IN PERSON

Randy White, PhD, is chief executive officer of Adnavance Technologies Inc. (Vancouver). He has 35 years of ex­perience in medical diagnostics and laboratory operations. Prior to joining Adnavance, he served as chief executive officer for two molecular diagnostics companies, Nanogen (San Diego) and Xenomics (New York City), where he spearheaded the commercialization of technologies and launched eight molecular diagnostic products. He can be reached at rwhite@adnavance.com.

To learn more about market stratification and open architecture for microarrays and other IVD products, IVD Technology editor Richard Park spoke with Randy White, chief executive officer of Adnavance Technologies Inc. (Vancouver). In this interview, White shares his views on where he thinks detection platform development is headed and the limits of light amplification. He also discusses metallized DNA, the expectations of molecular diagnostics, and the advantages of strategic partnerships.

IVD Technology: What have been the most significant advances in the area of detection technologies during the past few years?

Randy White: Real-time polymerase chain reaction (PCR) technology and its applications have grown considerably. But overall, technologies that require amplification and rely on some form of light detection like fluorescence, chemiluminescence, or light scattering will continue to dominate the market.

However, Adnavance is developing an entirely new technology that doesn’t require amplification and doesn’t require light detection. Adnavance is using the conductive properties of metallized DNA (MDNA). The metallized DNA concept is based on Jeremy Lee’s discovery that metal ions could penetrate into the center of double-stranded DNA and displace the hydrogen bonds. This process essentially transforms the DNA’s double helix into a small, highly conductive nanowire. The change in conductivity from hybridized DNA to metallized DNA is so large that it increases sensitivity exponentially.

Why have fluorescence and similar light amplification technologies continued to be the dominant formats throughout the IVD industry and various IVD products?

A lot of money is a stake for IVD manufacturers, and they tend to go with what they know will work, which generally is fluorescence or another form of light generation. Although there are other detection technologies, the holy grail in molecular diagnostics is to find a detection platform with enough sensitivity to eliminate the need for amplification. Unfortunately, the IVD industry has yet to find such a platform. Cantilevers were first reported in the late 1990s and claimed single molecule sensitivity, and other ultrasensitive technologies were introduced in that same time frame. Yet in the seven or eight years since their discovery, we haven’t seen any commercial products come onto the market to eliminate amplification technology. That tells us that those technologies are hard to control and hard to develop.

PCR and real-time PCR have been around for a long time, and most IVD manufacturers have adopted some form of that amplification. There is a definite interest in a more sensitive platform, but other available methods haven’t been commercially reliable.

What are currently the latest trends in developing detection technologies?

The latest trend in the industry has been IVD manufacturers simply accepting the fact that they have to do amplification and designing medical devices to include amplification inside the box. The biggest problem for the laboratory has been that to perform amplification, they had to first pay roughly $750,000 to build the necessary infrastructure, hire the staff, and buy the necessary equipment. Such requirements prevent most laboratories from performing the amplification process in-house. Only about 30% of U.S. labs perform molecular diagnostics, and even fewer hospitals. Many manufacturers have decided that there’s no way around amplification, so they’re including amplification inside the medical device itself to simplify the process.

Examining Traditional Strategies

What important role has PCR played and continues to play with detection technologies?

Essentially, PCR is a molecular Xerox machine. If you’re trying to find a bacterial sequence in a background of human DNA, PCR preferentially amplifies the target against a static background of human DNA. If a platform isn’t capable of detecting at low, sensitive levels, then some form of amplification has to be used. Most manufacturers opt for PCR.

What are some of the primary challenges that IVD manufacturers encounter when designing and developing detection technologies for their products?

The sensitivity of a detection platform is more or less inherent in its method. The platform is a function of the fundamental technology combined with the concentration of the target in the sample, and that’s the basic problem with the current detection systems on the market. Most detection systems need at least 1 million copies of DNA for detection, but the concentration of target DNA in a blood sample or a nasal swab for MRSA is only around 50,000–100,000 copies. So manufacturers have two choices. They can either develop an ultrasensitive detection platform or take a larger sample to obtain more of the target. Unfortunately, the latter is often not practical.

Are IVD manufacturers more inclined to produce detection technologies on their own in-house or to outsource and work with a partner or company that specializes in detection technologies?

There’s certainly stratification in the IVD marketplace. Large diagnostic companies are looking at smaller manufacturers to initially develop these novel technologies, but the large manufacturers have the financial resources to bring the technology forward as a commercial product. This is the case with direct detection methods. Obviously, smaller companies receive a lot of interest from these larger businesses in strategic partnering and development, so I think they’re keeping their ear close to the ground. Large IVD manufacturers are looking at all kinds of companies to find the technology that truly is going to be a platform.

How do IVD manufacturers overcome the challenges of making detection technologies more sensitive and event specific?

If an IVD company has the ability to do sample pre­treatment and reduce interference, it may be able to im­prove its platform’s sensitivity. However, the sensitivity of a given platform is determined by the combination of the number of targets in the sample and the inherent sensitivity of the detection system. Almost every detection system on the market uses some kind of light generation. Unfortunately, any time a company relies on light detection, it’s building an instrument that has to have excitation sources, mirrors, detectors, and filters, which adds cost to the product.

So how do manufacturers overcome these challenges? They explore cantilevered technology, fluorescence, and molecular beacons. They look for smaller companies like Adnavance with a technology that offers the opportunity to do direct DNA detection. With Adnavance, we’ve created a molecular nanowire that conducts electricity, so excitation sources, light detectors, mirrors, and filters are unnecessary. Our device has the ability to simply transform the DNA into a highly conductive molecule that can be measured. More importantly, it produces a differential measurement, which is a key part of the sensitivity. Once target hybridization is complete, we measure the conductivity. Then we metallize the DNA and measure the conductivity again. It is the change in conductivity that renders the ultrasensitivity.

How have developments in molecular diagnostics affected the developments of detection technologies?

The discovery of new markers is driving detection technology developments. The larger companies have previously dominated IVD markets through intellectual property, but molecular diagnostics is discovering more markers every week and many are freely licensed on reasonable terms. So technology, marker discovery, and innovative detection platforms are the three developments driving the molecular diagnostic market.

What is your perspective about molecular diagnostics? Is personalized medicine going to be one of the key areas or factors for growth in molecular diagnostics?

When PCR was first introduced to the market in the early 1990s, industry leaders said molecular diagnostics would be a billion-dollar industry by 1995. It wasn’t. In 1995, they said it would be a billion-dollar industry by 2000. It wasn’t, but it was close. In 2000, they said it would be a billion-dollar industry by 2003. And in 2001, the industry finally produced a billion dollars worth of sales thanks to the HIV, hepatitis C, and HPV products. So then, everyone was anticipating marker discovery at a much faster pace than what actually happened. Now, the worldwide molecular diagnostic market is worth $3.5 billion, and some expect it to be worth more than $10 billion by 2010. So the current market is finally growing at the rate originally predicted back in the 1990s, and it owes a lot of that to marker discovery.

The Promise of Direct Detection

What sort of detection technologies has Adnavance developed?

Our MDNA platform is an ultrasensitive direct-detection technology. Under strict conditions, certain metal ions can enter into the central core of double-strand DNA and replace the hydrogen bonds. That chain of metal ions running down the DNA backbone transforms the molecule into an incredible conductor that we can measure. That transformation produces a differential measurement, which is a lot easier to detect. Measuring the change is part of the sensitivity, but the change itself is so large that that’s what gives our detection technology its increased sensitivity.

How have Adnavance’s detection technologies been applied in diagnostic tests?

Several years ago, Adnavance began using synthetic sequences to develop the technology, but more recently we’ve moved to E. coli and staphylococcus sequences. We measured E. coli in a background of staph and staph in a background of E. coli because that’s the traditional R&D approach. Now the company is moving toward developing the technology into our preliminary product. Our first product to market is going to be for methicillin-resistant Staphylococcus aureus (MRSA). Currently, MRSA is responsible for 62% of hospital-acquired infections, so Adnavance views it as a very serious problem and the market is begging for a solution.

Our device has the ability to determine whether a patient is MRSA positive at the point of care, the hospital, within about two and a half hours. I recently spoke with the head of laboratory medicine for a large San Diego hospital chain. He indicated that the local hospitals had decided to screen all incoming patients for MRSA and the task posed a serious problem for his facility. A Canadian newspaper recently reported that all Toronto hospitals now screen every incoming patient for MRSA as well. So this is destined to be a huge market.

Has Adnavance established any other partner­ships or strategic alliances with other IVD companies to develop detection technologies?

Adnavance hasn’t established any partnerships with other IVD companies to date, although we are working on forming a partnership now. One of the things we want to ensure is that our medical device and the reagent system remain open. That’s important for us in strategic partnering. We’re making it an open-architecture system so it can fit into any of the workstations designed by some of the larger IVD manufacturers.

Hospital laboratories are our central focus, but the open architecture leaves the device well suited for an appropriate strategic partnership with a large diagnostic manufacturer. The device is small because there’s no need to include any light detection. The box itself is roughly the size of a small laptop computer and easily sits on any laboratory bench. It’s designed to be a push-button walk-away device, which means that existing personnel can run the tests without additional training. It’s also microarray based, so there’s only one chip per patient. The device is fully self-contained, including the waster, and the reagent package is disposable.

Preparing for the Future

How has the IVD industry changed based on your experience and expertise in the past decade?

Now that the genome has been unlocked, and there’s a new marker reported almost every week, the technology has changed, the rate of adoption has changed with it, and the discovery process and development are in full tilt. This is what’s driving the market forward. The worldwide market currently is estimated to be $3.5 billion in size, so the growth we were expecting in the previous decade is finally happening.

What challenges will emerge that IVD manufacturers will have to overcome in the future in developing detection technologies?

Obviously, the challenges are going to be increasing sensitivity and analyzing targets in a background of human DNA. For example, if an IVD developer could detect 500 copies per milliliter, that company could not secure a strong footing in the HIV market because the detection sensitivity needs to be at least 25 copies per milliliter or better. Many companies pursuing the HIV market are even striving to develop technologies capable of 1 copy per milliliter.

So if an IVD company has a device with a limit of detection of 500 copies per milliliter, that market is closed unless it incorporates some form of amplification that would assist detection. However, a highly sensitive system like that could be a viable platform because it would need only four of five cycles of PCR instead of 30, or maybe they could get by with linear amplification that doesn’t involve PCR. Still, Adnavance’s products would not only produce results faster, it would also do so with a lower cost structure and without the need for a commercial PCR license. So there’s certainly a challenge to push the limits of sensitivity and find viable ways to do that.

In a few short years, microarray fabrication has come a long way. Designers can now reproducibly create 1-micron-diameter electrodes where that would have been impossible a few years back. Without getting too technical, this is important because the sensitivity of Adnavance’s technology increases as the square of the diameter of the electrode decreases. For example, when there is a smaller-diameter electrode, for a given fixed concentration of targets, there will be a higher percentage of hybridization binding event on that smaller electrode and therefore increased signal.

What new trends can we expect to see this year and in the future in the area of detection technologies?

I think IVD manufacturers will see more technologies similar to Adnavance’s that will have significantly lowered the detection limit and have sensitivity consistent with direct detection in the analytical range for most molecular assays. Existing and new tests will be transitioned onto these direct detection platforms, and the current centralized market will begin to decentralize. Probably the most important IVD product change will be system complexity. More-streamlined instruments will appear, and they’ll be smaller in size and simpler to operate to the point where it opens the market to a much broader audience. Those are the two general trends I see in the industry in the next 10 years.