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UNC School of Medicine Scientists have shown for the first time that postnatal gene therapy may be able to prevent or reverse many deleterious effects of a rare genetic disorder called Pitt-Hopkins syndrome. This autism spectrum disorder features severe developmental delay, intellectual disability, breathing and movement abnormalities, anxiety, epilepsy, and mild but distinctive facial abnormalities.
The scientists, who report their results in the journal eLife, devised an experimental, gene-therapy-like technique to restore the normal activity of the gene deficient in people with Pitt-Hopkins syndrome. In newborn mice that otherwise model the syndrome, the treatment prevented the emergence of disease signs including anxiety-like behavior, memory problems, and abnormal gene expression patterns in affected brain cells.
“This first, proof-of-principle demonstration suggests that restoring normal levels of the Pitt-Hopkins syndrome gene is a viable therapy for Pitt-Hopkins syndrome, which otherwise has no specific treatment,” said senior author Ben Philpot, PhD, Kenan Distinguished Professor of Cell Biology and Physiology at the UNC School of Medicine and associate director of the UNC Neuroscience Center.
Most genes are inherited in pairs, one copy from the mother and one from the father. Pitt-Hopkins syndrome arises in a child when one copy of the gene TCF4 is missing or mutated, resulting in an insufficient level of TCF4 protein. Typically, this deletion or mutation occurs spontaneously in the parental egg or sperm cell prior to conception, or in the earliest stages of embryonic life following conception.
Only about 500 cases of the syndrome have been reported worldwide since it was first described by Australian researchers in 1978. But no one knows the syndrome’s true prevalence; some estimates suggest that there could be more than 10,000 cases in the United States alone.
Since TCF4 is a “transcription factor” gene, a master switch that controls the activities of at least hundreds of other genes, its disruption from the start of development leads to numerous developmental abnormalities. In principle, preventing those abnormalities by restoring normal TCF4 expression as early as possible is the best treatment strategy — but it hasn’t yet been tested.

A national study that enrolled a highly diverse group of pregnant women over 12 years found rising exposure to chemicals from plastics and pesticides that may be harmful to development.
Many of the chemicals that the women had been exposed to were replacement chemicals: new forms of chemicals that have been banned or phased out that may be just as harmful as the ones they replaced. The study also found many women had been exposed to neonicotinoids, a kind of pesticide that is toxic to bees.
Researchers measured 103 chemicals, mostly from pesticides, plastics, and replacement chemicals for BPA and phthalates, using a new method that captured dozens of chemicals or chemical traces from a single urine sample.
More than 80 percent of the chemicals were found in at least one of the women in the study, and more than a third of the chemicals were found in a majority of the participants. The study also found that some of these chemicals were present in higher amounts than seen in earlier studies.
“This is the first time we’ve been able to measure the amounts of chemicals in such a large and diverse group of pregnant women — not just identify chemicals,” said Tracey J. Woodruff, PhD, professor and director of the University of California, San Francisco (UCSF) Program on Reproductive Health and the Environment and co-director of the UCSF EaRTH Center, and the senior author of the study, appearing online May 10, 2022, in Environmental Science & Technology. “Our findings make clear that the number and scope of chemicals in pregnant women are increasing during a very vulnerable time of development for both the pregnant person and the fetus.”
Prenatal exposure to industrial chemicals can come from air, food, water, plastics, and other industrial and consumer products. Although these chemicals could be harmful to pregnancy and child development, few of these chemicals are routinely monitored in people.
The study included 171 women from California, Georgia, Illinois, New Hampshire, New York, and Puerto Rico who are part of the National Institutes of Health Environmental influences on Child Health Outcomes program. About one-third (34%) were white, 40% were Latina, 20% were Black, and the remaining 6% were from other or multiple groups.
The study found higher exposures for non-white women, those with lower educational attainment, or who were single or had been exposed to tobacco. But Latinas had especially high levels of parabens, which are used as preservatives, as well as phthalates and bisphenols, which are used in plastics.
“While pesticides and replacement chemicals were prevalent in all women, we were surprised to find that Latinas had substantially higher levels of parabens, phthalates and bisphenols,” said Jessie Buckley, PhD, associate professor of environmental health and engineering, as well as of epidemiology, at Johns Hopkins Bloomberg School of Public Health and first author of the study. “This could be the result of higher exposures to products with chemicals, such as processed foods or personal care products,” Buckley said.
Funding: Research reported in this publication was supported by the Environmental influences on Child Health Outcomes (ECHO) program, Office of The Director, National Institutes of Health, under Award Numbers U2COD023375 (Coordinating Center), U24OD023382 (Data Analysis Center), U24OD023319 (PRO Core), U2CES026542 (HHEAR), and UH3OD023251, UH3OD023272, UH3OD023275, UH3OD023287, UH3OD023290, UH3OD023318, UH3OD023342, UH3OD023349, UH3OD023347, UH3OD023365 (cohort grantees).

Women suffering from endometriosis, polycystic ovary syndrome (PCOS) and preeclampsia may be protected from future heart disease if they carry a specific common genetic variant on the surface of cells (insulin-like growth factor-1 receptor, or IGF1R). The research, from the Benz lab at the Buck Institute, suggests new options for personalized screening and surveillance for cardiovascular disease and, when combined with the team’s previous work, cancers.
Here’s the background: Women with endometriosis or polycystic ovary syndrome (PCOS) are known to have an increased risk of cardiovascular disease later in their lives, and a study by Buck Institute researchers suggests that there is a similar underlying process between these conditions. Furthermore, when combined with the team’s previous research, the same potential mechanism is linked to protection after experiencing preeclampsia against cardiovascular risk as well as the development of breast and other cancers, and may point to a shared mechanism of decreased risk among these three conditions.
It turns out that having IGF1R on the surface of cells can reduce the future risk of developing cardiovascular disease for women with endometriosis or PCOS, as the researchers report in the April 1 issue of Human Reproduction. This is the same gene variant that the researchers earlier identified in women who experience preeclampsia as providing protection against not only cardiovascular risk, but also the development of breast and other cancers.
“The interesting thing is that now we have similar findings in three different seemingly unrelated conditions,” said lead author Mark Powell, MD, MPH, a visiting scientist at the Buck Institute and Director of the Breast Cancer Prevention Project. Endometriosis is a chronic estrogen-dependent disorder affecting up to 10 percent of US women in their reproductive years, and the US incidence of PCOS is also up to 10 percent. Preeclampsia impacts a similar percentage of women and, according to the March of Dimes, is the cause of 15 percent of premature births in the United States. “What started out as largely an academic endeavor is turning out to impact a lot of women,” said Powell.
The explanation for the shared commonalities between these seemingly unrelated gynecologic disorders and cardiovascular risk may lie within the normal variation of a gene.
In the current study, the researchers analyzed data from more than 100,000 women to look for who carried a specific variant of a gene in the IGF1R, a protein on the surface of cells. The specific variation, known as carrying a T allele, occurs in 30 to 80 percent of women, depending on race and ethnicity.

Scientists have pinpointed a possible new target for treating patients with the blood cancer juvenile myelomonocytic leukemia (JMML), according to a study published today in eLife.
Their findings in zebrafish and JMML patients suggest that treatment using anti-inflammatories could be a possible new approach to combating the disease.
JMML is a highly aggressive blood cancer with poor outcomes for patients. Children with a relatively common developmental syndrome called Noonan Syndrome (NS) have a high risk of developing a condition similar to JMML, called myeloproliferative neoplasm, which can then progress to JMML. The most frequent genetic cause of JMML and NS is a mutation in the PTPN11 gene, which encodes the protein-tyrosine phosphatase SHP2.
“Hematopoietic stem and progenitor cells are considered to be the cells of origin for JMML,” says first author Maja Solman, Postdoctoral Fellow at the Hubrecht Institute, Utrecht, Netherlands. “Currently, hematopoietic stem cell transplantation is the only treatment for the disease, but it has a relapse rate of 50%. With such limited treatment options for JMML, we wanted to gain a better understanding of how the disease develops to identify other possible ways of targeting it.”
To do this, Solman and the team used a novel zebrafish model with a mutation in SHP2 — equivalent to the most common mutation in NS patients which can cause JMML. They used a technique called single-cell transcriptomics to examine the level of gene expression in the animals’ hematopoietic stem and progenitor cells. The analysis showed an increase in the number of monocyte and macrophage progenitor cells in the fish embryos, and that these cells expressed genes associated with the immune response.
The team next compared these results with their analysis of hematopoietic stem and progenitor cells, which contained SHP2 mutations, from the bone marrow of JMML patients. They found a similar pattern of proinflammatory gene expression in these cells as the one they identified in the zebrafish.
Finally, they treated the zebrafish embryos with an anti-inflammatory drug called dexamethasone. They found that the drug helped rescue JMML-like blood defects in the fish, suggesting that anti-inflammatories could one day be an important treatment strategy for JMML.
“Our work reveals striking similarities in the proinflammatory response of human and zebrafish cells containing SHP2 mutations, and shows that inhibiting this response can improve JMML-like symptoms in a zebrafish model,” concludes senior author Jeroen den Hertog, Group Leader and Managing Director at the Hubrecht Institute, and Professor of Molecular Developmental Zoology at Leiden University, Netherlands. “Together, these findings lay the groundwork for future studies to verify the effectiveness of anti-inflammatories as a potential new treatment approach for JMML patients.”
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Synapses are the contact points in the brain via which nerve cells ‘talk’ to each other. Disturbances in this communication lead to diseases of the nervous system, since altered synaptic proteins, for example, can impair this complex molecular mechanism. This can result in mild symptoms, but also very severe disabilities in those affected.
The interest of the two neurobiologists Professor Tobias Langenhan and Professor Manfred Heckmann, from Leipzig and Würzburg respectively, was aroused when they read in a scientific publication about a mutation that damages a synaptic protein. At first, the affected patients attracted scientists’ attention because the mutation caused them to go blind. However, doctors then noticed that the patients were also of above-average intelligence. “It’s very rare for a mutation to lead to improvement rather than loss of function,” says Langenhan, professor and holder of a chair at the Rudolf Schönheimer Institute of Biochemistry at the Faculty of Medicine.
The two neurobiologists from Leipzig and Würzburg have been using fruit flies to analyse synaptic functions for many years. “Our research project was designed to insert the patients’ mutation into the corresponding gene in the fly and use techniques such as electrophysiology to test what then happens to the synapses. It was our assumption that the mutation makes patients so clever because it improves communication between the neurons which involve the injured protein,” explains Langenhan. “Of course, you can’t conduct these measurements on the synapses in the brains of human patients. You have to use animal models for that.”
75 per cent of genes that cause diseases in humans also exist in fruit flies
First, the scientists, together with researchers from Oxford, showed that the fly protein called RIM looks molecularly identical to that of humans. This was essential in order to be able to study the changes in the human brain in the fly. In the next step, the neurobiologists inserted mutations into the fly genome that looked exactly as they did in the diseased people. They then took electrophysiological measurements of synaptic activity. “We actually observed that the animals with the mutation showed a much increased transmission of information at the synapses. This amazing effect on the fly synapses is probably found in the same or a similar way in human patients, and could explain their increased cognitive performance, but also their blindness,” concludes Professor Langenhan.
The scientists also found out how the increased transmission at the synapses occurs: the molecular components in the transmitting nerve cell that trigger the synaptic impulses move closer together as a result of the mutation effect and lead to increased release of neurotransmitters. A novel method, super-resolution microscopy, was one of the techniques used in the study. “This gives us a tool to look at and even count individual molecules and confirms that the molecules in the firing cell are closer together than they normally are,” says Professor Langenhan, who was also assisted in the study by Professor Hartmut Schmidt’s research group from the Carl Ludwig Institute in Leipzig.
“The project beautifully demonstrates how an extraordinary model animal like the fruit fly can be used to gain a very deep understanding of human brain disease. The animals are genetically highly similar to humans. It is estimated that 75 per cent of the genes involving disease in humans are also found in the fruit fly,” explains Professor Langenhan, pointing to further research on the topic at the Faculty of Medicine: “We have started several joint projects with human geneticists, pathologists and the team of the Integrated Research and Treatment Center (IFB) AdiposityDiseases; based at Leipzig University Hospital, they are studying developmental brain disorders, the development of malignant tumours and obesity. Here, too, we will insert disease-causing mutations into the fruit fly to replicate and better understand human disease.”
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A human enzyme converts chemicals produced by marine sponges and related synthetic derivatives into cell-killing compounds, shows a study published today in eLife.
The discovery suggests that it may be possible to develop new therapies for cancer or bacterial infections by taking advantage of this enzyme and similar natural or bioinspired compounds.
Pharmaceutical companies have studied compounds produced by marine sponges as potential anti-cancer therapies since the 1950s, when scientists discovered that one such compound was an effective treatment for a type of blood cancer.
“There are thousands of potential cell-killing compounds produced by marine sponges and other marine organisms, but exactly how they work to destroy cells is still unknown for most of them,” says Sébastien Britton, Principal Investigator at the Institute of Pharmacology and Structural Biology (Institut de Pharmacologie et de Biologie Structurale, IPBS), University of Toulouse, France. Britton is a co-senior author of the study alongside his colleagues Remi Chauvin and Yves Génisson, from the University of Toulouse.
Among natural products isolated from marine species with potential medicinal properties, a particular chemical that stems from marine sponges exhibits a unique structure. This structure combines alcohol and acetylene functions on a lipid backbone, providing so-called lipidic alkynyl carbinols compounds, with a long-remarked cell-killing ability.
To learn more about the cell-killing mechanisms of these compounds, the researchers focused on the most potent synthetic derivatives called dialkynylcarbinols, which are up to around 1,000 times more active than their sponge-produced natural parents. The team screened human haploid cells for mutations that made them resistant to being killed by dialkynylcarbinols. They found that mutations in a gene related to a human enzyme called HSD17B11 consistently rendered these compounds harmless to the cells.
The team next conducted a series of experiments showing that the HSD17B11 enzyme converts dialkynylcarbinols into an active form which then binds to multiple proteins involved in the ‘quality control mechanisms’ of cellular proteins. As a result, faulty proteins build up in the cells and eventually kill them.
Next, they tested the cancer cell-killing capacity of this HSD17B11-activated chemical on 15 different types of cancer cell. They showed that the compound was particularly effective at killing a rare type of paediatric bone cancer called osteosarcoma. By contrast, cancer cells lacking the HSD17B11 enzyme survived exposure to the compound.
HSD17B11 is just one member of a large family of enzymes called Short-chain Dehydrogenases/Reductases (SDRs), with over 500,000 representatives currently found in all living organisms. To begin exploiting the mechanism they identified, the team designed novel chemicals that were specifically converted into cell-killing compounds by other SDR enzymes, demonstrating the ability of these chemicals to selectively kill cells or organisms expressing a specific SDR.
“Marine sponges may produce these kinds of chemicals to hijack a predator’s enzymes, which in turn convert them into cell-killing compounds,” explains Britton.
“Together, our findings identify an untapped toolbox full of natural and synthetic chemical compounds which could be converted by widespread enzymes into potentially useful drugs. In the future, scientists may be able to use these chemicals to help treat specific cancers, while opening prospects to treat infectious diseases on the same principle.”
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During human birth, the fetus typically navigates a tight, convoluted birth canal by flexing and rotating its head at various stages. This complex process comes with a high risk of birth complications, from prolonged labor to stillbirth or maternal death. These complications were long believed to be the result of a conflict between humans adapting to walking upright and our larger brains.
Dilemma between walking upright and larger brains
Bipedalism developed around seven million years ago and dramatically reshaped the hominin pelvis into a real birth canal. Larger brains, however, didn’t start to develop until two million years ago, when the earliest species of the genus Homo emerged. The evolutionary solution to the dilemma brought about by these two conflicting evolutionary forces was to give birth to neurologically immature and helpless newborns with relatively small brains — a condition known as secondary altriciality.
A research group led by Martin Häusler from the Institute of Evolutionary Medicine at the University of Zurich (UZH) and a team headed up by Pierre Frémondière from Aix-Marseille University have now found that australopithecines, who lived about four to two million years ago, had a complex birth pattern compared to great apes. “Because australopithecines such as Lucy had relatively small brain sizes but already displayed morphological adaptations to bipedalism, they are ideal to investigate the effects of these two conflicting evolutionary forces,” Häusler says.
Typical ratio of fetal and adult head size
The researchers used three-dimensional computer simulations to develop their findings. Since no fossils of newborn australopithecines are known to exist, they simulated the birth process using different fetal head sizes to take into account the possible range of estimates. Every species has a typical ratio between the brain sizes of its newborns and adults. Based on the ratio of non-human primates and the average brain size of an adult Australopithecus, the researchers calculated a mean neonatal brain size of 180 g. This would correspond to a size of 110 g in humans.
For their 3D simulations, the researchers also took into account the increased pelvic joint mobility during pregnancy and determined a realistic soft tissue thickness. They found that only the 110 g fetal head sizes passed through the pelvic inlet and midplane without difficulty, unlike the 180 g and 145 g sizes. “This means that Australopithecus newborns were neurologically immature and dependent on help, similar to human babies today,” Häusler explains.
Prolonged learning key for cognitive and cultural abilities
The findings indicate that australopithecines are likely to have practiced a form of cooperative breeding, even before the genus Homo appeared. Compared to great apes, the brains developed for longer outside the uterus, enabling infants to learn from other members of the group. “This prolonged period of learning is generally considered crucial for the cognitive and cultural development of humans,” Häusler says. This conclusion is also supported by the earliest documented stone tools, which date back to 3.3 million years ago — long before the genus Homo appeared.
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Researchers at Karolinska Institutet in Sweden have mapped how the parasite Trypanosoma cruzi forms new variants that are more effective at evading the immune system and causing disease. Their findings can give rise to new methods for diagnosing, preventing and treating Chagas disease, which affects millions of people in Central and South America, causing thousands of deaths every year. The study is published in the journal eLife.
Trypanosoma cruzi infection is chronic and can lead to Chagas disease, which causes severe symptoms in the gastrointestinal tract and heart. The parasite has many genes that can vary extensively, which enables it to evade the immune system. How it does this, however, is still largely unknown.
A scientific collaboration involving researchers at Karolinska Institutet has now shown that Trypanosoma cruzi can form new variants that are combinations of different strains. These hybrids are often better at circumventing the immune system and causing disease. By mapping the genome of the parental strains and their offspring over time, the researchers have a detailed picture of how these hybrids are formed. Their results show that the hybrids initially contain all DNA from both parentals, but that the amount of DNA is then gradually decreased until it ends up at the right level. The researchers also found that there is frequent reshuffling of genetic material in a process known as genetic recombination.
“This knowledge is important since the exchange of genetic material can lead to new gene variants that make the parasite more dangerous,” says principal investigator Björn Andersson, professor of genome analysis at the Department of Cell and Molecular Biology, Karolinska Institutet. “A better understanding of how this process works can help us develop new methods for diagnosing, preventing and treating Chagas disease, which is a huge problem in Central and South America.”
The study is based on parasite strains that spontaneously formed hybrids in the laboratory. The researchers isolated DNA from both the parental parasites and many of their offspring and mapped the entire genome using large-scale DNA sequencing.
“We’ll now be studying material from nature and from patients to map in greater detail how the parasite goes about varying its genes,” he continues. “We’re also working on improving the diagnosis of Chagas disease in Bolivia.”
The study was a collaboration between Karolinska Institutet, Universidade Federal de Santa Catarina in Brazil and the London School of Hygiene and Tropical Medicine in the UK and was supported by grants from, primarily, the Swedish Research Council and CAPES in Brazil.
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