Backed by approximately £2.3 million ($4.3 million) in funding from the UK’s Biotechnology and Biological Science Research Council and Engineering and Physical Sciences Research Council, a consortium comprising about 20 scientists from four UK-based institutions is developing ‘optical biochips’ for applications in cell-based drug discovery, point-of-care diagnostic applications, and veterinary diagnostics, the BBSRC said last week.
The consortium members hail from the University of Wales College of Medicine; the departments of physics and biology at Cardiff University; the microtechnologies group at the University of Wales, Bangor; and the Gray Cancer Institute in London, Paul Smith, the consortium’s principal investigator and a professor and chair of the cancer biology department at the University of Wales College of Medicine, told Cell-Based Assay News last week.
In addition, the consortium has partnerships with several UK-based companies, including Leicestershire, UK-based BioStatus, whose far-red fluorescent probe reagents will be the basis of miniaturized cell-based assays for protein translocation being developed by the consortium; and UK-based IQE, which will supply the specialized epitaxial wafers necessary to manufacture the biochips, Smith said.
The consortium’s near-term goal is to develop and commercialize optical biochips that are literally laser chips made out of the semiconductor gallium arsenide, which possesses unusual light-emitting qualities. By using microsurfacing and sculpting techniques, the researchers then hope to design the chips for specific purposes.
“So it’s really taking semiconductor technology to its light-emitting level, and then working with those chips to make them into quite different analytical devices,” Smith explained. “This means that with the scale we can go down to, we can make blind chips which sense the presence and characteristics of cells, and they can be made very small.
“This would have application in any area where cell-based assays are important — for example, the diagnosis of cancer,” he added. “Or, for example, HIV detection, where you are trying to detect a particular form of blood cell; or parasitology, where you’re looking for parasites within cells. And of course, situations where you can control the cells for [a] purpose, such as cell-based screens for drug discovery.”
Though strictly an academic endeavor at this point, there are definite plans farther down the road to spin out a biotech startup based on the new tech, Smith said.
“The optical biochip [project] was one of six chosen in 2003 by the joint research council,” Smith said. “We received about £2.3 million for the project, and that is grant funding that comes directly to us. But we are charged with looking at exploitation. So it’s not just the straight technology — we are charged with doing something with it, as well, or laying down the foundations for that.”
According to Smith, the consortium is currently building an intellectual property portfolio in three main areas. First, it is developing “new ways of identifying the movement of molecules within cells,” Smith said, much like many of the popular assay technologies on the market, such as Molecular Devices’ Transfluor or BioImage’s Redistribution assays.
“Translocation assays are a major part of drug discovery now,” Smith said. “Sixty percent of all prescription drugs hit the cell in the same way — they hit GPCR receptors, and translocation of molecules as signals of a receptor being hit is very important. But how can we do that without ever scanning the cell at that resolution? We’re working on IP right now that will allow us to look on blind chips for translocation.”
The second area, Smith said, is for “specialized surfaces, and how we go about screening specialized surfaces that will impart functional changes on cells.
“Functionalized surfaces — where you put proteins and peptides and molecules onto a surface — have been used to elicit different changes in cells, despite their attachment,” he said. “We’re developing a high-throughput screening approach to look at how microfabrication and nanofabrication on surfaces can actually be used in the same way.”
The third major area, Smith said, is the laser chip design itself, particularly the logistics of controlling the speed of the laser pulses and enabling simultaneous detection of multiple fluorescent signals from samples. The first proof-of-principle prototypes of the chip have actually used LEDs for laser excitation, but future chips will make use of the semiconductor technology.
As for detection of fluorescent signals from the chip, Smith said the consortium is exploring a variety of options, with waveguide sensing currently in the lead.
“The lowest options are to use waveguide concepts to take the light off the chip to an appropriate detector,” he said. “The idea is to close all the detection right down on the chip, so it becomes illuminating and sensing at the same time.”
The consortium currently has a relationship with an undisclosed “very large UK company,” Smith added, “where we’re trying to establish [how] that might be done with very high fidelity.”
For cell-based drug screening applications, the consortium recently signed an agreement with BioStatus to use its flagship far-red-emitting fluorescent dye DRAQ-5 and its variants as a way to develop multiplexed fluorescent assays.
Of course, as one of the co-founders of BioStatus, and a current member of its scientific advisory board, Smith’s relationship with the company goes back farther than this most recent agreement. In fact, BioStatus was a spin-out based on technology developed at Cardiff University and De Montfort University, also located in the UK.
“That technology is being used on the chips because they are far-red emitting,” Smith said. “From the telecommunications side, there is a long history of using far-red and infrared wavelengths. But in biological assays, there have been relatively few developed, because most of the laser devices that are used are blue emitting.
“So GFP, for example, upon blue excitation emits in the green, but there are now red variants, too,” he added. “People are moving to red variants because the excitation is less damaging to cells, and also it leaves available to you the rest of the visible spectrum.”
DRAQ-5 also offers the advantage of having been validated by several drug discovery outfits as a key reagent to complement popular translocation assays such as the aforementioned Transfluor and Redistribution (see related article in this issue, “BioStatus — Though on the Block …”). This opens the door for the possibility of future partnerships with the companies that market these products in which the assays might be shrunk to a lab-on-a-chip scale.
Since the prototypes of the chip platform are not yet perfected, it might be several months before the consortium has a meaningful customer to disclose, or seriously discusses the formation of a spin-out company. But Smith said that it expects to have finalized prototypes before the year is out, and that it will continue to seek partnerships to exploit the chip’s potential.
The first such partnership, in fact, is in place, although Smith declined to identify the collaborator. “It’s a much larger UK company, which is taking forward one set of applications that would use the fluorochrome technologies on chips for a specific purpose in the veterinary area of applications,” he said.
An interview conducted for a separate article with BioStatus CEO Stefan Ogrodzinski revealed that this application would be for mastitis detection in cow’s milk, an application whose payoff potential dwarves that of drug discovery or point-of-care diagnostics.
In terms of human biology applications, however, Smith said that the consortium would probably concentrate on the cancer biology field.
“And that splits into two areas,” Smith said. “First, whether or not the chips can be used in a really useful way in drug discovery, and that will likely relate to a large global pharmaceutical company that has interest in that area, and that we’ve had initial talks with. And second, whether we can develop real, small healthcare devices, and I would think that this would be the eventual spin-out of the whole consortium.”