Study Identifies New Set of Genes That May Explain Why People with Down Syndrome Have a Higher Risk of Leukemia – DocWire News

A study which appeared in the journal Oncotarget sheds light on why people with Down syndrome are at higher risk of Leukemia. Researchers pinpointed a new set of genes overexpressed in endothelial cells of individuals with Down syndrome, thus creating an environment conducive for leukemia.

Down syndrome occurs in approximately in one in 700 babies, and individuals with the syndrome not only development physical impairments, they have a greatly augmented risk of developing leukemia. Specifically, people with Down syndrome have a 500-fold risk of developing acute megakaryoblastic leukemia (AMKL) and a 20-fold risk of being diagnosed with acute lymphoblastic leukemia (ALL).

In this study, researchers used skin samples from patients with Down syndrome to create induced pluripotent stem cells (iPSC). They subsequently differentiated the iPSC cells into that were then endothelial cells. The researchers observed that the endothelial cell genetic expression produced altered endothelial function throughout cell maturation. We found that Down syndrome, or Trisomy 21, has genome-wide implications that place these individuals at higher risk for leukemia, says co-lead author Mariana Perepitchka, BA, Research Associate at the Manne Research Institute at Lurie Childrens via a press release. We discovered an increased expression of leukemia-promoting genes and decreased expression of genes involved in reducing inflammation. These genes were not located on chromosome 21, which makes them potential therapeutic targets for leukemia even for people without Down syndrome.

Our discovery of leukemia-conducive gene expression in endothelial cells could open new avenues for cancer research, said co-lead author Yekaterina Galat, BS, Research Associate at the Manne Research Institute at Lurie Childrens.

Fortunately, advances in iPSC technology have provided us with an opportunity to study cell types, such as endothelial cells, that are not easily attainable from patients, stated senior author Vasil Galat, PhD, Director of Human iPS and Stem Cell Core at Manne Research Institute at Lurie Childrens and Research Assistant Professor of Pathology at Northwestern University Feinberg School of Medicine. If our results are confirmed, we may have new gene targets for developing novel leukemia treatments and prevention.

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Study Identifies New Set of Genes That May Explain Why People with Down Syndrome Have a Higher Risk of Leukemia - DocWire News

Patenting Stem Cell Inventions in India- What to Expect? – Lexology

Stem cells offer hope as a promising treatment option for various diseases and are the future of medicine. Embryonic stem cells, have been at the heart of many debates globally, in view of the embryonic destruction or manipulation that their generation may require. Converging between research and law, patent law and policy grant yet throw their own challenges to obtaining exclusivity.

In India, in addition to satisfying the criteria of novelty and inventive step, inventions need to fall outside the realm of Section 3 of the Patents Act, to be patentable. Presenting an additional bar to patentability, Section 3 enlists inventions which are not patentable. Owing to this section it is oftentimes the case that the claim scope granted in India is quite different from that granted in other jurisdictions.

Public order and morality

Over the years, the Indian Patent Offices perspective on the issue of patentability of inventions involving embryonic stem cells, appears to have changed. This change in stance is apparent from the changes in the Manual of Patent Office Practice and Procedure. The 2005 draft of said guidelines treated the use of human or animal embryos for any purpose against public order and morality and prohibited the same from patentability. This restriction however, was removed from the subsequent draft of the guidelines and has not reappeared ever since.

Inspite of this change in the guidelines, the Patent Office till date raises the public order and morality objection under section 3(b) of the Patents Act, on stem cell related inventions (both methods and stem cell products). The concern most frequently expressed is the possibility of destruction of human embryos. The prosecution history of several cases shows that an objection on public order and morality has been raised even if the claims do not call out embryonic stem cells but the specification mentions the possibility of use of embryonic stem cells. The objection is frequently overcome by excluding any reference to embryonic stem cells from the claims and by disclaiming the use of embryonic stem cells in the operation of the invention.

However, the approach of treating stem cell research against public order and morality appears to be in contrast to public policy in India. The National Guidelines for Stem Cell Research (published by ICMR and DBT under the Ministry of Science and Technology) prescribe conditions subject to which research on stem cells should be conducted. The conditions include verification that the blastocysts used are spare embryos. The guidelines also permit establishment of new human embryonic stem cell lines from spare embryos subject to the approval of certain committees. Clearly, these government guidelines permit safe and responsible stem cell research, including research on embryonic stem cells.

Moreover, it is a well-known fact that not every invention involving embryonic stem cells would necessitate destruction of human embryos and a lot of research is based on embryonic stem cell lines. Therefore, the indiscriminate imposition of objections under Section 3(b) requires change.

Parts of Plants or Animals and Products of Nature

While claims relating to methods of isolation and propagation of stem cells are frequently granted, the Indian Patent Office appears to have never granted even a single application with claims directed to stem cells per se.

This brings us to another common objection frequently encountered in stem cell applications, namely, Section 3(j) which prohibits from patentability plants and animals in whole or any part thereof other than micro-organisms but including seeds, varieties and species and essentially biological processes for production or propagation of plants and animals. Another commonly encountered objection is of Section 3(c) which bars the patentability of any living thing or non-living substance occurring in nature.

There is no judicial precedent that could throw light on what exactly constitutes parts of plants and animals under Section 3(j). The Patent Office considers any cell or tissue derived from plants or animals as parts of plants or animals leading to refusal of cell claims under this ground. Claims related to compositions comprising stem cells are also frequently refused as the compositions are treated as indirectly claiming stem cells. There have been some exceptions though, such as patent number 333231, where a composition comprising stem cells was granted.

A moot issue here is whether cells are actually parts of animals/plants or whether they can be treated as microorganisms. While the Patents Act permits the patentability of microorganisms (that do not occur in nature), the term microorganism has not been defined in either the Act or the manuals that the Patent Office has issued so far. In fact, even the TRIPS agreement which mandates member states to grant patents in relation to microorganisms does not define the term. The European Patent Office recognizes all generally unicellular organisms with dimensions beneath the limits of vision which can be propagated and manipulated in a laboratory. (T 0356/93) as microorganisms.

Since the Patents Act does not limit the scope of the term microorganism and if one were to accept the literary or dictionary meaning of the term microorganism, it would appear that the Patents Act does not prohibit from the scope of patentability cells, which are not visible to the naked eye or which are so small that they require a microscope for viewing.

Moreover, stem cells like induced pluripotent stem cell and human parthenogenetic stem cells, which are somatic cells or oocytes that have been induced to develop the characteristics of unrestrained propagation and ability to develop into any cell type, are markedly distinct from the parent cell from which they are derived and are new cell types altogether. Such cells are indeed creations of man and cannot qualify as an animal part. They are also not living substances that occur in nature and being purely man made fall outside the prohibitory restraint of Section 3(c).

In the absence of judicial precedents and well defined guidelines, the law in India in relation to patentability of stem cell research is at a nascent stage. The Indian Patent Office has been following an unwritten code in the examination of these applications but the approach currently adopted is debatable. It is important to offer robust patent protection to encourage innovation in all fields. While there has been some change in the Patent Offices approach to patentability of stem cells and claims related to methods of producing, culturing and isolation of stem cells, culture media for stem cells, etc., are commonly granted, there is still a lot that can be patented but is currently not. Hopefully, India will see some judicial precedents in the future that will clarify the patentability issues that this field is struggling with.

This article was first published by Legal Era

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Patenting Stem Cell Inventions in India- What to Expect? - Lexology

Scientists May Have Discovered a Way to to Slow Aging by Direct Reprogramming of Human Cells – SciTechDaily

Skin fibroblasts were successfully reprogrammed into the smooth muscle cells (red) and endothelial cells (white) which surround blood vessels. The cells nuclei are shown in blue. Credit: Bersini, Schulte et al. CC by 4.0

Salk study is the first to reveal ways cells from the human circulatory system change with age and age-related diseases.

Salk scientists have used skin cells called fibroblasts from young and old patients to successfully create blood vessels cells that retain their molecular markers of age. The teams approach, described in the journal eLife on September 8, 2020, revealed clues as to why blood vessels tend to become leaky and hardened with aging, and lets researchers identify new molecular targets to potentially slow aging in vascular cells.

The vasculature is extremely important for aging but its impact has been underestimated because it has been difficult to study how these cells age, says Martin Hetzer, the papers senior author and Salks vice president and chief science officer.

Research into aging vasculature has been hampered by the fact that collecting blood vessel cells from patients is invasive, but when blood vessel cells are created from special stem cells called induced pluripotent stem cells, age-related molecular changes are wiped clean. So, most knowledge about how blood vessel cells age comes from observations of how the blood vessels themselves change over time: veins and arteries become less elastic, thickening and stiffening. These changes can contribute to blood pressure increases and a heightened risk of heart disease with age.

From left: Martin Hetzer and Simone Bersini. Credit: Salk Institute

In 2015, Hetzer was part of the team led by Salk President Rusty Gage to show that fibroblasts could be directly reprogrammed into neurons, skipping the induced pluripotent stem cell stage that erased the cells aging signatures. The resulting brain cells retained their markers of age, letting researchers study how neurons change with age.

In the new work, Hetzer and his colleagues applied the same direct-conversion approach to create two types of vasculature cells: vascular endothelial cells, which make up the inner lining of blood vessels, and the smooth muscle cells that surround these endothelial cells.

We are among the first to use this technique to study the aging of the vascular system, says Roberta Schulte, the Hetzer lab coordinator and co-first author of the paper. The idea of developing both of these cell types from fibroblasts was out there, but we tweaked the techniques to suit our needs.

The researchers used skin cells collected from three young donors, aged 19 to 30 years old, three older donors, 62 to 87 years old, and 8 patients with Hutchinson-Gilford progeria syndrome (HGPS), a disorder of accelerated, premature aging often used to study aging.

The resulting induced vascular endothelial cells (iVECs) and induced smooth muscle cells (iSMCs) showed clear signatures of age. 21 genes were expressed at different levels in the iSMCs from old and young people, including genes related to the calcification of blood vessels. 9 genes were expressed differently according to age in the iVECs, including genes related to inflammation. In patients with HGPS, some genes reflected the same expression patterns usually seen in older people, while other patterns were unique. In particular, levels of BMP-4 protein, which is known to play a role in the calcification of blood vessel, were slightly higher in aged cells compared to younger cells, but more significantly higher in smooth muscle cells from progeria patients. This suggests that the protein is particularly important in accelerated aging.

The results not only hinted at how and why blood vessels change with age, but confirmed that the direct-conversion method of creating vascular endothelial and smooth muscle cells from patient fibroblasts allowed the cells to retain any age-related changes.

One of the biggest theoretical implications of this study is that we now know we can longitudinally study a single patient during aging or during the course of a treatment and study how their vasculature is changing and how we might be able to target that, says Simone Bersini, a Salk postdoctoral fellow and co-first author of the paper.

To test the utility of the new observations, the researchers tested whether blocking BMP4 which had been present at higher levels in smooth muscle cells developed from people with HGPS could help treat aging blood vessels. In smooth muscle cells from donors with vascular disease, antibodies blocking BMP4 lowered levels of vascular leakiness one of the changes that occurs in vessels with aging.

The findings point toward new therapeutic targets for treating both progeria and the normal age-related changes that can occur in the human vascular system. They also illustrate that the direct conversion of fibroblasts to other mature cell types previously successful in neurons and, now, in vascular cells is likely useful for studying a wide range of aging processes in the body.

By repeating what was done with neurons, weve demonstrated that this direct reprogramming is a powerful tool that can likely be applied to many cell types to study aging mechanisms in all sorts of other human tissues, says Hetzer, holder of the Jesse and Caryl Philips Foundation Chair.

The team is planning future studies to probe the exact molecular mechanisms by which some of the genes they found to change with age control the changes seen in the vasculature.

Reference: Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome by Simone Bersini, Roberta Schulte, Ling Huang, Hannah Tsai and Martin W Hetzer, 8 September 2020, eLife. DOI: 10.7554/eLife.54383

Other researchers on the study were Ling Huang and Hannah Tsai of Salk. The work was supported by grants from the National Institutes of Health, the NOMIS Foundation and an AHA-Allen Initiative in Brain Health and Cognitive Impairment award made jointly through the American Heart Association and the Paul G. Allen Frontiers Group. Simone Bersini was supported by the Paul F. Glenn Center for Biology of Aging Research at the Salk Institute.

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Scientists May Have Discovered a Way to to Slow Aging by Direct Reprogramming of Human Cells - SciTechDaily

Induced Pluripotent Stem Cells Market Global Growth Analysis and Forecast to 2024 | Top Players (BlueRock Therapeutics, Corning Life Sciences, EMD…

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Study: The Speed Neurons Fire Impacts Their Ability to Synchronize – Lab Manager Magazine

Research conducted by the Computational Neuroscience Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) has shown for the first time that a computer model can replicate and explain a unique property displayed by a crucial brain cell. Their findings, published Sept. 8 ineLife, shed light on how groups of neurons can self-organize by synchronizing when they fire fast.

The model focuses on Purkinje neurons, which are found within the cerebellum. This dense region of the hindbrain receives inputs from the body and other areas of the brain in order to fine-tune the accuracy and timing of movement, among other tasks.

"Purkinje cells are an attractive target for computational modeling as there has always been a lot of experimental data to draw from," said professor Erik De Schutter, who leads the Computation Neuroscience Unit. "But a few years ago, experimental research into these neurons uncovered a strange behavior that couldn't be replicated in any existing models."

These studies showed that the firing rate of a Purkinje neuron affected how it reacted to signals fired from other neighboring neurons.

Cell membranes have a voltage across them due to the uneven distribution of charged particles, called ions, between the inside and outside of the cell. Neurons can shuttle ions across their membrane through channels and pumps, which changes the voltage of the membrane. Fast firing Purkinje neurons have a higher membrane voltage than slow firing neurons.

Image modified from "How neurons communicate: Figure 2," by OpenStax College, Biology (CC BY 4.0)

The rate at which a neuron fires electrical signals is one of the most crucial means of transmitting information to other neurons. Spikes, or action potentials, follow an "all or nothing" principleeither they occur, or they don'tbut the size of the electrical signal never changes, only the frequency. The stronger the input to a neuron, the quicker that neuron fires.

But neurons don't fire in an independent manner. "Neurons are connected and entangled with many other neurons that are also transmitting electrical signals. These spikes can perturb neighboring neurons through synaptic connections and alter their firing pattern," explained De Schutter.

Interestingly, when a Purkinje cell fires slowly, spikes from connected cells have little effect on the neuron's spiking. But, when the firing rate is high, the impact of input spikes grows and makes the Purkinje cell fire earlier.

"The existing models could not replicate this behavior and therefore could not explain why this happened. Although the models were good at mimicking spikes, they lacked data about how the neurons acted in the intervals between spikes," De Schutter said. "It was clear that a newer model including more data was needed."

Fortunately, De Schutter's unit had just finished developing an updated model, an immense task primarily undertaken by now former postdoctoral researcher, Dr. Yunliang Zang.

Once completed, the team found that for the first time, the new model was able to replicate the unique firing-rate dependent behavior.

In the model, they saw that in the interval between spikes, the Purkinje neuron's membrane voltage in slowly firing neurons was much lower than the rapidly firing ones.

"In order to trigger a new spike, the membrane voltage has to be high enough to reach a threshold. When the neurons fire at a high rate, their higher membrane voltage makes it easier for perturbing inputs, which slightly increase the membrane voltage, to cross this threshold and cause a new spike," explained De Schutter.

The researchers found that these differences in the membrane voltage between fast and slow firing neurons were because of the specific types of potassium ion channels in Purkinje neurons.

"The previous models were developed with only the generic types of potassium channels that we knew about. But the new model is much more detailed and complex, including data about many Purkinje cell-specific types of potassium channels. So that's why this unique behavior could finally be replicated and understood," said De Schutter.

When a group of Purkinje neurons fire rapidly, loose synchronization occurs. This can be seen by the spikes occurring in groups at regular intervals (highlighted in yellow). When Purkinje neurons fire slowly, this synchronization does not occur.

OIST

The researchers then decided to use their model to explore the effects of this behavior on a larger-scale, across a network of Purkinje neurons. They found that at high firing rates, the neurons started to loosely synchronize and fire together at the same time. Then when the firing rate slowed down, this coordination was quickly lost.

Using a simpler, mathematical model, Dr. Sungho Hong, a group leader in the unit, then confirmed this link was due to the difference in how fast and slow firing Purkinje neurons responded to spikes from connected neurons.

"This makes intuitive sense," said De Schutter. He explained that for neurons to be able to sync up, they need to be able to adapt their firing rate in response to inputs to the cerebellum. "So this syncing with other spikes only occurs when Purkinje neurons are firing rapidly," he added.

The role of synchrony is still controversial in neuroscience, with its exact function remaining poorly understood. But many researchers believe that synchronization of neural activity plays a role in cognitive processes, allowing communication between distant regions of the brain. For Purkinje neurons, they allow strong and timely signals to be sent out, which experimental studies have suggested could be important for initiating movement.

"This is the first time that research has explored whether the rate at which neurons fire affects their ability to synchronize and explains how these assemblies of synchronized neurons quickly appear and disappear," said De Schutter. "We may find that other circuits in the brain also rely on this rate-dependent mechanism."

The team now plans to continue using the model to probe deeper into how these brain cells function, both individually and as a network. And, as technology develops and computing power strengthens, De Schutter has an ultimate life ambition.

"My goal is to build the most complex and realistic model of a neuron possible," said De Schutter. "OIST has the resources and computing power to do that, to carry out really fun science that pushes the boundary of what's possible. Only by delving into deeper and deeper detail in neurons, can we really start to better understand what's going on."

- This press release was originally published on theOIST website

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Study: The Speed Neurons Fire Impacts Their Ability to Synchronize - Lab Manager Magazine