Monthly Archives: July 2022

Ultima CEO Gilad Almogy, Ph.D./courtesy of Ultima Genomics

The information stored within the confines of the human genome is some of the most important data we can use in the diagnosis of disease, prevention efforts and therapeutics. Despite the fact that the technology to conduct whole genome sequencing (WGS) has been around for decades, financial barriers have stood in the way not just for patients and doctors looking for information, but for researchers as well.

Leveraging over $600 million in funding and five years of hard work, Newark, California-based Ultima Genomics has designed a way to surmount that financial barrier lowering the cost of a human genome from the realm of $1,000 to just $100.

Ultima has achieved this through the use of its sequencing architecture which replaces the traditional flow cell, a channel that contains all of the surfaces where chemistry and imaging occur during sequencing, with a silicon wafer. The technology serves the same function but at a lower cost with larger surface area, allowing for billions of reads. The process is easier to scale, amounting in large volumes of genetic data, and avoids costly and complicated fluidics.

The company also touts novel scalable chemistry, which combines the speed, efficiency and read lengths of natural nucleotides with the accuracy and scalability of endpoint detection. Add machine learning at the genome scale that can deliver accurate results and youve got yourself a cost-effective and useful human genome ready for interpretation.

Why it Matters

The importance of cost goes beyond simply enabling access to a larger quantity of existing genomic solutions. It also enables qualitatively different experiments to be envisioned and executed, not just once, but routinely, Ultima CEO Gilad Almogy, Ph.D. said in an interview with BioSpace. This can enable scientists to ask new questions they previously couldnt answer, and it can change the way genomic information is incorporated into the broader healthcare system.

The $100 genome stands to make genomics research that was once thought of as impossible, possible. In 2020, an article celebrating the 20th anniversary of Nature Reviews Genetics discussed the future of genetics and genomics research. In the piece, Stacey Gabriel, senior director of the genomics platform at the Broad Institute, commented that the real promise of genome sequencing lies in true population-scale sequencing at the scale of tens of millions of individuals that would enable the comprehensive, unbiased study of the human genome and the variations found within it.

Genomic research has provided physicians with a wealth of knowledge about genes that can increase a persons risk of developing a certain condition, such as the BRCA2 gene which is linked to an increased risk of developing breast and ovarian cancer. However, without the ability to conduct large-scale studies, simply understanding the role that one gene or a handful of genetic mutations plays in developing disease is often not enough information to elucidate the genome's full impact. With scalable and cost-effective WGS, it will become much easier for researchers to understand the parties within our genome that contribute to the manifestation of disease, which could ultimately lead to targeted therapeutics.

Genomic Data can Inform Treatment

Gabriel stated that she believes WGS should become a part of the electronic health record. There are plenty of good reasons to collect and include genomic data as it relates to health and disease. Beyond using this data to understand the risk someone is at for a certain condition, genomic information can help direct treatment. For example, some cancer therapies specifically target genetic mutations or alterations that have occurred in the tumor microenvironment. If patients and physicians have access to more affordable genomic testing, they can use the information to choose a targeted therapy that will work best for them.

We envision a future where in nearly every interaction patients have with the healthcare system, their genomic information will be sequenced to reveal not just their inherited DNA, but also what changes in their bodies are encoded into circulating DNA, RNA, methylation and proteomics, Almogy said.

Early Application

The $100 genome is already proving its worth. Researchers from Stanford University utilized the low-cost genomic sequencing to investigate the trajectories in precancerous polyps to early colorectal adenocarcinoma. The paper, not yet peer-reviewed but published on bioRxiv, demonstrated the technologys ability to observe changes in DNA methylation that occur early in the malignant transformation process, providing clues as to what happens at a molecular level when a polyp turns cancerous. This type of research could one day translate into clinical use, where physicians could use genomic sequencing to detect DNA changes in cells that might signal the danger of an impending malignant tumor.

Low-cost genomics helps therapeutic development in a couple of fundamental ways, Almogy said. Firstly, many companies seek to understand the genomic drivers of disease by sequencing populations and looking for associations between variants and disease. This type of work inherently requires large numbers to be useful, and the $100 genome certainly enables larger studies in a wider variety of populations. Second, low-cost genomics enables large-scale experiments to reveal the function of many genes.

Ultima isnt prepared to stop at $100 though. As evidenced by its recent collaboration with Exact Sciences, the goal is to continue driving the price down. The companies entered into a long-term supply agreement in June aimed at lowering the cost of sequencing and improving patient access to genomics-based testing. As part of the alliance, Ultima and Exact will develop one or more of Exacts advanced cancer diagnostic tests that will be developed using Ultimas technology. Earlier in June, Ultima paired with Olink Holding AB to combine the latter's Explore assay with its sequencing system to enable larger-scale projects.

Were currently in early access mode, so were focused on optimizing the platform with our initial customers before making it available for broad commercial launch next year, Almogy explained. "Beyond that, we continue to develop improvements in the architecture, because for us the $100 genome is only the beginning and were committed to continuously [driving] down the cost of genomic information.

Read this article:
Here's how the $100 Human Genome will Change Medicine - BioSpace

Like most geneticists, Ryan Doan learned in school that the vast majority of the genome is useless so-called junk DNA that doesnt code for proteins. But in 2014, while doing postdoctoral research, Doan started to rethink that belief. He was bothered by the fact that autism genetics research, which has largely focused on the coding genome, hasnt made the progress many had hoped for especially in providing autistic people with genetic information that informs potential treatments.

Were not finding as much as we wouldve thought, says Doan, assistant professor of pediatrics at Boston Childrens Hospital in Massachusetts. The next best place is trying to branch out into the noncoding regions.

Now, Doans autism research is primarily focused on the largely unexplored 99 percent of the genome that lies beyond the protein-coding exome. According to his unpublished work, at least 3 percent of autistic people have noncoding mutations that contribute to their condition.

The future seems bright, but the noncoding space will be difficult for quite a while. Ivan Iossifov

Aided by new databases and cheaper whole-genome sequencing, many autism genetics researchers are, like Doan, taking tentative steps into the wide-open noncoding space. Their results so far are mixed, and the challenges remain large. Whole-genome sequencing still costs two or three times as much as exome sequencing, which limits sample size, and the effects of noncoding mutations are likely to be more subtle than those of their coding counterparts, Doan and other scientists say. But many say they hope that probing noncoding DNA will unearth genetic causes of autism for more people and reveal new details about the conditions biology.

The future seems bright, but the noncoding space will be difficult for quite a while, says Ivan Iossifov, associate professor of genetics at Cold Spring Harbor Laboratory in New York. For now, everyone is simply taking baby steps, he says very expensive baby steps.

Researchers had no way to navigate the noncoding genomes 3 billion base pairs until the launch of the Encyclopedia of DNA Elements (ENCODE) in 2003. A little more than a decade later, its spinoff, psychENCODE, started to map gene regulatory elements within that vast uncharted space in the human brain and other tissues work that is still underway.

Those maps made it possible for researchers to begin devising targeted strategies to explore the links, if any, between noncoding mutations and autism. It might be tempting to search the entire noncoding space to ensure that important mutations connected to autism arent missed especially given how little is known about the DNA there. But starting with stretches of DNA with known functions, such as the promoters and enhancers that help regulate a genes expression, stands to increase the likelihood that any discovered mutations will be meaningful.

Some people are very agnostic to location, says Santhosh Girirajan, associate professor of genomics at Pennsylvania State University. And some are looking at some star in some galaxy somewhere.

Promoters the focus of Doans study are located next to the genes they regulate. Enhancers, which may be farther away, carry more mutations in autistic people than in their non-autistic siblings, according to a 2021 analysis. In autistic people, genes linked to autism also tend to have an overabundance of transposons sections of noncoding DNA that can jump randomly around the genome and disrupt other genes another study found.

Iossifov is surveying yet another source of noncoding DNA: stretches located within genes called introns. About 6 percent of autistic people have an intron mutation that likely contributes to their condition, according to his 2021 analysis of these sections in nearly 2,000 autistic children and their non-autistic siblings. To bolster the finding, his team is studying gene expression levels, reasoning that if a gene with an intron mutation has atypical expression in autistic people, its likely that mutation is involved in the condition.

Early results look promising, Iossifov says. Expression abnormalities in a gene are rare enough that they can be used as this very useful filter for pointing at de novo noncoding mutations which might be contributory.

For researchers who are exploring the entire noncoding space, machine learning is proving to be a useful tool. A 2018 analysis of whole genomes from nearly 2,000 families with one autistic and one non-autistic child, for example, initially turned up no relevant noncoding mutations compared with controls. But using a machine-learning tool that identifies multiple types of noncoding variants revealed an excess of mutations in promoter regions among the autistic participants.

Similarly, only a neural network trained on functional genomics data could spot differences between autistic children and their non-autistic siblings across some 200,000 noncoding variants in another 2021 study. More noncoding mutations occurred near autism-linked genes in children with autism than in those without. Overall, though, noncoding mutations occurred equally closely to the nearest gene in both autistic and non-autistic people, highlighting the challenge of identifying these causal mutations, the investigators wrote.

Noncoding and coding mutations may contribute to autism in similar proportions: they are found in about 4.3 and 5.4 percent of autistic children, respectively, according to a 2019 analysis that used machine learning to estimate an individual mutations likelihood of contributing to the condition.

Yet a third strategy involves looking at the whole noncoding space but limiting the analysis to a cohort thats more likely to have rare mutations. A February study of 22 families with high rates of inter-family marriage, for example, found likely disease-causing variants in promoters and enhancers for five autism-linked genes. The team is now using CRISPR to study the variants functions in cells, as well as repeating the work in a new cohort of African children with autism.

Eventually, all of this information in aggregate will be able to tell us about the molecular mechanisms underlying autism, says lead investigator Maria Chahrour, assistant professor of genetics and neuroscience at the University of Texas Southwestern Medical Center in Dallas.

Even when a noncoding mutation contributes to autism, its individual effect is small, the results so far suggest. That means noncoding mutations probably arent acting on their own to cause autism, Girirajan says. Rather, several may act together or in tandem with a coding mutation.

How noncoding mutations affect the genome might also be far more subtle and difficult to nail down than for coding mutations. A given mutation may matter in only one cell type or at a specific point in development, for example. Parsing this kind of complexity, while enormously challenging, could help to explain autisms heterogeneity, Girirajan says. Autism subtypes might reflect not just mutations in a specific gene, but how a genes expression varies across time.

Eventually, all of this information in aggregate will be able to tell us about the molecular mechanisms underlying autism. Maria Chahrour

Its so complex. We are living in a naive land where everything is genes, Girirajan says. What we are not thinking about is gene regulation at different stages of development and tissues. Oh gosh.

To move forward, Girirajan and others say, the field needs to build up whole-genome databases in a big way: At present, autism researchers have access to the exomes of around 50,000 autistic people, and even that has been barely enough to find results in the much simpler coding space, Doan says.

For the noncoding space, you cut your samples 5-fold, but increase complexity 50-fold, he says. You have a huge power problem and thats just something we have to deal with for a while.

Geneticists also need to refine the maps that autism researchers are using to find their way. The ENCODE project, for one, is working to release data on the time periods and cell types in which promoters, enhancers and other regulatory elements influence genes.

Still, results from other fields are encouraging: Other neuropsychiatric conditions are now linked to many mutations in the noncoding region. Of 22 regions implicated in schizophrenia in one large study, for example, 13 are located in noncoding regions within or between genes.

In autism, this is still behind, Iossifov says, but adds that it is only a matter of time before similar findings emerge. Theres no doubt.

Cite this article: https://doi.org/10.53053/WHLV1876

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The final frontier: Autism geneticists take on the noncoding genome | Spectrum - Spectrum

With its multiple variants such as Delta and Omicron, the COVID-19 pandemic highlighted the need for genomic surveillance, to monitor virus evolution and its implications on transmission dynamics and response measures like vaccines. Sequencing informationprovides crucial decision-making information during epidemics and pandemics. On 8-9 June 2022, WHOs Eastern Mediterranean Regional Office convened a meeting in Egypt with partner organizations and countries to discuss the framework for integratedrespiratory pathogen surveillance including the role of genomic surveillance.The regional laboratory focal point set the scene:

Currently, 19 out of the 22 countries in the Eastern Mediterranean Region have genomic sequencing capabilities. A regional network has been established to enable all countries to have access to sequencing, and to strengthen their capacities coherentlyand collaboratively to be able to detect, investigate and respond to COVID-19 and other emerging and re-emerging infectious diseases with epidemic and pandemic potential.

- Dr Amal Barakat, Regional Laboratory Focal Point, WHO

Some highlights from stories shared by countries in the meeting:

Following the significant increase in molecular diagnostic capacity for SARS-CoV-2 in the country enabling up to 250,000 tests per day, the National Influenza Centre at the Ministry of Health (MOH) recognized early that the need for SARS-CoV-2 sequencingwas also increasing. To address this, Morocco set up a national consortium of four laboratories two public and two private to cover different geographic regions in the country.

The Consortium enables us to address genomic surveillance needs by bringing in the capacities and capabilities of the private sector. This was a major achievement and presents an opportunity for us as we think about the next generation of publichealth surveillance.

- Professor Hisham Ouzmil, National Influenza Centre, Morocco

The MOH Central Public Health Laboratory (CPHL) serves as WHOs regional reference laboratory for COVID-19. The CPHL linked with national and local academic partners to strengthen workforce capacities, increase national genomic surveillance coverage,and develop algorithms for selecting cases for sequencing so that virological trends associated with different sub-populations such as travelers, severely ill patients and cases from different geographic regions could be well understood.

Genomics have helped us to better understand the epidemiology of COVID-19 in Oman. Linking genomic data to epidemiological and clinical data, and analyzing trends from other countries maximizes the utility and power of genomics. We are happy towork with other countries, share our experiences and strengthen collaborations as we learn lessons for future pandemic preparedness.

- Dr Hanan Alkindi, Central Public Health Laboratory, Oman

A massive effort was undertaken to expand genomic surveillance so that the viral phylo-dynamics could be understood in all geographic regions of the country and to look at patterns among severe cases, travel-related cases, post-vaccination cases and re-infections.

More than 60,000 SARS-CoV-2 samples have been sequenced from around the country. We have the opportunity to use the capacity established for various public health threats and are ready for future emergencies.

- Dr Ahmed Albarraq, Public Health Authority, Saudi Arabia

Outputs from the meeting and reflections from countries on the role of genomics during the COVID-19 pandemic and future emergencies will enable the Region to plan effectively and focus attention on the future of integrated respiratory pathogen surveillanceinclusive of genomic surveillance. The regional operational framework for integrated surveillance is being finalized and will be available later this year including the opportunities for genomic surveillance in the context of the recently launchedGlobal Genomic Surveillance Strategy for Pathogens with Pandemic and Epidemic Potential 20222032.

The 10-year Global strategy will enable countries in the Eastern Mediterranean Region, as well as other regions, to capitalize on the gains made and to solidify the role of genomics in future public health practice. Click here to learn more about the Global Genomic Surveillance Strategy for Pathogens with Pandemic and Epidemic Potential 20222032.

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The Eastern Mediterranean Region reflects on genomic sequencing and its future within integrated surveillance of respiratory viruses - World Health...

Contributed Commentary by Per Hammer, Cytiva

July 15, 2022 | Historically, the heavily regulated biopharma industry has been slow to adopt new technologies. However, a shift toward automation is vital to ensure that next-generation solutionssuch as cell and gene therapiesare produced at scale.

Less than one in five senior pharma executives strongly believe that frontier technologies, such as artificial intelligence, are widely adopted to support automation and increase the speed of specific processes. With cell therapies approved by global regulatory bodies, it is time to accelerate smart technologies and cell and gene therapy manufacturing.

Todays cell therapy treatments are often made on a small-scale, include manual preparation steps, and are produced for a clinical trial setting. Researchers spend days processing cellular material, monitoring its growth during the expansion phase, and preparing for re-administration to the patient. This process is demonstrated in administering autologous treatments so that every patient receives a unique living drug.

Though the current process is complex, it offers inspiring outcomes. For example, on April 1, 2022, the Food and Drug Administration (FDA) approved Kite Pharmas Yescarta, a chimeric antigen receptor (CAR) T-cell therapy for adult patients with large B-cell lymphoma. This kind of cancer is usually resistant to initial treatment and relapses within one year. With FDA approval, Yescarta (axicabtagene ciloleucel) is now the second-line treatment, a first for an autologous CAR T-cell therapy.

Cell Therapy Enters Mainstream

The exceptional results emerging from cell therapy clinical trials suggest we are entering a new phase of medical treatmentone where we can expect far more from our healthcare interventions than we ever imagined. Following the regulatory approval of autologous CAR T-cell therapies, the global cancer treatment landscape is changing, and the future is bright.

The success of COVID-19 vaccines signaled the arrival of the genomic medicines ageone where we hope to see cell and gene therapies deliver long-term remission and even cures for patients with some of the most complex diseases. According to the Alliance for Regenerative Medicine 2021 Annual Report, nearly 60% of the ongoing regenerative medicine clinical trials studied prevalent diseases by the end of the calendar year. But to get these powerful treatments to those who need them, we must have an automated manufacturing infrastructure that can generate cell therapies to meet increased demand in the coming years.

Saving Time Through Automation

Time is of the utmost importance, as biopharma manufacturing involves patient cells that have limited viability. Manual approaches to cell therapy production are time-consuming, and tasks such as checking cells at regular intervals during expansion are laborious. Another time-draining factor is the workflow and cleaning routines involved in maintaining a safe lab environment.

Automated solutions reduce or remove many of these challenges. After setting up a process, an operator can focus on other things while critical parameters such as temperature, pH level, gas transfer, and flow rates are monitored and controlled without human intervention.

Reducing Risks for Better Results

Manual cell processing solutions are complex, with many checkpoints across isolation, expansion, harvesting, and preservation stages. Unfortunately, each of these steps increases the risk potential. Despite the research teams expertise, there is still a chance that materials could be inadvertently contaminated during numerous open stages.

Additionally, limited process control can lead to difficulties in achieving high reproducibility. An automated modular solution minimizes these risks by bringing multiple steps within a closed, highly regulated, and controlled system.

Improving Manufacturing Efficiency

Changing a manufacturing process requires multiple manual routines and adjustments that must be checked and documented. However, documentation and protocols are less helpful when a customized process is used because they only apply to that specific setup.

Standardization would effectively improve manufacturing efficiency. This approach would ensure that what is learned in one project can be referenced in future work, with data and documentation applicable across different technology applications. A modular chain of connected systems allows for process variation with instruments running in customized configurations. Additionally, having control of an individual instrument leads to the straightforward use of built-in software and sensors.

Automated Manufacturing: The Way Forward for Cell and Gene Therapy

By using automated manufacturing to minimize human interaction, time, and resource requirements, it is possible to increase production speed and lower some risks and costs associated with commercialization.

The industry is ever-changing and adjusting its complex, yet exciting challenges will take some time. However, automation can create a significant advantage over competitors, providing the tools needed to produce cell therapies with the highest levels of safety and efficacy for patients.

Per Hammer has two decades of experience in the biopharma industry, mainly supporting customers in academics through process development and manufacturing. Per joined Cytiva in 2001, taking on several distinct roles in the company. Most recently, he progressed from Product Manager Leader for the Bioprocess Automation and Digital Team to Senior Global Product Manager for the Cell & Gene Therapy Automation and Digital Solutions. He can be reached at per.hammer@cytiva.com.

The rest is here:
Automating the Genomic Medicines of the Future - Bio-IT World