Monthly Archives: March 2020

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.

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

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

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