Category Archives: Genome

A genomic sequencing process that once took 30 hours or more can now be completed in a few minutes.

NVIDIA announced this week it will provide a free 90-day license to its Parabricks Genome Analysis Toolkit to enable researchers to leverage graphic processor units (GPUs) in their race to find a cure for the COVID-19 coronavirus.

The goal is to not just better understand how thecoronavirus is constructed to help develop a potential cure, but also discoverwhy it is more lethal to some individuals than others, says Kimberly Powell, vicepresident and general manager for healthcare at NVIDIA.

See also: 5 Places to Take Online AI Courses While You Ride Out COVID-19

The challenge is processing the massive amount of data requiredto sequence genome data. Many cloud service providers have been making computecapacity available to well over 50,000 researchers. NVIDIA is now moving tomake a potentially critical toolkit for analyzing that data available for freeas well.

Sequencing genome data clearly plays a key role in achievingthat latter goal sooner than later because GPUs can accelerate by as much as 50times the analysis of sequence data using algorithms that were createdspecifically to apply artificial intelligence (AI) to genome research, says Powell.A sequencing process that once took 30 hours or more can now be completed in afew minutes, says Powell.

However, the sequencing data now needed urgently as a matter of public safety resides in everything from documents to imaging applications. The Parabricks Genome Analysis Toolkit makes it easier, among other things, to aggregate and analyze all that data, says Powell.

There is no way you could make sense of all that datawithout AI, says Powell.

That research will also eventually play a critical role in helping to determine the original source of the virus. In fact, Powell says its already been established the COVID-19 virus was created outside of a lab and that it existed as far back as October/November of 2019.

COVID-19 researchers are naturally pursuing multiple linesof investigation. Rather than access to compute resources becoming an inhibitorin conducting that research, IT vendors are collectively moving to make sureresearchers have as much compute and storage resources available as required.

It will be interesting to see how much of the current spirit of cooperation will endure once the current crisis has passed. Its probable that not only will the COVID-19 coronavirus return; its also worth noting COVID-19 is only one in a series of coronavirus instances that are becoming more lethal with each new iteration. One of the potential benefits of all the resources being poured into COVID19 research is that pipelines, patterns, and processes are being created that could be applied to other research projects, notes Powell.

There is, of course, no guarantee a cure will be found. The common cold is a form of a coronavirus that has thwarted research efforts since the proverbial dawn of time. However, there may be a greater appreciation of AI may manifest itself should researcher find a cure. After all, its not likely any of that research could have been carried out in a timely manner with relying on AI to quite possibly save humanity than many are worried AI will replace.

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NVIDIA Makes Available Free Toolkit to Aid COVID-19 Research - RTInsights

NIEL, Belgium, March 24, 2020 /PRNewswire/ -- eTheRNA Immunotherapies nv ('eTheRNA' or 'The Company'), a clinical-stage company developing vaccines and immunotherapies from its proprietary mRNA TriMix platform, today announced that a consortium has been formed with North American and European partners to develop a novel mRNA vaccine against CoV-2 and preclinical development has started. Chinese partners may be added in the consortium in due course.

Administered intranasally, the proposed vaccine is intended primarily for high risk populations such as healthcare workers and families of confirmed cases. It is also designed to be protective against future variations of the virus by targeting conserved epitopes from the whole CoV-2 genome. eTheRNA and its partners EpiVax, Nexelis, REPROCELL and CEV* have extensive experience in the mRNA vaccine field and this will help accelerate progress towards clinical trials with patient enrolment expected in early 2021.

Steven Powell, eTheRNA's CEO, explained the aims of the consortium: "Viral variation means traditional medicinal and preventive vaccine approaches may fall short when confronted with seasonal or outbreak situations. A vaccine to defend against current and future outbreaks of coronavirus and other respiratory viral pathogens should be robust against viral genome changes, provide a platform that enables rapid introduction of a new viral target, be easy and safe to administer and be scaleable and suitable for stockpiling. The innovative vaccine program we have started with our partners incorporates all of these essential features."

Traditional vaccines are based on generating an antibody response to outer surface viral protein targets. However, viral variation may greatly reduce the effectiveness of this approach. For example, the SARS-CoV-2 outer surface spike protein (S) is less than 40% homologous to SARS-CoV-1. Furthermore, it has also been reported in several cases that vaccines with suboptimal antibody response (too low or not neutralizing) have facilitated viral entry and been linked to disease enhancement.

The eTheRNA consortium's approach selects conserved epitopes from the whole viral genome. Creating a vaccine that mounts a strong cellular (T cell) based response against these epitopes offers a better chance to overcome viral variability. Intranasal delivery has been chosen since the mucosa of the upper respiratory tract are the immune system's primary line of defense. A strong nasal T cell effector and memory response is claimed to fight viral replication, colonization of the lung and thus disease. mRNA has also been demonstrated to induce strong T cell responses by intranasal delivery.

The development programme has been initiated and is focused on a vaccine candidate that integrates 3 different technologies:

"While valuable initiatives and strong support are being deployed into the development of medicinal and vaccine solutions for immediate use against SARS-CoV-2, it is also important that development of solutions for the longer term should also start as soon as possible," concluded Powell. "Our target is to bring this into clinical testing in early 2021."

Information for editors

About eTheRNA immunotherapies

eTheRNA immunotherapies is a clinical-stage company developing innovative immunotherapies from its proprietary mRNA TriMix platform. eTheRNA was established in January 2013 as a spin-off from the VUB university in Belgium and is developing products for the treatment of cancer and infectious disease.

About TriMix

The TriMix platform, on which eTheRNA's immunotherapies are based, comprises three mRNAs encoding proteins (caTLR4, CD40L and CD70) that work to deliver optimal activation of dendritic cells. These cells behave as immune response mediators and mobilize the immune system to attack cancer cells through inducing a T-cell response. Clinical proof of concept for TriMix-based immunotherapies has been established through an extensive dataset demonstrating clinical benefits in advanced melanoma patients.

About EpiVax

EpiVax is a 21-year old privately held biotechnology company located in Providence, Rhode Island. Scientists at EpiVax, led by co-founders Annie De Groot, MD and Bill Martin, lead in the fields of immunogenicity risk assessment and computational vaccinology with expertise in T cell epitope prediction, immune modulation, and rapid vaccine design. EpiVax's broad portfolio of projects includes vaccines and immunotherapies for infectious diseases, autoimmunity and cancer. EpiVax's proprietary in silico immunogenicity screening toolkits for therapeutics and vaccines, ISPRI and iVAX, are employed in advancing the research of a global roster of companies. Visit http://www.epivax.com for more information.

About Nexelis

With unrivaled expertise in immunology on both sides of the client/CRO relationship, and operating sites in North America (East and West Coast) and Europe, Nexelis is a leading provider of assay development and advanced laboratory testing services in the infectious diseases, metabolic diseases, and oncology fields. Our versatile team of scientists, working with our advanced technology platforms, were instrumental in the development, qualification, validation, and large-scale sample testing of assays that supported the FDA filing of almost 100 new molecular entities, including blockbuster vaccines, anti-viral drugs, and immunotherapy, gene and cell therapy products. Visit http://www.nexelis.com for more information.

About REPROCELL

REPROCELL was established in 2003 to accelerate medical research via cutting-edge stem cell and human tissue-based technologies, including the use of novel transfection reagents and RNA-based methods for the generation of induced pluripotent stem cells. REPROCELL has further diversified its portfolio of products and services to include predictive drug discovery services in human fresh tissues, technologies for the manufacture of bioengineered human tissues, industry-leading gene editing technology and one of the largest commercial repositories of ethically sourced human tissue. Visit http://www.reprocell.com for more information.

About CEV

The Centre for the Evaluation of Vaccination (CEV) of the University of Antwerp, headed by Prof. Pierre Van Damme, is a clinical trial centre specialized in the conduct of vaccine trials. It has performed Phase I until Phase IV clinical trials in all age groups. The CEV is internationally known for its professional and qualitative vaccine clinical trial facility and organisation and is therefore a regular partner in vaccine clinical trials, i.e. for EU funded clinical trials, for investigator-driven vaccine trials as well as for industry funded clinical trials. For more information visit https://www.uantwerpen.be/en/research-groups/centre-for-evaluation-vaccination/

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media@etherna.be

Or

Richard HayhurstRHAprMobile +44 (0)7711-821-527richard@rhapr.eu

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SOURCE eTheRNA

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eTheRNA Launches an International Consortium and Starts Development of Cross-strain Protective CoV-2 mRNA Vaccine for High Risk Populations - BioSpace

An emergency room physician, initially unable to diagnose a disoriented patient, finds on the patient a wallet-sized card providing access to his genome, or all his DNA. The physician quickly searches the genome, diagnoses the problem and sends the patient off for a gene-therapy cure. Thats what a Pulitzer prize-winning journalist imagined 2020 would look like when she reported on the Human Genome Project back in 1996.

The Human Genome Project was an international scientific collaboration that successfully mapped, sequenced and made publicly available the genetic content of human chromosomes or all human DNA. Taking place between 1990 and 2003, the project caused many to speculate about the future of medicine.

In 1996, Walter Gilbert, a Nobel laureate, said, The results of the Human Genome Project will produce a tremendous shift in the way we can do medicine and attack problems of human disease. In 2000, Francis Collins, then head of the HGP at the National Institutes of Health, predicted, Perhaps in another 15 or 20 years, you will see a complete transformation in therapeutic medicine. The same year, President Bill Clinton stated the Human Genome Project would revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.

It is now 2020 and no one carries a genome card. Physicians typically do not examine your DNA to diagnose or treat you. Why not? As I explain in a recent article in the Journal of Neurogenetics, the causes of common debilitating diseases are complex, so they typically are not amenable to simple genetic treatments, despite the hope and hype to the contrary.

The idea that a single gene can cause common diseases has been around for several decades. In the late 1980s and early 1990s, high-profile scientific journals, including Nature and JAMA, announced single-gene causation of bipolar disorder, schizophrenia and alcoholism, among other conditions and behaviors. These articles drew massive attention in the popular media, but were soon retracted or failed attempts at replication. These reevaluations completely undermined the initial conclusions, which often had relied on misguided statistical tests. Biologists were generally aware of these developments, though the follow-up studies received little attention in popular media.

There are indeed individual gene mutations that cause devastating disorders, such as Huntingtons disease. But most common debilitating diseases are not caused by a mutation of a single gene. This is because people who have a debilitating genetic disease, on average, do not survive long enough to have numerous healthy children. In other words, there is strong evolutionary pressure against such mutations. Huntingtons disease is an exception that endures because it typically does not produce symptoms until a patient is beyond their reproductive years. Although new mutations for many other disabling conditions occur by chance, they dont become frequent in the population.

Instead, most common debilitating diseases are caused by combinations of mutations in many genes, each having a very small effect. They interact with one another and with environmental factors, modifying the production of proteins from genes. The many kinds of microbes that live within the human body can play a role, too.

Since common serious diseases are rarely caused by single-gene mutations, they cannot be cured by replacing the mutated gene with a normal copy, the premise for gene therapy. Gene therapy has gradually progressed in research along a very bumpy path, which has included accidentally causing leukemia and at least one death, but doctors recently have been successful treating some rare diseases in which a single-gene mutation has had a large effect. Gene therapy for rare single-gene disorders is likely to succeed, but must be tailored to each individual condition. The enormous cost and the relatively small number of patients who can be helped by such a treatment may create insurmountable financial barriers in these cases. For many diseases, gene therapy may never be useful.

The Human Genome Project has had an enormous impact on almost every field of biological research, by spurring technical advances that facilitate fast, precise and relatively inexpensive sequencing and manipulation of DNA. But these advances in research methods have not led to dramatic improvements in treatment of common debilitating diseases.

Although you cannot bring your genome card to your next doctors appointment, perhaps you can bring a more nuanced understanding of the relationship between genes and disease. A more accurate understanding of disease causation may insulate patients against unrealistic stories and false promises.This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Why Sequencing the Human Genome Failed to Produce Big Breakthroughs in Disease - Discover Magazine

By Jessica Hamzelou

ALEX PLAVEVSKI/EPA-EFE/Shutterstock

Two strains of the new coronavirus are spreading around the world, according to an analysis of 103 cases. But the World Health Organization insists that there is no evidence that the virus has been changing. So how many strains are there, and why does it matter?

Viruses are always mutating, especially RNA viruses like this one, coronavirus SARS-CoV-2. When a person is infected with the coronavirus, it replicates in their respiratory tract. Every time it does, around half a dozen genetic mutations occur, says Ian Jones at the University of Reading, UK.

When Xiaolu Tang at Peking University in Beijing and colleagues studied the viral genome taken from 103 cases, they found common mutations at two locations on the genome. The team identified two types of the virus based on differences in the genome at these two regions: 72 were considered to be the L-type and 29 were classed S-type.

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A separate analysis by the team suggests that the L-type was derived from the older S-type. The first strain is likely to have emerged around the time the virus jumped from animals to humans. The second emerged soon after that, says the team. Both are involved in the current global outbreak. The fact that the L-type is more prevalent suggests that it is more aggressive than the S-type, the team say.

There do appear to be two different strains, says Ravinder Kanda at Oxford Brookes University in the UK. [The L-type] might be more aggressive in transmitting itself, but we have no idea yet how these underlying genetic changes will relate to disease severity, she says.

I think its a fact that there are two strains, says Erik Volz at Imperial College London. Its normal for viruses to undergo evolution when they are transmitted to a new host.

It is vital to know how many strains of the virus exist. Around the world, multiple groups are working on a vaccine for the virus. Any vaccine will need to target features that are found in both strains of the virus in order to be effective.

The differences between the two identified strains are tiny. In fact, they cant really be considered to be separate strains, says Jones. And many of the genetic differences wont affect the production of proteins, and so wont change the way the virus works, or the symptoms it causes, he says. One is not more deadly than the other.

In all practical terms, the virus is as it was when it originally emerged, says Jones. Theres no evidence it is getting any worse. The sentiment is echoed by the World Health Organization. The study by Tang and colleagues only suggests there is some genetic diversity of the virus it doesnt mean it is changing, a representative told New Scientist.

But we cant say for sure. The study only represents 103 cases. A larger, online database has collated the sequencing results from 166 cases. Both represent a drop in the ocean of the almost 100,000 officially reported cases.

Jones says we can expect more strains to emerge. Epidemiologists generally agree that, once a person is infected with the coronavirus, they are unlikely to be infected again unless the virus mutates to allow it to overcome the immune systems defences.

This selection pressure could lead to the outbreak of a new strain, says Jones. This is the case with seasonal flu new variants crop up every year that can infect people whether or not theyve had flu in the past.

We could see the same pattern emerge for the new coronavirus in the coming years, says Jones. I dont see it going away any time soon.

Journal reference: National Science Review, DOI: 10.1093/nsr/nwaa036

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Coronavirus: Are there two strains and is one more deadly? - New Scientist News

In the unprecedented outbreak of a new coronavirus sweeping the world, the germs genetic material may ultimately tell the story not just of where it came from, but of how it spread and how efforts to contain it failed.

By tracking mutations to the virus as it spreads, scientists are creating a family tree in nearly real time, which they say can help pinpoint how the infection is hopping between countries.

When scientists in Brazil confirmed that countrys first case of coronavirus late in February, they were quick to sequence the germs genetic code and compare it with over 150 sequences already posted online, many from China.

The patient, a 61-year-old from So Paulo, had traveled in Italys northern Lombardy region that month, so Italy was likely where he acquired the infection. But the sequence of his virus suggested a more complex story, linking his illness back to a sick passenger from China and an outbreak in Germany.

As a virus spreads, it mutates, developing random changes in single genetic letters in its genome. By tracking those changes, scientists can trace its evolution and learn which cases are most closely related. The latest maps already show dozens of branching events.

The data is being tracked on a website called Nextstrain, an open-source effort to harness the scientific and public health potential of pathogen genome data. Because scientists are posting data so quickly, this is the first outbreak in which a germs evolution and spread have been tracked in so much detail, and almost in real time.

nextstrain.org

The work of the genome sleuths is helping show where containment measures have failed. It also makes clear that countries have faced multiple introductions of the virus, not just one. Eventually, genetic data could pinpoint the original source of the outbreak.

In Brazil, researchers were able to use gene data to show that its first case, and a second one found later, were not very closely related, says Nuno Faria at the University of Oxford. Samples of the virus from the two patients had enough differences to indicate that they must have been acquired in different locations.

When combined with the patient travel information, this indicates that the two confirmed cases in Brazil are the result of separate introductions to the country, Faria wrote in a discussion of his findings.

Faria Lab

Since there is no vaccine, experts say the best chance of stopping the virus is through aggressive public health measures, like finding and isolating people whove been exposed.

And thats where the viruss evolutionary tree is useful, helping to trace the spread of the germ and detect where containment is and isnt working.

The genetic data shows that the virus entered Europe multiple times. It also now suggests that an outbreak in Munich in January, which researchers believed was caught early, might not have been successfully contained.

Since February 1, about a fourth of new infectionsin Mexico, Finland, Scotland, and Italy as well as the first case in Brazilappeared genetically similar to the Munich cluster, says Trevor Bedford, a researcher at the Fred Hutchinson Cancer Research Center and one of the creators of Nextstrain.

Patient 1 of the Munich branch was a 33-year-old German businessman from Bavaria who became sick with a sore throat and chills on January 24. Investigators say before feeling ill he'd met with a Chinese business partner visiting from Shanghai, who herself later tested positive for the virus.

Within four days, more employees of the company, Webasto, tested positive. Although the company closed its headquarters, it wasnt enough. According to the genetic data, the Munich event could be linked to a decent part of the overall European outbreak, which includes more than 3,000 cases in Italy.

An extremely important take home message here is that just because a cluster has been identified and contained doesnt actually mean this case did not seed a transmission chain that went undetected until it grew to be [a] sizable outbreak, Bedford posted to Twitter.

Thats exactly what viral detectives think may have happened in Washington State in the US, where a first case was discovered nearly six weeks ago. In February, though, when they sequenced the virus from a new case, they found it shared a specific mutation with the first one.

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That meant the two were related and the virus had been silently spreading inside the US all along. Since then, Washington has reported 27 cases and nine deaths, including people who died earlier without being properly diagnosed.

In the wake of the Washington outbreak, critics have blamed the US Centers for Disease Control and Prevention for limiting who could get tested, effectively blinding experts to the course of the outbreak.

Originally posted here:
Gene sleuths are tracking the coronavirus outbreak as it happens - MIT Technology Review

The field of genomics has made fantastic progress in the fields of biomedical research and clinical development. This is good news for patients and excellent news for investors, as the field of genomics is expected to pay large dividends in finance in the coming decade.

Despite being a relatively new field in the space of biology research, genomics has made massive advances in science and medicine in the past few years. Research into the human genome has led to the development of personalized medicine, changing the clinical landscape for cancer treatment and rare genetic diseases, in particular. The cost associated with mapping one genome has dramatically dropped in a very short space of time, costing millions of dollars and years of effort at the start to now costing in the hundreds of dollars per sequence that is delivered in a matter of days. This has allowed worldwide entry into this space, and an explosion of new discoveries and advances.

The global genomics market size is expected to reach USD 31.1 billion by 2027, registering a CAGR of 7.7% over the forecast period, according to a new report by Grand View Research, Inc. Significant changes in disease management processes along with advancements in genomics and personalized medicine are expected to propel the market.

Grand View Research is a U.S.-based market research and consulting company, providing syndicated as well as customized research reports and consulting services. Headquartered in San Francisco, the companys analysts and consultants report in-depth analysis on 46 industries across 25 major countries worldwide. With the help of an interactive market intelligence platform, Grand View Research helps Fortune 500 companies and renowned academic institutes understand the global and regional business environment.

The report that was recently published makes several suggestions as to what is anticipated to be leading this growth. The consumables and reagents deliverable segment is expected to register the highest growth rate, owing to high costs and volume associated with reagents needed for sequencing. This field is filled by companies that service actual research companies, and oftentimes are the main operating costs of lab testing.

The computational services deliverable segment is also set to expand at a considerable CAGR from 20202027 owing to the increasing demand for computational sequence alignment and analysis among molecular biologists. Interpreting sequencing data is a somewhat complicated process, and software and people capable of interpreting the results are at an ever-increasing demand in this space.

In terms of investment into future research and development for predictive biomarkers targeted toward diagnosis and patient monitoring, substantial investments by biotechnology and pharmaceutical companies have contributed significantly to the revenue generated by the biomarker discovery application segment. Clinical trials using genomics sequencing have oftentimes been wildly successful, driving more and more disease-based research to consider its use for new treatment strategies, as well as a search for biomarkers at a breakneck speed.

The success of use of genomic sequencing is a worldwide affair, and the Asian Pacific region is a potentially lucrative market for genomics, and is anticipated to expand at the highest CAGR of 9.1%. Regionally, genomics is being used everywhere, particularly in North America and Europe, but also in Asia, South America, the Middle East, and Africa.

Key companies in the genomics market tend to be located in the United States or Europe, and the largest players include 23andMe; F. Hoffmann-La Roche Ltd.; BGI; Myriad Genetics Inc.; Danaher.; Pacific Biosciences; Illumina; Agilent Technologies; Thermo Fisher Scientific, Inc.; Foundation Medicine; Oxford Nanopore Technologies; and Bio-Rad Laboratories.

Of these companies, an increasing pool of market innovators mostly from 23andMe, Oxford Nanopore Technologies, and Veritas Genetics (each having launched breakthrough genomic technologies in recent years) are also contributing toward market development. 23andMe in particular has expertise in developing direct-to-consumer genomic tests targeted toward disease prognosis and has received FDA approval for its commercialization.

MinION, a sequencing device from Oxford Nanopore Technologies, is witnessing significant traction owing to its ability to sequence any fragment length of DNA in real time. In the same field, Veritas Genetics is offering an affordable solution for a complete readout of a genomic sequence. A few years ago, it was only possible to procure this information if ordered by a doctor, but now these tests can be taken by anyone curious about their DNA and costs approximately USD 1,000. Veritas Genetics has also begun the commercialization of this technique for newborns genomic sequencing applications in China.

Genomic sequencing and biomarker identification is hardly the only source of income in the field of genomics. Other deliverables besides products and services include functional genomics in basic laboratory research and aspects of costs associated; the study of epigenetics and computer data analysis associated with large data sets; and genomics end-use, in clinical and research laboratories, academic and government institutes, hospitals and clinics, and of course pharmaceutical and biotechnology companies.

Link:
Genomics Research Market Worth to Exceed $31 Billion by 2027 - Clinical OMICs News

A trial in prostate cancer known GUNS (Genomic Umbrella Neoadjuvant Study) uses a multi-arm, multistage adaptive design to test targeted therapies in patients with high-risk localized disease by matching neoadjuvant therapies to baseline genomic alterations. At the Society of Urologic Oncology annual meeting, Martin Gleave, MD, of the University of British Columbia in Vancouver, sat down with Urology Times to discuss the rationale behind the trial, its unique multistage design, and other biomarker-driven trials currently underway.

Explain what the GUNS (Genomic Umbrella Neoadjuvant Study) trial is and the rationale behind it.

What we've learned from several decades of neoadjuvant studies prior to radical prostatectomy is that when we use androgen deprivation therapy, even for long periods of time (out to 8 months), when we combine androgen deprivation therapy with more potent androgen receptor (AR) pathway inhibitors out to 6 months, or even when we combine androgen deprivation therapy with chemotherapy, all of these regimens have been shown to prolong life in advanced disease. But when we combine them in the neoadjuvant space, our ability to get complete responses continued to be less than 10%.

Also see:5-year cancer control comparable for focal therapy, RP

So despite using combinations of regimens that are life prolonging in the advanced space, these failed to achieve a high level of complete response, which is quite different from what we see with systemic therapies in breast cancer or in bladder cancer, where neoadjuvant regimens are associated with a 30% complete response rate when they improve survival in advanced disease.

That's a conundrum. Why is it that in prostate cancer, despite having systemic therapies that are very active, can't we achieve complete response rates similar to those of other solid cancers? One of the rationales for the GUNS trial is understanding, using genomics, the heterogeneity of localized prostate cancer, where different subgroups may have variable responsiveness to different regimens. Hence, using genomic segmentation of localized disease to identify subgroups that may be more or less susceptible to AR or androgen deprivation-type therapies, may be more susceptible to chemotherapy, or may be more susceptible to a PARP inhibitor will allow us to then potentially use combination regimens to push the complete response rate higher.

How is the GUNS trial being conducted?

GUNS stands for Genomic Umbrella Neoadjuvant Study, in which men with high-risk localized prostate cancer are enrolled. We then sequence their needle biopsies and during the first 8 weeks of therapy, they're treated with androgen deprivation therapy plus apalutamide [ERLEADA], an AR antagonist. It takes us about 8 weeks to get that sequencing done.

Based upon their sequence, they are then assigned to one of four different groups. If their tumor has genes that would predict for increased androgen responsiveness, they would be assigned to Group 1 and then be randomized to more intensive therapy by adding abiraterone [ZYTIGA] on top of apalutamide in a randomized fashion. Group 2 enrolls patients who have an aggressive tumor. They've lost p10, they've lost p53, and their tumors are associated with poor response to androgen deprivation therapy. Group 2 patients are then randomized between AR pathway inhibitor therapy alone, plus or minus chemotherapy, in the hope that the addition of chemotherapy would increase benefit in that genomic subpopulation.

Group 3 would capture about 6% to 8% of patients who have alterations in DNA repairBRCA, FANCA, and others that have been associated with sensitivity to PARP inhibitionand they would receive the master protocol therapy, ADT plus apalutamide, with a PARP inhibitor, niraparib. Group 4 comprises the 5% of patients who have an immunogenic type of cancer because of alterations in MSI, Lynch syndrome, or CDK12. They receive a PD-L1 inhibitor with that therapy.

Again, GUNS uses a multi-arm, multistage adaptive design that allows certain arms to identify what we call conditional lethality. So based upon patients' tumor group, their genomic sequence, and their therapy, if we can increase complete response rates above 20%, that would be of interest and that arm gets expanded. If they don't, then the arm gets dropped in the first 20 patients, which is an early "go" or "no-go" signal. It allows certain arms to be dropped off early, other arms to grow, and new arms to be added as new targeted therapies and new understanding of genomic markers emerge over the coming years.

What other biomarker trials are currently underway?

At the University of Washington, there is a neo-PARP study, which is looking at PARP inhibitor monotherapy in the small segmented population that is germline DNA repair altered. In breast cancer, PARP inhibitors are associated with up to a 30% complete response rate. Whether or not we see that with monotherapy in prostate cancer will be tested in that trial. There are other trials being conducted using various immunotherapy and neoadjuvant strategies based upon immune infiltrate or that characterize the immune infiltrate changes with hormone therapy and with PD-L1 inhibitors as an example.

The challenge has been the time and cost required for getting a genomic signature. Ultimately, many alterations occur in small subgroups of patients. To try and capture 10% of the population in one trial is very inefficient and costly. What the GUNS trial tries to do is allow us to capture as many subtypes as possible, bundle them in one trial, test them in an adaptive way, drop those that are not promising, and expand on those that are.

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Study will test targeted PCa therapies based on genomic alterations - Urology Times

As soon as he learned about the existence of ancient wheat specimens at University College Londons Petrie Museum of Egyptian Archaeology from a 2018 BBC documentary, Richard Mott of the UCL Genetics Institute wanted to study them. The samples likely contained bits of ancient wheat DNA, he reasoned, which could yield valuable insights into the history of cultivation of this all-important crop species.

Archaeobotanists at UCL helped Mott and a team of collaborators choose a handful of well-preserved husks from the museums collection of ancient emmer wheat, a variety native to the Near East and one of the first crops to be domesticated in the region, from which the researchers selected two husks for DNA extraction. After carefully removing the husks from the box, photographing them, and wrapping them in foil, the scientists transported the centuries-old plant material to a freshly bleached cleanroom used exclusively to process ancient and forensic samples.

Its fascinating to see this gene flow happening in an area important for human history.

M. Timothy Rabanus-Wallace, Leibniz Institute of Plant Genetics and Crop Plant Research

There, team member Laura Botigu, a population geneticist and visiting researcher from the Centre for Research in Agricultural Genomics (CRAG) in Barcelona, Spain, donned a hairnet, two Tyvek suits, two pairs of latex gloves, and a maskpart of a protocol designed to avoid contaminating the samples with her own cells. Uncertain how the delicate husks would hold up to the standard decontamination protocol of bleaching the samples, Botigu bleached one and left the second untouched. Then, to lyse the plants cells, she put the samples in a rotator that gently shook the husks inside an oven over the next several days. Finally, she used a centrifugation protocol to separate any DNA from the degraded cell walls and proteins.

Once the samples had been prepped and delivered to the UCL Genomics facility for sequencing, it was a waiting game to see if the procedure had yielded any readable wheat DNA. This is the more stressful part, Botigu says. Because they lack the type of protective collagen matrix found in bones, plants dont preserve ancient DNA as well as animals. You finish, the DNA is theoretically extracted, but you dont see it in the tube, says Botigu. Youre in the blind until you hear back from the sequencing services.

Within just a few weeks, the team got good news. For the husk that Botigu had bleached, about two-thirds of the reads aligned with genomes of modern wild and domesticated emmer wheat varietiesa relatively good success rate for ancient DNA, according to evolutionary geneticist Michael Scott, a postdoc in Motts lab who conducted the bioinformatics analysis of the sequences. The first surprise was how well it worked, he says. It appears that the dry conditions in Egypt were good for DNA preservation. The unbleached husk had yielded a smaller quantity of sequences, but those fragments mostly matched the ones in the bleached sample, validating the identity of those sequences as coming from the ancient wheat samples rather than from contaminants.

The museum wheat, which carbon dating showed was from between 1130 and 1000 BC, was genetically much more similar to modern domesticated varieties than to modern wild ones, suggesting that the plant lineage the samples came from had already been domesticated. Specifically, the sequences most resembled those of modern domesticated strains grown in Turkey, Oman, and India. There was also evidence for genetic exchange between the museum wheat strain and the wild emmer wheat that grew in the Levant, a large region in the Eastern Mediterranean that was a center of agricultural development in the Neolithic period, and where emmer was first cultivated. The genetic exchange could have occurred before the wheats introduction to Egypt from the Levant, says Scott. Alternatively, its possible that the ancient Egyptians wheat was able to interbreed with wild wheat in the Southern Levant thanks to interactions between the people in the two regions.

ANCIENT HUSKS: These wheat specimens were analyzed for ancient DNA by researchers at University College London.

CHRIS STEVENS

With big data and with a really good analysis method they were able to detect this gene flow, says M. Timothy Rabanus-Wallace, an agricultural geneticist at the Leibniz Institute of Plant Genetics and Crop Plant Research in Germany who coauthored a perspective published alongside the study in Nature Plants last October. Its fascinating to see this gene flow happening . . . in an area important for human history.

The bioinformatics analysis also uncovered some genetic variants in the ancient samples that werent found in any of the modern emmer wheat genomes the researchers studied. If these variants helped the wheat survive in arid locations around the Near East, perhaps introducing those sequences into modern varieties could help make them more sustainable or more drought resistant, Scott says, though he admits that this is very much just an idea.

The detection of ancient genetic variation is a notable achievement because wheat genomes are largethree to five times the length of a human genomeand repetitive, making the analysis . . . incredibly complex, says James Breen, head of the bioinformatics core at the South Australian Health and Medical Research Institute who reviewed the study and coauthored the perspective with Rabanus-Wallace, a PhD student in his lab at the Australian Centre for Ancient DNA at the time. So being able to find unique pieces of DNA in that genome is very difficult. He adds that after a couple of additional validation tests performed by the UCL team, he was convinced that the data that came out was legitimately ancient.

Botigu and Scott emphasize that the study is primarily a proof of concept that museum-kept plant samples can yield readable genetic material. We were able to look at DNA from specimens that had been stored in the museum for over 90 years without special preservation conditionsthe museum was actually even bombed and flooded during wartime, says Scott. We think our study helps demonstrate the importance of museum collections as sources of genetic data, whichin combination with new samplescan be used to uncover the history of selection on crops and their movement around the globe.

I think thats one of the biggest values of ancient DNA in plants, adds Nathan Wales, an archaeologist at the University of York who was not involved in Scott and Botigus studyto draw connections between different cultures and the different agricultural products they were growing and trading, and seeing how that changed over time.

Jef Akst is managing editor of The Scientist. Email her atjakst@the-scientist.com.

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Ancient Wheat Genome Reveals Clues to the Agricultural Past - The Scientist

(Photo : Photo by Leon Hoffman on Flickr)

One of the more shocking breakthroughs evolving from genomic sequencing of ancient hominin DNA is the realization that all human beings outside Africa have remnants of DNA in their genomes that don't belong to today's human species.

The roughly six billion people here on Earth whose current ancestry does not belong to Africa must have inherited between one and two percent of their genome from our closest though now extinct ancestors: the Neanderthals.

In connection to this, the Oceanians and the East Asians have also gotten a small degree of ancestry from the Denisovans, the Homo Sapiens' another close relative.

To date, a new study, which Science Advances published, recommends that ancient people who lived in Africa may also have reproduced with old hominins. Essentially, these are non-existent species related to Homo sapiens.

Additionally, the interbreeding outside Africa took place after the Homo sapiens ancestors, according toHeritage Daily, "expanded out of Africa into new environments."

It was the place where they had sex with Neanderthals, as well as the related Denisovans. More so, such mating has led to new and fresh discoveries.

ALSO READ:Hard Plant Foods Are Included In the Diet of Early Humans, Scientists Say

It's undoubtedly thinkable that anywhere between 92 and 98.5% of the origin in humans who don't live in Africa at present does definitely arise from the expansion outside Africa.

However, people know now, theremnantscame from ancient species whose descendants left Africa hundreds and hundreds of years before that. Intuitions into reproducing have been led by the ancient genome's much greater availability from outside of Africa.

This is because both Eurasia's dry and cold environments are far better at the preservation of DNA, tropical Africa's wet heat.

However, one's understanding of the connection between the olden human ancestors within Africa, as well as their link to ancient humans starts to deepen.

In a study of ancientDNA from southern Africain 2017, it was investigated that16 ancient genomesfrom people living over the last 10,000 years. This indicated that the African population history was complex. More so, the history of African populations was complex.

There was not only a single human group across Africa when they came into expansion about 10,000 years ago.

Seemingly now, that there was possibly gene-flow into the oldenAfrican Homo sapienspopulation that there was potentially gene-flow into ancient African Homo sapiens populations from an ancient descendant.

One of the ways in which this can happen is for the people to expand outside Africa, have Sex with the Neanderthals, and migrate back to Africa.

Certainly too, this has been, this has been exhibited in one of the recent studies.

The new study provides proof that there may have been gene-flow into the descendants of West Africans "directly from a mysterious archaic hominin."

In addition, the scholars compared the Denisovan DNA and Neanderthal, with that from four contemporary populaces from West Africa.

Utilizing some sophisticated mathematics, they then, develop a statistical model to further explain the relationships between the ancient hominins and modern Africans.

Link:
Ancient People in Africa May Have Reproduced With an Extinct Species - Science Times

Early proponents of genome sequencing made misleading predictions about its potential in medicine.

An emergency room physician, initially unable to diagnose a disoriented patient, finds on the patient a wallet-sized card providing access to his genome, or all his DNA. The physician quickly searches the genome, diagnoses the problem and sends the patient off for a gene-therapy cure. Thats what a Pulitzer prize-winning journalist imagined 2020 would look like when she reported on the Human Genome Project back in 1996.

The Human Genome Project was an international scientific collaboration that successfully mapped, sequenced and made publicly available the genetic content of human chromosomes or all human DNA. Taking place between 1990 and 2003, the project caused many to speculate about the future of medicine. In 1996, Walter Gilbert, a Nobel laureate, said, The results of the Human Genome Project will produce a tremendous shift in the way we can do medicine and attack problems of human disease. In 2000, Francis Collins, then head of the HGP at the National Institutes of Health, predicted, Perhaps in another 15 or 20 years, you will see a complete transformation in therapeutic medicine. The same year, President Bill Clinton stated the Human Genome Project would revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases.

It is now 2020 and no one carries a genome card. Physicians typically do not examine your DNA to diagnose or treat you. Why not? As I explain in a recent article in the Journal of Neurogenetics, the causes of common debilitating diseases are complex, so they typically are not amenable to simple genetic treatments, despite the hope and hype to the contrary.

The idea that a single gene can cause common diseases has been around for several decades. In the late 1980s and early 1990s, high-profile scientific journals, including Nature and JAMA, announced single-gene causation of bipolar disorder, schizophrenia, and alcoholism, among other conditions and behaviors. These articles drew massive attention in the popular media, but were soon retracted or failed attempts at replication. These reevaluations completely undermined the initial conclusions, which often had relied on misguided statistical tests. Biologists were generally aware of these developments, though the follow-up studies received little attention in popular media.

There are indeed individual gene mutations that cause devastating disorders, such as Huntingtons disease. But most common debilitating diseases are not caused by a mutation of a single gene. This is because people who have a debilitating genetic disease, on average, do not survive long enough to have numerous healthy children. In other words, there is strong evolutionary pressure against such mutations. Huntingtons disease is an exception that endures because it typically does not produce symptoms until a patient is beyond their reproductive years. Although new mutations for many other disabling conditions occur by chance, they dont become frequent in the population.

Instead, most common debilitating diseases are caused by combinations of mutations in many genes, each having a very small effect. They interact with one another and with environmental factors, modifying the production of proteins from genes. The many kinds of microbes that live within the human body can play a role, too.

A silver bullet genetic fix is still elusive for most diseases.

Since common serious diseases are rarely caused by single-gene mutations, they cannot be cured by replacing the mutated gene with a normal copy, the premise for gene therapy. Gene therapy has gradually progressed in research along a very bumpy path, which has included accidentally causing leukemia and at least one death, but doctors recently have been successful treating some rare diseases in which a single-gene mutation has had a large effect. Gene therapy for rare single-gene disorders is likely to succeed, but must be tailored to each individual condition. The enormous cost and the relatively small number of patients who can be helped by such a treatment may create insurmountable financial barriers in these cases. For many diseases, gene therapy may never be useful.

The Human Genome Project has had an enormous impact on almost every field of biological research, by spurring technical advances that facilitate fast, precise and relatively inexpensive sequencing and manipulation of DNA. But these advances in research methods have not led to dramatic improvements in treatment of common debilitating diseases.

Although you cannot bring your genome card to your next doctors appointment, perhaps you can bring a more nuanced understanding of the relationship between genes and disease. A more accurate understanding of disease causation may insulate patients against unrealistic stories and false promises.

Written by Ari Berkowitz, Presidential Professor of Biology; Director, Cellular & Behavioral Neurobiology Graduate Program, at the University of Oklahoma.

Originally published on The Conversation.

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Sequencing the Human Genome Was Supposed to Revolutionize Treatment of Disease Heres Why It Failed - SciTechDaily