Patients who have had high-risk polyps removed from their bowel can probably wait five years, rather than three, until their next colonoscopy without increasing their risk of colon and rectal cancer. This is shown by two new studies published in the New England Journal of Medicine, in which researchers from the Karolinska Institutet have participated. The findings, from ”Colonoscopy Intervals and Colorectal Cancer Incidence after Adenoma Removal” and “Colorectal Cancer Risk among Patients with Serrated Polyps” could reduce the number of examinations and thus the burden on both patients and the healthcare system.
Every year, around 1.9 million people worldwide are diagnosed with bowel cancer. To prevent the disease, many countries have introduced screening programmes that enable more polyps to be detected and removed before cancer develops.
However, some patients are assessed as being at increased risk of developing new polyps or cancer and are therefore recommended to undergo regular follow-up colonoscopies. These examinations are resource-intensive for the healthcare system and can be perceived as burdensome for patients.
The first results from the European Polyp Surveillance (EPoS) study, a large randomised research project on follow-up after polyp removal, are now being presented. In the EPoS II study, 10 799 patients across eight European countries who had previously had high-risk adenomas – a type of polyp – removed were followed up. Participants were randomised to undergo their first follow-up colonoscopy after either three or five years.
Low risk in both groups
After five years of follow-up, the risk of colorectal cancer was very low in both groups. Among those who waited five years for their first check-up, 0.77 per cent developed cancer, compared with 0.82 per cent among those examined after three years. Nor did the researchers observe any clear differences in how far the cancer had progressed when it was detected.
At the same time, the longer follow-up interval meant that the number of colonoscopies fell sharply. During the follow-up period, nearly 4200 fewer examinations were carried out in the group that waited five years for their first follow-up.
”More than 99 per cent of patients did not develop colorectal cancer within five years of the polyps being removed. “The results suggest that we need to reassess when these patients should be called in for their next colonoscopy,” says Hans-Olov Adami, Professor Emeritus at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet, who coordinated the Swedish part of the research project.
At the same time, the researchers are presenting results from the parallel EPoS III study, which involved 1,861 patients with so-called serrated polyps, another type of polyp that can also be a precursor to cancer. In that group, too, the risk of cancer was low. After five years, around one per cent of the participants had developed colorectal cancer and none had died from the disease.
“The low risk of cancer was observed in both patients with high-risk adenomas and those with serrated polyps. This also underlines the importance of the first colonoscopy, as the studies are based on the polyps having been detected and completely removed,” says Hans-Olov Adami.
Many people who report with TB symptoms at South Africa’s public sector clinics do not receive TB tests. Testing more of these people is one of the most effective things we can do to reduce rates of TB disease and death, according to a major new modelling study.
While South Africa has made substantial progress against tuberculosis (TB), we are not on track to meet key targets set for 2030. This is according to a new modelling paper published in the journal Global Health Action.
TB incidence in South Africa was projected to decline by 46% by 2030, relative to a 2015 baseline. The World Health Organization (WHO) End TB target adopted by South Africa aimed at an 80% reduction in incidence. TB mortality was projected to decline by 54%, against the End TB target of 90%.
The researchers also published uncertainty intervals around these estimates. Even though these intervals are relatively wide, their upper limits are below the End TB targets, suggesting that it is unlikely that South Africa will reach the targets by 2030. The modelling however also identified interventions that could help South Africa get closer to the targets.
The new research is an extension of Thembisa, an existing mathematical model of HIV and TB in South Africa. University of Cape Town epidemiologist Dr Leigh Johnson, who is the lead author of the new study, is also the key driving force behind Thembisa.
Identifying what works
The researchers estimated which of a long list of interventions would have the greatest impact against TB. In technical terms, they looked at how varying 27 different parameters linked to TB interventions impacted projected TB incidence and mortality from 2025 to 2040 by calculating correlation coefficients (see the paper for a more nuanced explanation).
They found that the greatest reductions in TB would be achieved if a high percentage (89%) of people reporting with TB symptoms were tested using new point-of-care TB tests. This would result in a 49% reduction in average TB incidence and a 67% reduction in average TB mortality, relative to a scenario in which there are no changes to current programmes. TB symptoms include persistent cough, chest pain, night sweats, fever, and unexplained weight loss. There is good evidence that many people who report with these symptoms at clinics are not offered molecular TB tests.
The World Health Organization earlier this year recommended the use of such new point-of-care TB tests. These tests aren’t yet in general use in South Africa, although they are being evaluated in pilot projects. The new tests can be run on both sputum and tongue swabs. For now, most molecular TB tests in South Africa still involve someone producing a sputum sample – which some people struggle with – and the sample being transported to a lab for testing.
The researchers also found that high rates of door-to-door testing with the new point-of-care tests could reduce TB incidence and mortality by 38% and 49% respectively, while combining high rates of door-to-door testing and digital chest X-ray screening in asymptomatic individuals could reduce TB incidence and mortality by 17% and 21%.
Even without the new tests, there are substantial gains to be had if testing was stepped up in people with symptoms. TB incidence could be reduced by as much as 29% if the level of sputum testing in individuals seeking care for TB symptoms were increased to the upper bound considered by the researchers.
Once people have been diagnosed with TB and start taking TB treatment, they typically become non-infectious within around two weeks. Diagnosing people more quickly thus results in people remaining infectious for shorter periods, thus slowing TB transmission.
Other influential parameters identified by the researchers include the extent to which COVID-19-related behaviour changes are sustained, the rate at which people living with HIV start taking antiretroviral treatment (untreated HIV is a major driver of TB), and the combined uptake and efficacy of 3HP, a relatively new form of TB preventive therapy.
Testing is the key
“We found that the rate of testing in people seeking treatment for TB symptoms is the most important driver of future TB incidence and mortality,” wrote the authors.“This finding is not surprising given the historically low rates of TB testing. In studies of patients seeking treatment for TB symptoms in South African health facilities, the proportion who received a TB test has been highly variable, ranging from 3% to 84%, with a median of only 30%. Similarly low rates have been reported in other countries with high TB burdens.”
The study authors write that these low rates of testing reflect the non-specificity of TB symptoms and healthcare workers’ concerns about the cost and time required to collect sputum specimens and to send them to a central laboratory for molecular testing. In one South African study, they point out that 36% of all people attending clinics had symptoms suggestive of TB.
“Conducting TB testing in such a large fraction of primary care attendees may be infeasible,” they write.
“Achieving high levels of testing in people with TB symptoms could require levels of laboratory testing beyond current testing capacity. However, new point-of-care tests performed on tongue swabs or sputum present an important opportunity to increase levels of TB testing in symptomatic individuals at reduced cost, without placing additional strain on laboratories.”
In addition to reduced cost, the new point-of-care tests also offer quicker results and have lower operational requirements. The main potential benefit of these tests over existing lab tests is thus that they are likely to be used much more frequently.
Regardless of the testing platform, the study authors argue there is a need to strengthen adherence to existing guidelines for systematic testing of all patients with symptoms suggestive of TB and that we need a larger healthcare workforce dedicated to TB diagnosis, better supply chains, and better monitoring systems to identify where and why symptomatic patients are not being tested.
Disclosure: The study reported on here was supported by the Gates Foundation. Spotlight receives funding from the Gates Foundation, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
A SANBS and Round Table Southern Africa partnership has helped bring more than 600 new donors into the blood donation network
A new five-part docuseries, Tafel Toure, from Round Table Southern Africa takes viewers inside the community projects driven by its members across the country. One episode takes viewers to the SANBS donor centre in Welkom, where Round Table members see first-hand what happens when ordinary South Africans make the decision to give blood and why those donations matter to patients in need.
The episode comes at a critical time for South Africa’s blood supply, with SANBS blood stock levels having declined below five days’ cover. The blood service is urging eligible South Africans to donate and help replenish stocks, particularly as regular donations are essential to maintaining a safe and sufficient blood supply.
For Round Table member and regular blood donor Stephan Theunissen, giving blood has become part of how he contributes to his community. The documentary follows him at the SANBS donor centre in Welkom as he shares why he continues to donate and encourages others to do the same.
“Giving blood is one of the simplest ways we can make a difference in our communities. You may never know whose life your donation will touch, but knowing that something as simple as taking an hour out of your day could help someone in need is what keeps me coming back and encouraging others to donate too,” says Theunissen.
Alongside Stephan’s personal experience, SANBS Donor Relations Practitioner Bronwyn Petersen takes viewers beyond the donation chair, explaining who can donate and why different blood components are needed.
“O-negative can be given to anyone in an emergency, and plasma helps stop severe bleeding and stabilise patients in trauma. Together, they’re often the first things a hospital reaches for when every second counts, which is why we always need more donors of both,” says Bronwyn.
Viewers are taken through the donation process alongside the presenter, offering a behind-thescenes look at what happens from the moment a donor arrives at the centre to the point where their donation becomes part of the blood supply.
The episode also highlights the growing impact of the SANBS and Round Table Southern Africa partnership, which has contributed to more than 600 new donors and over 100 blood drives.
As South Africa marks Heritage Month, the partnership provides a powerful example of how community action and a shared commitment to giving back can create a lasting impact.
“Round Table Southern Africa has always believed that real impact starts when ordinary people choose to get involved. Our partnership with SANBS is a powerful example of that. Through TafelToere, we hope to not only showcase what our members are doing in their communities, but also inspire more South Africans to put up their hands, donate blood and make a difference. One donation, one hour and one decision can ultimately help save a life,” says Wessels Dreyer, incoming President of Round Table Southern Africa.
Monique Schreiner, Senior Manager: Donor Relations at the South African National Blood Service, says the partnership demonstrates how community-driven action can help strengthen the country’s blood supply.
“We have fallen below five days’ blood stock cover, and this is a critical reminder of why regular blood donation matters. Every day, patients across South Africa rely on blood and blood products for emergency care, surgery and ongoing medical treatment. Partnerships such as the one with Round Table Southern Africa help us reach new donors and show people the real impact of their decision to donate,” says Schreiner.
She adds that the documentary offers viewers a behind-the-scenes look and builds greater understanding of the blood donation journey.
“Blood donation is a powerful example of how an individual act can have a far-reaching impact. Through this documentary, we have an opportunity to show people what happens behind the scenes and remind eligible South Africans that their decision to donate can help ensure blood is available when a patient needs it most.”
For Round Table, the episode is an opportunity to encourage more young men to see blood donation as a simple but meaningful way to contribute to their communities. The call, however, extends beyond Round Table’s membership, with eligible first-time, regular and lapsed donors all encouraged to play their part in maintaining South Africa’s blood supply
.Watch the Round Table Southern Africa docuseries, Tafel Toure, and follow Stephan Theunissen and the SANBS team as they take viewers behind the scenes of blood donation.
A new preclinical study led by investigators from Mass General Brigham offers a potential explanation for two longstanding questions in allergy: Why do allergies often emerge only after repeated exposure, and why do people with one allergy frequently develop others? The findings are published in Immunity.
The team’s earlier work revealed that sensory neurons can directly sense certain allergens and help start the allergic immune response. The new study shows that these neurons do not simply detect allergens in the moment but can retain a metabolically encoded record of previous exposures that allows them to respond more strongly to later exposures, even after the original allergen is gone.
“Now that we know what may cause people to become allergic and pick up more sensitivities, we can design ways to stop it from happening,” said senior author Caroline L. Sokol, MD, PhD, a physician-scientist at Mass General Brigham.
“What is especially encouraging is that allergic memory in neurons faded with time in our models,” Sokol said. “We are now investigating whether we can deliberately reset this memory, which could ultimately offer a way to reduce the risk of developing allergies.”
The study grew from a familiar clinical observation – people tend to encounter the same pollen, pets or foods repeatedly before developing an allergy. Drawing on her perspective as a clinician, scientist and allergy sufferer, Sokol wondered whether the nervous system might help explain this delay.
“Neurons are known for their ability to form memories,” Sokol said. “We asked whether an initial allergen exposure might leave a trace – not enough on its own to trigger a full allergic response, but enough to prime the neurons to respond more strongly the next time.”
To test this idea, the researchers modelled recurrent allergen exposure in mice and found that an initial exposure activates a specific signaling pathway in neurons. This pathway not only primes them to later respond to the same allergen, as the team hypothesized, but also to other allergens that share the same enzymatic activity but have different molecular structures.
This suggests that sensory neurons may remember a shared feature of allergens rather than their precise molecular identity. This cross-allergen response may help explain why developing sensitivity to one allergen can increase susceptibility to others.
Healthcare access in South Africa is increasingly shifting towards prevention, early intervention and more accessible primary healthcare. Yet for many communities, accessing healthcare can still mean long waiting times, travel and delays in receiving care.
As pressure on the healthcare system continues, there is an opportunity to make better use of healthcare professionals who are already accessible within communities.
For many people, the pharmacist’s role has traditionally been associated primarily with dispensing medication. But the profession has evolved significantly. Pharmacists are increasingly contributing to medicine optimisation and adherence, chronic disease support, health screening and other primary healthcare services within their scope of practice.
According to Tanya Ponter, Pharmacy Director at Dis-Chem, pharmacists are equipped with skills that extend well beyond the dispensing of medicines.
“Pharmacists are trained to interrogate symptoms, review evidence and metrics that identify risk and make life saving decisions under pressure. Their expertise places them in a unique position to support patients beyond the traditional dispensing function and contribute to earlier intervention and better health outcomes.”
This evolving role is particularly important as South Africa looks for ways to improve access to primary healthcare. Pharmacists are often accessible within communities and can provide guidance, identify potential health risks and, where appropriate, refer patients to other healthcare professionals. What’s more, they are the most accessible clinical touchpoint for consumers and are always available to provide expert advice at no cost to patients.
“Expanded pharmacist-led services have the potential to reduce existing pressure on the healthcare system, with these professionals often being a first point of contact for patients in communities. Their presence can help address appropriate healthcare needs earlier and potentially reduce unnecessary demand on higher levels of care,” says Ponter.
With rising rates of chronic conditions like diabetes, hypertension, and HIV, pharmacists play an ongoing role in long-term wellness. To support complex patients who often take multiple pills, they offer guidance and medication reviews to simplify regimens and eliminate unnecessary or duplicate treatments.
As South Africa marks World Pharmacists Day, Ponter states that the profession should increasingly be viewed as an integral part of the country’s primary healthcare ecosystem.
“Pharmacists should not simply be seen as the final step between patients and prescriptions. They can help bridge the gap between communities and healthcare by supporting prevention, identifying risks earlier and helping patients navigate the healthcare system, particularly when barriers make accessing other healthcare services more difficult,” Ponter concludes.
Children prescribed GLP-1 medications for weight loss, prediabetes or type 2 diabetes are at risk for nutritional deficiencies – diagnosed in nearly one in six patients (16.8%) within the first year – according to new research from scientists at Northwestern University and Ann & Robert H. Lurie Children’s Hospital of Chicago.
Vitamin D deficiency was the most common, identified in 12.4% of children within one year of GLP-1 treatment, the study found.
“As appropriate paediatric use of GLP-1s becomes more widespread, we need to understand the risks during periods of rapid growth and pubertal development,” said senior author Justin Ryder, associate professor of surgery and paediatrics at Northwestern University Feinberg School of Medicine and vice chair of research for the department of surgery at Lurie Children’s. “Nutrients such as vitamin D, iron and calcium are of particular concern during adolescence, when deficiencies may have lasting implications for skeletal health and overall development.”
“Nutritional support needs to play a critical role once treatment with a GLP-1 medication is initiated,” he said. “In our study, however, we found that only 5% of patients received nutritional counselling within 30 days of GLP-1 treatment and less than 25% received nutritional counselling within 6 months.”
The scientists used national administrative claims data from 2017 to 2022 covering over 100 million patients to identify 2,031 GLP-1 users aged 10–17 years who met continuous enrollment criteria and had no prior diagnosis of nutritional deficiency. In this sample, the most prescribed GLP-1s were liraglutide (78.6%), dulaglutide (10.4%) and semaglutide (9.1%).
“We hope that our study findings bring much-needed recognition to the importance of proactive nutritional management when GLP-1s are prescribed to children, as opposed to waiting until a nutritional deficiency is diagnosed,” Ruder said. “Knowing the risks, we are in a much better position to prevent harm to children treated with GLP-1s during a pivotal period in their lives.”
Researchers at National Jewish Health have identified a key way oestrogen receptor alpha (ERα) helps protect the right side of the heart in pulmonary hypertension. The preclinical findings reveal that ERα preserves the survival and movement of endothelial cells, which line blood vessels, allowing the stressed heart to maintain the small vessels it needs to function.
The study, published online Sept. 10 in Arteriosclerosis, Thrombosis, and Vascular Biology, may help explain an important difference between women and men with pulmonary hypertension and points to a potential path for developing therapies tailored to the right ventricle, the chamber that pumps blood through the lungs.
Pulmonary hypertension causes abnormally high pressure in the blood vessels of the lungs. That pressure forces the right ventricle to work harder, and a patient’s outlook depends heavily on how well the chamber adapts. Although women are more likely to develop certain forms of pulmonary hypertension, their right ventricles often function better than those of men. Researchers have been working to understand the biology behind that apparent paradox.
“We know that the right ventricle is a major driver of survival in pulmonary hypertension, but we still have very few treatments designed specifically to protect it,” said pulmonologist Tim Lahm, MD, senior author of the study and a researcher at National Jewish Health. “These findings show that oestrogen receptor alpha is doing important work inside the blood vessels of the right heart, particularly in females, by helping endothelial cells survive, move and build the vascular network the heart needs under stress.”
Using preclinical models of pulmonary hypertension and right ventricular pressure overload, researchers examined how ERα affects the endothelial cells that line blood vessels in the right side of the heart. When normal ERα function was disrupted, these cells were less able to migrate, form vessel-like networks and maintain the capillaries needed to support the heart under increased pressure. The effects were more pronounced in females and included increased endothelial cell death, greater enlargement of the right ventricle and reduced capillary density.
Single-nucleus RNA sequencing provided additional insight into the underlying mechanisms. In females with impaired ERα function, endothelial cells showed reduced activity in pathways involved in cell movement and increased activity in pathways associated with cell death. These changes were not observed to the same degree in males, further supporting a sex-specific role for the receptor.
“A healthy network of capillaries is essential when the right ventricle is working against increased pressure,” Dr Lahm said. “By showing how ERα supports that network, this work gives us a more precise biological target to investigate.”
The findings do not establish oestrogen or ERα-targeted therapy as a treatment for patients yet, but are an important first step. Additional research is needed to confirm the mechanism in people and determine whether it can be translated into a safe and effective therapy.
Initial chest radiograph in a 47-year-old man with silicosis showing subtle opacities in the right lower zone. CMAJ, 2026.
A case study in the Canadian Medical Association Journal describes a 47-year-old man who visited an emergency department for a minor injury to his lung and was found to have lung nodules after a computed tomography (CT) scan. He was diagnosed with silicosis. He had worked with engineered stone for the past 10 years for a company that made countertops and, after diagnosis, he was advised to stop exposure.
During the next 18 months, after referral to an occupational lung disease clinic, the patient’s lung condition worsened. He is currently awaiting assessment for a lung transplant.
“This case example supports calls for regulatory reform, mandatory surveillance, and proactive worker education in industries using engineered stone,” writes Dr Susan Tarlo, respiratory physician at University Health Network (UHN) and professor of medicine, Department of Medicine and Dalla Lana School of Public Health at the University of Toronto, Toronto, Ontario, with coauthors. “It underscores the health risks from the absence of adequate occupational health monitoring.”
Linking cases of silicosis to working with engineered stone has been fairly recent, with the earliest cases reported in the early 2010s in Spain and Italy then other parts of the world.
People who work in small businesses that may use dry cutting and processing techniques may be more vulnerable than those working at larger companies who mandate wet cutting and safety protocols. A large proportion of people affected are immigrants or members of racialised or marginalised communities who may face language barriers, lack insurance, or lack access to occupational health supports.
Australia has banned the use of engineered stone because of the health hazards associated with manufacturing.
The authors urge awareness for workers and health care practitioners.
“Health care providers should consider this diagnosis in patients working with engineered stone, and in countertop manufacturing and fitting, since early identification and removal from further exposure can greatly improve the prognosis.”
“In the absence of a ban on the use of engineered stone, increased knowledge among workers and health care practitioners is essential for implementing preventive measures, raising clinical awareness, informing policy decisions, and guiding future public health interventions,” the authors conclude.
Emergency contraception containing mifepristone prevents more pregnancies with fewer side effects than some other common emergency contraceptive pills such as levonorgestrel, according to a new Cochrane review involving 87 trials.
Emergency contraception is used to prevent pregnancy after unprotected sex. It can be used when no contraception was used or if a contraceptive method fails, as with a broken condom, or in the event of sexual assault.
Common methods of emergency contraception include copper intrauterine devices and pills. The most widely used pill is levonorgestrel, a progestin-only medication sold in many countries as “Plan B,” “Next Choice,” or similar brand names. An alternative is the Yuzpe regimen, an older method that combines oestrogen and progestin.
More effective, fewer side effects
The review, led by researchers from Oregon Health & Science University, USA, pooled data from 87 randomised controlled trials involving approximately 36 000 women of reproductive age. The majority of studies (79 trials) were conducted in China, with additional trials from the UK, Cuba, and multi-country settings. The authors compared mifepristone against levonorgestrel, the Yuzpe regimen, and copper intrauterine devices.
Compared with levonorgestrel, both low-dose (under 25mg) and mid-dose mifepristone (25-50mg) prevented more pregnancies and were associated with fewer overall side effects. Low-dose mifepristone showed a 27% relative reduction in pregnancies compared with levonorgestrel. This was rated as high-certainty evidence, meaning that further research is very unlikely to change the result.
When compared with the Yuzpe regimen, mifepristone showed an even larger advantage, cutting pregnancy risk substantially while also sharply reducing rates of nausea and vomiting. Evidence comparing mifepristone with copper intrauterine devices remained too limited to draw firm conclusions, based on only two included trials.
“Mifepristone in low-to-mid doses is a highly effective emergency contraceptive option that clinicians should know about,” explains Dr Shaalini Ramanadhan, lead author of the review. “As an anti-progestin, it works differently than the other steroid hormone-based methods like levonorgestrel and combined oestrogen and progestin pills to delay or block ovulation. This different mechanism is part of why it has a different side-effect profile compared to the other two methods.”
The main trade-off identified across nearly all comparisons was a lower risk of nausea and vomiting with mifepristone, but a higher likelihood of delayed menstruation compared with other types of emergency contraception. Given that a delay in menstruation could be interpreted as a sign of treatment failure or pregnancy, the authors explain that this side effect could be a potential source of stress and anxiety for individuals seeking emergency contraception.
Where reported, however, treatment satisfaction was equal to or higher among those who received mifepristone versus alternative methods.
Political and legal barriers limit access
Despite the strong evidence behind the drug’s effectiveness as emergency contraception, the authors note there are still many barriers to access.
In some countries, drug authorities have approved mifepristone at higher doses (typically 200 mg) in combination with misoprostol specifically for medical termination of early pregnancy, not as emergency contraception. Scientific evidence is growing around the potential use of mifepristone and other anti-progestins as a routine method of contraception, for treating fibroids, for preventing and treating breast cancer, and for treating abnormal bleeding. However, because mifepristone is widely associated with abortion, it also faces intense political scrutiny, legal restrictions, and targeted bans and barriers in various countries.
Expanding options for emergency contraception is important. The evidence shows that mifepristone has benefits beyond abortion care, including as an effective form of emergency contraception. In some countries, recognition of this additional use may help expand access, increase familiarity with the medication, and create new opportunities for people to benefit from it.
– Dr Shaalini Ramanadhan, Oregon Health & Science University
A new study led by Stanford Medicine found the brain is two separate organs adjacent to one another. The finding could aid research into devastating neurological diseases.
AI image generated with Grok
For centuries, scientists have thought of the brain as a single, unified organ. But new research led by Stanford Medicine reveals that what we call the brain is two distinct organs that evolved independently over hundreds of millions of years.
The discovery overturns a prevailing model of brain development. For decades researchers have subscribed to the theory that there is a single progenitor cell early in development that gives rise to the entire brain. This model suggested all parts of the brain shared a common developmental origin.
The new research finding shows that the human brain consists of two ancient nervous systems cleverly packaged together — a more primitive part that regulates our hearts’ beating, our breathing and other functions, and another that makes us distinctly human, capable of poetry, mathematics and wondering about our own origins.
The discovery could help explain why scientists have struggled for decades to grow certain types of brain cells in the laboratory — and it opens new avenues for studying devastating diseases that affect the brain stem, such as spinal muscular atrophy (also known as SMA) and amyotrophic lateral sclerosis (also known as ALS or Lou Gehrig’s disease).
“We’ve shown for the first time that the front of the brain arises from a totally different progenitor cell than the back of the brain,” said Kyle Loh, PhD, associate professor of developmental biology. “Our discovery means that we can now grow neurons from the back of the brain, the hindbrain, in a petri dish and study their functions.”
The findings were published in Nature Neuroscience Sept. 18. Loh is the senior author. Graduate students Carolyn Dundes and Rayyan Jokhai are co-first authors of the research.
Two brains
The adult brain has three main regions: the forebrain, midbrain and hindbrain. The forebrain handles higher-level thinking — language, consciousness and abstract reasoning. In contrast, the hindbrain, located at the back of the skull and often called the brain stem, controls essential, automatic functions that keep us alive: breathing, sleeping, and regulating our heartbeat and hunger urges. The hindbrain neurons also control the muscles of the face, tongue and throat, which affect speech and swallowing.
Despite the critical importance of the hindbrain, scientists have struggled for decades to generate human hindbrain neurons in the laboratory. This gap has hampered research into devastating diseases affecting the brain stem, including spinal muscular atrophy and amyotrophic lateral sclerosis.
SMA is a leading genetic cause of death in children under 1 year of age. ALS, which is often diagnosed between the ages of 40 and 70, affects both the forebrain and the hindbrain. In both disorders, certain hindbrain neurons gradually cease to function, and the patient loses the ability to swallow, which can cause pneumonia when food or liquid is inhaled into the lungs; eventually, patients lose the ability to breathe.
The researchers’ breakthrough came from studying the earliest moments of embryonic development, during a stage called gastrulation when the body first takes shape. Jokhai and Dundes discovered that the hindbrain follows a separate developmental path, running in parallel to — rather than branching off from — the pathway that creates the forebrain and midbrain.
The researchers learned this from examining developing mouse embryos. They identified two different brain progenitor cells. One, which expresses a gene called Otx2, is destined to become the forebrain and midbrain. The other, which expresses a gene called Gbx2, is committed to forming the hindbrain. They showed that these two cell populations never overlap; they are mutually exclusive from the earliest stages of development.
The team then examined the DNA packaging, or chromatin, in these cells. Chromatin is a way cells determine which genes can be easily accessed and which are bundled away out of reach. What they found was striking: The anterior neural ectoderm (future forebrain and midbrain) and posterior neural ectoderm (future hindbrain) have fundamentally different chromatin configurations. These differences essentially locked each progenitor cell into its respective fate, like travelers on parallel tracks that never cross.
“Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” Jokhai said.
This revelation explained decades of frustration in the field — scientists had been trying to turn one type of progenitor cell into another that it is fundamentally incapable of becoming.
“In stem cell biology, people are always fixated with creating the end cell type, like the neuron,” Jokhai said. “But it’s important to begin at the earliest stages of embryonic development. Our careful attention to that early time point allowed us to find this fundamental split in brain development.”
Growing hindbrain neurons
Armed with this knowledge, the researchers for the first time successfully coaxed human pluripotent stem cells (a kind of cell that can create any cell in the human body) to become functional hindbrain motor neurons in the laboratory. These lab-grown neurons displayed all the hallmarks of authentic hindbrain cells: They exhibited waves of electrical activity called action potentials and made proteins that identify the segments of the hindbrain that control facial and swallowing muscles.
Finally, the researchers looked back over 550 million years of evolutionary time. They found the same two-origin brain pattern in chickens; zebrafish; and, remarkably, in acorn worms, tiny creatures living on the ocean floor that share a distant common ancestor with humans. Jellyfish, which diverged from humans about 600 to 700 million years ago, have two nervous systems at different ends of their body.
“Our research suggests that evolution took two existing neural systems and pushed them together spatially,” Loh said. “Having the brain as one organ would probably be more efficient, but we rely on this primordial way to make the brain as two separate pieces.”
“I was surprised at our findings because the word ‘brain’ implies a contiguous organ that likely has a singular origin,” Jokhai said. “But even 500 million years ago, there were these separate neural systems, which now almost operate as one, which is very cool.”
The research also has implications for investigating treatments for SMA, ALS and other conditions affecting the brain stem. Until now, studying these diseases has been nearly impossible because scientists cannot obtain brain stem tissue from living patients. The ability to grow these neurons in a dish opens new possibilities for understanding what goes wrong. There’s even an unexpected connection to obesity treatment: The hindbrain contains circuits that regulate hunger — which is precisely how weight-loss drugs like semaglutide work.
The researchers would like to extend their studies to determine the developmental origins of the spinal cord and to learn exactly how SMA and ALS compromise the function of hindbrain neurons.
“Now we have a model to better understand these devastating diseases, and work toward regenerative therapies for them,” Jokhai said. “This is a very exciting new frontier in brain research.”
