Lifeboat Foundation

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.”

During cell division, a ring forms around the cell equator, which contracts to divide the cell into two daughter cells. Together with researchers from Heidelberg, Dresden, Tübingen and Harvard, Professor Jan Kierfeld and Lukas Weise from the Department of Physics at TU Dortmund University have succeeded for the first time in synthesizing such a contractile ring with the help of DNA nanotechnology and to uncover its contraction mechanism.

The results have been published in the journal Nature Communications (“Triggered contraction of self-assembled micron-scale DNA nanotube rings”).

In synthetic biology, researchers try to recreate crucial mechanisms of life in vitro, such as cell division. The aim is to be able to synthesize minimal cells. The research team led by Professor Kerstin Göpfrich from Heidelberg University has now synthetically reproduced contractile rings for cell division using polymer rings composed of DNA nanotubes.

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.

Researchers at Rutgers and Emory University are gaining insights into how schizophrenia develops by studying the strongest-known genetic risk factor.

When a small portion of chromosome 3 is missing—known as 3q29 deletion syndrome—it increases the risk for schizophrenia by about 40-fold.

Researchers have now analyzed overlapping patterns of altered gene activity in two models of 3q29 deletion syndrome, including mice where the deletion has been engineered in using CRIPSR, and human brain organoids, or three-dimensional tissue cultures used to study disease. These two systems both exhibit impaired mitochondrial function. This dysfunction can cause energy shortfalls in the brain and result in psychiatric symptoms and disorders.

In a recent study published in Nature Communications, researchers developed a modular synthetic biology toolkit for Aspergillus oryzae, an edible fungus used in fermented foods, protein production, and meat alternatives.

Study: Edible mycelium bioengineered for enhanced nutritional value and sensory appeal using a modular synthetic biology toolkit. Image Credit: Rattiya Thongdumhyu/Shutterstock.com.

The advent of CRISPR gene editing, along with nanopore genome sequencing and single-cell RNA sequencing, has allowed the study of host-microbe interactions with newfound accuracy and power. The studies taking advantage of these tools have provided insights with never-before seen precision and, excitingly, have revealed surprising findings on principles of host-microbe interactions. This special issue reviews and interprets host immunological and developmental interactions with the resident microbiome. The articles reflect on evolutionary principles guiding how hosts interact with their commensal microbiota and offer new techniques and directions for research that we hope will advance the field in the years to come.

This issue is available to buy in print. Visit our information for readers page for purchasing options.

New research presented early ahead of this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024, Barcelona, 27–30 April) from a team of researchers in the Netherlands shows how the latest CRISPR-Cas gene editing technology can be used to eliminate all traces of the HIV virus from infected cells in the laboratory, raising hopes of a cure.

Exploring the cutting edge of genetic engineering, the development of programmable recombinases and zinc finger domains is ushering in a new era of precision in DNA manipulation. These advances enable precise genomic alterations, from single nucleotide changes to the insertion of large DNA segments, potentially transforming the landscape of therapeutic gene editing and opening new possibilities in personalised medicine.