Epigenetics company Base Genomics has launched with a team of leading scientists and clinicians with the aim of setting a new gold standard in DNA methylation detection. The company has closed an oversubscribed seed funding round of US$11 million to accelerate development of its TAPS technology, initially focusing on developing a blood test for early-stage cancer and minimal residual disease. The funding round was led by Oxford Sciences Innovation.
DNA methylation is an epigenetic mechanism involved in gene regulation and has been shown to be one of the most promising biomarkers for detecting cancer through liquid biopsy. The existing industry standard for mapping DNA methylation degrades DNA and reduces sequence complexity, however, limiting scientific discovery and clinical sensitivity. Base Genomics’ new technology, TAPS, overcomes these issues and generates significantly more information from a given sample, creating new opportunities in research and clinical application.
Dr Anna Schuh, CMO, Base Genomics, commented: “In order to realize the potential of liquid biopsies for clinically meaningful diagnosis and monitoring, sensitive detection and precise quantification of circulating tumour DNA is paramount. Current approaches are not fit for purpose to achieve this, but Base Genomics has developed a game-changing technology which has the potential to make the sensitivity of liquid biopsies a problem of the past.”
First developed at Ludwig Institute for Cancer Research Branch at the University of Oxford, TAPS is a novel chemical reaction that converts methylated cytosine to thymine under mild conditions. Unlike the industry standard technology, bisulfite sequencing, TAPS does not degrade DNA, meaning that significantly more DNA is available for sequencing. TAPS also better retains sequence complexity, cutting sequencing costs in half and enabling simultaneous epigenetic and genetic analysis.
Dr Vincent Smith, CTO, Base Genomics said: “[TAPS] has the potential to have an impact on epigenetics similar to that which Illumina’s SBS chemistry had on Next Generation Sequencing.”
Base Genomics is led by a highly experienced team of scientists and clinicians, including Dr Smith, a world-leader in genomic product development and former Illumina VP; Dr Schuh, Head of Molecular Diagnostics at the University of Oxford and Principal Investigator on over 30 clinical trials; Drs Chunxiao Song and Yibin Liu, co-inventors of TAPS at the Ludwig Institute for Cancer Research, Oxford; and Oliver Waterhouse, previously an Entrepreneur in Residence at Oxford Sciences Innovation and founding team member at Zinc VC.
Waterhouse, founder and CEO, Base Genomics, said: “The ability to sequence a large amount of high-quality epigenetic information from a simple blood test could unlock a new era of preventative medicine. In the future, individuals will not just be sequenced once to determine their largely static genetic code, but will be sequenced repeatedly over time to track dynamic epigenetic changes caused by age, lifestyle, and disease.”

Beckman Coulter’s Access SARS-CoV-2 IgG assay is now available in markets accepting the CE Mark, the company said in statement 15 June. It has already shipped tests to more than 400 hospitals, clinics and diagnostics laboratories in the United States and has begun shipping to customers globally. Beckman Coulter has more than 16,000 immunoassay analysers worldwide and has increased manufacturing to deliver more than 30 million tests a month.
Many of Beckman Coulter’s analysers can deliver up to 400 routine tests an hour. The Access SARS-CoV-2 IgG test can also be run on Beckman Coulter’s Access 2 analyser, a compact table-top analyser enabling high-quality serology testing to be carried out in small hospitals and clinics.
The Access SARS-CoV-2 IgG Assay is a qualitative immunoassay that detects IgG antibodies directed to the receptor-binding domain of the spike protein of the novel coronavirus that is driving the ongoing global pandemic. It is believed that these antibodies have the potential to be neutralizing antibodies and may play a role in lasting immunity. The test has a confirmed 99.8% specificity and 100% sensitivity at 18 days post PCR confirmed positive test. The assay uses immobilized virus antigens on magnetic particles to capture IgG antibodies from patient serum or plasma samples and reveals them using labelled anti-IgG antibodies.
Commenting on the assay, Shamiram R. Feinglass, M.D., MPH, Chief Medical Officer, Beckman Coulter, said: “An IgG antibody assay such as the test Beckman Coulter has developed can provide valuable information regarding community levels of immunity that will inform public health decision making and rollout of a vaccine when one does become available. The very high sensitivity and specificity of this assay provides a high positive predictive value, even when the overall incidence of disease is low. Additionally, since our assay can be run on multiple different types of analysers, it can be adapted to a variety of healthcare settings to best meet the needs of each community.”

by Dr Tolga Durak
Around the world, organizations are building next-generation research facilities intended to encourage communication, collaboration and creativity. However, these new spaces must overcome a wide range of complex challenges to meet the needs of researchers today and in the future. This article explores five important questions that should be considered in order to build an innovation space that is safe, successful and productive.

Fundamental questions for good design

Research facility design and construction is evolving rapidly, as organizations around the world strive to create work environments that meet the needs of today’s scientists. Whether these new spaces are relatively small-scale makerspaces, large pharmaceutical manufacturing plants, or tightly regulated high-containment laboratories, they are being built to foster communication, collaboration, and innovation, often in ways that depart significantly from the traditional R&D rubric. As a result, every stage of the process – from initial site assessment, architectural design, and construction and continuing all the way through to ongoing maintenance and operation – must be approached with fresh eyes. To get started, design and construction teams must consider the following five fundamental questions.
1. Who is going to work in the facility and what will they need to be successful?
Most research projects now span multiple disciplines, and laboratory spaces often need to accommodate the varied needs of biologists, chemists, engineers, physicists and/or others – all working together but with different methods. Research facility design must accommodate each specialty’s unique requirements across a wide spectrum that includes equipment, infrastructure (electrical, ventilation, etc), information technology (IT), workflow and compliance. In addition, designers must factor in flexibility, so workspaces can adapt as the research advances and needs change.
2. What is required for compliance?
Navigating regulatory boards and obtaining approvals can be a complex, time-consuming, and expensive process, especially for clinical research facilities. Typically, these structures must be constructed in compliance with Good Laboratory Practice (GLP) regulations, Good Manufacturing Practice (GMP) regulations, and other guidelines and mandates from local, state and federal jurisdictions. In addition, laboratories that research or use infectious agents or other biological hazards must comply with regulations based on the degree of the health-related risk associated with the work being conducted. The four biosafety levels (BSLs) of containment – BSL-1, BSL-2, BSL-3, and BSL-4 – aim to safeguard against the accidental release of pathogenic organisms and other biohazards and may involve airflow systems, containment rooms, sealed container storage, waste management, decontamination procedures, and security capabilities. Clearly, the challenges of compliance need to be tackled early in the design process because meeting all of the requirements can take years, which increases the risk that research priorities change and/or that key staff moves on to other projects.
3. How sustainably can we build it?
When people think about sustainable research facility design, they usually focus on power and water consumption. Granted, researchers typically use lots of heat-generating equipment (which then require complementary cooling solutions). Their labs also generally need extensive ventilation, sophisticated sensor networks, uninterrupted power supplies – as well as back-up redundancies for all of these systems. However, in a broader sense, sustainable research facility design also addresses the health and well-being of the workforce. That means air quality, natural light, workflow and productivity considerations, material selection, and all related aesthetics can drive design and construction processes as well.
4. How will the needs of this facility change?
Science is constantly evolving, and research priorities will shift over time. Likewise, technology, regulations and workforce needs will change too. Flexibility and adaptability need to be key considerations of every plan, and designers and developers have to strike a balance between short- and long-term needs. In some cases, permanent or portable modular components may be the most efficient and cost-effective options.
5. Is building the best business decision?
For some organizations, the best business decision may be to share laboratory space, rather than to build their own. Entering into a partnership, collaboration or lease agreement with an organization that is already operating a facility can expedite research results, reduce costs, ease the burden of meeting compliance requirements and even stimulate innovation. Of course, benefits like those must be weighed against potential disadvantages, such as the lack of customization, loss of control and the risks associated with failure to protect intellectual property.

Summary

Thoughtful consideration of these five key questions will help you create an innovation space that will meet your research needs today and for years to come. As you work through your answers to each one, be sure to solicit input from architects, engineers, builders and others who have the experience and expertise to guide you in the process. Adopting a team approach is essential to building a next-generation innovation space that is that is safe, successful and productive.
The author
Tolga Durak PhD
Environment, Health and Safety Office, Professional
Education, MIT, Cambridge, MA 02139, USA
E-mail: tdurak@mit.edu

by Dr Carsten Lange
Flow cytometry is a powerful technique for the detailed analysis of complex populations which, over the last two decades, has evolved from a staple technique of the research laboratory into an essential part of the modern clinical laboratory.
Some of the current ‘norms’ for clinical flow cytometry include its critical use for phenotyping hematological malignancies, as well as playing a vital role – along with other testing methods – in diagnosing disease, informing treatment plans and monitoring patients. Only time can tell how this powerful analytical technology will contribute to the clinical lab of the future. We can, however, anticipate that it will only continue to increase in importance, based on technical innovations that have driven the evolution of flow cytometry over the last decade.
In addition to today’s applications in disease diagnostics, the power of this technology continues to be used in cell biology research and pharmaceutical discovery. This evolution has been made possible by a higher number of analytical parameters to measure cells in suspension. The first cytometers were systems capable of merely three or four parameters, using a single laser and four detectors, and were the size of a small car. Today, however, flow cytometers (including cell sorters) can analyse more than 30 parameters, and new technology in benchtop analysers can deliver exponentially better performance in a smaller footprint.
Shifting paradigms
This paradigm shift, toward higher performance in a small instrument, is driven by clinical laboratories that want to capture the power of flow cytometric analysis, but don’t want to invest a significant amount of time in learning the instrumentation. The democratization of flow cytometry is enabled by key advances in technology. Advantage is being taken of prominent concepts in other scientific fields, such as the telecommunications industry, to allow the subsystems to be miniaturized while at the same time providing even better performance. These compact high-performance systems not only deliver better performance than historically expensive systems, but they are also easy to set up, operate and maintain, enabling a greater number of clinical laboratories to maximize the power of flow cytometry.
The power to see more
Performance of flow cytometers is typically measured by their capacity to resolve and their sensitivity to detect dim and/or rare populations. In this regard, efficient light management for optimal excitation and emission of fluorochrome-tagged cells is critical to performance.
With conventional flow cytometers, laser excitation sources are optimized by shaping and focusing light through a series of lenses and filters onto a flow cell where cells are hydrodynamically focused. However, newer flow cytometers use unique laser designs that are focused onto a flow cell with integrated optics. These systems can ensure increased excitation of the dyes not only on (and within) cells, but also increased collection of the emitted light for integration and measurement. When designing a compact clinical cytometer, the use of fibre optics to carry light is an efficient way of transmission, providing flexibility in laying out system components. These cables capture emitted light to deliver it onto a unique detector array, reducing crosstalk between channels, which improves performance.
Another recent development is a key concept borrowed from the telecommunications industry, the wavelength division multiplexer (WDM), which is used for light detection and measurement. Wavelength division multiplexing is a method used to deconstruct and measure multiple wavelengths of light as signals that relate to analytical parameters. The detectors used to measure each parameter are avalanche photodiodes (APDs), which are highly sensitive semiconductor devices. By contrast, conventional clinical cytometers to date have (and continue to use) photomultiplier tubes (PMTs). The major advantages of using APDs over PMTs include but are not limited to:

1. enhanced linearity;
2. 4–5 times the quantum efficiency;
3. higher dynamic range, 106 versus 103;
4. smaller size and about one-tenth the cost.

Shows the WDM of the first commercially available clinical cytometer to use compact APDs which reduce the overall instrument footprint (DxFLEX, Beckman Coulter). Each WDM contains optical and detector components to selectively measure specific wavelengths. This improves light collection for higher sensitivity to detect dim populations.
The WDM’s innovative and simple design uses a single bandpass filter to select the various colours of light. This contrasts with traditional clinical cytometers, which use a series of dichroic steering filters and bandpass filters that bounce the light along an array, leading to successively less available light, resulting in diminishing light collection efficiency, and ultimately compromising fluorescence sensitivity and resolution.
Simplifying high complexity
Leveraging the linearity of detection systems that use APDs in the operation of the cytometer can be dramatically simplified owing to the predictability of the signals. The linear gain and the normalization performed during the daily quality control routine takes care of the relative variations during instrument set-up commonly seen in instruments. Further, setting up a highcomplexity assay is simplified by using a software gain-only adjustment. The linearity of gain adjustment also simplifies the typically arduous task of spectral compensation which has been the barrier for many to push to a higher number of colours/ parameters. To maximize the benefit of the APD linearity, new software algorithms have been developed that facilitate set-up and analysis of high-complexity experiments by simplifying compensation.
It is now possible to create a compensation library that stores the APD gain settings and spectral spill-over coefficients for every parameter and multicolour combination. This allows users to make a virtual spectral compensation matrix selecting various single colours from the library. In addition, the library can intelligently adjust the compensation values when gains are adjusted owing to the predictive responses of linear APDs. The result is a dramatically simplified and intuitive method of setting up high-complexity applications.
The size factor
For most cytometers, measuring size of particles less than 300|nm is difficult because they deliver relative sizing information using forward scattered light from the 488|nm blue laser. For these systems, particles of less than 1|mm (1000|nm) usually fall below the noise threshold of the laser and detector subsystems. In contrast, newer systems use principles of Mie scattering, which predicts that with lower wavelengths of excitation there will be an increased amount of scattered light and improved resolution.
Therefore, measuring scattered light from a shorter-wavelength 405|nm violet laser versus a longer-wavelength 488|nm blue laser will allow the system to resolve smaller particles. The use of the violet side scatter parameter enables systems to detect particles of less than 0.2|mm (200|nm) in size, enabling excellent resolution of microparticles.
The future is now
Combining powerful performance and innovative design and technology, it is possible to deliver a compact, easy-to-use flow cytometer. Pushing the ‘norms’ of conventional flow cytometry, today’s – and tomorrow’s – cytometers simplify high-complexity applications in the clinical laboratory, as well as a deeper understanding in the frontier applications of hematopoietic cancers. Flow cytometry remains a powerful tool for interrogating complex questions. Today’s clinical laboratories want to harness that power and are demanding smaller and more powerful flow cytometers that are more affordable and easier to use. Using innovation, engineers can deliver solutions to meet the challenge.
The author
Carsten Lange PhD
Beckman Coulter GmbH, 47807 Krefeld, Germany

E-mail: clange@beckman.com DxFLEX flow cytometer: https://www.mybeckman.uk/flow-cytometry/instruments/dxflex