Proteins are often called the building blocks of life.
While true, the analogy evokes images of Lego-like pieces snapping together to form intricate but rigid blocks that combine into muscles and other tissues. In reality, proteins are more like flexible tumbleweeds—highly sophisticated structures with “spikes” and branches protruding from a central frame—that morph and change with their environment.
This shapeshifting controls the biological processes of living things—for example, opening the protein tunnels dotted along neurons or driving cancerous growth. But it also makes understanding protein behavior and developing drugs that interact with proteins a challenge.
While recent AI breakthroughs in the prediction (and even generation) of protein structures are a huge advance 50 years in the making, they still only offer snapshots of proteins. To capture whole biological processes—and identify which lead to diseases—we need predictions of protein structures in multiple “poses” and, more importantly, how each of these poses changes a cell’s inner functions. And if we’re to rely on AI to solve the challenge, we need more data.
Thanks to a new protein atlas published this month in Nature, we now have a great start.
A collaboration between MIT, Harvard Medical School, Yale School of Medicine, and Weill Cornell Medical College, the study focused on a specific chemical change in proteins—called phosphorylation—that’s known to act as a protein on-off switch, and in many cases, lead to or inhibit cancer.
The atlas will help scientists dig into how signaling goes awry in tumors. But to Sean Humphrey and Elise Needham, doctors at the Royal Children’s Hospital and the University of Cambridge, respectively, who were not involved in the work, the atlas may also begin to help turn static AI predictions of protein shapes into more fluid predictions of how proteins behave in the body.
Let’s Talk About PTMs (Huh?)
After they’re manufactured, the surfaces of proteins are “dotted” with small chemical groups—like adding toppings to an ice cream cone. These toppings either enhance or turn off the protein’s activity. In other cases, parts of the protein get chopped off to activate it. Protein tags in neurons drive brain development; other tags plant red flags on proteins ready for disposal.
All these tweaks are called post-translational modifications (PTMs).
PTMs essentially transform proteins into biological microprocessors. They’re an efficient way for the cell to regulate its inner workings without needing to alter its DNA or epigenetic makeup. PTMs often dramatically change the structure and function of proteins, and in some cases, they could contribute to Alzheimer’s, cancer, stroke, and diabetes.
For Elisa Fadda at Maynooth University in Ireland and Jon Agirre at the University of York, it’s high time we incorporated PTMs into AI protein predictors like AlphaFold. While AlphaFold is changing the way we do structural biology, they said, “the algorithm does not account for essential modifications that affect protein structure and function, which gives us only part of the picture.”
The King PTM
So, what kinds of PTMs should we first incorporate into an AI?
Let me introduce you to phosphorylation. This PTM adds a chemical group, phosphate, to specific locations on proteins. It’s a “regulatory mechanism that is fundamental to life,” said Humphrey and Needham.
The protein hotspots for phosphorylation are well-known: two amino acids, serine and threonine. Roughly 99 percent of all phosphorylation sites are due to the duo, and previous studies have identified roughly 100,000 potential spots. The problem is identifying what proteins—dubbed kinases, of which there are hundreds—add the chemical groups to which hotspots.
In the new study, the team first screened over 300 kinases that specifically grab onto over 100 targets. Each target is a short string of amino acids containing serine and threonine, the “bulls-eye” for phosphorylation, and surrounded with different amino acids. The goal was to see how effective each kinase is at its job at every target—almost like a kinase matchmaking game.
This allowed the team to find the most preferred motif—sequence of amino acids—for each kinase. Surprisingly, “almost two-thirds of phosphorylation sites could be assigned to one of a small handful of kinases,” said Humphrey and Needham.
A Rosetta Stone
Based on their findings, the team grouped the kinases into 38 different motif-based classes, each with an appetite for a particular protein target. In theory, the kinases can catalyze over 90,000 known phosphorylation sites in proteins.
“This atlas of kinase motifs now lets us decode signaling networks,” said Yaffe.
In a proof-of-concept test, the team used the atlas to hunt down cellular signals that differ between healthy cells and those exposed to radiation. The test found 37 potential phosphorylation targets of a single kinase, most of which were previously unknown.
Ok, so what?
The study’s method can be used to track down other PTMs to begin building a comprehensive atlas of the cellular signals and networks that drive our basic biological functions.
The dataset, when fed into AlphaFold, RoseTTAFold, their variants, or other emerging protein structure prediction algorithms, could help them better predict how proteins dynamically change shape and interact in cells. This would be far more useful for drug discovery than today’s static protein snapshots. Scientist may also be able to use such tools to tackle the kinase “dark universe.” This subset of kinases, more than 100, have no discernible protein targets. In other words—we have no idea how these powerful proteins work inside the body.
“This possibility should motivate researchers to venture ‘into the dark’, to better characterize these elusive proteins,” said Humphrey and Needham.
The team acknowledges there’s a long road ahead, but they hope their atlas and methodology can influence others to build new databases. In the end, we hope “our comprehensive motif-based approach will be uniquely equipped to unravel the complex signaling that underlies human disease progressions, mechanisms of cancer drug resistance, dietary interventions and other important physiological processes,” they said.
Two major astronomy research programs, called EMU and PEGASUS, have joined forces to resolve one of the mysteries of our Milky Way: where are all the supernova remnants?
A supernova remnant is an expanding cloud of gas and dust marking the last phase in the life of a star, after it has exploded as a supernova. But the number of supernova remnants we have detected so far with radio telescopes is too low. Models predict five times as many, so where are the missing ones?
The new image reveals thin tendrils and clumpy clouds associated with hydrogen gas filling the space between the stars. We can see sites where new stars are forming, as well as supernova remnants.
In just this small patch, only about 1 percent of the whole Milky Way, we have discovered more than 20 new possible supernova remnants where only 7 were previously known.
These discoveries were led by PhD student Brianna Ball from Canada’s University of Alberta, working with her supervisor, Roland Kothes of the National Research Council of Canada, who prepared the image. These new discoveries suggest we are close to accounting for the missing remnants.
So why can we see them now when we couldn’t before?
The Power of Joining Forces
I lead the Evolutionary Map of the Universe or EMU program, an ambitious project with ASKAP to make the best radio atlas of the southern hemisphere.
EMU will measure about 40 million new distant galaxies and supermassive black holes to help us understand how galaxies have changed over the history of the universe.
For any telescope, the resolution of its images depends on the size of its aperture. Interferometers like ASKAP simulate the aperture of a much larger telescope. With 36 relatively small dishes (each 12m in diameter) but a 6km distance connecting the farthest of these, ASKAP mimics a single telescope with a 6km wide dish.
That gives ASKAP a good resolution, but comes at the expense of missing radio emission on the largest scales. In the comparison above, the ASKAP image alone appears too skeletal.
To recover that missing information, we turned to a companion project called PEGASUS, led by Ettore Carretti of Italy’s National Institute of Astrophysics.
PEGASUS uses the 64m diameter Parkes/Murriyang telescope (one of the largest single-dish radio telescopes in the world) to map the sky.
Even with such a large dish, Parkes has rather limited resolution. By combining the information from both Parkes and ASKAP, each fills in the gaps of the other to give us the best fidelity image of this region of our Milky Way galaxy. This combination reveals the radio emission on all scales to help uncover the missing supernova remnants.
Linking the datasets from EMU and PEGASUS will allow us to reveal more hidden gems. In the next few years we will have an unprecedented view of almost the entire Milky Way, about a hundred times larger than this initial image, but with the same level of detail and sensitivity.
We estimate there may be up to 1,500 or more new supernova remnants yet to discover. Solving the puzzle of these missing remnants will open new windows into the history of our Milky Way.
Strips of Suboxone, a combination of buprenorphine and naloxone used to treat substance use disorder.
The onset of the Covid-19 pandemic led to a sea change in addiction medicine — in particular, increased access to buprenorphine, a drug commonly used to treat opioid use disorder.
Now, new data show that despite the medication’s wider availability, deaths involving buprenorphine still constitute a small fraction of overall drug mortality.
The research, published Friday in JAMA Network Open, offers new insight into the impact of emergency policies enacted in early 2020 to slow Covid’s spread while preserving access to addiction care. The changes allowed doctors to issue new buprenorphine prescriptions via telemedicine, making the medication far more accessible for patients in rural areas or without access to transportation.
Buprenorphine, however, is itself an opioid, and is regulated as a controlled substance. While most doctors and health officials welcomed the changes, a small minority expressed concern that increasing buprenorphine access could have unintended consequences.
Those concerns were largely unfounded, according to the new research, which was authored by top addiction researchers at the Centers for Disease Control and Prevention and the National Institute on Drug Abuse.
While deaths involving buprenorphine did tick upward in the months following the policy changes, they increased at a significantly lower rate than overall drug deaths. Between July 2019 and June 2021, the share of opioid-related deaths involving buprenorphine dropped from 3.6% to 2.1%.
Among those who died of buprenorphine-involved overdoses, just 20% were specifically receiving medications used to treat opioid use disorder, meaning the drug was likely acquired illegally.
More broadly, nearly 93% of deaths involving buprenorphine also involved other substances, meaning that fewer than 1 in 600 opioid-involved deaths is attributable to buprenorphine alone.
The study’s publication comes amid a broader movement to increase access to addiction medications. In December, Congress passed legislation eliminating a requirement that doctors wishing to prescribe the medication obtain a special license known as an “X-waiver.”
Federal regulators also announced plans to make the emergency telehealth provisions enacted in 2020 permanent. In addition, Covid-era rules allowing patients to take home weeks’ worth of methadone, another common and highly effective treatment for opioid addiction, will also become permanent. A similar study published last year showed that methadone-related deaths did not increase despite the new flexibilities.
Still, access to buprenorphine is not without its challenges. Some pharmacies have reported that the Drug Enforcement Administration still conducts raids on facilities filling telemedicine prescriptions for buprenorphine, despite the new rules.
Separately, doctors across the U.S. have reported increased difficulty with buprenorphine “inductions,” or the process of giving patients their first dose. As the drug supply has become more contaminated by fentanyl, buprenorphine has become more likely to cause severe withdrawal symptoms, leading patients to seek treatment using alternatives like methadone — or avoid treatment altogether.
Two papers show that large language models, including ChatGPT, can pass the USMLE
Two artificial intelligence (AI) programs — including ChatGPT — have passed the U.S. Medical Licensing Examination (USMLE), according to two recent papers.
The papers highlighted different approaches to using large language models to take the USMLE, which is comprised of three exams: Step 1, Step 2 CK, and Step 3.
The first paper, published on medRxivopens in a new tab or window in December, investigated ChatGPT’s performance on the USMLE without any special training or reinforcement prior to the exams. According to Victor Tseng, MD, of Ansible Health in Mountain View, California, and colleagues, the results showed “new and surprising evidence” that this AI tool was up to the challenge.
Tseng and team noted that ChatGPT was able to perform at >50% accuracy across all of the exams, and even achieved 60% in most of their analyses. While the USMLE passing threshold does vary between years, the authors said that passing is approximately 60% most years.
“ChatGPT performed at or near the passing threshold for all three exams without any specialized training or reinforcement,” they wrote, noting that the tool was able to demonstrate “a high level of concordance and insight in its explanations.”
“These results suggest that large language models may have the potential to assist with medical education, and potentially, clinical decision-making,” they concluded.
The second paper, published on arXivopens in a new tab or window, also in December, evaluated the performance of another large language model, Flan-PaLM, on the USMLE. The key difference between the two models was that this model was heavily modified to prepare for the exams, using a collection of medical question-answering databases called the MultiMedQA, explained Vivek Natarajan, an AI researcher, and colleagues.
Flan-PaLM achieved 67.6% accuracy in answering the USMLE questions, which was about 17 percentage points higher than the previous best performance conducted using PubMed GPT.
Natarajan and team concluded that large language models “present a significant opportunity to rethink the development of medical AI and make it easier, safer and more equitable to use.”
ChatGPT, along with other AI programs, have been showing up as the subject — and sometimes as the co-author — of new research papers focused on testing the technology’s usefulness in medicine.
Of course, healthcare professionals have also expressed concerns over these developments, especially when ChatGPT is being listed as an author on research papers. A recent article from Natureopens in a new tab or window highlighted the uneasiness from would-be colleagues and co-authors of the emerging technology.
One objection to the use of AI programs in research was based on whether they can be truly capable of making meaningful scholarly contributions to a paper, while another objection emphasized that AI tools can’t consent to be a co-author in the first place.
The editor of one of the papersopens in a new tab or window that listed ChatGPT as an author said it was an error that would be corrected, according to the Nature article. Still, researchers have published several papers now touting these AI programs as useful tools in medical education, research, and even clinical decision making.
Natarajan and colleagues concluded in their paper that large language models could become a beneficial tool in medicine, but their first hope was that their findings would “spark further conversations and collaborations between patients, consumers, AI researchers, clinicians, social scientists, ethicists, policymakers and other interested people in order to responsibly translate these early research findings to improve healthcare.”
Increased injection drug use has led to a spike in cases of the life-threatening heart condition endocarditis, with cases rapidly accelerating since the onset of Covid-19.
The increased case count is one of the lesser-known side effects of the deadly addiction epidemic. But patients with endocarditis, an inflammation of the heart lining caused by infection, require complex, thoughtful care — care that the U.S. health system is ill-equipped to provide.
With drug deaths hovering at an all-time high and endocarditis cases among drug users up nearly tenfold in the last decade, physicians, researchers, and health officials have begun to confront the problem with more urgency. In particular, doctors are coming to terms with a basic reality: Their hospitals often have few protocols for treating endocarditis patients who use opioids and the withdrawal they’ll likely experience upon admission.
“We’re taking steps in the right direction, but we need to do much more,” said Daniel DeSimone, an infectious diseases specialist at the Mayo Clinic in Minnesota. “We need to do better with regard to managing opioid withdrawal in the hospital.”
In areas with high rates of injection drug use, infectious disease outbreaks are nothing new. In the past decade alone, the U.S. has seen outbreaks of HIV and hepatitis C associated with increased opioid use.
Between 2011 and 2022, the rate of new endocarditis among patients with opioid use disorder increased dramatically, according to new research published by the National Institute on Drug Abuse and scientists at Case Western Reserve University. Among drug users, most endocarditis infections stem from the use of non-sterile syringes, allowing bacteria to enter the bloodstream and, eventually, the heart.
Among people with opioid use disorder, the rate of endocarditis jumped from 4 per million per day to 30 per million per day. The sharpest increase occurred between 2021 and 2022 — a spike that the study’s authors attribute to the Covid-19 pandemic.
Care for endocarditis, which is not always caused by drug use, typically consists of a course of antibiotics delivered by IV drip. Some patients receive what’s known as a PICC line, a larger form of IV used when they’ll require medication for several weeks. Many cases require surgery to repair or replace damaged heart valves.
Such care is complicated to begin with. But for patients with addiction, each of those steps adds a new layer of complexity — in particular, lengthy hospital stays and ensuing withdrawal for patients accustomed to regular opioid use.
“You have someone that has very strong physical dependence to opioids, they go into the hospital, and they go into withdrawal, and that withdrawal can be very, very severe,” Nora Volkow, NIDA’s director and the co-author of the recent study, said in an interview. “They may leave the hospital against medical advice, because they’re not being treated for the severity of the withdrawal symptoms.”
Even when patients’ withdrawal is treated, Volkow said, patients “stay throughout the whole hospitalization as needed — and then they get released with no linkage to treatment or care.”
Keeping patients in the hospital, however, is only half the battle. In cases where patients remain in treatment, many still don’t receive the resources they need, or the expertise their care requires.
Even once patients’ infection and heart condition has been addressed, discharging them from the hospital can present unique challenges. Many of those who inject drugs are also experiencing dangerous or unpredictable housing situations, and those whose addictions remain untreated often quickly return to use.
Many of those patients soon wind up readmitted to the hospital for repeat infections. In recent years, such cases have engendered frustration from hospitals and additional stigma among health providers — even leading to public debates about whether patients with multiple endocarditis cases are worthy of additional care.
As a result, some doctors seek long-term care facilities where their patients can recuperate in a more stable environment. Even in those cases, however, the U.S. health infrastructure poses major obstacles.
“I can’t tell you the number of times I’ve had skilled nursing facilities say they will not accept a patient with addiction, because of challenges getting them methadone or getting them buprenorphine, or other reasons that seem to be code for stigma,” said Ashish Thakrar, an addiction physician and postdoctoral fellow at the University of Pennsylvania’s National Clinician Scholars Program.
The spike in cases, and growing recognition that the U.S. health system is ill-equipped to treat complex patients experiencing addiction, has spurred calls for improving treatment standards.
The American Heart Association last year issued new recommendations for endocarditis care that revolve around treating the patient’s underlying addiction. The AHA’s multidisciplinary approach, in an ideal scenario, would include input from doctors in at least four fields: cardiology, cardiac surgery, infectious disease, and addiction medicine or addiction psychiatry.
The Department of Justice has weighed in as well, issuing guidance and announcing a number of settlements and new lawsuits aimed at forcing health care facilities to admit patients who’ve been prescribed addiction medications like methadone or buprenorphine.
While some experts welcome the new guidance, they concede that in some cases it’s impossible to live up to.
“Most hospitals don’t have addiction consult services,” Thakrar said. “Most hospitals are not going to have access to addiction expertise, and in part that’s because hospitals haven’t paid for it. It hasn’t been a priority. … A lot of hospitals don’t have specialty services, so a lot of providers and cardiologists might be left without anyone to call.”
The resulting void forces other doctors — in this case, cardiologists or infectious disease specialists — to treat their patients’ addiction, which they’re sometimes ill-equipped to do.
DeSimone, the infectious disease specialist who was the lead author for the AHA’s new recommendations, acknowledged those doctors may be uncomfortable providing addiction medications, like writing a prescription for buprenorphine or connecting their patients with a methadone clinic.
The failure to provide comprehensive care is a big missed opportunity, Volkow said, because patients hospitalized with endocarditis are a “captive audience” for addiction care. A hospital, she argued, provides patients with medications, food, shelter, and safety — in other words, an ideal setting to begin addiction treatment.
Moreover, patients whose addictions remain untreated leave the hospital at even higher risk.
The condition “may require heart valve repair or complete replacement,” DeSimone said. “That typically requires the use of prosthetic material — and particularly for patients who inject drugs, that hardware now predisposes you to getting infected again.”
The increase in infective endocarditis has taken place amid a broader debate about the impact of “harm-reduction” strategies — services including syringe exchange, which data shows as highly effective at preventing infectious disease transmission.
In recent years, however, local governments in Indiana and West Virginia have moved to limit or outright close syringe exchange services. Even left-leaning leaders, like President Biden or California Gov. Gavin Newsom, have resisted the opening of proposed supervised injection sites that would provide syringe services alongside medical supervision for people using drugs.
Last year, conservative media caused an uproar by falsely reporting that the Biden administration planned to use federal money to distribute sterile pipes used to consume methamphetamine or fentanyl, among other drugs. In response, the White House issued a formal denial — and lawmakers from both parties introduced legislation meant not only to ban the use of federal funds for sterile pipes, but also to prevent government money from being spent, for the first time, on clean syringes.
While the $30 million allocation for harm-reduction services last year was unprecedented, critics say it wasn’t enough. And when communities lack access to services like syringe exchange, Volkow said, the results are easy to predict.
“During the Covid pandemic, many of the community services that exist to support people that take drugs — including, for example, syringe exchange programs — were closed,” Volkow said.
She added: “You can look at it throughout the whole world: Areas closing their syringe exchange programs are followed by outbreaks for HIV, and we’re seeing the same thing with hepatitis C. We can very much predict it is also associated with infectious endocarditis.”
Perinatal pathologist Mana Parast in her lab in La Jolla, Calif., at the University of California, San Diego.
When Mana Parast examines a placenta, she knows she may never find the answers she seeks. She’s hunting for clues — strips of dead tissue that signal autoimmune disease, white blood cells in the lining of the umbilical cord that point to an infection, thickening that could suggest blood wasn’t flowing freely to the fetus.
She wants to be able to tell a parent what she thinks went wrong.
Parast is one of just a few physician-scientists in the U.S. specializing in perinatal pathology, an overlooked and underfunded field tasked with analyzing fetal tissue, placentas, and other so-called products of conception to sleuth out why a mother miscarried — and hopefully, prevent further losses.
After a miscarriage or stillbirth, placentas — the temporary organ that protects and nourishes a fetus for the duration of a pregnancy — can harbor important evidence. While the majority of pregnancy loss is the result of genetic abnormalities, tightly wound umbilical cords, placentas that suddenly stop growing, and evidence of scarring are also clues in the 100 to 120 cases Parast and her team investigate each year. But for all of perinatal pathology’s promise, every case, even the ones considered “solved,” reveals just how little modern medicine knows about pregnancy loss, and how much there is still to learn.
“I don’t think we should underestimate the utility of placenta pathology,” Parast, who serves as director of the perinatal pathology service at University of California, San Diego, said. “Having said that, it’s not a crystal ball.” It’s rare to identify a single cause for a fetal death, especially after the first trimester. And while there are a few causal explanations for pregnancy loss — conditions in which no fetus could ever survive — most are merely correlational.
Hospital pathologists like Parast are also trying to offer comfort. In the U.S., as many as 1 in 4 pregnancies end in miscarriage or stillbirth. Those who experience pregnancy loss often feel personally responsible. “When an answer or explanation for their loss was given, [parents] were less likely to blame themselves,” said Jonah Bardos, an OB-GYN at the University of Miami and the co-author of a 2015 national survey on public misconceptions of miscarriage.
But pathologists with perinatal expertise are increasingly worried about the pressure they face to produce definitive cause of death determinations from law enforcement officials. Police and prosecuting attorneys have always had an interest in investigating pregnancy loss — acting on the suspicion that some miscarriages and stillbirths are intentionally caused by, or otherwise the fault of, the mother. Between 1973 and 2020, there have been more than 1,700 cases of arrests, detentions, and “equivalent deprivations of personal liberty” of pregnant people, according to the nonprofit Pregnancy Justice. In a post-Roe era, legal experts worry similar cases may gain more traction going forward.
Pathologists hope to be prepared. Less than two weeks after the Dobbs decision was finalized, the College of American Pathologists called for a special committee to meet to discuss its implications for the field. “We wanted them to think about it from the point of, where could a pathologist get tripped up — could get in trouble — doing what they’ve always done?” said Emily Volk, a physician and president of the college.
Over the next four months, group members, including Parast, met regularly to develop new guidelines. They aim to address pressing concerns, including when a pathologist can identify evidence of an abortion (and when they cannot) and how to properly dispose of tissues. Volk expects the results to be published sometime this spring, though they will need regular refinement to keep pace with state legislation.
“We’re very much in the middle of all of that right now,” Parast said.
Michael Caplan, a forensic pathologist with more than 30 years of experience in autopsy labs in five states, knows the day will come when he’ll need the kind of guidance those groups could provide. For example, if he examines a fetus and finds no fetal or placental abnormality, will the absence of evidence be used as evidence for self-managed abortion?
“I can see it coming down,” Caplan said. “There is going to be … pressure to report these things.” He added: “We need to decide as a group how we’re going to handle these situations.”
“We need to decide as a group how we’re going to handle these situations.”
Michael Caplan, forensic pathologist
In May 2015, Susan Valoff had packed her bag for the hospital, dropped her son Peter off at day care, and put in a half day at work. That afternoon, she was scheduled to deliver her second child, a boy to be named James Owen, via C-section. But when Valoff arrived at her obstetrician’s San Diego office for her final appointment, the exam that just one week ago had revealed a steady fetal heartbeat was now eerily silent. An ultrasound confirmed James had died.
After James was delivered, Valoff and her husband, Scott, held their baby. A photographer, provided by the hospital, took the only pictures they would ever have of their son. The couple decided against an autopsy, but they did agree to share the placenta for examination by a pathologist contracted by the hospital. Six days later, Valoff received the results.
The pathologist identified inflammation in the placenta — perhaps resulting from some infection of the amniotic fluid. He hinted that this may have caused the loss. But Valoff said these findings left her with more questions than answers. Her pregnancy had been “high-risk”: She was 45 years old, conceived James using IVF, and had undergone a C-section before — all of which increased her risk of miscarriage or stillbirth. Surely that had something to do with James’ death.
Online, Valoff found a pathologist who specialized in stillbirth and infection. He had recently retired, but recommended she reach out to Parast, who worked just down the road. Parast agreed to provide a second opinion. Inflammatory cells indeed indicated infection, she concluded. But she didn’t think that was to blame. Instead, Parast suggested that James died as a result of villitis, an inflammatory condition that restricts fetal growth.
While a detailed perinatal pathology is not exactly comforting, it can offer some of the clarity that parents like Valoff crave. “That’s the story you tell yourself and everyone you know the whole rest of your life,” Valoff, now 53, said. “That story matters.”
Valoff later discovered that the first report came from a pathologist who didn’t specialize in placentas. That kind of expertise is rare: There are just 700 members of the Society for Pediatric Pathology globally, and pathologists with expertise in the placenta — what Parast calls “the diary of intrauterine life” — make up just a fraction of their ranks.
They take their work seriously. “Our only job is to provide as much information [to the patient] as possible to make the best decision possible for her and her subsequent pregnancies,” Parast said. Or at least that’s what she believed — until she heard about an incident at the U.S.-Mexico border wall.
Parast looks over microscopic images of placental cells in her lab. Sandy Huffaker for STAT
The placenta on the examination table was like any other. But it came from a migrant woman who was 35 weeks pregnant when she fell at the border wall, Parast recalled. Her baby was stillborn. The medical examiner in San Diego was now investigating whether or not she had intentionally harmed the fetus.
Parast agreed to take a look. There was clear evidence of a placental abruption, which happens when the placenta separates from the uterine wall before birth, Parast remembers writing in her report. But Parast knew that did not indicate anything about intent. She doesn’t recall ever hearing back about the outcome of the case.
Parast had interacted with law enforcement before. In a residency rotation at the Atlanta medical examiner’s office, Parast often reviewed difficult cases, including those involving children. But she said she failed to appreciate the entwinement of medicine and the law until authorities asked her to look into the migrant woman’s miscarriage.
“That was my first aha moment of, what are you asking me?” Parast said.
In hindsight, it’s clear that reproductive medical researchers have been walking a vanishingly thin line. For decades, they have worked to unravel the mysteries of pregnancy loss to help patients who want to have children get pregnant and carry safely to term. But they’ve also been building a body of knowledge that, in the wrong hands, may be used against women who lose their pregnancies.
To many families, the work of perinatal pathologists is invaluable. Doctors now know that diagnosing and treating autoimmune conditions like lupus can help people carry a child to term. They also have a far better understanding of how to screen for the embryos with the best chance of a healthy pregnancy during the IVF process. And patients, too, are armed with the knowledge they need to monitor their own pregnancies, such as by keeping fetal movement journals that could help them recognize an issue in time to swiftly act.
“It’s the pathologist that provides the basis for all the clinical care that comes after,” Volk said.
But many losses still can’t be prevented, and some fetal deaths can not be explained. A person could do everything “wrong,” and still have a perfectly healthy live birth. And person could do everything “right,” and lose their pregnancy anyway. “The public sentiment is a little skewed by how much we’ve gotten the message that we can control things,” said Lara Freidenfelds, a science historian and author of “The Myth of the Perfect Pregnancy: A History of Miscarriage in America.”
In a courtroom, that narrative of control can have devastating consequences. Autopsy reports and related findings can form the basis of homicide, “feticide,” child abuse, and assault charges. To date, U.S. women have been investigated for everything from attempting suicide to falling down the stairs while pregnant.
Even the esoteric language of pathology may itself pose a risk. Take a term like “molar pregnancy,” which describes a tumor that develops in the uterus. Doctors know that if an embryo is present, it isn’t viable, but others might not. “That may not be clear to the patient from whom that specimen came,” Volk said, “but it also may not be clear to a district attorney or a lay policymaker or a lay state representative.”
In 2006, a 16-year-old named Rennie Gibbs delivered a stillborn daughter, who she named Samiya, at a hospital in Mississippi. Gibbs was later charged with “depraved heart murder” — which could carry a lifetime prison sentence — after a medical examiner ruled the cause of death was “cocaine toxicity.” Gibbs had used illicit substances while pregnant. But expert witnesses challenged the notion that cocaine could be said to cause a stillbirth, as it hasn’t been proven to end pregnancies. These same biomedical researchers also identified the more likely cause of Gibbs’ stillbirth: the umbilical cord wrapped around Samiya’s neck — a factor no one could control. In 2014, after years of legal proceedings, a judge finally dismissed Gibbs’ case.
These cases can happen anywhere, even in ostensibly blue states. In California, twocases of women prosecuted for using drugs while pregnant, and later losing their pregnancies, have recently captured public attention. “Prosecutors don’t have to be anti-abortion ideologues to prosecute people,” said Farah Diaz-Tello, senior counsel and legal director for If/When/How, a reproductive justice organization. Rather, “it’s an allegiance to their interpretation of law and order.”
Parast at her UCSD lab.
The gap between the scientific doubt inherent to medicine and the legal certainty a court desires can leave pathologists in a bind. “There is no such thing as absolute determination,” Parast said. “If anyone said so, they’re lying.”
Caplan, the forensic pathologist, has walked this line before. He has dedicated his life to giving a voice to the dead, but he said decades of experience have only taught him how little he knows.
As a forensic pathologist working in the medical examiner’s office in the 1990s, Caplan struggled to reach definitive conclusions in cases of children who died of SIDS. So he went back to school to train in pediatric pathology. There, and in the years since, he’s learned about differences in anatomy, physiology, and responses to injury across the lifespan that help him do his job — and the shortcomings of forensic methods like the widely disproven 17th-century “float test” that some U.S. officials still use to determine if a baby was born alive.
To Caplan, being able to confront the horizon of scientific knowledge can be empowering in a difficult and delicate line of work.
“I know that my limitations aren’t from my lack of effort,” he said.
Yet Caplan worries about what might happen if other pathologists fail to stick to the scope of their expertise. “I can’t change my objective findings,” Caplan said. But, he added, pathologists should “never, ever overextend the interpretation” of those findings.
As individuals, forensic and hospital pathologists are limited in the steps they can take to advance reproductive justice, while still doing their jobs. They can push back on the use of flawed methods like the floatation test, or provide expert opinions in court that cast scientific doubt on a prosecutor’s claims.
They can even take care not to speculate about things like self-managed abortion in their autopsy reports. “I would never use that language, ever, on a fetal death certificate,” Caplan said. Without definitive evidence, he would opt for a phrase like “fetal death of undetermined cause.” While subjective musings could be incorporated in a “comment” or “opinion” section, Caplan argues “it is better to allow opinions to be expressed and expanded in legal proceedings such as depositions and trials.”
But pathologists will need support, including as they continue their research. “I think there’s a concern that fear of committing a felony will make researchers or physicians more reluctant to engage in this kind of research,” said Robert Silver, an OB-GYN at the University of Utah who specializes in pregnancy loss, “and it will also make families more reluctant to engage in this kind of research.”
Guidelines from professional organizations like the College of American Pathologists will help, as would solidarity with other medical and non-medical specialties, including reproductive justice advocates, politicians, and lawyers. For example, in September, California abolished a law that had previously required coroner’s investigations into all stillbirths. Even in states where abortion is now illegal, similar legislation could, at a minimum, shield some pregnant people from criminal charges.
Back in Parast’s lab in La Jolla, the pathologist feels a mix of fear and fierce determination to keep providing her patients answers. “As a researcher, you don’t set out and think, I want to do research at the edge of what’s controversial — especially in this area that’s so underfunded,” she said. “You’re in this area because you have a passion for women’s health.”
Sarcomas are rare cancers arising in bone, muscle, fat, or cartilage and account for about 20% of the cancers diagnosed in people under the age of 20. Now, researchers from Omico, the Garvan Institute of Medical Research, and UNSW Sydney report several genes that cause sarcoma have been identified in the first comprehensive genetic map of sarcomas.
“Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility,” wrote the researchers. “Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1,644 sporadic cases and 3,205 matched healthy elderly controls.”
The researchers found that one in 14 individuals diagnosed with sarcoma carries a clinically important gene. The researchers also identified a previously unrecognized genetic pathway specific to sarcomas.
“The findings uncovered by this research are so important because by understanding how individuals develop sarcomas, we move closer to earlier detection and better treatments,” explained Mandy Ballinger, PhD, lead author of the paper, and group leader of the genetic cancer risk group at Garvan.
“Cancer is fundamentally a genetic disease, and genomics is the key to unlocking its secrets. This international collaboration has developed new methods for mapping the genetic basis for cancer and identified new heritable pathways that increase cancer risk. These findings fill important gaps in the missing heritability of cancer,” said David Thomas, head of the Genomic Cancer Medicine Laboratory at Garvan and CEO of Omico, a non-profit nationwide network of genomic cancer research and treatment centers.
The map and findings pave the way for people with a family history of sarcoma to test for their genetic risk of developing the disease.
Restricted cross-border collaborations among governments, biotech companies and scientists severely curb the speed at which treatments for rare diseases could emerge. Clinical trials for rare disease treatments find it hard to recruit participants in the U.S.
Harsha Rajasimha, PhD, is founder and CEO of IndoUSrare
“There might only be a few patients in the United States for some rare diseases, and they are likely already enrolled in a trial. Researchers have to go outside the U.S. to find and recruit patients for new therapeutic programs,” says Harsha Rajasimha, PhD, founder and CEO of IndoUSrare, a non-profit on a mission to accelerate therapies for rare diseases by bridging efforts in India and the US. He is also the founder of Jeeva Informatics, a technology startup dedicated to developing inclusive software solutions for clinical trials.
Rajasimha’s foray into social entrepreneurship arose as a detour from his research career in genomics and data science that spanned roles at the NIH and the FDA, when he and his wife had a child born with Edward’s Syndrome in 2012.
“We were told that it was not a viable baby,” said Rajasimha. “That changed my perspective as a data researcher and exposed me to what families go through in this diagnostic odyssey.” Interacting with patients, their families, patient advocates and researchers in India and the U.S. led Rajasimha to establish IndoUSrare, a 501c3 nonprofit organization headquartered in Northern Virginia in 2019.
A recent report released by RARE-X, a global data sharing platform for rare diseases, estimates that there are 10,867 rare genetic diseases worldwide. These affect nearly 350 million people globally, including 30 million in the U.S. Less than ten percent of these disorders have any available treatments. When treatments do emerge for rare diseases, their costs put them beyond reach for most patients worldwide. For instance, the FDA recently approved the drug Hemgenix for hemophilia B that has been decades in the making, with the eye-watering cost of $3.5 million per dose.
“The clinical trial group for Hemgenix was only 54 subjects,” says Rajasimha. “If there had been a better mechanism for US researchers to engage in cross-border cooperation with researchers in India, perhaps they could have had a larger, more diverse trial sample.”
It might not be obvious, but the patient population recruited for orphan drug trials is in most instances a key factor in drug pricing. The larger the global distribution of the drug’s target population, and hence market, the less expensive the drug is likely to be, says Rajasimha. Moreover, for countries like India that offer grants to patients with rare diseases for treatment, drug manufacturers are partially reimbursed by the government, lowering drug prices further. Rajasimha emphasizes, engaging the Indian patient population during early R&D phases will accelerate timelines for patient recruitment and help reduce the cost of drug development.
The Indian subcontinent is home to nearly 25% of the world’s population, with an estimated 70 million patients with rare diseases. Yet fewer than 2% clinical trials include participants from the Indian subcontinent – most volunteers are based in the US and Europe. “This has created a longstanding divide,” says Rajasimha. “We must think about this problem on a global basis because for any given rare disease, patients are very small in number, and geographically distributed globally.”
Patti Engel, RN, BSH, is CEO and president at EngageHealth
Patti Engel, RN, BSN, CEO and president at EngageHealth, a rare diseases market research firm, says there are three major actions that could help rare disease patients: heightened awareness, accessible genetic tests and insurance coverage.
“Increased awareness of various rare diseases would help clinicians quickly recognize symptoms and pursue a diagnosis. Free or low-cost genetic tests would eliminate the need to rule out multiple conditions and get a quicker diagnosis,” said Engel. “This could allow patients to access medications or investigational products, and, hopefully, slow or halt disease progression. Insurance coverage would help patients access potentially life-saving therapies.”
EngageHealth is conducting a study in collaboration with IndoUSrare, in the U.S., India and China, to uncover motivators and deterrents for patients and families to participate in clinical research. Engel hopes this study will provide practical insights that drug developers could use to recruit patients with rare diseases in interventional trials that measure the safety or efficacy of potential therapeutic agents and non-interventional trials that help researchers understand rare diseases mechanisms and the experiences of patients and their families.
IndoUSrare, Engage Health, and Ginkgo Leaf Rare Disease Family Care Center are conducting a study to understand the cultural motivators and deterrents for rare disease patients and their caregivers in participating in clinical trials.
Mobilizing Indian healthcare policies
Unlike the U.S., India has lacked a unified organization advocating for rare diseases. So, in parallel to establishing IndoUSrare, Rajasimha co-founded the Organization for Rare Diseases India (ORDI) and advocated for a policy in India similar to the U.S. Orphan Drug Act, which provides financial incentives to attract companies to develop drugs for rare diseases.
“We have advocated in India over the last 10 years. This resulted in the national policy for rare diseases in India, which is very encouraging,” says Rajasimha. “This includes a nearly $60,000 USD grant from the government per patient toward their rare disease treatment. It’s not sufficient for certain rare diseases, where treatments can cost over $1 million. But it’s good enough for diseases like inborn errors of metabolism where nutritional supplements and other care options exist.”
The Indian grant for patients with rare diseases could be a game-changer for global rare disease R&D on many levels. “This makes India a potential market in global orphan drug launch strategies for biopharmaceutical sponsors in the U.S. and Europe who have predominantly taken the U.S. FDA, EMA, Japan approvals approach,” says Rajasimha. “It’s a long time before these products are commercially launched for patients in the rest of the world.”
The government grant for a lifetime of rare disease treatment in India, also makes setting up treatment sites for clinical trials in India a viable option, based on the economics of drug pricing and target patient population. “It’s an exciting time for all rare disease patients, but also for the biotechnology industry to accelerate their drug development programs and reconsider their global launch strategies, making India an important part of their launch strategy,” says Rajasimha.
Reaching, recruiting and retaining Indian patients in U.S. clinical trials
Essential prerequisites in driving clinical development programs for rare disease treatments include the development of inclusive patient registries and natural history studies. Sponsoring companies generally obtain this data from public databases developed by the NIH and patient advocacy foundations. While there is increasing awareness for the need for a global outlook in developing such registries, nearly 90% patient registries are still U.S. and Europe-centric and primarily Caucasian.
“If a patient does not exist in these registries, they just don’t exist when it’s time to analyze data and design strategies for clinical trials or commercial launches. Until the NIH’s All of Us precision medicine research initiative, programs suffered from severe lack of diversity,” says Rajasimha. “We are encouraging the Indian diaspora to contribute and participate in patient registries and natural history studies.”
Most parents of rare disease patients in India avoid programs that do not offer treatments. This often leads to disappointments. “When a clinical trial comes up, patients who have been participating in natural history studies get preference because they have baseline data against which the new treatment can be assessed for safety and efficacy,” says Rajasimha.
IndoUSrare conducts awareness programs across India to inform patient groups of such facts. Rajasimha points out that U.S.-based patient advocacy groups are more focused on developing registries and conducting natural history studies, which in time leads to the development of new therapies through collaborations with biotech companies.
In addition to the clinical trial processes, IndoUSrare educates patient groups on the risks and benefits of clinical trials, highlighting reasons as to why they should consider participation. “Clinical trials are likely to be better than standard-of-care, because the FDA would not approve a new drug to be tested on humans unless the benefit over the standard-of-care far outweighed the risk,” says Rajasimha.
Culturally aware clinical trial software
One of the barriers in reaching, recruiting, and retaining patients with rare diseases worldwide for clinical trials based in the U.S. and Europe is language. Online information on clinical trials is almost exclusively provided in English. “We need information on clinical trials and healthcare related to rare diseases, made available in local Indian languages to generate awareness among rural and urban populations across India, and among medical doctors, geneticists, and professionals,” says Rajasimha.
However, the barrier is more than linguistic, it’s cultural. Although direct translations of information available in English get across basic messages, software platforms must be culturally aligned to recruit and retain patients over the duration of clinical trials. Most clinical trial management software has been built with the Western, English-speaking population in mind.
“With growing adoption of decentralized virtual telemedicine approaches, there is need for multilingual and multicultural software platforms. That’s where Jeeva Informatics is headed,” says Rajasimha. “We need clinical trial software to be culturally aware and truly inclusive. We can bring in diversity, but if the platform doesn’t communicate in the patients’ language, in the style that each underrepresented minority population expects, patients are unlikely to stay and complete the trial.”
In addition to a lack of inclusivity, rare disease clinical trials generally lack efficiency from a time, cost and quality point of view. This unmet need led Rajasimha to establish Jeevatrials, an inclusive decentralized clinical trial (DCT) platform, which is being used for several rare disease patient registries, natural history studies, and cell and gene therapy trials in the U.S. and India.
“We want to increase the representation of Asian and Indian diaspora in clinical trials through this inclusive software, not just from a language point of view, but by being culturally aware,” says Rajasimha. “For example, various Indian communities observe different religious and social holidays, requiring culturally aware calendar scheduling. Other barriers include technology savviness. We make sure the software has the right features to engage and retain all patients in these clinical studies. We don’t want technology to be a barrier, but an enabler.”
Data sharing and privacy
Cross-border collaborations require safe and seamless data-sharing systems.
Data sharing across borders is not a technical problem, but a governance problem, which remains unsolved. Research data, including de-identified and aggregate data, remains largely inaccessible, even for non-profit organizations such as IndoUSrare.
“While India, China and other countries have massive whole-genome sequencers now and are sequencing either gene panels, exomes, or whole genomes, those datasets are available within those regions, but not necessarily shared globally,” says Rajasimha. “This is a major barrier that has to be overcome if we have to truly achieve cross-border collaborations and approach this as a global problem.”
Barriers in data sharing primarily stem from data protection and privacy concerns. The Indian Council for Medical Research (ICMR), that had set up a rudimentary rare disease national patient registry was recently hacked by ransomware and the attackers’ IP addresses were traced to neighboring countries. The registry remains inaccessible.
The Indian government’s efforts on health data regulations, akin to the US HIPAA (Health Information Portability and Accountability Act) or the EU GDPR (Global Data Production Regulation Act), are still a work in progress. However, India’s success in implementing financial data protection for digital payments makes Rajasimha optimistic about similar efforts in protecting health related data.
“A push is being made from the Prime Minister’s office for health data. That revolution is probably coming very soon, but we are not there yet,” says Rajasimha. “Patient advocacy groups in collaboration with medical researchers would be ideally suited to create, manage and steward such patient registries as they have a sense of urgency to drive these drug development programs. They can potentially collaborate with multiple biopharmaceutical companies to share data and drive drug development programs.”
Major programs
IndoUSrare is focusing on five programs at present. The first is a patient concierge service where the team compiles publicly available information from the NIH, FDA and other databases globally, for patients who contact the organization for assistance. “We encourage patients to go back to their respective medical doctors and seek medical advice based on that information,” says Rajasimha. “It’s a free service provided to any patient, anywhere in the world.”
IndoUSrare’s second program, the patient foundation alliance, helps identify, contact, and engage patients with rare diseases in India and include them in patient registries and other organizational efforts in the U.S. The program, which includes 33 advocacy organizations covering over 500 rare diseases and 25,000 patients, continues to expand.
The third program is the corporate alliance. “Ultimately, the goal of patient groups is to get a treatment option for a disease where no FDA-approved treatment exists, which is true for 93% of rare diseases,” says Rajasimha. In such cases, patient groups must collaborate with industry and induce them to develop new therapies. “Our corporate alliance program engages small, medium and large companies in partnership. We have five industry members, and aim to expand to more than 20 next year.”
IndoUSrare’s fourth program is to create a network of medical geneticists across India that comprises their research core. At present, the research core comprises about 80 medical geneticists trained by doctors who run the 10 centers of excellence for rare diseases recognized by the Indian government. “We access this network when a new member organization joins us,” says Rajasimha. “We ask them how many patients they have seen with this particular mutation or disease in their clinic, and we usually hear back from a handful of these doctors each time. We then connect the doctors and the patient groups.” For diseases that have no patient organizations in India, IndoUSrare provides resources in collaboration with organizations like Global Genes to help set up a new organization in India that then drives the program forward.
And finally, IndoUSrare advocates for rare disease issues with patient alliance members, and the EveryLife foundation by communicating with senators and congressmen in the U.S. at the bicameral and bilateral rare disease congressional caucus and the India caucus. Similarly, in India, IndoUSrare’s member organizations provide public comments on draft policies issued by the Ministry of Health and Family Welfare, DST [Department of Science and Technology], and DBT [Department of Biotechnology].
“We want to make rare disease, biotechnology and orphan drug development a core part of Indo-US relationships. It’s a win-win relationship. It’s not all charity or humanitarian but a necessity for a thriving cell and gene therapy industry to be able to recruit patients, which is the biggest bottleneck in therapy development,” says Rajasimha.
FDA draft policies box Asians and Pacific Islanders together. Lumping nearly half the world’s population into one box not only limits the diversity achievable in clinical trials, it poses a barrier in engaging the Indian diaspora. No statistics are available on the number of individuals of Indian origin participating in US clinical trials because all Indians are grouped under the same Asian and Pacific Islander radio button.
“We are encouraging the FDA to break that down because each subpopulation is unique. Indians and more broadly Asians continue to be underrepresented in US healthcare. It’s important we understand each subpopulation under the Asian and Pacific Islander umbrella,” says Rajasimha. “About 3.2% of clinical trial participants in the US are Asian American or Pacific Islander whereas the overall population is more like 6.8% of the US population. That’s about 50% less than their proportion in the US population. Globally, the underrepresentation is even more severe.”
Funding
The patient population recruited for orphan drug trials is in most instances a key factor in drug pricing
Funding rare disease clinical trials beyond the U.S., often comes with limiting conditions. Some U.S. funders require patients to travel to the U.S. to be enrolled in clinical trials, which can pose logistic problems. Rajasimha believes getting patients from anywhere in the world to qualified clinical trial sites in the US or Europe, is feasible for one-and-done treatments, such as cell and gene therapies, if remote long-term follow-ups are made possible for safety studies.
“For drug repurposing, small molecule-based or biologics-based studies there are very well qualified sites in India and countries in Africa where patients can be treated,” says Rajasimha. However, in these cases it is vital that sponsors make the drug commercially available in countries where patients are located after the clinical trial concludes, so that patients retain access to these treatments.
“U.S. companies don’t want to commercially launch the drug in India. Instead, they want to make drugs available to patients in India through a compassionate use program or an expanded access program where the sponsor hires a third-party nonprofit CRO that manages the logistics so that the supply chain is protected,” says Rajasimha. “This is an unsustainable model.”
Discussions among multiple stakeholders are needed for global collaborations that could make treatments for rare diseases available in India and other countries on a commercial basis.
Financial support for IndoUSrare’s charitable programs primarily relies on corporate partners and industry collaborations through their corporate alliance membership program. The nonprofit charges a nominal $50 membership fee for the patient alliance program from foundation members. IndoUSrare is currently seeking collaborations with orphan drug companies and philanthropic organizations to fund its diverse programs.
Some researchers are thinking outside the box to try to combat the growing antibiotic resistance crisis. One of the innovations has been the development of “living medicines” which use one living bacterium to kill another. In a new study, researchers developed a modified (non-pathogenic) version of Mycoplasma pneumoniae that attacks Pseudomonas aeruginosa—which is resistant to many types of antibiotics and is a common source of infections in hospitals. The modified M. pneumoniae was used in combination with low doses of antibiotics that would otherwise not work on their own.
The M. pneumoniae treatment significantly reduced lung infections in mice and doubled mouse survival rate compared to no treatment. Administering a single, high dose of the treatment showed no signs of toxicity in the lungs. And, once the treatment had finished its course, the immune system cleared the modified bacteria in a period of four days.
P. aeruginosa infections are difficult to treat, in part, because the bacteria forms biofilms which have an increased resistance to antibiotics.
One particularly challenging infection occurs when biofilms grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a condition that affects one in four (9–27%) patients who require intubation. The incidence exceeds 50% for patients intubated because of severe COVID-19. VAP can extend the duration in the intensive care unit for up to thirteen days and kills up to one in eight patients (9–13%).
In this study, M. pneumoniae was engineered to dissolve biofilms by equipping it with the ability to produce various molecules including pyocins—toxins naturally produced by bacteria to kill or inhibit Pseudomonas. To test its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of patients in intensive care units. They found the treatment penetrated the barrier and successfully dissolved the biofilms.
“We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” said María Lluch, PhD, staff scientist in the lab of Luis Serrano Pubul, PhD, at the Centre for Genomic Regulation (CRG) at the Catalan Institution for Research and Advanced Studies (ICREA) in Barcelona, Spain, and CSO at Pulmobiotics.
M. pneumoniae is one of the smallest known bacterial species. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for manipulation. One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue.
“The bacterium can be modified with a variety of different payloads—whether these are cytokines, nanobodies, or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” said Serrano.
In addition to designing the “living medicine,” Serrano’s research team is also designing new proteins that can be delivered by M. pneumoniae to target inflammation caused by P. aeruginosa infections. The inflammatory response is orchestrated by the release cytokines. One type of cytokine—IL-10—has well-known anti-inflammatory properties and is of growing therapeutic interest.
Research published by Serrano’s lab in the journal Molecular Systems Biology designed new versions of IL-10 optimized to treat inflammation. The cytokines were designed to be created more efficiently and to have higher affinity, meaning fewer cytokines are needed to have the same effect.
They then engineered strains of M. pneumoniae that expressed the new cytokines and tested their efficacy in the lungs of mice with acute P. aeruginosa infections. The engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild-type IL-10 cytokine.
“Live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases,” noted Ariadna Montero Blay, a PhD student in the Serrano lab. “Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”
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