Publisher Health

Rice University scientists have enlisted widely used cancer therapy systems to control gene expression in mammalian cells, a feat of synthetic biology that could change how diseases are treated.
The lab of chemical and biomolecular engineer Xue Sherry Gao discovered a way to further tap the therapeutic potential of proteolysis targeting chimeras (PROTACs), small molecules that are used as effective tools for treating cancer, immune disorders, viral infections and neurodegenerative diseases.
Gao and collaborators reengineered the PROTAC molecular infrastructure and showed it can be used to achieve chemically induced dimerization (CID), a mechanism by which two proteins bind together only in the presence of a specific third molecule known as an inducer. The research is described in a study published in the Journal of the American Chemical Society.
“The novelty of this is the extent of control that combining these two mechanisms gives us over inducing gene activation at desired locations in the body and for desired durations,” Gao said.
“Small molecules can act as a switch to turn gene expression on and off,” she said. “Temporal control is a result of the fact that small molecules are metabolized by living organisms. What this means is that you can schedule for a certain gene to be expressed for a certain amount of time.
“In terms of spatial control, we can deliver the system only to the organ or site of the body where it is needed,” Gao continued. “You don’t need to have the medication go through your whole body and generate unnecessary and harmful toxicity.”
The CID mechanism is a key part of many biological processes, and over the past two decades scientists have devised a host of ways to engineer it to serve medical, research and even manufacturing needs. The development highlights the growing impact of synthetic biology, which takes an engineering approach to biological systems, repurposing their mechanisms to harness new resources.

Sirolimus, formerly known as rapamycin. is an example of a molecule that can act as an inducer and form CID systems with multiple cell pathways in the body. Discovered in 1972 in soil bacteria on Easter Island, the compound has been used as an antitumor and immunosuppressant drug. More recently, it was touted as a potential anti-aging drug after researchers discovered it could interfere with a cellular pathway that activates lysosomes, organelles responsible for cleaning up damaged cells.
“CID systems are attractive tools because they enable precise control over molecular interactions, which in turn can activate or inhibit biological outcomes, such as, for example insulin production in a diabetic patient or tumor growth in a cancer patient,” Gao said.
“Right now there are only a limited number of functional and efficient CID systems,” she added. “I wanted to address this unmet need. I saw PROTACs, which are already being used with good results as therapies, as an opportunity to expand the CID toolbox.”
PROTACs work by targeting specific proteins, such as those found in a tumor, causing them to disintegrate. One side of the molecule binds to a targeted harmful protein, another side flags down a specific enzyme that initiates protein degradation and a third element connects the two sides together.
“You can think of this mechanism as similar to a smart missile that relies on a sensor to track its target,” Gao said. “The vocabulary is suggestive in this sense, too, since the protein you want to destroy is called a ‘target protein,’ and the part of the PROTAC system that binds to the target protein is called a ‘warhead.’ We are hijacking this system to control gene expression instead.”
The advantage of PROTACs over other drugs is that they can be effective in small doses and do not lead to the development of drug resistance. There are over 1,600 PROTAC small molecules approved for cancer therapy, acting on more than 100 human protein targets.

“PROTACs are very efficient and act with great specificity against oncogenic proteins, which are proteins encoded by certain activated or dysregulated genes that have a potential to cause cancer,” Gao said. “We wanted to harness that efficiency and precision and put it to work in a new way. We redesigned PROTAC from a protein-degradation system to a gene-activation system.
“Ultimately, I hope this will prove useful in the context of treating real diseases,” she continued. “The ability to regulate when and where genes are activated in the body could help solve a wide range of medical problems. My main goal with this project is to have a small molecule-controlled gene expression system, including the CRISPR genome editors.”
Gao is Rice’s T.N. Law Assistant Professor of Chemical and Biomolecular Engineering and an assistant professor of bioengineering and chemistry. The study was developed in collaboration with the Zheng Sun lab at Baylor College of Medicine.
The National Science Foundation (2143626), the Robert A. Welch Foundation (C-1952), the National Institutes of Health (HL157714, HL153320, DK111436, AG069966, ES027544), the John S. Dunn Foundation, the Clifford Elder White Graham Endowed Research Fund, the Cardiovascular Research Institute at Baylor College of Medicine, the Dan L. Duncan Comprehensive Cancer Center (P30CA125123), the Specialized Programs of Research Excellence (P50CA126752), the Gulf Coast Center for Precision Environmental Health (P30ES030285) and the Texas Medical Center Digestive Diseases Center (P30DK056338) supported the research.

An advanced imaging-based method from scientists at Scripps Research offers a new way of studying mitochondria, which are best known as the “powerhouses” of cells.
In their report on February 14, 2023, in the Journal of Cell Biology, the scientists described a set of techniques that enables the imaging and quantification of even subtle structural changes inside mitochondria, and the correlation of those changes with other processes ongoing in cells.
Mitochondria are involved not only in energy production, but also in several other critical cellular functions, including cell division and cell-preserving responses to various types of stress. Mitochondrial dysfunctions have been observed in a host of diseases including Alzheimer’s, Parkinson’s disease and different cancers, and researchers are eager to develop treatments that can reverse these dysfunctions. But the scientific tools for studying the fine details of mitochondria structure have been limited.
“We now have a powerful new toolkit for detecting and quantifying structural, and thus functional, differences in mitochondria — for example, in diseased versus healthy states,” says study senior author Danielle Grotjahn, PhD, assistant professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
The co-first authors of the study were Grotjahn lab members Benjamin Barad, PhD, a postdoctoral research associate, and Michaela Medina, a PhD candidate.
Mitochondria are one of the many membrane-bound molecular machines, or “organelles,” that dwell within the cells of plants and animals. Typically numbering in the hundreds to thousands per cell, mitochondria have their own small genomes, and have a distinctive structure with an outer membrane and a wavy inner membrane where key biochemical reactions occur. Scientists know that the appearances of mitochondrial structures can change dramatically depending on what the mitochondrion is doing, or what stresses are present in the cell. These structural changes therefore can be highly useful markers of cell conditions, though until now there hasn’t been a good method for detecting and quantifying them.

In the study, Grotjahn’s team put together a computational toolkit to process imaging data from a microscopy technique called cryo-electron tomography (cryo-ET) — which essentially images biological samples in three dimensions, using electrons instead of light. The researchers’ “surface morphometrics toolkit,” as they call it, enables the detailed mapping and measurement of the structural elements of individual mitochondria. This includes the bends of the inner membrane and the gaps between membranes — all potentially useful markers of important mitochondrial and cellular events.
“It allows us essentially to turn the beautiful 3-D pictures of mitochondria we can get from cryo-ET into sensitive, quantitative measurements — which we can potentially use to help identify the detailed mechanisms of diseases, for example,” Barad says.
The team demonstrated the toolkit by using it to map structural details on mitochondria when their cells are subjected to endoplasmic reticulum stress — a type of cell stress that is seen often in neurodegenerative diseases. They observed that key structural features such as the curvature of the inner membrane, or the minimum distance between inner and outer membranes, changed measurably when under this stress.
With their successful, proof-of-principle demonstrations of the new toolkit, the Grotjahn lab will now use it for studying in more detail how mitochondria respond to cellular stresses or other changes induced by diseases, toxins, infections and even pharmaceuticals.
“We can compare the effects on mitochondria in cells treated with a drug versus the effects on untreated mitochondria, for example,” Medina says. “And this approach is not limited to mitochondria — we can also use it to study other organelles within cells.”
“Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline,” was co-authored by Benjamin Barad, Michaela Medina, Daniel Fuentes, Luke Wiseman and Danielle Grotjahn, all of Scripps Research.
The research was funded in part by the National Institutes of Health (R01NS095892, RF1NS125674) and the American Cancer Society.

Researchers at NYU College of Dentistry have developed a single score to describe the level of cytokines in the saliva, and this score is linked with the severity of clinical gum inflammation, according to a study published in the journal PLOS ONE.
While more research is needed to test the “cytokine score,” it could hold promise for measuring how well a patient responds to treatment for gum disease, predicting gum disease recurrence, or detecting ongoing inflammation related to systemic diseases.
“Periodontal inflammation is not just apparent upon examination, but is reflected in the patient’s saliva,” said Angela Kamer, DMD, MS, PhD, associate professor of the Ashman Department of Periodontology & Implant Dentistry at NYU Dentistry and the study’s senior author.
Periodontal (or gum) disease is a chronic, inflammatory condition that affects roughly half of adults. Marked by inflamed gums, which can bleed and detach from the tooth, periodontal disease results from the complex interaction between an imbalance of healthy and unhealthy bacteria under the gumline and the immune system’s response. This response produces high levels of cytokines — small proteins that signal the immune system — in the inflamed gums, especially pro-inflammatory cytokines such as IL-8, IL-1?, IL-6 and TNF?.
Periodontal disease is also associated with systemic conditions including cardiovascular disease, diabetes, and Alzheimer’s. Scientists believe that gum inflammation contributes to these conditions through both indirect pathways (cytokines boosting systemic inflammation) and direct pathways (cytokines traveling to a specific organ like the heart or brain), but studying this is difficult due to the challenge of measuring cytokines in the fluid found deep in the pockets in the gums.
Fortunately, cytokines are also found in the saliva, which is easier to collect. In the PLOS ONE study, the researchers wanted to know if clinically detected gum inflammation could predict the level of cytokines found in saliva.

“Salivary cytokines are a window into the molecular make-up of the oral environment,” said Vera Tang, DDS, MS, clinical assistant professor of the Ashman Department of Periodontology & Implant Dentistry at NYU Dentistry and the study’s first author.
The researchers evaluated the gums and saliva of 67 adults, ages 45 and older, who had some degree of periodontal disease but were otherwise healthy. To measure their clinical periodontal inflammation, the researchers used a formula called the Periodontal Inflamed Surface Area (PISA), which is calculated using measurements of the depth of pockets in the gums and bleeding upon probing. PISA provides a single measure of periodontal inflammation; a higher PISA score indicates worse inflammation.
Participants were also asked to spit into sterile tubes to capture saliva samples, which were then analyzed to measure a range of both pro- and anti-inflammatory cytokines: IL-1?, IL-6, IL-8, IL-13, TNF-?, and IL-10. Led by statistician Malvin Janal, PhD, the researchers used two different ways (the Cytokine Component Index and Composite Inflammatory Index) to combine these cytokines into a single score.
They found that PISA scores were significantly associated with the new cytokine scores, independent of other factors including age, gender, smoking, and body mass index (BMI). The higher a cytokine score, the greater the periodontal inflammation.
“This demonstrates that a single score encompassing several salivary cytokines correlates with the severity of periodontal inflammation,” said Leena Palomo, DDS, MSD, professor and chair of the Ashman Department of Periodontology & Implant Dentistry at NYU Dentistry, and a study coauthor.
The researchers caution that more research is needed to validate the cytokine score in patients with different health conditions, as well as those with all levels of periodontal disease, including healthy gums and early-stage gum disease. However, if the cytokine score is validated in larger and more diverse patient populations, it could be used to better understand periodontal disease progression and recurrence, as well as the potential connection to other systemic conditions.
“With treatment for gum disease, such as scaling and planing, we know that the PISA score goes down. It would be interesting to see if the cytokine score also drops — or, if it persists, look into what that means,” added Kamer. “Is it picking up an underlying cause, like ongoing inflammation from systemic disease? Or if someone has a hyperinflammatory response, which we’d know from a high cytokine score, can it predict if periodontitis will recur or progress in the future? We hope to look into these questions in future research.”
Additional study authors include Babak Hamidi, DDS, MPH, Cheryl Barber, MS, MPH, and Benjamin Godder, DMD, of NYU Dentistry. This research was funded by the National Institutes of Health (R03-DE023139).

Researchers from the National Institutes of Health (NIH) used computational modeling to uncover mutations in the human genome that likely influenced the evolution of human cognition. This groundbreaking research in human genomics could lead to a better understanding of human health and the discovery of novel treatments for complex brain disorders. The study is to be published in Science Advances.
Human cognition is a defining feature of human evolution, setting us apart from other primates. Despite over 100 million mutations since the human-chimp split, only a small fraction has been found to be significant. To navigate this vast landscape of genomic changes, researchers from the National Library of Medicine (NLM) and the National Cancer Institute (NCI) created an artificial intelligence (AI) model of gene regulation in the human brain. The model identified thousands of mutations likely impacting neocortical development and facilitating the acquisition of mathematical abilities through altered brain gene regulation mechanisms.
When the human genome was sequenced in 2001, researchers learned that only 2% of the sequence of our genome is used for coding genes that, in turn, translate into proteins. This is the sequence information that is being used by every single cell. The function of the other 98% of our DNA — often referred to as “noncoding DNA” — remains relatively unknown. It is believed that 95% of disease associations hide within these noncoding parts of our genome.
The research group of Ivan Ovcharenko, PhD, senior investigator in the Computational Biology Branch of NLM’s Intramural Research Program teamed up with the research group of Sridhar Hannenhalli, PhD, senior investigator in NCI’s Center for Cancer Research to create an AI model that measures the effect of noncoding genome mutations on human brain function and development. This led to the identification of a group of noncoding mutations disrupting brain regulatory pathways and potentially causing various complex brain disorders, including autism.
“There are treasure islands within the sea of noncoding DNA in the human genome that are critically important for regulating human genes,” said Dr. Ovcharenko. “Mutations in these regions are largely benign, but there is a class of mutations which detrimentally impact the function of regulatory regions in the brain and affect cellular activity there. By being able to address the impact of individual mutations, we are advancing towards understanding the mechanism of complex diseases and disorders and paving the way for the development of novel therapeutic approaches.”
According to study authors, this fundamental work in human genomics is likely to have a long-ranging impact on human health and advance the research of the complex nature of the human brain.

T-cells that are part of our immune system are central in the protection against infections and cancer. With the help of TCRs, the cells recognize foreign invaders and tumor cells.
“It was previously unknown how variable human TCR genes are,” says Gunilla Karlsson Hedestam, professor at the department of microbiology, tumor and cell biology at Karolinska Institutet and the study’s lead author.
Using deep sequencing of blood samples, the researchers examined TCR genes in 45 people originating from sub-Saharan Africa, East Asia, South Asia and Europe. The researchers showed that these genes vary greatly between different persons and population groups. The results were confirmed by analyses of several thousand additional cases from the 1000 Genomes project.
“We found that every individual, other than identical twins, has a unique set of TCR gene variants. These differences reveal possible mechanisms underlying the wide range of responses to infections and vaccines that we observe at the population level,” says Martin Corcoran, the first author of the study.
“We discovered 175 new gene variants, which doubles the number of known TCR gene variants. An unexpected and surprising finding is that certain gene variants originate from Neanderthals and one of these is present in up to 20% of modern humans in Europe and Asia.”
Gunilla Karlsson Hedestam explains that the variation in these genes cannot be detected with the standard methods used in whole genome sequencing, but with the development of specialized deep sequencing methods and analysis software that allow highly precise definition of B- and T-cell receptor genes, this is now possible.

“As these genes are among the most variable in our genome, the results also provide new information about how our immune system has developed over the course of history, says Martin Corcoran. We are particularly interested in uncovering the function of the TCR variants we have inherited from Neanderthal ancestors. The frequency of these variants in modern humans suggests an advantageous function in our biology and we are keen to understand this,” adds Martin Corcoran.
The findings and the new TCR gene database the researchers now publish can be of great importance in the development of new therapeutic approaches in the future.
“Understanding human genetics is fundamental for the development of targeted treatments. The methods described in the study provide new opportunities, not the least in the cancer field where T-cells are central to several promising forms of immunotherapy,” says Gunilla Karlsson Hedestam.
The results can also shed light on other areas of research.
“The findings can lead to the development of new diagnostics and therapies in a range of medical disciplines, including precision medicine,” says Gunilla Karlsson Hedestam.
What is the next step in your research?
“We are now investigating the functional significance of several of the newly discovered gene variants and how this variation impacts our T-cell responses. We are also planning extended studies involving large groups of individuals to examine the role of TCR gene variation in diseases we know involve T cells, such as infectious diseases, cancer, and autoimmune disorders,” says Gunilla Karlsson Hedestam.
Main funding for the study comes from an ERC Advanced Grant and the Swedish Research Council.

Multiple births, a short interval between pregnancies and mothers with a maternal physical or mental health condition are more at risk of having a low birth rate baby according to Swansea University researchers.
Every year 20 million children are born with a birth weight below 2,500 grams, and considered low birthweight (LBW) babies The study, by researchers at the National Centre for Population Health and Wellbeing Research, looked to understand the risk factors for LBW so that resources and interventions could be scheduled effectively.
The cohort study comprised 693,377 children born in Wales between 1st January 1998 and 31st December 2018. Participants were selected from the National Community Child Health database.
The research team anonymously linked multiple routinely collected administrative datasets to gain a deeper understanding of the risk factors associated with LBW.
The research revealed mothers at the highest risk of having a low birth weight baby included: Those expecting more than one baby (twins, triplets etc.); Those who with a pregnancy interval of less than one year; and, Those with maternal physical and mental health conditions, including diabetes, anaemia, depression, severe mental illness, anxiety, and use of anti-depressant medication during pregnancy.Additional risk factors included: Smoking; alcohol-related hospital admission; substance misuse; and evidence of domestic abuse; and, maternal age (35+), along with living in a deprived area.This study suggests that the most important factors in reducing the risk of LBW include the following: Address multiple births (e.g., in assisted reproduction practices) Addressing factors associated with pre-term births (previous history of pre-term birth) Addressing maternal health, such as reducing smoking, investing in maternal mental health, addressing substance use (alcohol/drugs), Treating underlying health conditions (diabetes/anaemia), And promoting pregnancy planning to give an adequate pregnancy interval and healthy weight of the mother, especially for those in deprived urban areas.Lead researcher Amrita Bandyopadhyay said: “The most important risk factors include maternal factors such as smoking, maternal weight, substance misuse record, maternal age along with deprivation, pregnancy interval and birth order of the child.
“Resources to reduce the prevalence of LBW should focus on improving maternal health, reducing pre-term births, increasing awareness of a sufficient pregnancy interval, and providing adequate support for mothers’ mental health and wellbeing.”
Professor Kieran Walshe, Director of Health and Care Research Wales, which funded the research, said: “This 20-year study provides valuable insight into the variety of risk factors that can lead to low birth weight.
“It is a powerful example of how researchers can use routinely collected data to help improve care for both mothers and babies without putting additional pressures on frontline healthcare professionals.
“The findings offer tangible recommendations about where to focus efforts to mitigate the incidence of low birth weight in newborns.”