Is There a Blind Spot in the Oversight of Human Subject Research?
Human experimentation has come a long way since congressional hearings in the 1970s exposed patterns of abuse. Where yesterday's patients were protected only by the good conscience of physician-researchers, today's patients are spirited past hazards through an elaborate system of oversight and informed consent. Yet in many ways, the project of grounding human research on ethical foundations remains incomplete.
As human research has become a mainstay of career and commercial advancement among academics, research centers, and industry, new threats to research integrity have emerged.
To be sure, much of the medical research we do meets exceedingly high standards. Progress in cancer immunotherapy, or infectious disease, reflects the best of what can be accomplished when medical scientists and patients collaborate productively. And abuses of the earlier part of the 20th century--like those perpetrated by the U.S. Public Health Service in Guatemala--are for the history books.
Yet as human research has become a mainstay of career and commercial advancement among academics, research centers, and industry, new threats to research integrity have emerged. Many flourish in the blind spot of current oversight systems.
Take, for example, the tendency to publish only "positive" findings ("publication bias"). When patients participate in studies, they are told that their contributions will promote medical discovery. That can't happen if results of experiments never get beyond the hard drives of researchers. While researchers are often eager to publish trials showing a drug works, according to a study my own team conducted, fewer than 4 in 10 trials of drugs that never receive FDA approval get published. This tendency- which occurs in academia as well as industry- deprives other scientists of opportunities to build on these failures and make good on the sacrifice of patients. It also means the trials may be inadvertently repeated by other researchers, subjecting more patients to risks.
On the other hand, many clinical trials test treatments that have already been proven effective beyond a shadow of doubt. Consider the drug aprotinin, used for the management of bleeding during surgery. An analysis in 2005 showed that, not long after the drug was proven effective, researchers launched dozens of additional placebo-controlled trials. These redundant trials are far in excess of what regulators required for drug approval, and deprived patients in placebo arms of a proven effective therapy. Whether because of an oversight or deliberately (does it matter?), researchers conducting these trials often failed in publications to describe previous evidence of efficacy. What's the point of running a trial if no one reads the results?
It is surprisingly easy for companies to hijack research to market their treatments.
At the other extreme are trials that are little more than shots in the dark. In one case, patients with spinal cord injury were enrolled in a safety trial testing a cell-based regenerative medicine treatment. After the trial stopped (results were negative), laboratory scientists revealed that the cells had been shown ineffective in animal experiments. Though this information had been available to the company and FDA, researchers pursued the trial anyway.
It is surprisingly easy for companies to hijack research to market their treatments. One way this happens is through "seeding trials"- studies that are designed not to address a research question, but instead to habituate doctors to using a new drug and to generate publications that serve as advertisements. Such trials flood the medical literature with findings that are unreliable because studies are small and not well designed. They also use the prestige of science to pursue goals that are purely commercial. Yet because they harm science- not patients (many such studies are minimally risky because all patients receive proven effective medications)- ethics committees rarely block them.
Closely related is the phenomenon of small uninformative trials. After drugs get approved by the FDA, companies often launch dozens of small trials in new diseases other than the one the drug was approved to treat. Because these studies are small, they often overestimate efficacy. Indeed, the way trials are often set up, if a company tests an ineffective drug in 40 different studies, one will typically produce a false positive by chance alone. Because companies are free to run as many trials as they like and to circulate "positive" results, they have incentives to run lots of small trials that don't provide a definitive test of their drug's efficacy.
Universities, funding bodies, and companies should be scored by a neutral third-party based on the impact of their trials -- like Moody's for credit ratings.
Don't think public agencies are much better. Funders like the National Institutes of Health secure their appropriations by gratifying Congress. This means that NIH gets more by spreading its funding among small studies in different Congressional districts than by concentrating budgets among a few research institutions pursuing large trials. The result is that some NIH-funded clinical trials are not especially equipped to inform medical practice.
It's tempting to think that FDA, medical journals, ethics committees, and funding agencies can fix these problems. However, these practices continue in part because FDA, ethics committees, and researchers often do not see what is at stake for patients by acquiescing to low scientific standards. This behavior dishonors the patients who volunteer for research, and also threatens the welfare of downstream patients, whose care will be determined by the output of research.
To fix this, deficiencies in study design and reporting need to be rendered visible. Universities, funding bodies, and companies should be scored by a neutral third-party based on the impact of their trials, or the extent to which their trials are published in full -- like Moody's for credit ratings, or the Kelley Blue Book for cars. This system of accountability would allow everyone to see which institutions make the most of the contributions of research subjects. It could also harness the competitive instincts of institutions to improve research quality.
Another step would be for researchers to level with patients when they enroll in studies. Patients who agree to research are usually offered bromides about how their participation may help future patients. However, not all studies are created equal with respect to merit. Patients have a right to know when they are entering studies that are unlikely to have a meaningful impact on medicine.
Ethics committees and drug regulators have done a good job protecting research volunteers from unchecked scientific ambition. However, today's research is plagued by studies that have poor scientific credentials. Such studies free-ride on the well-earned reputation of serious medical science. They also potentially distort the evidence available to physicians and healthcare systems. Regulators, academic medical centers, and others should establish policies that better protect human research volunteers by protecting the quality of the research itself.
After spaceflight record, NASA looks to protect astronauts on even longer trips
At T-minus six seconds, the main engines of the Atlantis Space Shuttle ignited, rattling its capsule “like a skyscraper in an earthquake,” according to astronaut Tom Jones, describing the 1988 launch. As the rocket lifted off and accelerated to three times the force of Earth's gravity, “It felt as if two of my friends were standing on my chest and wouldn’t get off.” But when Atlantis reached orbit, the main engines cut off, and the astronauts were suddenly weightless.
Since 1961, NASA has sent hundreds of astronauts into space while working to making their voyages safer and smoother. Yet, challenges remain. Weightlessness may look amusing when watched from Earth, but it has myriad effects on cognition, movement and other functions. When missions to space stretch to six months or longer, microgravity can impact astronauts’ health and performance, making it more difficult to operate their spacecraft.
Yesterday, NASA astronaut Frank Rubio returned to Earth after over one year, the longest single spaceflight for a U.S. astronaut. But this is just the start; longer and more complex missions into deep space loom ahead, from returning to the moon in 2025 to eventually sending humans to Mars. To ensure that these missions succeed, NASA is increasing efforts to study the biological effects and prevent harm.
The dangers of microgravity are real
A NASA report published in 2016 details a long list of incidents and near-misses caused – at least partly – by space-induced changes in astronauts’ vision and coordination. These issues make it harder to move with precision and to judge distance and velocity.
According to the report, in 1997, a resupply ship collided with the Mir space station, possibly because a crew member bumped into the commander during the final docking maneuver. This mishap caused significant damage to the space station.
Returns to Earth suffered from problems, too. The same report notes that touchdown speeds during the first 100 space shuttle landings were “outside acceptable limits. The fastest landing on record – 224 knots (258 miles) per hour – was linked to the commander’s momentary spatial disorientation.” Earlier, each of the six Apollo crews that landed on the moon had difficulty recognizing moon landmarks and estimating distances. For example, Apollo 15 landed in an unplanned area, ultimately straddling the rim of a five-foot deep crater on the moon, harming one of its engines.
Spaceflight causes unique stresses on astronauts’ brains and central nervous systems. NASA is working to reduce these harmful effects.
NASA
Space messes up your brain
In space, astronauts face the challenges of microgravity, ionizing radiation, social isolation, high workloads, altered circadian rhythms, monotony, confined living quarters and a high-risk environment. Among these issues, microgravity is one of the most consequential in terms of physiological changes. It changes the brain’s structure and its functioning, which can hurt astronauts’ performance.
The brain shifts upwards within the skull, displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes.
That’s partly because of how being in space alters blood flow. On Earth, gravity pulls our blood and other internal fluids toward our feet, but our circulatory valves ensure that the fluids are evenly distributed throughout the body. In space, there’s not enough gravity to pull the fluids down, and they shift up, says Rachael D. Seidler, a physiologist specializing in spaceflight at the University of Florida and principal investigator on many space-related studies. The head swells and legs appear thinner, causing what astronauts call “puffy face chicken legs.”
“The brain changes at the structural and functional level,” says Steven Jillings, equilibrium and aerospace researcher at the University of Antwerp in Belgium. “The brain shifts upwards within the skull,” displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes. Some of the displaced cerebrospinal fluid goes into cavities within the brain, called ventricles, enlarging them. “The remaining fluids pool near the chest and heart,” explains Jillings. After 12 consecutive months in space, one astronaut had a ventricle that was 25 percent larger than before the mission.
Some changes reverse themselves while others persist for a while. An example of a longer-lasting problem is spaceflight-induced neuro-ocular syndrome, which results in near-sightedness and pressure inside the skull. A study of approximately 300 astronauts shows near-sightedness affects about 60 percent of astronauts after long missions on the International Space Station (ISS) and more than 25 percent after spaceflights of only a few weeks.
Another long-term change could be the decreased ability of cerebrospinal fluid to clear waste products from the brain, Seidler says. That’s because compressing the brain also compresses its waste-removing glymphatic pathways, resulting in inflammation, vulnerability to injuries and worsening its overall health.
The effects of long space missions were best demonstrated on astronaut twins Scott and Mark Kelly. This NASA Twins Study showed multiple, perhaps permanent, changes in Scott after his 340-day mission aboard the ISS, compared to Mark, who remained on Earth. The differences included declines in Scott’s speed, accuracy and cognitive abilities that persisted longer than six months after returning to Earth in March 2016.
By the end of 2020, Scott’s cognitive abilities improved, but structural and physiological changes to his eyes still remained, he said in a BBC interview.
“It seems clear that the upward shift of the brain and compression of the surrounding tissues with ventricular expansion might not be a good thing,” Seidler says. “But, at this point, the long-term consequences to brain health and human performance are not really known.”
NASA astronaut Kate Rubins conducts a session for the Neuromapping investigation.
NASA
Staying sharp in space
To investigate how prolonged space travel affects the brain, NASA launched a new initiative called the Complement of Integrated Protocols for Human Exploration Research (CIPHER). “CIPHER investigates how long-duration spaceflight affects both brain structure and function,” says neurobehavioral scientist Mathias Basner at the University of Pennsylvania, a principal investigator for several NASA studies. “Through it, we can find out how the brain adapts to the spaceflight environment and how certain brain regions (behave) differently after – relative to before – the mission.”
To do this, he says, “Astronauts will perform NASA’s cognition test battery before, during and after six- to 12-month missions, and will also perform the same test battery in an MRI scanner before and after the mission. We have to make sure we better understand the functional consequences of spaceflight on the human brain before we can send humans safely to the moon and, especially, to Mars.”
As we go deeper into space, astronauts cognitive and physical functions will be even more important. “A trip to Mars will take about one year…and will introduce long communication delays,” Seidler says. “If you are on that mission and have a problem, it may take eight to 10 minutes for your message to reach mission control, and another eight to 10 minutes for the response to get back to you.” In an emergency situation, that may be too late for the response to matter.
“On a mission to Mars, astronauts will be exposed to stressors for unprecedented amounts of time,” Basner says. To counter them, NASA is considering the continuous use of artificial gravity during the journey, and Seidler is studying whether artificial gravity can reduce the harmful effects of microgravity. Some scientists are looking at precision brain stimulation as a way to improve memory and reduce anxiety due to prolonged exposure to radiation in space.
Other scientists are exploring how to protect neural stem cells (which create brain cells) from radiation damage, developing drugs to repair damaged brain cells and protect cells from radiation.
To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
Additionally, NASA is scrutinizing each aspect of the mission, including astronaut exercise, nutrition and intellectual engagement. “We need to give astronauts meaningful work. We need to stimulate their sensory, cognitive and other systems appropriately,” Basner says, especially given their extreme confinement and isolation. The scientific experiments performed on the ISS – like studying how microgravity affects the ability of tissue to regenerate is a good example.
“We need to keep them engaged socially, too,” he continues. The ISS crew, for example, regularly broadcasts from space and answers prerecorded questions from students on Earth, and can engage with social media in real time. And, despite tight quarters, NASA is ensuring the crew capsule and living quarters on the moon or Mars include private space, which is critical for good mental health.
Exploring deep space builds on a foundation that began when astronauts first left the planet. With each mission, scientists learn more about spaceflight effects on astronauts’ bodies. NASA will be using these lessons to succeed with its plans to build science stations on the moon and, eventually, Mars.
“Through internally and externally led research, investigations implemented in space and in spaceflight simulations on Earth, we are striving to reduce the likelihood and potential impacts of neurostructural changes in future, extended spaceflight,” summarizes NASA scientist Alexandra Whitmire. To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
A newly discovered brain cell may lead to better treatments for cognitive disorders
Swiss researchers have discovered a third type of brain cell that appears to be a hybrid of the two other primary types — and it could lead to new treatments for many brain disorders.
The challenge: Most of the cells in the brain are either neurons or glial cells. While neurons use electrical and chemical signals to send messages to one another across small gaps called synapses, glial cells exist to support and protect neurons.
Astrocytes are a type of glial cell found near synapses. This close proximity to the place where brain signals are sent and received has led researchers to suspect that astrocytes might play an active role in the transmission of information inside the brain — a.k.a. “neurotransmission” — but no one has been able to prove the theory.
A new brain cell: Researchers at the Wyss Center for Bio and Neuroengineering and the University of Lausanne believe they’ve definitively proven that some astrocytes do actively participate in neurotransmission, making them a sort of hybrid of neurons and glial cells.
According to the researchers, this third type of brain cell, which they call a “glutamatergic astrocyte,” could offer a way to treat Alzheimer’s, Parkinson’s, and other disorders of the nervous system.
“Its discovery opens up immense research prospects,” said study co-director Andrea Volterra.
The study: Neurotransmission starts with a neuron releasing a chemical called a neurotransmitter, so the first thing the researchers did in their study was look at whether astrocytes can release the main neurotransmitter used by neurons: glutamate.
By analyzing astrocytes taken from the brains of mice, they discovered that certain astrocytes in the brain’s hippocampus did include the “molecular machinery” needed to excrete glutamate. They found evidence of the same machinery when they looked at datasets of human glial cells.
Finally, to demonstrate that these hybrid cells are actually playing a role in brain signaling, the researchers suppressed their ability to secrete glutamate in the brains of mice. This caused the rodents to experience memory problems.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Andrea Volterra, University of Lausanne.
But why? The researchers aren’t sure why the brain needs glutamatergic astrocytes when it already has neurons, but Volterra suspects the hybrid brain cells may help with the distribution of signals — a single astrocyte can be in contact with thousands of synapses.
“Often, we have neuronal information that needs to spread to larger ensembles, and neurons are not very good for the coordination of this,” researcher Ludovic Telley told New Scientist.
Looking ahead: More research is needed to see how the new brain cell functions in people, but the discovery that it plays a role in memory in mice suggests it might be a worthwhile target for Alzheimer’s disease treatments.
The researchers also found evidence during their study that the cell might play a role in brain circuits linked to seizures and voluntary movements, meaning it’s also a new lead in the hunt for better epilepsy and Parkinson’s treatments.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Volterra.