To what extent are exceptional human achievements influenced by genetic factors? This question, dating back to the early days of human genetics, seems to be easier to address today as modern molecular methods make it possible to analyze DNA of individuals throughout history. But how reliable are the answers in this day and age?
PHILADELPHIA — Scientists at the University of Pennsylvania’s Perelman School of Medicine have developed a new method to create human artificial chromosomes (HACs) that could revolutionize gene therapy and other biotechnology applications. The study, published in Science, describes an approach that efficiently forms single-copy HACs, bypassing a common hurdle that has hindered progress in this field for decades.
Artificial chromosomes are lab-made structures designed to mimic the function of natural chromosomes, the packaged bundles of DNA found in the cells of humans and other organisms. These synthetic constructs have the potential to serve as vehicles for delivering therapeutic genes or as tools for studying chromosome biology. However, previous attempts to create HACs have been plagued by a major issue: the DNA segments used to build them often link together in unpredictable ways, forming long, tangled chains with rearranged sequences.
The Penn Medicine team, led by Dr. Ben Black, sought to overcome this challenge by completely overhauling the approach to HAC design and delivery. “The HAC we built is very attractive for eventual deployment in biotechnology applications, for instance, where large-scale genetic engineering of cells is desired,” Dr. Black explains in a media release. “A bonus is that they exist alongside natural chromosomes without having to alter the natural chromosomes in the cell.”
Ubiquitous Potential
While many gene-editing therapies are focused on fatal genetic diseases, epigenetic editing’s safety profile may enable the treatment of more common diseases. The fact that no underlying changes are made to the DNA sequence “offers some additional safety assurances for this approach compared to some others where the risk/benefit [ratio] needs to be maybe a little different before you would employ those technologies,” Kane told BioSpace.
Additionally, because most common diseases are not driven by genetic mutations, epigenetic editing may be a better fit. “Most of those diseases are driven from expression levels being at an unhealthy level,” Kane said. “That is something that a tool like epi[genetic] editing is uniquely well-suited to address.”
In support of a major collaborative project to store massive amounts of data in DNA molecules, a Los Alamos National Laboratory–led team has developed a key enabling technology that translates digital binary files into the four-letter genetic alphabet needed for molecular storage.
“Our software, the Adaptive DNA Storage Codec (ADS Codex), translates data files from what a computer understands into what biology understands,” said Latchesar Ionkov, a computer scientist at Los Alamos and principal investigator on the project. “It’s like translating from English to Chinese, only harder.”
DNA offers a compact way to store huge amounts of data cost-effectively. Los Alamos National Laboratory has developed ADS Codex to translate the 0s and 1s of digital computer files into the four-letter code of DNA.
Acute myeloid leukemia (AML) is a rare and aggressive hematologic malignancy. AML progresses rapidly and is indicated by an excess of immature white blood cells. It is caused by high mutational burden over the span of a person’s life. One signature mutated gene includes the tumor suppressor gene TP53. Normally, TP53 helps make protein to stop oncogenesis or the formation of tumors. However, mutated TP53 loses that function and commonly results in AML. Unfortunately, those that have a TP53 mutation have an extremely aggressive tumor that is resistant to conventional chemotherapy drugs and results in poor prognosis. Other standard treatments include stem-cells transplants, and sometimes targeted drugs such as intracellular pathway inhibitors. Although many treatments are routine and help the patient reduce symptoms, there is no cure. Extensive research is currently being done by researchers and physicians to identify new approaches for AML treatment.
One novel therapy used in other hematologic malignancies includes chimeric antigen receptor (CAR)-T cell therapy. This therapy takes immune T cells (responsible for lysing or kill infections) from the patient or a donor and engineers them to target the tumor. Normally, these T cells would not recognize tumor growth, therefore, the engineered CAR-T cells are programmed to elicit an immune response and recognize surface markers on the tumor to lyse it. This therapy has been successful in other leukemias such as B-cell acute leukemia, and researchers are working to overcome treatment resistant AML using the same approach.
A recent article in EMBO Molecular Medicine, by Drs. Markus Manz, Stephen Boettcher and others, demonstrate that TP53-mutated AML is resistant to CAR-T cell therapy as a single agent, but can be overcome through combination therapy. Manz and Boettcher are principal investigators from the University of Zurich and the Department of Medical Oncology and Hematology at the University Hospital Zurich (USZ) and focus on mechanisms surrounding hematological diseases. The Zurich team first reported why TP53-mutated AML is resistant to CAR-T cell therapy. Using various models, it was noted that the engineered T cells quickly become ‘exhausted’ or inactive due to overstimulation or surrounding stimuli. The team further studied the underlying mechanism in this disease by concluding that TP53-deficient cells caused resistance through several metabolic pathways. Moreover, these pathways including the mevalonate and Wnt pathways were identified to improve therapeutic efficacy.
Stanford and McMaster University researchers created an artificial intelligence (AI) model to design molecules that inhibit the growth of Acinetobacter baumannii, a common drug-resistant bacteria. They synthesized and validated six structurally novel molecules that demonstrated antibacterial activity against A. baumannii and other phylogenetically diverse bacterial pathogens. This study represents a significant step toward the practical application of generative AI approaches for antibiotic discovery and drug discovery in general.
The research article, “Generative AI for designing and validating easily synthesizable and structurally novel antibiotics,” was published in Nature Machine Intelligence.
Among the most critical issues in contemporary medicine is the worldwide spread of factors contributing to antibiotic resistance. In 2019, drug-resistant infections were responsible for an estimated 4.95 million deaths. As new antibiotics are being developed slower than the spread of antimicrobial resistance determinants, this figure is expected to reach 10 million annually by 2050.
A recent study published in Nature reveals a potential link between a type of bacteria associated with dental plaque and treatment-resistant colorectal cancer. The Gram-negative, anaerobic bacterium, Fusobacterium nucleatum, was found in 50% of tumors tested, suggesting it may protect tumor cells from cancer-fighting drugs. This discovery opens avenues for new treatments and screening methods. Colorectal cancer, a leading cause of cancer deaths in the United States, is increasingly affecting younger demographics, with cases doubling among those younger than age 55 between 1995 and 2019. While the study doesn’t directly tie the bacterium to this trend, its implications raise questions about its role in rising cases among younger individuals. F. nucleatum has been suspected in colorectal cancer growth. It possesses two subspecies, one of which is capable of evading immune response and promoting tumor formation. These findings suggest a potential mechanism for its journey from the oral cavity to the colon, defying stomach acid’s toxic effects. Future research may explore developing antibiotics targeting specific bacterial subtypes or using genetically modified bacteria for targeted drug delivery into tumors. Understanding the microbiome’s role in cancer risk represents a crucial frontier in cancer research. Click here to read more.
Humans have always been storytellers. Weaving tales, exchanging knowledge, and planning for the future are quintessentially human endeavors that have shaped the course of our species. But when did this remarkable ability to communicate through language first emerge? Recent research suggests a far earlier origin than previously thought, shedding light on the fascinating journey of human evolution.
Dr. Steven Mithen, an esteemed archaeologist from the University of Reading, has delved deep into the annals of prehistory to uncover the roots of human speech. Contrary to conventional wisdom, which pegged the advent of language to around 200,000 years ago, Mithen’s groundbreaking analysis suggests a much more ancient beginning—approximately 1.6 million years ago, in the cradle of humanity, somewhere nestled in the vast expanse of eastern or southern Africa.
In his quest to unveil the origins of language, Mithen meticulously examined a plethora of evidence spanning archaeology, genetics, neurology, and linguistics. The culmination of his research paints a vivid picture of our ancestors’ journey towards spoken communication.
A research team led by Professor Yuanliang ZHAI at the School of Biological Sciences, The University of Hong Kong (HKU) collaborating with Professor Ning GAO and Professor Qing LI from Peking University (PKU), as well as Professor Bik-Kwoon TYE from Cornell University, has recently made a significant breakthrough in understanding how the DNA copying machine helps pass on epigenetic information to maintain gene traits at each cell division. Understanding how this coupled mechanism could lead to new treatments for cancer and other epigenetic diseases by targeting specific changes in gene activity. Their findings have recently been published in Nature.
Background of the Research.
Our bodies are composed of many differentiated cell types. Genetic information is stored within our DNA which serves as a blueprint guiding the functions and development of our cells. However, not all parts of our DNA are active at all times. In fact, every cell type in our body contains the same DNA, but only specific portions are active, leading to distinct cellular functions. For example, identical twins share nearly identical genetic material but exhibit variations in physical characteristics, behaviours and disease susceptibility due to the influence of epigenetics. Epigenetics functions as a set of molecular switches that can turn genes on or off without altering the DNA sequence. These switches are influenced by various environmental factors, such as nutrition, stress, lifestyle, and environmental exposures.
For the first time, scientists have developed artificial nucleotides, the building blocks of DNA, with several additional properties in the laboratory. The DNA carries the genetic information of all living organisms and consists of only four different building blocks, the nucleotides. Nucleotides are composed of three distinctive parts: a sugar molecule, a phosphate group and one of the four nucleobases adenine, thymine, guanine and cytosine. The nucleotides are lined up millions of times and form the DNA double helix, similar to a spiral staircase. Scientists from the UoC’s Department of Chemistry have now shown that the structure of nucleotides can be modified to a great extent in the laboratory.
The researchers developed so-called threofuranosyl nucleic acid (TNA) with a new, additional base pair. These are the first steps on the way to fully artificial nucleic acids with enhanced chemical functionalities. The study ‘Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage’ was published in the Journal of the American Chemical Society.
Artificial nucleic acids differ in structure from their originals.
