The brain is an incredibly complex and active organ that uses electricity and chemicals to transmit and receive signals between its sub-regions. Researchers have explored various technologies to directly or indirectly measure these signals to learn more about the brain. Functional magnetic resonance imaging (fMRI), for example, allows them to detect brain activity via changes related to blood flow.
Yen-Yu Ian Shih, PhD, professor of neurology and associate director of UNC’s Biomedical Research Imaging Center, and his fellow lab members have long been curious about how neurochemicals in the brain regulate and influence neural activity, blood flow, and subsequently, fMRI measurement in the brain.
A new study by the lab has confirmed their suspicions that fMRI interpretation is not as straightforward as it seems.
“Neurochemical signalling to blood vessels is less frequently considered when interpreting fMRI data,” said Shih, who also leads the Center for Animal MRI. “In our study on rodent models, we showed that neurochemicals, aside from their well-known signalling actions to typical brain cells, also signal to blood vessels, and this could have significant contributions to fMRI measurements.”
Their findings, published in Nature Communications, stem from the installation and upgrade of two 9.4-Tesla animal MRI systems and a 7-Tesla human MRI system at the Biomedical Research Imaging Center.
When activity in neurons increases in a specific brain region, blood flow and oxygen levels increase in the area, usually proportionate to the strength of neural activity. Researchers decided to use this phenomenon to their advantage and eventually developed fMRI techniques to detect these changes in the brain.
For years, this method has helped researchers better understand brain function and influenced their knowledge about human cognition and behaviour. The new study from Shih’s lab, however, demonstrates that this well-established neuro-vascular relationship does not apply across the entire brain because cell types and neurochemicals vary across brain areas.
Shih’s team focused on the striatum, a region deep in the brain involved in cognition, motivation, reward, and sensorimotor function, to identify the ways in which certain neurochemicals and cell types in the brain region may be influencing fMRI signals.
For their study, Shih’s lab controlled neural activity in rodent brains using a light-based technique, while measuring electrical, optical, chemical, and vascular signals to help interpret fMRI data. The researchers then manipulated the brain’s chemical signalling by injecting different drugs into the brain and evaluated how the drugs influenced the fMRI responses.
They found that in some cases, neural activity in the striatum went up, but the blood vessels constricted, causing negative fMRI signals. This is related to internal opioid signaling in the striatum. Conversely, when another neurochemical, dopamine, predominated signaling in striatum, the fMRI signals were positive.
“We identified several instances where fMRI signals in the striatum can look quite different from expected,” said Shih. “It’s important to be mindful of underlying neurochemical signaling that can influence blood vessels or perivascular cells in parallel, potentially overshadowing the fMRI signal changes triggered by neural activity.”
Members of Shih’s lab, including first- and co-authors Dominic Cerri, PhD, and Lindsey Walton, PhD, travelled to the University of Sussex in the United Kingdom, where they were able to perform experiments and further demonstrate the opioid’s vascular effects.
They also collected human fMRI data at UNC’s 7-Tesla MRI system and collaborated with researchers at Stanford University to explore possible findings using transcranial magnetic stimulation, a procedure that uses magnetic fields to stimulate the human brain.
By better understanding fMRI signaling, basic science researchers and physician scientists will be able to provide more precise insights into neural activity changes in healthy brains, as well as in cases of neurological and neuropsychiatric disorders.
A massive and long-awaited study of an experimental tuberculosis vaccine has kicked off in South Africa. Marcus Low reports.
Photo by National Cancer Institute
By Marcus Low for Spotlight
The first jabs in a much-anticipated clinical trial of an experimental tuberculosis (TB) vaccine have been administered at a clinical trial site at the University of the Witwatersrand in Johannesburg. Up to 20 000 people are anticipated to take part in the study, according to study sponsor, the Bill and Melinda Gates Medical Research Institute (Gates MRI).
The study will be conducted at 60 different sites in South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. The researchers estimate that between 50% and 60% of the study participants will be in South Africa.
The experimental vaccine called M72/AS01E (M72 for short) made waves in 2018 and 2019 when it was found to be around 50% effective at preventing people with latent TB infection from falling ill with TB over a three-year period in a phase 2b clinical trial. In June 2023, it was announced that, after some delays, $550 million in funding had been secured for a phase 3 study of the vaccine. Medicines or vaccines are typically only registered and brought to market after being shown to be safe and effective in large, phase 3 clinical trials.
While most cases of TB can be cured using a combination of four antibiotics for four or six months, TB rates are declining relatively slowly and it is widely thought that an effective vaccine would help bring TB rates down much more quickly. The World Health Organization estimates that at the level of protection seen in the phase 2b trial, the vaccine could potentially save 8.5 million lives and prevent 76 million people from falling ill with TB over a 25-year period. The one TB vaccine we already have, called bacille Calmette-Guerin (BCG), is over a century old and only provides limited protection against severe illness for children and no protection for adolescents or adults.
“Reaching Phase 3 with an urgently needed TB vaccine candidate is an important moment for South Africans because it demonstrates that there is a strong local and global commitment to fight a disease that remains distressingly common in our communities,” said Dr Lee Fairlie, national principal investigator for the trial in South Africa, in a media statement released by Gates MRI.
“South Africa also has considerable experience with TB- and vaccine-related clinical trials and a strong track record for protecting patient safety and generating high quality data essential for regulatory approvals.”
Fairlie is also the Director of Maternal and Child Health at the Wits Reproductive Health and HIV Institute at Wits University.
The initial response from TB activists was positive.
“TB Proof (a South African TB advocacy group) is delighted that the M72 phase 3 trial has been launched,” the organisation’s Ruvandhi Nathavitharana and Ingrid Schoeman told Spotlight. “Having an effective TB vaccine is critical for TB elimination efforts.”
While he said it is good to finally see the phase 3 trial of M72 get underway, Mike Frick, TB co-director at Treatment Action Group, a New York-based TB advocacy organisation, went on to say:
“The fact that we had to wait so long between phase II and phase III says everything one needs to know about the headwinds – financial, political, commercial – that TB research is up against.”
How the study will work
Half of the up to 20 000 study participants will receive the M72 jab and the other half a placebo. The vaccine is administered as two intramuscular injections given a month apart. After being jabbed, study participants, all aged 15 to 44, will be followed for four years from the date of the first study participant being enrolled to see if they fall ill with TB.
“The plan is to complete enrolment in 2 years,” Fairlie and Alemnew Dagnew, clinical lead for the trial, told Spotlight in response to written questions. They explained that the actual duration of the trial will depend on how long it takes for 110 people in the study to fall ill with TB. According to the Gates MRI statement, the study is expected to take around five years to complete.
According to Fairlie and Dagnew, the majority of study participants (around 18 000 people) will be people who are HIV negative and who have latent TB infection – that is to say people who have TB bacteria in their lungs, but who are not ill with TB. Latent TB infection is thought to be very common in South Africa and only around 10% of people with latent infection ever fall ill with TB. In the study, latent infection will be tested for using a type of test called an IGRA (Interferon-Gamma Release Assay).
Around 1000 HIV negative people with no TB infection will also be recruited to the study. This is being done to make sure the vaccine is safe and effective in this group of people – while latent infection will be tested for in the study, in the real world such testing may not always be feasible prior to vaccination.
It is anticipated that 1000 of the 20 000 study participants will be people living with HIV. Establishing how well the vaccine works in people living with HIV is important since around 13% of people in South Africa are living with HIV and HIV substantially increases the risk of falling ill with TB. The main phase 2b study of M72 did not include people living with HIV although another phase 2 study looked specifically at the safety and immunogenicity of M72 in people living with HIV – according to Fairlie and Dagnew, “that trial “was completed and supported the inclusion of such participants in a phase 3 trial”.
Smaller than previously thought
When funding for the phase 3 trial was announced last year, it was estimated that 26 000 people would participate in the study. That number has now been revised down to 20 000.
“As a result of ongoing discussions between the institute and our funders, the decision was taken to review the study protocol with the intent of simplifying the study given its size and complexity. This will not affect the safety of the trial. It is common to continue to refine a protocol. We found a way to expedite the study that would potentially allow us to offer the public health impact of this vaccine to those in need sooner. All partners, including the trial funders, are fully aligned to the protocol refinements,” Fairlie and Dagnew explained to Spotlight.
“Some assumptions used to inform the design of the first protocol were deemed overly conservative, so the clinical team used slightly less conservative assumptions on vaccine efficacy and TB incidence rate, thus allowing for a reduction in the number of participants in the trial, while still retaining the primary goal of confirming the safety and efficacy of the M72/AS01-E-4 vaccine for prevention of TB, guided by the final results of the phase 2b study completed several years ago.”
Planning for access
The development of M72 has taken a somewhat unusual path – with the pharmaceutical company GSK leading development up to the end of phase 2b and then largely passing the baton to Gates MRI with the conclusion of a licensing deal in 2020. GSK has come in for some criticism for not moving more quickly after the initial publication of the phase 2b results in 2018. A ProPublica article published last year suggested that the development of M72 slowed because GSK were focussing on more profitable vaccines.
According to the Gates MRI statement, GSK continues to provide technical assistance to the Gates MRI, supplies the adjuvant component of the vaccine for the phase 3 trial, and will provide the adjuvant post licensure should the trial be successful. An adjuvant is an agent included in the vaccine that improves the immune response elicited by the vaccine – in the case of M72/AS01E the AS01E refers to the adjuvant made by GSK.
This ongoing dependence on a single company for the adjuvant has some activists worried. “We are concerned about reports that scaling this vaccine may be difficult due to limited availability of the vaccine adjuvant. Access for everyone who needs it should be part of the early phases of the research process – not an afterthought,” said Nathavitharana and Schoeman.
“The press release announcing the study’s start in several places refers to the ‘complexity’ of ‘developing and ensuring access’ to a new vaccine. Part of the unspoken complexity here is the opaque licensing deal GSK and Gates MRI signed in 2020 in which GSK gave rights to develop and commercialise M72 to Gates MRI while retaining control over the AS01E adjuvant,” Frick told Spotlight. “There are legitimate concerns that the fine print of this arrangement could work against equitable access, but terms of the licence remain unknown to the public.”
When asked about supply concerns, Gates MRI told Spotlight: “Gates MRI collaboration with GSK includes provisions to ensure there is sufficient supply of adjuvant for the clinical development and first adoption in low-income countries with high TB burden, at an affordable price, should the vaccine candidate be successful in phase 3 trials and approved for use. For broader implementation, GSK has committed to working with its partners to ensure there is sufficient supply.”
Disclosure: The Gates MRI is a non-profit subsidiary of the Bill and Melinda Gates Foundation. Spotlight receives funding from the Bill and Melinda Gates Foundation. Spotlight is editorially independent and a member of the South African Press Council.
Surgeons prepare the pig kidney for transplantation. Credit: Massachusetts General Hospital
Massachusetts General Hospital (MGH) has announced the world’s first successful transplant of a genetically-edited pig porcine) kidney into a 62-year-old man living with end-stage kidney disease (ESKD). Surgeons from the Mass General Transplant Center conducted the four-hour-long surgery on Saturday, March 16. The procedure marks a major milestone in the quest to provide more readily available organs to patients. Mass General Brigham is an internationally recognised leader in transplantation services, providing advanced care for a wide spectrum of organ and tissue transplants throughout its renowned academic medical system.
Under the leadership of Leonardo V. Riella, MD, PhD, Medical Director for Kidney Transplantation, Tatsuo Kawai, MD, PhD, Director of the Legorreta Center for Clinical Transplant Tolerance, along with Nahel Elias, MD, Interim Chief of Transplant Surgery and Surgical Director for Kidney Transplantation, a genetically-edited pig kidney with 69 genomic edits was successfully transplanted into a living patient.
Mass General Brigham has a rich history in organ transplant innovation, including the world’s first successful human organ transplant (kidney) performed at Brigham and Women’s Hospital in 1954 and the nation’s first penile transplant, performed at MGH in 2016. Mass General Brigham transplantation programs draw upon the deep, integrated expertise of some of the world’s leading transplant physicians and scientists who collaborate across experienced multidisciplinary teams to advance medicine and improve the lives of patients.
“Mass General Brigham researchers and clinicians are constantly pushing the boundaries of science to transform medicine and solve significant health issues facing our patients in their daily lives,” said Anne Klibanski, MD, President and CEO, Mass General Brigham. “Nearly seven decades after the first successful kidney transplant, our clinicians have once again demonstrated our commitment to provide innovative treatments and help ease the burden of disease for our patients and others around the world.”
“The tireless commitment of our clinicians, researchers and scientists to improving the lives of our transplant patients – both current and future – is at the very heart and soul of academic medicine and what it means to work and provide care at Mass General Brigham,” said David F. M. Brown, MD, President, Academic Medical Centers, Mass General Brigham. “We are so thankful to the incredible staff throughout our hospitals who helped make this surgery a success, and to the patient for his bravery and courage.”
“The success of this transplant is the culmination of efforts by thousands of scientists and physicians over several decades. We are privileged to have played a significant role in this milestone. Our hope is that this transplant approach will offer a lifeline to millions of patients worldwide who are suffering from kidney failure,” Kawai said.
The pig kidney was provided by eGenesis, from a pig donor that was genetically-edited using CRISPR-Cas9 technology to remove harmful pig genes and add certain human genes to improve its compatibility with humans. Additionally, scientists inactivated porcine endogenous retroviruses in the pig donor to eliminate any risk of infection in humans. Over the past five years, MGH and eGenesis have conducted extensive collaborative research, with the findings published in Nature in 2023.
This successful procedure in a living recipient is a historic milestone in the emerging field of xenotransplantation – the transplantation of organs or tissues from one species to another – as a potential solution to the worldwide organ shortage. According to the United Network for Organ Sharing (UNOS), more than 100 000 people in the U.S. await an organ for transplant and 17 people die each day waiting for an organ. A kidney is the most common organ needed for transplant, and end-stage kidney disease rates are estimated to increase 29-68% in the U.S. by 2030, according to literature published in the Journal of the American Society of Nephrology.
The patient, Mr. Richard ‘Rick’ Slayman of Weymouth, Mass., is recovering well at MGH and is expected to be discharged soon.
“The real hero today is the patient, Mr Slayman, as the success of this pioneering surgery, once deemed unimaginable, would not have been possible without his courage and willingness to embark on a journey into uncharted medical territory. As the global medical community celebrates this monumental achievement, Mr Slayman becomes a beacon of hope for countless individuals suffering from end-stage renal disease and opens a new frontier in organ transplantation,” said Joren C. Madsen, MD, DPhil, Director of the MGH Transplant Center.
Mr Slayman said in a statement, “I have been a Mass General Transplant Center patient for 11 years and have the highest level of trust in the doctors, nurses, and clinical staff who have cared for me. When my transplanted kidney began failing in 2023, I again trusted my care team at MGH to meet my goals of not just improving my quality of life but extending it. My nephrologist, Dr Winfred Williams, MD and the Transplant Center team suggested a pig kidney transplant, carefully explaining the pros and cons of this procedure. I saw it not only as a way to help me, but a way to provide hope for the thousands of people who need a transplant to survive. I want to thank everyone at MGH who has cared for me, especially Dr Williams, Dr Kawai, the surgeon who performed my first kidney transplant and now this one, and Dr Riella, who has orchestrated the logistics behind this new transplant. They have supported me during every step of the journey, and I have faith they will continue to do so.”
Mr Slayman, who has been living with Type 2 diabetes and hypertension for many years, previously received a kidney transplant from a human deceased donor in December 2018, performed at MGH by Kawai, after being on dialysis seven years prior. The transplanted kidney showed signs of failure approximately five years later and Mr Slayman resumed dialysis in May 2023. Since resuming dialysis, he encountered recurrent dialysis vascular access complications requiring visits to the hospital every two weeks for de-clotting and surgical revisions, significantly impacting his quality of life and a common problem among dialysis patients.
“The continued success of this groundbreaking kidney transplant represents a true milestone in the field of transplantation. It also represents a potential breakthrough in solving one of the more intractable problems in our field, that being unequal access for ethnic minority patients to the opportunity for kidney transplants due to the extreme donor organ shortage and other system-based barriers. This health disparity has been the target of many national policy initiatives for over 30 years, with only limited success. An abundant supply of organs resulting from this technological advance may go far to finally achieve health equity and offer the best solution to kidney failure – a well-functioning kidney – to all patients in need. I commend Mr Slayman, who has been my patient for many years, for his courageousness in becoming a trailblazer in the field of transplantation,” Williams said.
The procedure was performed under a single FDA Expanded Access Protocol (EAP) – known as compassionate use – granted to a single patient or group of patients with serious, life-threatening illnesses or conditions to gain access to experimental treatments or trials when no comparable treatment options or therapies exist. Mr. Slayman also received infusion of novel immunosuppressant drugs, tegoprubart, provided by Eledon Pharmaceuticals, Inc., and ravulizumab, provided by Alexion Pharmaceuticals, Inc.
Few realise the extent of the global burden of tuberculosis (TB) or know how many people still succumb to this disease every year. The Centres for Disease Control in the United States estimates that two billion people – a quarter of the world’s population – may be infected with TB, with 10.6 million becoming ill each year. Although TB is preventable and treatable, around 3 500 people lose their lives to it every day, making up an annual mortality rate of 1.3 million people. This means that TB ranks third to only COVID-19 and HIV/Aids as the world’s most deadly infectious disease.
These statistics are alarming and demand immediate attention from all sectors of society. It is crucial to recognise the potential of technology and digital platforms in revolutionising treatment outcomes. By harnessing the power of innovation, we can transform the way in which TB is diagnosed, treated and managed, ultimately saving lives and reducing the burden of this disease.
Equally as sobering is the fact that around 30 percent of people who become ill with TB are missed by healthcare screenings and do not get the care they need, leading to poor outcomes and an increased spread of the disease, especially in remote, rural and underserved communities. People infected with TB do not necessarily become ill but can pass on the bacteria that causes the infection to between ten and fifteen other people through coughing, sneezing or the transfer of saliva. Approximately 10% of those infected go on to develop an active form of disease at some time in their lives.
TB in South Africa
In South Africa, the first-ever National Tuberculosis Prevalence Survey, published in 2018, found that the country is one of 30 countries with the highest prevalence of TB in the world. When adjusted for population size, it is often ranked as the country with the highest prevalence in the word.
The power of digital healthcare has the potential to change this scenario radically. The greatest challenges we face are the low rate of diagnosis and poor access to – and compliance with – treatment. That’s where digital platforms have such a significant role to play.
How digital can make a difference
Digital health platforms have the potential to revolutionise the fight against TB by improving early detection, enhancing treatment adherence and strengthening healthcare delivery systems. Through the integration of mobile applications, telemedicine, artificial intelligence (AI) and big data analytics, we can address the key challenges of TB diagnosis, treatment access and patient support.
Firstly, digital tools enable early detection and diagnosis of TB cases. Advanced imaging techniques, supported by AI algorithms, can swiftly identify TB-related abnormalities in medical images, facilitating prompt intervention and preventing the progression of the disease. Predictive analytics can also forecast TB outbreaks and hotspot areas, enabling healthcare authorities to take proactive measures to contain the spread of the disease.
Secondly, digital health platforms facilitate remote consultations and monitoring, which is particularly beneficial for patients in remote or underserved areas. By providing timely medical intervention and personalised support, these platforms promote treatment adherence and improve patient outcomes.
Thirdly, mobile health applications empower patients to actively participate in their care management. Through features such as medication reminders, digital health checks and access to educational resources, individuals can adhere to treatment protocols better, ultimately contributing to improved health outcomes.
In addition, digital health platforms streamline healthcare delivery by facilitating data interoperability and real-time monitoring of TB trends. Innovative technologies such as TB Check, the free service application of the South African National Department of Health, are revolutionising TB testing as they are being used to determine the risk of contracting TB and to provide guidelines on how to access testing and treatment.
Further, applications such as One Impact, a comprehensive digital health platform, connects individuals with TB support groups, provides access to TB services and enables the reporting of difficulties in accessing care. By leveraging such platforms, national TB programmes can gain valuable insights into the needs and concerns of affected communities, leading to more responsive and effective service delivery.
TB is treatable and curable, especially when patients are diagnosed early, have access to the medication they need and can be carefully monitored throughout their treatment programme.
As we observe World TB Day on 24 March, it is encouraging to know that the integration of digital health platforms provides immense promise in transforming TB outcomes. To realise this potential, collaboration among governments, healthcare providers, technology companies and civil society organisations is essential. By prioritising investment in innovative solutions and leveraging digital technologies, we can accelerate progress towards the elimination of TB and save countless lives. It is time to harness the power of technology to combat TB and create a healthier, TB-free world for all.
The “Thrive 5” are five conditions to ensure an infant in the first year of life has what they need for healthy development. Those conditions include environmental stimulation, nutrition, neighbourhood safety, positive caregiving and regular circadian rhythms and sleep. Simple, and yet, it has not yet been prioritised for many reasons including the fact that researchers had not provided empirical data to support making the Thrive 5 a public health priority.
Researchers at Washington University in St. Louis think it’s time to change that. In new research published in JAMA Pediatrics, Deanna Barch and Joan Luby make the case that “Thrive Factor” is a key element of healthy human brain, behavioural and cognitive development.
“When they have access to these basic supports, even in the face of adverse environments, it enhances their brain development, cognition (measures of IQ) and social-emotional development,” said Luby, MD, the university’s Samuel and Mae S. Ludwig Professor of Child Psychiatry at the School of Medicine.
There have been plenty of studies touting the benefits of individual thrive factors, such as encouraging breast-feeding to facilitate growth in general, but this new study looks at several key factors known to influence brain development and shows their relationship to outcomes at age 3.
“The novelty here is putting them all together and thinking of them as a constellation of things that are necessary and important for a child to be able to thrive,” said Barch, PhD, vice dean of research, a professor of psychological & brain sciences in Arts & Sciences and the Gregory B. Couch Professor of Psychiatry at the School of Medicine.
The study is part of a change in thinking in the child development field as scientists have learned that much of our health is not just genetically predetermined but is powerfully influenced by the psychosocial environment. The human brain is still undergoing rapid development at birth, and researchers are trying to understand the environmental factors that shape this development.
The study of 232 infants and their mothers looked at positive factors in the environment in the foetal period and first year of life that enhance brain development, minimise negative behaviours and increase cognitive outcomes. Participants were evaluated on social disadvantage indexes beginning in utero and early life T-Factor scores were also calculated. As infants approached age 3, they were re-evaluated for social, emotional and cognitive development along with using MRIs to scan brain structure.
The results were clear that T-Factor is powerful: Even infants coming from adverse conditions and under-resourced backgrounds can have healthy development if they get their Thrive 5.
The researchers note that policymakers and paediatric primary care providers should be informed about the importance of focusing on elements of the T-Factor and how they can lead to many downstream advantages for both the child and society.
It may seem obvious to anyone that a baby needs care, sleep, food, stimulation and safety but “nobody has particularly focused on or prioritised the importance of this during foetal development and in the first year of life to enhance critical developmental outcomes,” Luby said.
“The Thrive Factor provides a solid foundation for healthy development. It has been underappreciated in primary care just how malleable the brain is to experience,” Luby added.
Barch said the next step will be setting up interventions to test in randomised controlled trials. Another advantage to T-Factor is it is highly feasible to share and promote in broad populations.
Interventions would likely take the form of multiple Zoom sessions with parents to educate and coach them on how to best provide each thrive factor. But that would just be the start, since parents need resources to help them provide thrive factors.
Though T-Factor can help kids overcome adverse conditions, Barch emphasised the need for understanding just how tough those adverse conditions can be on a new parent.
“If you’ve never suffered from financial adversity, you don’t understand how hard that makes life,” she said.
Parents can struggle to provide conditions to thrive because they may have to support many people in their household, may not have adequate number of rooms to ensure easier child sleep training, must work multiple jobs and can’t get away to breast feed, and live in unsafe neighbourhoods that keep them in a constant state of vigilance.
Though education can help caregivers, it will take public policy interventions to ensure parents can access all the Thrive Factors, especially when it comes to access to safe housing and adequate income to support even these basic needs of developing infants.
“We need to make it so families can have the resources necessary to provide these core things to kids because it’s going to have such a big impact on kids’ development across the course of their lifespan,” she said.
