DNA Nanomachines Are Opening Medicine to the World of Physics – Singularity Hub

When I imagine the inner workings of a robot, I think hard, cold mechanics running on physics: shafts, wheels, gears. Human bodies, in contrast, are more of a contained molecular soup operating on the principles of biochemistry.

Yet similar to robots, our cells are also attuned to mechanical forcesjust at a much smaller scale. Tiny pushes and pulls, for example, can urge stem cells to continue dividing, or nudge them into maturity to replace broken tissues. Chemistry isnt king when it comes to governing our bodies; physical forces are similarly powerful. The problem is how to tap into them.

In a new perspectives article in Science, Dr. Khalid Salaita and graduate student Aaron Blanchard from Emory University in Atlanta point to DNA as the solution. The team painted a futuristic picture of DNA mechanotechnology, in which we use DNA machines to control our biology. Rather than a toxic chemotherapy drip, for example, a cancer patient may one day be injected with DNA nanodevices that help their immune cells better grab ontoand snuff outcancerous ones.

For a long time, said Salaita, scientists have been good at making micro devices, hundreds of times smaller than the width of a human hair. Its been more challenging to make functional nano devices, thousands of times smaller than that. But using DNA as the component parts is making it possible to build extremely elaborate nano devices because the DNA parts self-assemble.

Just as the steam engine propelled civilization through the first industrial revolution, DNA devices may fundamentally change medicine, biological research, and the development of biomaterials, further merging man and machine.

When picturing a tiny, whirling machine surveying the body, DNA probably isnt the first candidate that comes to mind. Made up of long chains of four lettersA, T, C, and GDNA is normally secluded inside a tiny porous cage in every cell, in the shape of long chains wrapped around a protein core.

Yet several properties make DNA a fascinating substrate for making mechano-machines, the authors said. One is its predictability: like soulmates, A always binds to T, and C with G. This chemical linking in turn forms the famous double helix structure. By giving the letters little chemical additions, or swapping them out altogether with unnatural synthetic letters, scientists have been able to form entirely new DNA assemblies, folded into various 3D structures.

Rather than an unbreakable, immutable chain, DNA components are more like Japanese origami paper, or Lego blocks. While they cant make every single shapetry building a completely spherical Death Star out of Legothe chemistry is flexible enough that scientists can tweak its structure, stiffness, and coiling by shifting around the letters or replacing them with entirely new ones.

In the late fall of 1980, Dr. Nadrian Seeman was relaxing at the campus pub at New York University when he noticed a mind-bending woodcut, Depth, by MC Escher. With a spark of insight, he realized that he could form similar lattice shapes using DNA, which would make it a lot easier for him to study the molecules shape. More than a decade later, his lab engineered the first artificial 3D nanostructurea cube made out of DNA molecules. The field of DNA nanotechnology was born.

Originally considered a novelty, technologists rushed to make increasingly complex shapes, such as smiley faces, snowflakes, a tiny world map, and more recently, the worlds smallest playable tic-tac-toe set. It wasnt just fun. Along the way, scientists uncovered sophisticated principles and engineering techniques to shape DNA strands into their desired structures, forming a blueprint of DNA engineering.

Then came the DNA revolution. Reading and writing the molecule from scratch became increasingly cheaper, making it easier to experiment with brand-new designs. Additional chemical or fluorescent tags or other modifications gave scientists a direct view of their creations. Rather than a fringe academic pursuit, DNA origami became accessible to most labs, and the number of devices rapidly explodeddevices that can sense, transmit, and generate mechanical forces inside cells.

If you put together these three main components of mechanical devices, you begin to get hammers and cogs and wheels and you can start building nano machines, said Salaita.

Salaita is among several dozen labs demoing the practical uses of DNA devices.

For example, our cells are full of long-haul driver proteins that carry nutrients and other cargo throughout their interior by following specific highways (it eerily looks like a person walking down a tightrope). Just as too much traffic damages our roadways, changes in our cells logistical players can also harm the cells skeleton. Here, scientists have used DNA handles to measure force-induced changes like stretching, unfolding, and rupture of molecules involved in our cells distribution system to look for signs of trouble.

Then there are DNA tension sensors, which act like scales and other force gauges in our macroscopic world. Made up of a stretchable DNA spring to extend with force, and a fluorescent ruler that measures the extension, each sensor is anchored at one end (generally, the glass bottom of a Petri dish) and binds to a cell at the other. If the pulling force exceeds a certain threshold, the spring unfolds and quenches the fluorescent light in the ruler, giving scientists a warning that the cellular tugging is too strong.

The work may sound abstruse, but its implications are plenty. One is for CAR-T, the revolutionary cancer treatment that uses gene therapy to amp up immune cells with better graspers to target tumor cells. The kiss of death between graspers and tumors are extremely difficult to measure because its light and fleeting. Using a DNA tension sensor, the team was able to track the force during the interaction, which could help scientists engineer better CAR-T therapies. A similar construct, the DNA tension gauge tether, irreversibly ruptures under too much force. The gauge is used to track how stem cells develop into brain cells under mechanical forces, and how immune cells track down and recognize foreign invasion.

[Immune] T cells are constantly sampling cells throughout your body using these mechanical tugs. They bind and pull on proteins on a cells surface and, if the bond is strong, thats a signal that the T cell has found a foreign agent, explained Salaita. DNA devices provide an unprecedented look at these forces in the immune system, which in turn could predict how strongly the body will mount an immune response.

To the authors, however, the most promising emerging DNA devices dont just observethey can also generate forces. DNA walkers, for example, uses DNA feet to transport (and sort) molecular cargo while walking down a track also made of DNA strands. When the feet bind to the track (A to T, C to G), it releases energy that propel the walker forward.

Even more exciting are self-assembling DNA machines. The field has DNA-based devices that transmit, sense and generate mechanical forces, the authors said. But eventually, their integration will produce nanomachines that exert mechanical control over living systems.

As costs keep dropping, the authors believe well witness even more creative and sophisticated DNA nanomachines.

Several hiccups do stand in the way. Like other biomolecules, foreign DNA can be chopped up by the bodys immune system as an invader. However, the team believes that the limitation wont be a problem in the next few years as biochemistry develops chemically-modified artificial DNA letters that resist the bodys scissors.

Another problem is that the DNA devices can generate very little forceless than a billionth the weight of a paperclip, which is a little too low to efficiently control forces in our cells. The authors have a solution here too: coupling many force-generating DNA units together, or engineer translators that can turn electrical energy into mechanical forcesimilar to the way our muscles work.

Fundamentally, any advancements in DNA mechanotechnology wont just benefit medicine; they will also feed back into the design of nanomaterials. The techniques, tools and design principlesare not specific to DNA, the authors said. Add in computer-aided design templates, similar to those used in 3D printing, and potentially anyone can dream up a nano-machine design and make it a reality, said Salaita.

Image Credit: Emory University. DNA mechanotechnology expands the opportunities for research involving biomedicine and materials sciences, says Khalid Salaita, right, professor of chemistry at Emory University and co-author of the article, along with Aaron Blanchard, left, a graduate student in the Salaita Lab.

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DNA Nanomachines Are Opening Medicine to the World of Physics - Singularity Hub

PTPRU, As A Tumor Suppressor, Inhibits Cancer Stemness By Attenuating | OTT – Dove Medical Press

Jiayi Gu,1,* Zhiqi Zhang,2,* Tingyuan Lang,3,* Xinlin Ma,1 Linxi Yang,1 Jia Xu,1 Cong Tian,4 Kun Han,4 Jiangfeng Qiu1

1Department of Gastrointestinal Surgery, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200127, Peoples Republic of China; 2Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth Peoples Hospital, Shanghai 200233, Peoples Republic of China; 3Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400030, Peoples Republic of China; 4Department of Medical Oncology, Shanghai Jiao Tong University Affiliated Sixth Peoples Hospital, Shanghai 200233, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Jiangfeng QiuDepartment of Gastrointestinal Surgery, Renji Hospital Shanghai Jiao Tong University School of Medicine, No.160 Pujian Road, Pudong New Area, Shanghai 200127, Peoples Republic of ChinaTel +86 138 1687 3899Fax +86 21 6373 0455Email qif0228@126.com

Background: PTPRU is an important signaling molecule that regulates a variety of cellular processes; however, the role of PTPRU in cancer development has remained elusive. Here, we report that PTPRU serves as a tumor suppressor that inhibits cancer stemness by attenuating Hippo/YAP signaling pathway.Methods: Primary cancer cells and cell line cells were used in the study. The gene expression data were downloaded from R2 analysis and visualization platform and KaplanMeier analysis was performed to study the relationship between survival and PTPRU expression. qRT-PCR and Western blot were employed to study the expression of target genes in tissues and cells. Sphere and colony formation, proliferation, migration activities and the expression of stem cell and EMT markers were employed for characterizing the stemness. Gene manipulation was achieved by lentivirus-mediated gene delivery system. Luciferase reporter gene assay was used to study the transcriptional activity of the promoter, and ChIP-qPCR was employed to study the target binding sequence of the protein. Spearman correlation analysis was performed to study the correlation between two genes. Students t-test was used for determination of the significance between two experimental groups.Results: PTPRU is downregulated in colorectal and gastric cancer tissues and cancer stem cells. High expression of PTPRU predicts poor prognosis. Overexpression of PTPRU attenuates the stemness of gastric cancer stem cells and knockdown of PTRPU improves the maintenance of the stemness of cancer stem cells. Mechanistic analysis showed that PTPRU inhibits Hippo/YAP signaling by suppressing the expression of YAP in a transcriptional level. Overexpression of YAP restored PTPRU-induced inhibited stemness of gastric cancer stem cells.Conclusion: PTPRU serves as a tumor suppressor that inhibits the stemness of cancer stem cell by inhibiting Hippo/YAP signaling pathway.

Keywords: PTPRU, cancer stem cells, Hippo/YAP signaling, gastric cancer, colorectal cancer

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Keeping the Gene Expression of Sex Chromosomes in Balance – Technology Networks

Researchers at Karolinska Institutet in Sweden have uncovered a chromosome-wide mechanism that keeps the gene expression of sex chromosomes in balance in our cells. The findings shed light on molecular reasons for early miscarriage and could be important for the emerging field of regenerative medicine. The study is published in Nature Structural and Molecular Biology.

The genes in our cells are packaged into 23 large units of DNA called chromosomes. The sex chromosomes, X and Y, differ from all other chromosomes in that they are only present as one active copy per cell instead of two. This renders a copy-number imbalance between genes located on sex chromosomes and the rest of our genome. Now researchers at Karolinska Institutet have figured out how our cells manage to double the expression of X-chromosome genes to achieve balance.

By examining gene expression dynamics in fine detail in female and male embryonic and somatic cells, the researchers found that genes on the X chromosome produced waves of gene products at a faster tempo than other chromosomes.

"The X chromosome generates 'bursts' of gene expression at higher rate that other chromosomes, pointing to the involvement of special DNA elements called enhancers in maintaining an elevated X-chromosome expression" says Bjrn Reinius, the principal investigator at the Department of Medical Biochemistry and Biophysics, who directed the study.

In female cells, carrying two X chromosomes, the increased tempo established on one X-chromosome copy during the same developmental window in which the second X-copy became inactivated. 'X inactivation' is a previously characterized mechanism that keeps one X chromosome silent in women, resulting in patches of cells expressing either the maternal or paternal copy. Male cells, carrying only one X chromosome, instead maintained a constantly fast rhythm of expression throughout developmental phases and cell types.

"Failure to establish X-chromosome dosage compensation during the early female embryogenesis is lethal and leads to early spontaneous abortion" Reinius says. "With the new knowledge, we better understand how the cells' gene expression network becomes destabilised."

According to the researchers, the findings represent a breakthrough in understanding sex-chromosome gene regulation. Understanding these chromosome-wide mechanisms could also be important in the field of regenerative medicine, since the reprogramming of cells may disturb the X-chromosome dosage balance in a gender-specific manner.

Reference: Larsson, Coucoravas, Sandberg and Reinius. 2019.X-chromosome upregulation is driven by increased burst frequency. Nature Structural and Molecular Biology. DOI: https://doi.org/10.1038/s41594-019-0306-y.

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Keeping the Gene Expression of Sex Chromosomes in Balance - Technology Networks