Genetics Archive

Friday, March 19, 2010

Cell Levitation to Build 3D Matrix Structures

Jokes about needing special glasses aside, Nature Nanotechnology published a letter on March 14, 2010 describing progress in three dimensional cell culture technology from Glauco Souza, et. al. at the Texas M.D. Anderson Cancer Center. According to the research team, prior attempts at 3-D culture have included “protein based gel environments or rotational/agitation-based bioreactors” and yet “broad, practical application of such methods has not been achieved.” The novel method they describe uses magnetic fields to manipulate cells which have endocytosed “gold-hydrogels” which incorporate magnetic iron oxide. Once the cells have taken up the iron in the hydrogel, a magnetic field is applied which levitates the cells, allowing them to grow in a three dimensional architecture as opposed to the standard two dimensional fashion.

One benefit of this technology as reported in the letter is the flexibility of the cell culture medium. Current products available use a fixed chemical environment in their scaffolding to support three dimensional growth of cells. Because certain cell populations have specific metabolic requirements which must be met by the culture medium, the fixed chemical environment of existing 3-D culture techniques may preclude specific cell populations from being used. However, because this technology does not rely on a chemical environment, cell lines are not limited by the medium they grow in but rather the ability to take in the iron laced hydrogel.

The researchers state the potential applications of their work include “biotechnology, drug discovery, stem cell research, or regenerative medicine.” They go on to say, “Indeed, a potential long-term goal is the possibility of accomplishing the ‘engineering’ of normal tissues or complex organs.” The technology has been licensed to n3D Biosciences out of Houston, Texas.

M. D. Anderson press release: 3-D Cell Culture: Making Cells Feel Right at Home

Abstract in Nature Nanotechnology: Three-dimensional tissue culture based on magnetic cell levitation

Link: n3D Biosciences...

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Wednesday, February 17, 2010

Molecular DNA Reader Speeds Up Genome Sequencing

A research team from Arizona State University headed by Stuart Lindsay, director of the Biodesign Institute Center for Single Molecule Biophysics, has developed a new approach to detecting DNA base pairs. The technology, which utilizes advanced microscopes to identify the effect that a given nucleoside makes on an electron-tunneling junction, may become a leading contender as a standard sequencing modality of the future.

Lindsay's team relies on the eyes of nanotechnology, scanning tunneling- (STM) and atomic force- (ATM) microscopes, to make their measurements. The microscopes have a delicate electrode tip that is held very close to the DNA sample. In their latest innovation, Lindsay's team made two electrodes, one on the end of microscope probe, and another on the surface, that had their tiny ends chemically modified to attract and catch the DNA between a gap like a pair of chemical tweezers. The gap between these functionalized electrodes had to be adjusted to find the chemical bonding sweet spot, so that when a single chemical base of DNA passed through a tiny, 2.5 nanometer gap between two gold electrodes, it momentarily sticks to the electrodes and a small increase in the current is detected. Any smaller, and the molecules would be able to bind in many configurations, confusing the readout, any bigger and smaller bases would not be detected.
At this scale, which is just a few atomic diameters wide, quantum phenomena are at play where the electrons can actually leak from one electrode to the other, tunneling through the DNA bases in the process. Each of the chemical bases of the DNA genetic code, abbreviated A, C, T or G, gives a unique electrical signature as they pass between the gap in the electrodes. By trial and error, and a bit of serendipity, they discovered that just a single chemical modification to both electrodes could distinguish between all 4 DNA bases.

"We were quite surprised about binding to bare electrodes because, like many physicists, we had always assumed that the bases would just tumble through. But actually, any surface chemist will tell you that the bases have weak chemical interactions with metal surfaces."

Next, Lindsay's group is hard at work trying to adapt the reader to work in water-based solutions, a critically practical step for DNA sequencing applications. Also, the team would like to combine the reader capabilities with the carbon nanotube technology to work on reading short stretches of DNA.

Universal DNA reader expedites code sequencing ...

Article in Nano Letters: Electronic Signatures of all Four DNA Nucleosides in a Tunneling Gap

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Monday, February 8, 2010

Biodegradable Scaffold Helps Incubate Stem Cells for Safer, Faster Growth

Growing stem cells efficiently and preventing contamination is a major stumbling block in developing them for therapeutic applications. Still these days, animal byproducts are used in Petri dishes that grow stem cells, leading to infection that may trigger an immune response once these cells are transplanted into the body. To overcome this issue, researchers at University of Washington in Seattle have developed a 3 dimensional structure to serve as a nesting site for stem cells to comfortably grow and propagate.

Zhang's [Miqin Zhang, UW professor of materials science and engineering] cylindrical scaffold is made of chitosan, found in the shells of crustaceans, and alginate, a gelatinous substance found in algae. Chitosan and alginate have a structure similar to the matrix that surrounds cells in the body, to which cells can attach. Different processing techniques can make the scaffold out of interconnected pores of almost any size, Zhang said.
Researchers first seeded the scaffold with 500,000 embryonic stem cells, and after 21 days the scaffold was completely saturated. The cells infiltrated the structure, Zhang added, unlike other materials where cells often grow only on the surface.

To retrieve the cells, researchers immersed the scaffold in a mild solution. The structure is biodegradable and so dissolved to release the stem cells. One also could implant the stem cell-covered scaffold directly into the body.

Analysis of gene activity and testing in the lab and in mice showed that the new stem cells retained the same properties as their predecessors.

Other researcher groups are also looking for alternatives to feeder layers. The leading contenders are scaffolds coated with custom proteins designed to mimic the key properties of the animal cells in the feeder layer. Such products are expensive and difficult to produce in a consistent manner, Zhang said. The proteins also get used up in a few days and have to be replaced, making them costly and time-consuming for everyday use.

"Our scaffold is made of natural materials that are already FDA-approved for food and biomedical applications. Also, these materials are unlimited, and the cost is cheap," she said.

Press release: 3-D scaffold provides clean, biodegradable structure for stem cell growth ...

Abstract in Biomaterials: Feeder-free self-renewal of human embryonic stemnext term cells in 3D porous natural polymer scaffolds

Images: Top: The UW's biodegradable scaffold was built as a cylinder which was then cut into dime-sized slices. Bottom: A magnified view of the scaffold shows the pores, each about a tenth of a millimeter wide, where stem cells can grow.

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Friday, January 29, 2010

Faster, Cheaper DNA Sequencing Technology Now Available

Life Technologies of Carlsbad, California has released its latest genome sequencing device, the SOLID 4 System. The company promises sequencing of 100 gigabases at a cost of $6,000 and an optional upgrade later this year that will drop it down to $3,000. The system is already selling like hot cakes with an order for 100 units coming in from Ignite Institute, a new non-profit that is building North America's largest sequencing facility.

The company introduced the Applied Biosystems SOLiD(TM) 4 Sequencing System, the most advanced next-generation genomic analysis sequencing system on the market, generating up to 100 gigabases of mappable sequence data per run at a cost of $6,000 per genome. The system, which leverages proprietary advances in sequencing chemistry, will be available as an upgrade for all SOLiD installations in the first quarter of 2010. The company also announced that in the second half of the year, the SOLiD 4 System can be upgraded with the SOLiD 4hq package, which will generate up to 300 gigabases of mappable sequence data per run and deliver unprecedented accuracy of 99.99 percent, enabling customers to sequence the highest quality whole genome for a cost of $3,000.
Concurrent with the launch of the SOLiD 4 System, researchers will also be able to reduce overall sequencing costs by automating their workflow through the introduction of the Applied Biosystems EZ Bead(TM) System. The EZ Bead System dramatically improves the efficiency of sample preparation and reduces hands-on and turnaround time by as much as 90 percent.

Features from the SOLID 4 product page:

Scalable system - 100 GB today, extendable to 300 GB with the SOLiD™ 4hq System upgrade

Superior accuracy - More than 80% of the bases have quality values >30 for higher confidence in your results

Uniform coverage - Total Precision reagents improve coverage to enable the discovery of rare variants in difficult (GC/AT-rich) regions of the genome for fewer false negatives

Expanded application support - Barcoded paired-end sequencing that detects somatic mutations, novel splice variation, and fusion transcripts with less input material

Automated sample preparation - 80% reduction in hands-on time

Press releases: Life Technologies Brings Genomic Sequencing Closer to the Clinic...; Life Technologies and Ignite Institute Partner to Create Largest Next Generation Genomic Sequencing Facility in North America...

Product page: SOLiD™ 4 System...

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Wednesday, January 13, 2010

Los Alamos' Acoustic Flow Cytometry Going to Market

Life Technologies recently released a flow cytometer, an analyzer to sort through large quantities of cells, that features acoustic focusing technology developed at Los Alamos National Laboratory. The device essentially creates a regulated stream of individual cells, allowing for fast and precise identification of each cell passing in front of the laser.

From a LANL press release:

The Attune Acoustic Focusing Cytometer is based on a portfolio of intellectual property developed at Los Alamos National Laboratory (LANL), for which Life Technologies holds the exclusive commercial license rights. The field of flow cytometry was originally invented at LANL in the 1960s. The Bioscience Division at LANL currently is home to the National Flow Cytometry Resource (NFCR), a center for the development and application of flow cytometry technology.

From the product page:

With the Attune™ instrument, you can control your sample concentration, the flow rate, the number of photons you detect, the length of your experiment, the number of samples you run, and more.

Offers small footprint to fit in any lab and on all standard lab benches

Accommodates standard tissue culture hoods for convenient aseptic work

Provides a “greener” solution due to low sheath

Eliminates need for a separate fluidics cart with fluidics on-board

Includes change-it-yourself optical filters

Offers added convenience by locating filter holder under the lid

Provides violet and blue laser combination for choice of six analysis colors

Here's a company promo video for the Attune cytometer:

Press releases: Attune Acoustic Focusing Cytometer Brings Technology Developed at LANL to the Marketplace...; Applied Biosystems Debuts Industry's First Acoustic Flow Cytometer...

Product page: Attune Acoustic Focusing Cytometer...

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Monday, January 4, 2010

New Features in Geneious Pro 4.8 Sequencing Software

Biomatters Ltd out of Auckland, New Zealand has released a new version of its Geneious software package for "manipulating, finding, sharing, and exploring biological data such as DNA sequences or proteins, phylogenies, 3D structure information, publications, etc."

Here are the new features of the software:

Imports SOLiD and Solexa sequences as well as 454 sequences. The new, fast de novo assembler is capable of assembling a 5 mb bacterial genome for half a million sequences generated by the Sanger and 454 high-throughput methods in under 30 minutes while maintaining the most user-friendly environment available for research in the life sciences. Other new features in Geneious Pro 4.8 include:
Ultra-fast de novo assembler

Primer extension support

Primer design on alignments and assemblies

Map primer to sequence

Trim by primers

Batch export

Import FastQ, CsFasta, Qual file formats

Add, remove and combine enzymes from lists

Find in translated sequence

Quality statistics on chromatograms

Statistics: read length and chromatogram quality

Bundled EMBOSS Tools

Product page: Geneious 4.8...

Press release: Geneious Pro 4.8 released - over 15 new features...

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Monday, December 28, 2009

First Bioprinters Available for Life Sciences Research

Building artificial tissue replacements cell by cell has been a subject of science fiction writers for many years. Now Organovo of San Diego, CA partnered with Invetech of Melbourne, Australia to develop printers that can layer three dimensional structures out of various cell types.

InformationWeek reports:

The technology works by using a robot to lay down cells in precise positions in three dimensions, accurate to within 20 microns. "It's similar to the way a laser printer prints by putting solid particles in place," [Organovo CEO Keith] Murphy, told InformationWeek. The 3D medical printer puts down objects on 2D layers, one on top of the other. The particles used in the construction are made up of stem cells, formed into tiny spheres and cylinders.
The stem cells are available for research purposes from companies including Life Technologies and Invitrogen. When the device is used for treatment, cells will come from the patient, such as bone marrow, or fatty adipose tissues, where stem cells can be harvested. "Because they come from the patient, there's no risk of having a rejection," Murphy said. These are adult stem cells, not the fetal stem cells that have been politically controversial.

Researchers take a cross-section picture of the object they want to build, such as an artery. "We use that as a map to paint by numbers," he said.

Objects take about an hour to build, and then the cells fuse together on their own in the course of 24-48 hours, locking the object in shape.

From the press release:

The printer, developed by Invetech, fits inside a standard biosafety cabinet for sterile use. It includes two print heads, one for placing human cells, and the other for placing a hydrogel, scaffold, or support matrix. One of the most complex challenges in the development of the printer was being able to repeatedly position the capillary tip, attached to the print head, to within microns. This was essential to ensure that the cells are placed in exactly the right position. Invetech developed a computer controlled, laser-based calibration system to achieve the required repeatability.
Invetech plan to ship a number of 3D bio-printers to Organovo during 2010 and 2011 as a part of the instrument development program. Organovo will be placing the printers globally with researchers in centers of excellence for medical research.

Read on at InformationWeek...

Organovo press release: Organovo Receives Delivery of First Commercial 3D Bioprinters...

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Tuesday, December 8, 2009

Point-of-Care Genetic Testing While-U-Wait

Yesterday we heard the prediction that genetics wasn't going to produce any cures anytime soon, just more tests that would give fuel to our prejudices and traits to assign to whole populations and races.

Today, we learn that glorious future may come faster Genetic testing is already being used in clinical applications, specifically testing patients' sensitivity to medications that are known to be related to heredity. A big roadblock to screening more people is that blood has to be sent to the lab for testing, which often takes weeks while prescribing needs may not be able to wait that long. Nanosphere out of Northbrook, IL recently received FDA clearance for technology, called Verigene, that could soon be used in point-of-care applications to screen for certain genetic sequencing within a matter of a few hours.

A snippet from Technology Review:

A patient's blood is injected into a disposable cartridge, which holds a glass slide dotted with DNA. The plastic frame also houses a system of microfluidics chambers containing the reagents for a number of chemical reactions. When the cartridge is inserted into the Verigene instrument, mechanical valves and air pressure mix the reagents in different chambers, triggering a series of reactions.

Magnetic beads first pull out white blood cells, which are burst open using sonic energy, releasing fragments of DNA. Everything but the DNA is then washed away, and a solution of these DNA fragments flows over the glass slide. Target DNA binds to spots on the slide that have been printed with DNA sequences complementary to those of the target sequence. Gold nanoparticles, about 13 nanometers in diameter, then attach to the other end of captured DNA fragments, sandwiching the target. Each gold nanoparticle is coated with silver, expanding the diameter to half a micron, thus allowing it to be easily detected when hit with light.

Read on at Technology Review...

Product page: Verigene

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Monday, December 7, 2009

2010 Prediction: No Cures from Genetic Research, Just Racism

That's what Geoffrey Miller, writing in the Economist, would have us believe:

...the new genetics will reveal much less than hoped about how to cure disease, and much more than feared about human evolution and inequality, including genetic differences between classes, ethnicities and races.

...In 2010, GWAS [Genome-Wide Association Studies] fever will reach its peak. Dozens of papers will report specific genes associated with almost every imaginable trait—intelligence, personality, religiosity, sexuality, longevity, economic risk-taking, consumer preferences, leisure interests and political attitudes....

GWAS researchers will, in public, continue trumpeting their successes to science journalists and Science magazine. They will reassure Big Pharma and the grant agencies that GWAS will identify the genes that explain most of the variation in heart disease, cancer, obesity, depression, schizophrenia, Alzheimer’s and ageing itself. Those genes will illuminate the biochemical pathways underlying disease, which will yield new genetic tests and blockbuster drugs. Keep holding your breath for a golden age of health, happiness and longevity.

In private, though, the more thoughtful GWAS researchers are troubled. They hold small, discreet conferences on the “missing heritability” problem: if all these human traits are heritable, why are GWAS studies failing so often? The DNA chips should already have identified some important genes behind physical and mental health. They simply have not been delivering the goods.

Our natural instinct is to reject this prediction -- but we suppose the trait for skepticism was inherited as well.

More from the Economist...

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Thursday, November 19, 2009

Enigma ML System for Quick and Easy PCR

This week at MEDICA2009 in Düsseldorf, Enigma Diagnostics out of Wiltshire, UK is unveiling its new polymerase chain reaction (PCR) apparatus. The Enigma ML provides almost fool proof testing using single disposable reagent cartridges, and can be expanded to run multiple PCR tests in parallel using one control unit.

The Enigma ML has a modular, easily scalable architecture providing flexibility and choice in different healthcare settings. At entry level with a single processing module it is a compact, portable, inexpensive instrument ideally suited to settings where usage is lower and space is a premium e.g. in the doctor's office, pharmacy or intensive care unit. At the other end of the scale, multiple processing modules can be controlled by a single master unit allowing random-access, parallel running of different samples and tests.
It incorporates a clever, disposable cartridge which can accommodate either liquid or swab samples without any requirements for manual processing. All reagents and sample preparation tools are held on the self-contained cartridge and all steps are automated, minimising the risk of human error. The instrument also has a simple to use touch-screen for data entry and result reporting, plus an integrated label printer.

The system can perform multiplex, real-time PCR assays for both DNA and RNA targets.

Key features:

Fully automated real-time PCR system

rapid test (30 ~ 45 minutes to result)

multi-sample and scalable

accepts swabs and liquids (e.g. urine, blood plasma)

integrated sample preparation and analysis

low system price

small footprint (no specialist skills or cold storage requirements)

Press release: ENIGMA DIAGNOSTICS SHOWCASES ITS UNIQUE FULLY AUTOMATED rtPCR BASED ML (MINI-LABORATORY) INSTRUMENT FOR POINT-OFCARE TESTING AT MEDICA 2009... (.pdf)

Product page: Enigma ML ...

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Tuesday, November 17, 2009

Ultrafast Lab-on-a-Chip for Detection of Disease Biomarkers

Researchers from IBM Research in Zurich and the University Hospital of Basel in Switzerland developed a microfluidic device that uses capillary action to detect the presence of protein biomarkers for various disease types. The five square centimeter silicon-based lab-on-a-chip takes only fifteen seconds to perform its analysis.

Here are the five functional stages of the device:

Stage 1: A one microliter sample, 50 times smaller than a tear drop, is pipetted onto the chip, where the capillary forces begin to take effect.

Stage 2: These forces push the sample through an intricate series of mesh structures, which prevent clogging and air bubbles from forming.

Stage 3: The sample then passes into a region where microscopically small amounts of the detection antibody have been deposited. These antibodies have a fluorescent tag and similar to the antibodies within our body, they recognize the disease marker and attach to it within the sample. Only seventy picoliters (a volume one million times smaller than a tear) of these antibodies are used, making their dissolution in the passing sample extremely fast and efficient.

Stage 4: The most critical stage is called the "reaction chamber" and it measures 30 micrometers in width and 20 micrometers in depth, roughly the diameter of a strand of human hair. Similar to a common pregnancy test, in this stage the disease marker that was previously tagged is captured on the surface of the chamber. By shining a focused beam of red light, the tagged disease markers can be viewed using a portable sensor device that contains a chip similar to those used by digital cameras, albeit this one being much more sensitive. Based on the amount of light detected, medical professionals can visually confirm the strength of the disease marker in the sample to determine the next course of treatment.

Stage 5: Less a stage and more a part of the entire process is the capillary pump. The capillary pump, which has a depth of 180 micrometers, contains an intricate set of microstructures, the job of which is to pump the sample through the device for as long as needed and at a regular flow rate, just like the human heart. This pump makes the test accurate, portable and simple to use. IBM scientists have developed a library of capillary pumps so that tests needing a variety of sample

More from IBM Research: IBM Scientists Reinvent Medical Diagnostic Testing ...

Abstract in Lab on a Chip: Toward one-step point-of-care immunodiagnostics using capillary-driven microfluidics and PDMS substrates

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Monday, October 12, 2009

World's First Bioreactor Monitoring System for iPhone

If you're a lab tech who oversees cell culture growth in DASGIP bioreactor, you'll be happy to know that the firm has released an iPhone app to monitor the device. Perhaps now you can sit down to a round of Halo without too much anxiety about what's going on with your cultures.

Features from the product page:

Monitoring of device and alarm states by colored icons

Read and optional write access to process values and set- points

Online charts

Monitoring of all available reactors from multiple parallel systems

Supports network encryption and authentification

Supports DASGIP Control user levels and passwords.

Uses Microsoft Silverlight or Apple Software technology

DASGIP Remote Control meets IT security standards and can be configured according to various IT requirements. Depending on additional services provided at site, extended access may be possible:

Mobile access using iPhone and UMTS

Home access from Windows PC or Mac using a VPN connection

Product page: Remote Access from iPod and Webbrowser to DASGIP Control...

Press release: DASGIP Bioreactor System on the iPhone...

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Thursday, October 8, 2009

IBM's "DNA Transistor" May Lead to Cheap, Rapid DNA Sequencing

Cheap DNA sequencing is a holy grail for geneticists and advocates of personalized medicine. IBM has embarked on its own search for a technology, capable of bringing down personalized genome sequencing to $1,000. The technique they're currently pursuing involves running a DNA thread through a nanopore three nanometers wide. Inside would be an electrical sensor that can distinguish which of the four DNA bases is in proximity. If the DNA can be moved through the nanopore quickly enough with short pauses for base readings, the project researchers believe this approach will make genome sequencing common for clinical applications.

IBM Research is working to optimize a process for controlling the rate at which a DNA strand moves through a nano-scale aperture on a thin membrane during analysis for DNA sequencing. While scientists around the world have been working on using nanopore technology to read DNA, nobody has been able to figure out how to have complete control of a DNA strand as it travels through the nanopore. Slowing the speed is critical to being able to read the DNA strand. IBM scientists believe they have a unique approach that could tackle this challenge.
To control the speed at which the DNA flows through the microprocessor nanopore, IBM researchers have developed a device consisting of a multilayer metal/dielectric nano-structure that contains the nanopore. Voltage biases between the electrically addressable metal layers will modulate the electric field inside the nanopore. This device utilizes the interaction of discrete charges along the backbone of a DNA molecule with the modulated electric field to trap DNA in the nanopore. By cyclically turning on and off these gate voltages, scientists showed theoretically and computationally, and expect to be able prove experimentally, the plausibility of moving DNA through the nanopore at a rate of one nucleotide per cycle - a rate that IBM scientists believe would make DNA readable.

Image: A membrane containing the nanopore, funtionalized with metal contacts (orange) separated by dielectric materials (lime), devides a reservoir into a top part containing an ionic solution with a high concentration of single stranded DNA, and a bottom part, where the DNA will be translocated to. The DNA on the top reservoir is induced to go to the bottom reservoir by the action of a biasing voltage. In the absence of anything else, the DNA would translocate through the pore at a speed of several million bases per second. To control the passage of DNA trhough the nano-hole, voltages of appropriate polarity (not shown) are applied to the metal contacts inside the pore, which create an internal electric field that trap the DNA. By alternating the trapping voltages applied to the metal contacts, the DNA can be made ratchet from the top to the bottom reservoirs in a controlled way.

Press release: IBM Research Aims to Build Nanoscale DNA Sequencer to Help Drive Down Cost of Personalized Genetic Analysis...

(hat tip: Engadget)

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Philips' New Digital Photomultipliers May Replace Large, Imprecise, Power Hungry Tubes

Scientists at Philips have developed a new fully digital silicon photomultipliers (SiMP's) that may replace detectors within PET scanners as well as open up possibilities for other ultra-sensitive detectors for DNA sequencing and protein/DNA microarrays.

By integrating low-power CMOS electronics into the silicon photomultiplier chip, the team at Philips has developed a digital silicon photomultiplier in which each photon detection is converted directly into an ultra high speed digital pulse that can be directly counted by on-chip counter circuitry. In contrast to conventional silicon photomultipliers, the Philips digital silicon photomultiplier is therefore an all-digital (digital-in/digital-out) device. As a result, it produces faster and more accurate photon counts with extremely well defined timing of the first photon detection, both of which are important factors in applications such as medical imaging scanners and high-energy nuclear particle detectors.

The PET system detects pairs of gamma rays (high energy electromagnetic radiation) originating from a radioactive tracer, a small amount of which is injected into the patient prior to the scan. To image metabolic activity, PET typically uses a radioactive derivative of glucose called fluorodeoxyglucose (FDG). This compound mimics the behavior of glucose in the body and can be detected by the PET system.

For so-called ‘time-of-flight’ PET scanners, accurately determining the time at which the first photon arrives at the detector is extremely important. Philips’ digital silicon photomultiplier prototypes achieve a timing accuracy for the detection of the first photon of around 190 ps (full-width, half-maximum using a standard scintillator crystal (LYSO) at 511 keV for two detectors in coincidence).

Conventional silicon photomultipliers (SiPMs) consist of a two-dimensional array of avalanche photodiodes (APDs) each of which is connected in series with its own polysilicon ‘quenching’ resistor. All of these diode/resistor ‘microcells’ are then connected in parallel and the entire microcell array is reverse-biased to a voltage above the diodes’ normal breakdown voltage – typically in the range 30V to 70V. Operating in this so-called ‘Geiger mode’, the diodes are ultra-sensitive to single electron-hole pairs that result in individual diodes experiencing avalanche breakdown. These electron-hole pairs can be generated either by the absorption of a photon (the desired signal), or by thermal energy or electron tunneling (unwanted background noise). The unwanted background noise produced by thermally generated electron-hole pairs and/or electron tunneling, together with false counts due to defective microcells, are collectively referred to as the SiPM’s ‘dark count’.

To eliminate a conventional SiPM’s need for an external digitizing ASIC, the digital silicon photomultiplier developed by Philips equips each individual avalanche photodiode with its own 1-bit on-chip ADC (Analog to Digital Converter) in the form of a CMOS inverter. Each microcell that experiences avalanche breakdown therefore produces its own digital output that is captured, along with the digital outputs from all other triggered microcells, by an on-chip counter. The Philips digital SiPM therefore converts digital events (photon detections) directly into a digital photon count. As a result, it is capable of achieving significantly better resolution than conventional SiPMs.

To overcome the ‘dark count’ problem associated with conventional SiPMs, each microcell in the Philips digital SiPM is also equipped with an addressable static memory cell that can be used to disable or enable the microcell. Microcells that show high dark count levels can therefore be prevented from contributing false counts to the SiPM’s output. This facility allows the Philips’ digital SiPM to achieve better signal-to-noise ratios than conventional devices. Because defective microcells in the array can be disabled, it also helps to improve production yield.

Press release: Philips announces breakthrough in fully digital light detection technology...

Technology backgrounder: PHILIPS' FULLY DIGITAL LIGHT DETECTION TECHNOLOGY (.pdf)...

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Tuesday, September 29, 2009

Cancer Diagnosis Via Semiconductor

Researchers at the University of Toronto, led by Dr. Shana Kelly and Dr. Ted Sargent, are reporting in Nature that they have used a combination of nanoparticles and a microchip to determine the type and severity of a patient's cancer based on the signature of biomarkers that indicate the presence of cancer at the cellular level.

>Dr. Kelly's work demonstrates that the cells can be differentiated with these biomarkers because of the cellular genes that indicate aggressive or benign forms. The scanning electron micrograph illustrates the eight variable structures that the system can repeatably track with less than 5% variation. Analysis time is reported to be 30 minutes as compared with contemporary diagnostics tests which can take days.

The researchers' new device can easily sense the signature biomarkers that indicate the presence of cancer at the cellular level, even though these biomolecules - genes that indicate aggressive or benign forms of the disease and differentiate subtypes of the cancer - are generally present only at low levels in biological samples. Analysis can be completed in 30 minutes, a vast improvement over the existing diagnostic procedures that generally take days.
"Today, it takes a room filled with computers to evaluate a clinically relevant sample of cancer biomarkers and the results aren't quickly available," said Shana Kelley, a professor in the Leslie Dan Faculty of Pharmacy and the Faculty of Medicine, who was a lead investigator on the project and a co-author on the publication.

"Our team was able to measure biomolecules on an electronic chip the size of your fingertip and analyse the sample within half an hour. The instrumentation required for this analysis can be contained within a unit the size of a BlackBerry."

Press release: U of T researchers create microchip that can detect type and severity of cancer...

Nature: Programming nucleic acids detection sensitivity using controlled nanostructuring

University of Toronto: Shana Kelly Lab

(hat tip: Next Big Future)

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Friday, August 28, 2009

Leica Unveils New Single Cell Imaging Product Line

Leica has just announced a new confocal microscope system that provides one platform for performing common single cell imaging techniques like FLIM (fluorescence lifetime imaging) and FCS (fluorescence correlation spectroscopy). Additionally, the same system allows to use the newer, more precise confirmation methods like FCCS (fluorescence cross-correlation spectroscopy) and FLCS (fluorescence lifetime correlation spectroscopy).

The Leica TCS SMD Series integrates hardware and software from PicoQuant with the high-end confocal system Leica TCS SP5 II. Researchers can now control a complete SMD experiment via one interface, the LAS AF software from Leica Microsystems. The coordination of different hardware and software components for one SMD experiment is now a thing of the past.

Complex SMD technologies are no longer complicated due to the user-friendly design of the system series. Quick and easy operation is ensured by dedicated application wizards. They guide the user step-by-step through SMD experiments and significantly maximize the reproducibility of data. With the universal SMD raw data format, one and the same data file can be analyzed in various ways and leads to quantification with maximum content.

Press release: All in One: A Single Platform to Study the Dynamics of Cellular Processes ...

Product pages: Leica TCS SMD FCS, TCS SMD FLIM, TCS SMD FLCS

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Wednesday, August 19, 2009

Stem Cell Concentrator from ThermoGenesis Going to Market

ThermoGenesis out of Rancho Cordova, California is releasing a point-of-care device for concentrating stem cells derived from patients' bone marrow. The company promises a 15 minute processing time and consistently high yields of viable mononuclear cells.

Here's how you operate the Res-Q:

STEP 1 Fill the Res-Q™60 BMC with bone marrow aspirate using a syringe and the supplied clot filter. The needleless port protects the sample from contamination.
STEP 2 Place the Res-Q™60 BMC into a benchtop centrifuge and spin at 3200 rpm for 12 minutes to allow for the separation of the bone marrow components and capturing of the buffy coat into the collection chamber.

STEP 3 Remove device from centrifuge and place on processing tray to re-suspend the buffy coat.

STEP 4 Harvest 6-10 mL of a stem cell rich buffy coat. A 12" sterile line is provided to facilitate transfer of sample back into the surgical field if required.

Press release: THERMOGENESIS ANNOUNCES LAUNCH OF RES-Q SYSTEM...

Product page: Res-Q™60 BMC ...

Res-Q™60 BMC product brochure...

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Thursday, August 13, 2009

Systems Biology Graphical Notation: A Visual Language for Biology

Shown above is a summary of the physiology of a neuro-muscular junction in a newly introduced visual language called Systems Biology Graphical Notation (SBGN). Developed to standardize and simplify a knowledge database in an exploding field of Systems Biology, the language is touted to represent "networks of biochemical interactions in a standard, unambiguous way" in order to "foster efficient and accurate representation, visualization, storage, exchange and reuse of information on all kinds of biological knowledge, from gene regulation, to metabolism, to cellular signaling."

Caltech has released the following statement about SBGN:

SBGN will make it easier for biologists to understand each other's models and share network diagrams more easily, which, Hucka says, has never been more important than in today's era of high-throughput technologies and large-scale network reconstruction efforts. [Michael Hucka is a senior research fellow and codirector of the Biological Network Modeling Center at Caltech's Beckman Institute --ed.] A standard graphical notation will help researchers share this mass of data more efficiently and accurately, which will benefit systems biologists working on a variety of biochemical processes, including gene regulation, metabolism, and cellular signaling.
"Finally, and perhaps most excitingly," adds Hucka, "I believe that, just as happened with the engineering fields, SBGN will act as an enabler for the emergence of new industries devoted to the creation of software tools for working with SBGN, as well as its teaching and publication."

Previous graphical notations in biology have tended to be ambiguous, used in different ways by different researchers, and only suited to specific needs--for example, to represent metabolic networks or signaling pathways. Past efforts to create a more rigid notation failed to become accepted as a standard by the community. Hucka and his collaborators believe that SBGN should be more successful because it represents a more concerted effort to establish a standard by engaging many biologists, modelers, and software-tool developers. In fact, many of those involved in the SBGN effort are the same pioneers who proposed previous notations, demonstrating the degree to which they endorse SBGN as a new standard.

To ensure that this new visual language does not become too vast and complicated, the researchers decided to define three separate types of diagram, which describe molecular process, relationships between entities, and links among biochemical activities. These different types of diagrams complement each other by representing different "views" of the same information, presented in different ways for different purposes, but reusing most of the same graphical symbols. This approach reduces the complexity of any one type of diagram while broadening the range of what can be expressed about a given biological system.

To learn more about SBGN, follow these links:

Abstract in Nature Biotechnology: The Systems Biology Graphical Notation Nature Biotechnology 27, 735 - 741 (2009)

SBGN Project...

Press release: Caltech Scientists Help Launch the First Standard Graphical Notation for Biology...

Flashback: BioModels: a Computational Systems Biology Database

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Tuesday, August 11, 2009

Single Molecule Sequencer Reads Human DNA in Four Weeks

As we've reported in the last few years, Helicos BioSciences out of Cambridge, MA has been working on a revolutionary new method of sequencing DNA molecules. The technique does not require any cloning, amplification or ligation to be performed, but uses a novel combination of physics, chemistry, and computer vision to identify base pairs at an unprecedented speed. This week researchers from Stanford University and Howard Hughes Medical Institute are reporting the sequencing of an entire human genome using a Helicos machine within four weeks at a cheap cost of only $50,000.

The basics of the technology from Helicos BioSciences:

Within two flow cells, billions of single molecules of sample DNA are captured on an application-specific proprietary surface. These captured strands serve as templates for the sequencing-by-synthesis process:
Polymerase and one fluorescently labeled nucleotide (C, G, A or T) are added.

* The polymerase catalyzes the sequence-specific incorporation of fluorescent nucleotides into nascent complementary strands on all the templates.
* After a wash step, which removes all free nucleotides, the incorporated nucleotides are imaged and their positions recorded.
* The fluorescent group is removed in a highly efficient cleavage process, leaving behind the incorporated nucleotide.
* The process continues through each of the other three bases.
* Multiple four-base cycles result in complementary strands greater than 25 bases in length synthesized on billions of templates—providing a greater than 25-base read from each of those individual templates.

More about the announcement from Ars Technica...

Stanford press release: Professor sequences his entire genome at low cost, with small team...

Article in Nature Biotechnology: Single-molecule sequencing of an individual human genome

Product page: HeliScope™ Single Molecule Sequencer

Flashbacks: Helicos BioSciences Sequences Entire Genome from a Single Molecule of DNA; High Speed Sequencing of Single DNA