Category Archives: Transhuman News

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Safra - Life
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A quest to unravel the architecture of the double helix is revealing the subtle genetic orchestration of life

The genome packs into the nucleus in a manner consistent with the structure of a fractal globule, shown herea polymer state that is extraordinarily dense, but entirely unknotted. Credit: Olena Shmahalo/Quanta Magazine. Globule courtesy Miriam Huntley, Rob Scharein, and Erez Lieberman Aiden

FromQuanta Magazine(findoriginal story here).

The nuclei from a half-million human cells could all fit inside a single poppy seed. Yet within each and every nucleus resides genomic machinery that is incredibly vast, at least from a molecular point of view. It has billions of parts, many used to activate and silence genesan arrangementthat allows individual cells to specialize as brain cells, heart cells and some 200 other different cell types. Whats more, each cells genome is atwitter with millions of mobile pieces that swarm throughout the nucleus and latch on here and there to tweak the genetic program. Every so often, the genomic machinereplicates itself.

At the heart of the human genomes Lilliputian machinery is the two meters worth of DNA that it takes to embody a persons 3 billion genetic letters, or nucleotides. Stretch out all of the genomes in all of your bodys trillions of cells, saysTom Misteli, the head of the cell biology of genomes group at the National Cancer Institute in Bethesda, Md., and it would make 50 round trips to the sun. Since 1953, when James Watson and Francis Crick revealed the structure of DNA, researchers have made spectacular progress in spelling out these genetic letters. But this information-storage view reveals almost nothing about what makes specific genes turn on or off at different times, in different tissue types, at different moments in a persons day or life.

To figure out these processes, we must understand how those genetic letters collectively spiral about, coil, pinch off into loops, aggregate into domains and globules, and otherwise assume a nucleus-wide architecture. The beauty of DNA made people forget about the genomes larger-scale structure, saidJob Dekker, a molecular biologist at the University of Massachusetts Medical School in Worcester who has built some of the most consequential tools for unveiling genomic geometry. Now we are going back to studying the structure of the genome because we realize that the three-dimensional architecture of DNA will tell us how cells actually use the information. Everything in the genome only makes sense in 3-D.

Genome archaeologists like Dekker have invented and deployed molecular excavation techniques for uncovering the genomes architecture with the hope of finally discerning how all of that structure helps to orchestrate life on Earth. For the past decade or so, they have been exposing a nested hierarchy of structural motifs in genomes that are every bit as elemental to the identity and activity of each cell as the double helix.

A better genetic microscope A close investigation of the genomic machine has been a long time in coming. The early British microscopist Robert Hooke coined the wordcellas a result of his mid-17th-century observations of a thin section of cork. The small compartments he saw reminded him of monks living quarterstheir cells. By 1710, Antonie van Leeuwenhoek had spied tiny compartments within cells, though it was Robert Brown, of Brownian motion fame, who coined the wordnucleusto describe these compartments in the early 1830s. A half-century later, in 1888, the German anatomist Heinrich Wilhelm Gottfried von Waldeyer-Hartz peered through his microscope and decided to use the wordchromosomemeaning color bodyfor the tiny, dye-absorbing threads that he and others could see inside nuclei with the best microscopes of their day.

During the 20th century, biologists found that the DNA in chromosomes, rather than their protein components, is the molecular incarnation of genetic information. The sum total of the DNA contained in the 23 pairs of chromosomes is the genome. But how these chromosomes fit together largely remained a mystery.

Then in the early 1990s, Katherine Cullen and a team at Vanderbilt University developed a method to artificially fuse pieces of DNA that are nearby in the nucleusa seminal feat that made it possible to analyze the ultrafolded structure of DNA merely by reading the DNA sequence. This approach has been improved over the years. One of its latest iterations, calledHi-C, makes it possible to map the folding of entire genomes.

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Human Genome's Spirals, Loops and Globules Come into 4-D View

IMAGE:Australian researchers have developed a new genome editing technology that can target and kill blood cancer cells with high accuracy. Dr Brandon Aubrey, Dr Gemma Kelly and Dr Marco Herold (L-R)... view more

Credit: Walter and Eliza Hall Institute of Medical Research.

Melbourne researchers have developed a new genome editing technology that can target and kill blood cancer cells with high accuracy.

Using the technology, researchers from the Walter and Eliza Hall Institute were able to kill human lymphoma cells by locating and deleting an essential gene for cancer cell survival.

The research, published in the journal Cell Reports, provides a 'proof of concept' for using the technology as a direct treatment for human diseases arising from genetic 'errors'.

Dr Brandon Aubrey, Dr Gemma Kelly and Dr Marco Herold adapted the technology, called CRISPR, to specifically mimic and study blood cancers. The Walter and Eliza Hall Institute has one of the most advanced CRISPR laboratories in Australia, established and led by Dr Herold.

Dr Aubrey, who is also a haematologist at The Royal Melbourne Hospital, said the team used the CRISPR technology to target and directly manipulate genes in blood cancer cells.

"Using preclinical models, we were able to kill human Burkitt lymphoma cells by deleting MCL-1, a gene that has been shown to keep cancer cells alive," he said. "Our study showed that the CRISPR technology can directly kill cancer cells by targeting factors that are essential for their survival and growth. As a clinician, it is very exciting to see the prospect of new technology that could in the future provide new treatment options for cancer patients."

The CRISPR/Cas9 system works by efficiently locating and targeting particular genes of interest in the whole genome. It can either target the gene to introduce mutations that make the gene non-functional, or introduce changes that make mutated genes function normally again.

Dr Herold said pharmaceutical companies around the world were already investing millions of dollars to develop CRISPR as a tool for treating genetic diseases such as cancer.

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New genome-editing technology to help treat blood cancers

A study using super-resolution microscopy reveals that our genome is not regularly packaged and links these packaging differences to stem cell state

VIDEO:A study using super-resolution microscopy reveals that our genome is not regularly packaged and links these packaging differences to stem cell state. A multidisciplinary approach allowed scientists to view and... view more

In 1953 Watson and Crick first published the discovery of the double helix structure of the DNA. They were able to visualize the DNA structure by means of X-Ray diffraction. Techniques, such as electron microscopy, allowed scientists to identify nucleosomes, the first and most basic level of chromosome organisation. Until now it was known that our DNA is packaged by regular repeating units of those nucleosomes throughout the genome giving rise to chromatin. However, due to the lack of suitable techniques and instruments, the chromatin organisation inside a cell nucleus could not be observed in a non-invasive way with the sufficient resolution. Now, for the first time, a group of scientists at the CRG and ICFO in Barcelona, have been able to visualise and even count the smallest units which, packaged together, form our genome. This study was possible thanks to the use of super-resolution microscopy, a new cutting-edge optical technique that received the Nobel Prize in Chemistry in 2014. In combination with innovative quantitative approaches and numerical simulations, they were also able to define the genome architecture at the nano-scale. Most importantly, they found that the nucleosomes are assembled in irregular groups across the chromatin and nucleosome-free-DNA regions separate these groups.

Biologists and physicists have been working together to take a step forward in chromatin fibre observations and studies. "By using the STORM technique, a new super-resolution microscopy method, we have been able to view and even count nucleosomes across the chromatin fibers and determine their organisation. STORM overcomes the diffraction limit that normally restricts the spatial resolution of conventional microscopes and enables us to precisely define the chromatin fibre structure", states Prof. Melike Lakadamyali, group leader at ICFO.

This enabling technique allowed the researchers to go deeper and, by comparing stem cells to differentiated cells (specialised cells that have already acquired their role), they observed key differences in the chromatin fibre architectures of both cells. Pia Cosma, group leader and ICREA research professor at the CRG explains, "We found that stem cells have a different chromatin structure than somatic (specialised) cells. At the same time, this difference correlates with the level of pluripotency. The more pluripotent a cell is, the less dense is its packaging. It gives us new clues to understand the stem cells functioning and their genomic structure, which will be helpful for example, in studying cell reprogramming".

What scientists have found is that DNA is not regularly packaged with nucleosomes, instead nucleosomes are assembled in groups of varying sizes, called "nucleosome clutches" -because of their similarity to egg clutches-. They found that pluripotent stem cells have, on average, clutches with less density of nucleosomes. In addition, clutch size is related to the pluripotency potential of stem cells, meaning that the more pluripotent a cell is, the less nucleosomes are included in its clutches.

Even though all the cells in our body have the same genetic information, they are not expressing all the genes at the same time. So, when a cell specialises, some of the DNA regions are silenced or less accessible to the molecule that reads the genome: the RNA polymerase. Depending on the specialisation of the cells, different levels of DNA packaging will occur. This new work published in the prestigious journal Cell, establishes a new understanding of how the chromatin fibre is assembled and packaged forming a specific DNA structure in every cell.

This research definitively contributes to the understanding of a novel feature of stem cells and their DNA structure, which is important for maintaining an induced pluripotent state. A joint patent has been filed by ICFO and CRG, who are now exploring business opportunities for marketing the classification of "stemness" state of cells, ie, their degree of pluripotency. This technique could determine with single cell sensitivity the pluripotency potential of stem cells, thus having the capacity of becoming a standard method of quality control of stem or pluripotent cells before their use in cell therapy or research in biomedicine.

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This work has been carried out by scientists from the Centre for Genomic Regulation Maria Aurelia Ricci and ICREA Research Prof. Pia Cosma together with Dr. Carlo Manzo, ICREA Research Prof. Mara Garca-Parajo, and Prof. Melike Lakadamyali from the Institute of Photonic Sciences. The outcome of this study has shown the successful collaboration between biologists and physicists from two of the leading research institutes of their respective fields in Europe, both located in Barcelona. It reinforces the importance of having multidisciplinary collaborations in search for the advancement of science.

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Super-resolution microscopes reveal the link between genome packaging and cell pluripotency