people who get the vaccine. Instead, shots are more likely to prevent people from becoming severely ill. Many COVID-19 vaccines, for instance, are highly effective at preventing people from developing symptoms, particularly severe ones. But some vaccinated people might still get infected with the coronavirus (SN: 5/4/21).

That’s not an option with HIV since it never leaves the body, Zolla-Pazner says. “It’s a very different bar that we have to jump over for an HIV vaccine.”

Testing HIV vaccine candidates

To date, there have been only a handful of clinical trials to test the efficacy of potential HIV vaccines in people. Of the six trials that scientists saw to completion, only one vaccine candidate proved effective at preventing infection.

That lone successful trial, known as RV144, used a “prime-boost” strategy in which participants received a total of six shots. The four “prime” jabs contained a canarypox virus that is incapable of replicating in cells and carries the genetic instructions for select HIV proteins. The participants’ cells make those viral proteins and develop an immune response against them.

Then participants also received two “boosts,” an injection of an HIV protein fragment that is essential for the virus to enter cells. The hope was that participants would develop a strong, wide-ranging immune response, giving those people broad protection against a variety of HIV subtypes.

Ultimately, that vaccine strategy lowered the risk of infection by 31.2 percent in vaccinated participants compared with the unvaccinated group. Although the shot showed only modest efficacy, those results changed the field by homing in on what type of immune response people needed to prevent infection, Zolla-Pazner says.

“Up until then, there was this raging debate about whether T cells or antibodies were most important in terms of protection,” Zolla-Pazner says. The results from RV144, first published in December 2009 in the New England Journal of Medicine, suggested specific antibodies were the crucial factor in reducing the risk of infection. “That’s not to say that T cells are not important — they are. But I think it established the primacy of antibodies,” she notes. If researchers could push people to make protective HIV antibodies, then perhaps a vaccine was within reach.

More recently, however, the canarypox/protein strategy has produced some less-promising results. In February 2020 — as COVID-19 was spreading around the globe — researchers stopped a follow-up trial being conducted in South Africa that used the same vaccine platform with the goal of improving on the RV144 finding (SN: 2/3/20). The results from the trial didn’t lower the risk of HIV infection in vaccinated people, researchers reported March 25 in the New England Journal of Medicine.

This is where more money for HIV vaccine research could have helped, Zolla-Pazner says. “If you had the money up front and you use it as needed… [scientists] would be doing science more efficiently and therefore getting the answers more quickly.” That investment is especially crucial for early animal testing. Instead of spending decades testing approaches on a handful of animals at a time to see if something works, an influx of money could support more robust experiments. And that could speed promising approaches into the arms of clinical trial volunteers.  

Making the right immune response

There are now hopeful signs that vaccine developers working on a variety of platforms might be on the right track to make an effective shot that provides sterilizing immunity. Still, “I don’t think at this point we should be taking any approach off the table,” says Zolla-Pazner.

One approach is tapping into the idea that some infected people naturally make antibodies capable of attacking a wide assortment of HIV variants and stopping those viruses from infecting cells (SN: 7/20/17). These antibodies take a long time to develop. Sometimes they don’t develop until years after an HIV infection has taken hold, Haynes says. HIV vaccine-makers want to speed up the process.

There are several ways to do that. One, being tested now in a clinical trial led by Johnson & Johnson, is to spark a broad immune response using an HIV protein composed of a mosaic of different HIV strains circulating around the world. Another way is to teach the immune system to make broadly neutralizing antibodies.

To do that, researchers identify broadly neutralizing antibodies in people infected with HIV. Then they can analyze the steps the body took to create those immune proteins. The goal is to craft a vaccine that tells vaccinated people to make similar antibodies when exposed to specific viral fragments, says Kevin Saunders, a vaccinologist at the Duke Human Vaccine Institute.

In a December 2019 Science study, Saunders, Haynes and their colleagues showed that in vaccinated mice and rhesus macaques, they could spur the first steps of HIV antibodies that might eventually become broadly neutralizing. A separate effort by Feinberg and his colleagues recently showed that 97 percent of human participants in an early-stage clinical trial made those same rare immune cells when exposed to a piece of HIV engineered to specifically generate the cells.

Other groups are focusing on T cells to fight infection. Louis Picker and Klaus Früh, for instance, developed a vaccine that causes specialized T cells to kill other T cells infected with HIV, rather than relying on antibodies to prevent infection entirely, the team reported in March in Science Immunology.

The team had previously shown that around half of monkeys given the vaccine were protected. The animals became infected with SIV — the primate equivalent of HIV — but the virus couldn’t replicate very well and over time the infection went away, says Picker, an immunologist at Oregon Health & Science University in Portland. 

The next step is to move the vaccine into people. “Whatever we see in the clinical trial, it’s breaking new ground,” says Früh, a viral immunologist also at Oregon Health & Science University. “It’s the first time this has ever been done so we’re very excited about that.”   

After nearly four decades of trying, there is some light at the end of the tunnel. “I do believe we’ll get a vaccine, I really do,” Zolla-Pazner says. “But I don’t know how long that’s gonna take.”

About 19 million years ago, something terrible happened to sharks.

Fossils gleaned from sediments in the Pacific Ocean reveal a previously unknown and dramatic shark extinction event, during which populations of the predators abruptly dropped by up to 90 percent, researchers report in the June 4 Science. And scientists don’t know what might have caused the die-off.

“It’s a great mystery,” says Elizabeth Sibert, a paleobiologist and oceanographer at Yale University. “Sharks have been around for 400 million years. They’ve been through hell and back. And yet this event wiped out [up to] 90 percent of them.”

Sharks suffered losses of 30 to 40 percent in the aftermath of the asteroid strike that killed off all nonbird dinosaurs 66 million years ago (SN: 8/2/18). But after that, sharks enjoyed about 45 million years of peaceful ocean dominance, sailing through even large climate disruptions such as the Paleocene-Eocene Thermal Maximum — an episode about 56 million years ago marked by a sudden spike in global carbon dioxide and soaring temperatures — without much trouble (SN: 5/7/15).

Now, clues found in the fine red clay sediments beneath two vast regions of Pacific add a new, surprising chapter to sharks’ story.

Sibert and Leah Rubin, then an undergraduate student at the College of the Atlantic in Bar Harbor, Maine, sifted through fish teeth and shark scales buried in sediment cores collected during previous research expeditions to the North and South Pacific oceans.

“The project came out of a desire to better understand the natural background variability of these fossils,” Sibert says. Sharks’ bodies are made of mostly cartilage, which doesn’t tend to fossilize. But their skin is covered in tiny scales, or dermal denticles, each about the width of a human hair follicle. These scales make for an excellent record of past shark abundance: Like shark teeth, the scales are made of the mineral bioapatite, which is readily preserved in sediments. “And we will find several hundred more denticles compared to a tooth,” Sibert says.

The researchers weren’t expecting to see anything particularly startling. From 66 million years ago to about 19 million years ago, the ratio of fish teeth to shark scales in the sediments held steady at about 5 to 1. But abruptly — the team estimates within 100,000 years, and possibly even faster — that ratio dramatically changed, to 100 fish teeth for every 1 shark scale.

The sudden disappearance of shark scales coincided with a change in the abundances of shark scale shapes, which give some clues to changes in biodiversity. Most modern sharks have linear striations on their scales, which may offer some boost to their swimming efficiency. But some sharks lack these striations; instead, the scales come in a variety of geometric shapes. By analyzing the change in the different shapes’ abundances before and after 19 million years ago, the researchers estimated a loss of shark biodiversity of between 70 and 90 percent. The extinction event was “selective,” says Rubin, now a marine scientist at the State University of New York College of Environmental Science and Forestry in Syracuse. After the event, the geometric scales “were almost gone, and never really showed up again in the diversity that they [previously] did.”

There’s no obvious climate event that might explain such a massive shark population shift, Sibert says. “Nineteen million years ago is not known as a formative time in Earth’s history.” Solving the mystery of the die-off is at the top of a long list of questions she hopes to answer. Other questions include better understanding how the different denticles might relate to shark lineages, and what impact the sudden loss of so many big predators might have had on other ocean dwellers.

It’s a question with modern implications, as paleobiologist Catalina Pimiento of the University of Zurich and paleobiologist Nicholas Pyenson of the Smithsonian National Museum of Natural History in Washington, D.C., write in a commentary in the same issue of Science. In just the last 50 years, shark abundances in the oceans have dramatically declined by more than 70 percent as a result of overfishing and ocean warming. The loss of sharks — and other top marine predators, such as whales — from the oceans has “profound, complex and irreversible ecological consequences,” the researchers write.

Indeed, one way to view the study is as a cautionary tale about modern conservation’s limits, says marine conservation biologist Catherine Macdonald of the University of Miami, who was not involved with this study. “Our power to act to protect what remains does not include an ability to fully reverse or undo the effects of the massive environmental changes we have already made.”

Populations of top ocean predators can be important indicators of those changes — and unraveling how the ocean ecosystem responded to their loss in the past could help researchers anticipate what may happen in the near future, Sibert says. “The sharks are trying to tell us something,” she adds, “and I can’t wait to find out what it is.”

Around the world, volunteers are getting a vaccine developed to prevent tuberculosis in studies that have nothing to do with TB. Called Bacillus Calmette-Guérin, or BCG, the shot is being tested as a treatment for type 1 diabetes, Alzheimer’s disease, multiple sclerosis and even COVID-19.

BCG is a live but weakened version of Mycobacterium bovis, a relative of M. tuberculosis, the bacterium that causes the infectious lung disease known as TB. The vaccine has been around for 100 years and is routinely given to children in nearly all non-Western nations.

Almost as soon as BCG was introduced in the 1920s, researchers noticed a drop in infant deaths in some places where the vaccine was used. Later studies revealed that the vaccine protects against a range of infections. Much more recently, a single dose of the vaccine reduced the risk of respiratory infections in elderly study participants compared with those who got a placebo, according to an October 15 report in Cell.

The vaccine appears to boost immunity in some situations, but paradoxically, BCG may also calm an overactive immune system. It’s this soothing effect that made researchers take a look at BCG for autoimmune and inflammatory diseases, including eczema, asthma, allergies and multiple sclerosis. In MS, a disease in which the immune system attacks nerve cells in the brain and spinal cord, BCG appears to slow damage to the brain.

“Everybody kept getting signals, often from human data, saying this microorganism is doing beneficial things … whether it was allergy or autoimmunity or multiple sclerosis or diabetes,” says immunologist Denise Faustman of Harvard Medical School. “Over the last 10 years, that dataset has just grown and grown.” Faustman is testing BCG as a therapy for people with type 1 diabetes. In this autoimmune disease, the immune system attacks insulin-producing cells in the pancreas, leaving the body unable to make the insulin needed to control blood sugar levels.

“Everybody kept getting signals, often from human data, saying this microorganism is doing beneficial things … whether it was allergy or autoimmunity or multiple sclerosis or diabetes.”

Immunologist Denise Faustman, Harvard Medical School

Faustman is in the midst of a 150-person safety and efficacy trial of BCG in adults with type 1 diabetes. Her team previously showed, in a small study published in 2018, that the vaccine can safely improve blood glucose control in patients with long-term disease who continued taking insulin. The vaccine appears to reprogram immune cells to take up extra glucose, her team reported in iScience in May 2020.

Now, she and other researchers are digging into the basic science behind their observations, while also launching clinical trials of BCG in patients with type 1 diabetes, MS and Alzheimer’s. The scientists hope the answers will help drum up support for this line of research, which has drawn skepticism in the scientific community.

An unlikely treatment

Evidence of BCG’s unanticipated effects has been quietly accumulating for decades. In some settings the vaccine reduced the overall rate of infant death by about 30 percent, based on a 2016 systematic review in BMJ of both clinical trials and observational studies. In the 1980s, the vaccine became a standard immune-boosting treatment for people with bladder cancer. In a study reported in 2019 in JAMA Network Open, people who got BCG in childhood had a 2.5-fold lower risk for lung cancer as adults.

But none of this was on Faustman’s radar when her type 1 diabetes research led her to BCG. Her goal was to stop the autoimmune attack on beta cells, the cells in the pancreas that make insulin. Normally, beta cells respond to changes in blood glucose and release just enough insulin to trigger other cells to take up glucose from the blood and burn it up for energy.

In type 1 diabetes, immune system T cells destroy beta cells, so people with the disease must frequently monitor their blood glucose and inject insulin to keep glucose levels within a healthy range. Very high or very low glucose levels can cause coma or death. Over a lifetime, less extreme glucose fluctuations lead to blood vessel damage along with kidney, heart and vision problems.

In the late 1990s and early 2000s, Faustman’s team and others found that a molecule called TNF alpha, which is made by some immune cells, could selectively kill the T cells that attack beta cells. Among its many jobs, TNF alpha fights bacterial infections and helps the body make T regulatory cells, or T-regs, which act as referees to prevent collateral damage during immune responses. For reasons that are not well understood, in people with type 1 diabetes, T-regs are either too few or defective. Faustman and others found that TNF alpha boosted T-reg numbers and activity in mice and in human cells.

But giving TNF alpha directly wasn’t an option; it was expensive and hard to administer safely. So Faustman’s team searched for something that could trigger immune cells to make TNF alpha on their own. “The answer that kept popping up was BCG,” Faustman says.

Another research group led by immunologist Bhagirath Singh, then at the University of Alberta in Edmonton, Canada, had found in the 1990s that BCG and a related immune stimulant called complete Freund’s adjuvant, or CFA, could prevent type 1 diabetes in mice prone to the disease. CFA, which is made with dead M. tuberculosis, also protected pancreatic cell transplants in diabetic mice from destruction by the immune system.

Faustman’s team found similar results, as well as that diabetic mice given CFA began producing their own insulin; their pancreases seemed to be healing. The finding was intriguing, but in type 1 diabetes research, Faustman cautions, “everything works in the mouse.”

In 1994, an Israeli team used BCG and got blood sugar under control, with very little insulin use, in children recently diagnosed with the disease. The results, however, could not be replicated.

That didn’t deter Faustman. There are at least a dozen strains of the BCG organism used for vaccines, and scientists have learned that different strains have different effects on the immune system. Faustman’s team screened several strains to find one that could trigger TNF alpha and shift the balance between autoimmune T cells and T-regs in samples of white blood cells from people with type 1 diabetes.

With a strain in hand that worked, Faustman’s team recruited three adults who had been living for many years with type 1 diabetes, and had never been vaccinated with BCG. Each person got two injections of BCG, four weeks apart. The volunteers continued using insulin while their blood was checked for changes to T cells and levels of hemoglobin A1c, or HbA1c, which tells how well-controlled glucose is in the blood.

During the 20-week study, the researchers saw small changes to T cells, but no big improvement in HbA1c, the measurement that really matters to type 1 diabetes patients.

Wait for it

By this time, Faustman had met researchers from Rome who had found that BCG could reduce the likelihood that people with brain inflammation would develop multiple sclerosis — but the effect was most apparent after months to years. With this longer time frame in mind, Faustman checked in with the patients from her study annually to measure HbA1c levels. After year three, “the HbA1c’s were down 10 to 18 percent,” Faustman says. “It was not subtle.”

To put that into context, for every 10 percent drop in HbA1c, the risks of diseases caused by blood vessel damage — a major problem in people with diabetes — drop 25 to 44 percent. Faustman’s team added six more patients to the study, and all nine volunteers went at least three years with near-normal blood sugar levels. Three of those patients maintained these levels for five years, the team reported in npj Vaccines in 2018. And none of the patients reported episodes of blood sugar dropping too low.

The HbA1c shift was exciting, but Faustman was perplexed when she looked for its cause. The patients’ T-regs were more active, as expected, but levels of natural insulin did not go up, suggesting something else was helping to control blood sugar.

A clue came from the breakdown products, or metabolites, in the patients’ blood made when cells use glucose. Those metabolites were more abundant in the blood after patients received BCG. Faustman’s group also found that before BCG treatment, patients had lower levels of the metabolites than healthy people, which the researchers confirmed by studying blood from another 100 patients with type 1 diabetes.

Looking more closely, the team found that white blood cells — specifically monocytes — from people with type 1 diabetes took up less glucose than did the same cells in healthy people. But exposing patients’ monocytes to BCG in the lab corrected this defect in glucose metabolism, the researchers reported last year in iScience.

In the same study, the researchers gave a new group of patients three BCG injections in a year and observed that genes related to breaking down glucose were more active in the patients’ T cells and monocytes than before the shots.

“BCG was taking these underlying defects in diabetics, both in the immune system and metabolism, and correcting them towards normal,” Faustman says. BCG seems to give the patients a new way to dispose of glucose, she says.

Hope or hype?

Faustman’s work has generated a wide range of reactions from people within the type 1 diabetes community. Patients are excited by the possibility of an inexpensive treatment that, while not a cure, could make life easier. With type 1 diabetes on the rise, currently affecting 1.6 million people in the United States, and with the high cost of insulin, anything that could help patients regulate blood sugar without increasing insulin doses could have a big impact.

“Even if it’s in addition to current insulin therapy, it’s a great hope.”

Pediatric endocrinologist Siham D. Accacha, NYU Long Island School of Medicine

“Even if it’s in addition to current insulin therapy, it’s a great hope,” says Siham D. Accacha, a pediatric endocrinologist at NYU Long Island School of Medicine in Mineola, N.Y. Managing glucose levels takes a physical, mental and emotional toll on patients and their families, she says. Wearable glucose monitors and automatic insulin pumps help, but “we don’t have a treatment that could help improve blood sugar from inside,” she says. If BCG has a chance of doing that, she says, “I think it’s worth a try.”

Accacha adds that BCG has a long safety record; its risks are minuscule compared with other treatments for type 1 diabetes, such as drugs that suppress the immune system, which increases infection risk, or pancreas transplants, which also require immune suppression.

Faustman says patients are also encouraged by the findings because the research included people who have been living with diabetes for a long time, an average of 19 years. Most, if not all, other studies recruit only newly diagnosed people, says David Leslie, an endocrinologist at the University of London. “Anything that could work in established type 1 diabetes is a big deal,” he says.

On the flip side, some diabetes researchers and organizations have expressed concerns that Faustman’s work might generate false hope. Most recently, during the 2018 meeting of the American Diabetes Association, that organization, along with JDRF (formerly the Juvenile Diabetes Research Foundation), released a statement noting the small size of Faustman’s 2018 study, and that all of the volunteers continued taking insulin.

In an e-mail to Science News, a JDRF representative reiterated the original statement, adding: “We want every researcher in our field to be successful and we will be monitoring the progress made by Dr. Faustman.” Several type 1 diabetes researchers turned down requests to comment on Faustman’s latest work, including one who cited the small number of patients involved as a reason.

Leslie agrees that more data are needed to back up Faustman’s claims. He says he has heard negative reactions to Faustman’s work in private, but he doesn’t think they’re warranted. “It’s an interesting idea,” he says, one that “we shouldn’t throw away.”

Faustman has not received any BCG funding from two of the biggest type 1 diabetes research funders: the U.S. National Institutes of Health and JDRF. She says she thinks that’s because the work “flies in the face” of the field’s main efforts over the last 20 years, which include managing glucose levels with pumps and monitors, and detecting and treating type 1 diabetes as early as possible.

Faustman’s BCG work has been supported by private donors, including the Iacocca Family Foundation in Boston, or through fundraising by patients and their families. Because BCG is a generic vaccine costing an average of 50 cents a dose, there is little incentive for drug developers to pour money into studies for new uses. “It’s not sexy or money-making at all,” says Singh, whose own funding for studying BCG-related work dried up in 2001.

“The data will have to speak for themselves,” says Ofer Levy, director of the precision vaccines program at Boston Children’s Hospital. Levy studies BCG and is familiar with Faustman’s work. He says no one is encouraging people with diabetes to get in line for a shot of BCG. “We need rigorous clinical data,” he says. “But I do think that it’s a plausible hypothesis and very exciting area of research.”

Eyes on the off-targets

Faustman is part of a growing community of researchers who study BCG and its unintended effects. She calls them “off-target people.”

One of those researchers is Mihai Netea, an immunologist at the Radboud University in the Netherlands. He and his colleagues have shown that BCG triggers trained immunity, a nonspecific sort of memory that readies immune cells to react more strongly to any pathogen later on. It’s thought that this is how, in human studies, it protects against bacterial and viral infections, and is what’s led several research groups to test it as a prevention against COVID-19.

Netea’s team also reported in 2016 in Cell Reports that one shot of BCG triggers healthy volunteers’ monocytes to break down glucose at a higher rate, and increases the activity of genes required for glucose metabolism within the cells. Netea says he isn’t sure that these changes in immune cells are enough to affect glucose levels throughout the whole body, as Faustman posits.

In its ongoing trial, Faustman’s team is using radioactive glucose PET scanning to map out where the glucose goes after BCG vaccination. So far, they’ve seen increased glucose uptake in some of the places where monocytes and other immune cells are found, such as the spleen, bone marrow and descending aorta. After two years, she says, the liver starts to take up more glucose as well, suggesting it may play a role in BCG’s effect on blood glucose levels.

Faustman has teamed up with Harvard neurologist Steven Arnold to test BCG in Alzheimer’s patients. The breakdown of glucose is lower than normal in the brains of people with the disease, research has shown. Faustman thinks BCG may offer a reboot of glucose metabolism.

In 2019, a research team from Israel reported in PLOS ONE that among people treated for bladder cancer about a decade earlier, 2.4 percent who got BCG developed Alzheimer’s while 8.9 percent of those who didn’t developed the disease. Arnold’s study will enroll 30 people with early Alzheimer’s to receive two shots of BCG or a placebo four weeks apart. His team will measure patients’ cognitive abilities and biomarkers of disease in blood and cerebrospinal fluid over three months.

Faustman’s colleagues in Italy, neurologists Marco Salvetti and Giovanni Ristori of Sapienza University of Rome, have been pursuing BCG as a treatment for multiple sclerosis since the late 1990s. In a pilot study of 12 people with MS, Salvetti, Ristori and colleagues found that BCG reduced the patients’ chances of developing new areas of nerve cell damage in the brain.

For a second trial, the team recruited people who had not yet developed MS, but experienced one episode of MS symptoms, such as vision loss or muscle weakness. Thirty-three of those volunteers got one shot of BCG while 40 got a placebo. Over five years, those who got the vaccine were less likely to develop new or worsened areas of brain damage or experience disease flare-ups compared with people who received a placebo. By the end of the study, 70 percent of the placebo group had clinically diagnosed MS, compared with 42 percent of the vaccinated group, the team reported in 2014 in Neurology.

The Sapienza team has started another placebo-controlled trial recruiting people with signs of neurological damage that had been discovered by chance in MRIs done for unrelated reasons. People with this kind of damage have a high risk of developing MS after several years. Salvetti says he hopes to find out if BCG can serve as an option to lower these people’s risk for MS.

Salvetti is working with immunologist Giuseppe Matarese of the University of Naples Federico II to study the trial participants’ T-regs. Matarese’s group has found that T-regs from MS patients have trouble multiplying. In studies of mice with MS-like symptoms, BCG increases T-reg numbers. Matarese’s team plans to see if it does the same in people. The group is also examining T-regs from healthy volunteers given a single BCG shot in a separate study led by Netea.

Faustman continues to study T-regs. Although her earlier work suggests that BCG boosts breakdown of glucose in people with long-standing type 1 diabetes, she hopes to learn if T-regs can help those more recently diagnosed, whose beta cells may still have a chance to recover. Her team is testing this in a trial of 25 people with newly diagnosed disease. So far, patients in this trial who are under age 21 have experienced drops in HbA1c levels one and two years after receiving BCG, which the team reported last October at the virtual 2020 Federation of Clinical Immunology Societies meeting.

Faustman’s group is halfway through its 150-person Phase II clinical trial, and expects to finish in 2023. She presented unpublished data at the meeting suggesting that the shot increases the activity of a gene required for T-reg production. The HbA1c data are still being analyzed.

In early 2021, she asked the U.S. Food and Drug Administration for approval to start a trial in children with type 1 diabetes, but the agency asked her for more animal data. She hopes to go back to ask again later this year.

Accacha, whose practice would participate in the trial, says her patients’ parents are very interested in Faustman’s work, and eager to enroll their children. “They ask me every year, ‘What’s going on?’ ”

Thirteen-year-old Noah Shaw loves planets and has perfect pitch. He wants to be a scientist like his father Bryan Shaw, a biochemist at Baylor University in Waco, Texas. But Noah’s path to science may not be as smooth as it was for the elder Shaw.

Diagnosed with retinoblastoma as an infant (SN: 1/5/85), Noah now has only one eye and permanent blind spots in his vision. People with one eye, like Noah, and people who have blindness or limited vision, are underrepresented in science and face barriers in STEM education. “Most of the stunning imagery in science is inaccessible to people who are blind,” Bryan Shaw says. That makes him wistful because renderings of proteins hooked him on science.

In an effort to help make science more inclusive, Shaw and his colleagues have come up with bite-sized molecule models that take advantage of the mouth’s supersensitive touch sensors, which can perceive finer details than our fingertips can.

The team created gummy candy models of important proteins, including myoglobin, which provides oxygen to muscles, and also 3-D printed nonedible, nontoxic versions (SN: 3/16/15). Both can be popped in the mouth for investigation. Once the researchers attached lanyards to the nonedible models to prevent choking, the team tested how well 281 college students and 31 grade schoolers could tell edible or nonedible models apart while blindfolded.

Each student examined one protein model either by mouth or by hand. For every additional protein model that the students assessed, they had to determine whether the protein was the same as the first or different. A separate group of 84 college students did the test by eyesight with 3-D computer images of proteins instead of models.

Students correctly identified the proteins about 85 percent of the time, regardless of whether they used their mouths, fingers or eyes, the team reports May 28 in Science Advances. Such cheap, tiny models could help students learn about proteins regardless of vision acuity, Shaw says.

Shaw got the idea for this would-be educational tool while twirling a blackberry on his tongue. A blackberry’s bumpy exterior looks like a popular way that scientists depict proteins, in which each of the protein’s atoms is represented by a sphere. Stick thousands of atoms together, and the conglomerate resembles an elaborate berry — something the tongue might be able to tell apart by shape.

Many infants and toddlers explore the world by mouth. A student in Hong Kong made headlines in 2013 for teaching herself to read Braille with her lips. Yet the mouth’s remarkable sensing ability remains largely untapped in science education, Shaw says.

Shaw has patented the models and is eager for feedback. But taking the models from prototype to teaching tool will require more work. For instance, the researchers have access to professional equipment to print models and sterilize them between uses — something not all educators have.

Most importantly, the models would benefit from testing by students who are blind and those who have low vision. Input from these students will help Shaw’s team improve the models to better fit the students’ needs. Shaw has initiated conversations about the models with educators at the Texas School for the Blind and Visually Impaired in Austin. Noah did test the models, but the researchers didn’t include his data in the analysis.

This is not the first time that Noah has inspired his dad. Shaw previously codeveloped an app that has the potential to catch early signs of eye disease in childhood pictures. Regardless of whether Noah pursues science, his father has one wish: “I hope he does something cool.”