IN PERSON
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Michelle M. Hanna, PhD, is founder and CEO of Ribomed Biotechnologies Inc. (Phoenix). She can be reached at mmh@ribomed.com. |
To learn more about opportunities for IVD companies in defense-related diagnostics, IVD Technology editor Richard Park spoke with Michelle Hanna, PhD, founder and CEO of Ribomed Biotechnologies Inc. (Phoenix). When Hanna formed her business (then named Designer Genes Inc.) in 1999, her aim was to create a device that could test for early-stage cancer. After the 2001 terrorist attacks in the United States, a growing interest in bioterrorism detection led Ribomed to look at ways it could use its technologies for defense purposes.
IVD Technology: How did Ribomed first get involved in developing detection technologies for bioterrorism agents?
Michelle Hanna: At the time of its founding, Ribomed had just received funding from the National Cancer Institute. We were working on detection systems for tumor suppressor silencing through CpG methylation, which had nothing to do with biodefense. We had just developed an extremely robust, isothermal signal-generation and molecular-detection process called Abscription (abortive transcription) that can be used to detect protein, DNA, RNA, SNPs, or CpG methylation sites.
Then, about the time that we were finishing up Phase 1 of our funding, the terrorist attacks of September 11, 2001, occurred. After that, government grant money began to shift. We were contacted by the Defense Advanced Research Projects Agency (DARPA), which is a division of the U.S. Department of Defense (DoD).
DARPA was looking for new molecular detection technologies that could be used for extremely rapid and very accurate detection of environmental pathogens that would be a concern to first responders. We were working on an Abscription-based transcription signal- generation process through a small business innovation research (SBIR) grant and began to ask whether we could apply the same detection systems to look for pathogens. We had been applying our technology to cancer cells, but since it is a general molecular detection system, it can also be used to determine the presence of an RNA virus, or a protein toxin such as ricin, botulism, or Staphylococcus enterotoxin B in the environment.
This eventually led to a full-blown program under DARPA’s special projects office (SPO). We’ve just entered Phase 3 of this contract, toward the development of a device called the handheld isothermal silver standard sensor (HISSS).
So, DARPA sought out Ribomed?
The government was looking for a new signal-generation and molecular detection system that could be put into a device that was going to be taken out into the desert or taken onto submarines or into post offices, and would often be operated in dirty environments.
The most appealing thing about the Abscription process is that it doesn’t depend on polymerase chain reaction (PCR) in any way. In fact, it doesn’t amplify the target. It’s extremely robust and is not inhibited by blood components that, at 20 times the concentration, completely inhibit PCR and reverse transcriptase–PCR (RT-PCR). And it’s very thermostable. It works over a very broad temperature range.
Working with the Government
What are the terms of your contract with DARPA?
The contract is being run through Northrop Grumman, which is serving as the prime contractor and is building the device.
Everything is set up in phases. The process is very milestone based. Once we got past the initial seed money, which was on the order of a few hundred thousand dollars for the first year, we entered Phase 1, and DARPA provided several million dollars for the research and development.
The milestone for Phase 1 was that our Abscription-based protein and RNA–detection assays had to prove comparable to what are considered the gold standards: ELISAs for protein and RT-PCR for RNA.
After that, the project went into review and moved into Phase 2. This Phase was shifted mostly onto the shoulders of Northrop Grumman, which had to show that it could achieve the same levels of specificity with Abscription in a microfluidic device.
In November 2005, we moved into Phase 3. From there, Ribomed is developing tests for two other toxins—ricin and botulism—and for three RNA-related viruses. Our milestones are to be able to demonstrate high-level multiplexing: to detect all of these toxins and viruses present in a single sample at the same time, and to discriminate among them.
The finished device ultimately will be handheld and have a cartridge in it that contains enzymes and Ribomed’s reagents. The cartridge will function as a sort of razorblade for the detection razor. If you were taking it into the field and had some reason to suspect the presence of certain toxins or RNA viruses, you would load it up with reagents for that particular application.
There are nonclinical lab applications that the handheld tests could be used for as well.
What sort of competition did you encounter for these grants?
This particular DARPA process was sole sourced, meaning that we are the only group working on the device. Although DARPA’s SPO handles contracts in this manner, it’s not the way that DoD and Department of Homeland Security (DHS) funding usually occurs.
Our other contract, which was activated in December 2005, is through DHS’s Homeland Security Advanced Research Projects Agency to build an Abscription-based device to protect the food supply. It is designed to rapidly test for protein toxins and bacterial targets within 20 minutes. Ribomed is the prime contractor and will be developing the reagents and detection assays. The device will be built through a collaboration with Motors, Drives, and Controls Inc. (Hatfield, PA) and bioDevice Partners (Cohasset, MA). Again, the process is extremely milestone based. We have to develop a diagnostic and demonstrate it to DHS by August. And if we achieve that goal, we’ll have to get two devices into their hands by the end of the year.
As the department reviews the project milestones, it may or may not move all of the companies forward. Ultimately, the plan is to have a single device.
Are high sensitivity and high specificity the government’s main concerns?
I would say that specificity is probably the more important of the two. If the test does make an identification, it needs to be correct. That’s true both for false-positive and false-negative results. The consequences of discovering a bioterrorism agent are significant. And in fact, Abscription not only matched both ELISA-based protein detection and RT-PCR–based RNA detection, but also beat out RT-PCR severalfold in terms of specificity with a very low false-positive rate. Sensitivity is also important, although it really depends on the application.
After that, cost is a major driver. In order for these devices to be useful in protecting the food supply, for example, they have to be at enough places around the country to test a representative sample. So, one goal is to develop much more affordable molecular detection tests than are currently available.
Another concern, too, is ease of use. The people running these tests are not going to be trained scientists in a nice, clean clinical lab. They are going to be people out in the field, in an environment they may not be able to control.
Considering that the device is intended for field use, ease of use and avoidance of sample contamination must also be important considerations.
Yes, those are very important factors. Another major driver is the ability to have an isothermal reaction in a single temperature, as opposed to thermocycling. Currently, the PCR-based tests that are being conducted require a great deal of energy. DARPA wanted to develop something that could be run strictly on batteries. Since our process can be done isothermally at a much lower temperature than PCR or RT-PCR, it will use a lot less power.
Has the government provided a list of specific toxins that it wants Ribomed’s technology to be able to detect?
The targets for the device are very specific, but they can change as emerging infectious diseases change. For instance, if you looked at a list of primary disease concerns two years ago, you probably wouldn’t have found avian flu on there. Of course, now you would.
The idea is that the test should be flexible enough and general enough that if a new threat emerges, we can rapidly develop a new diagnostic and interface it fluidly into the devices that are being developed.
At this stage, the government’s concern is to be able to identify specific substances—toxins like ricin, botulism, and food poisoning. But with RNA viruses in particular, you never know from one year to the next what will emerge—whether it’s SARS (severe acute respiratory syndrome) or West Nile virus or avian flu.
What challenges did Ribomed encounter in adapting its technologies for biodefense applications?
Scientifically, making the transition was quite easy. Abscription can be formatted just as easily for proteins or RNA detection as for the methylation that we were looking at. So, that really wasn’t the difficult part.
What was a bit of a challenge was finding clean space to work in. We had to set up a biosafety level 2 facility, which we didn’t have and is difficult to find in Phoenix. We actually had to build a lab in order to take on the contract.
The second challenge was finding people who had experience and were comfortable working with toxins. The sorts of people that we had working for the company were doing simple DNA work and methylation. They weren’t used to working with toxins.
Finding Customers
Who is the eventual market for the device Ribomed is building for DARPA? Is it earmarked more for military purposes, or are there civilian applications as well?
Originally, it was going to be strictly for military use and environmental testing. However, as the project has moved forward, there’s begun to be some interest in rapid diagnostics and assessment on-site, to perform blood tests or similar types of tests to see if somebody has been exposed to a potential threat.
The first uses will be military because those are the agencies that are funding the technology, but the same device could then also be used in the civilian population for similar types of rapid response.
The market is huge. And it becomes even larger if you think beyond the traditional first responders—about having detection devices on subways or trains or in stadiums, anyplace that could potentially be a target for a bioterrorism attack. It’s the type of technology that can be used for on-site assessment when you don’t have time to send samples back to a clinical lab.
When working with local governments, cost becomes an increasing factor. Is this something you are addressing during product development?
Originally, when I saw the design for what the HISSS device would do, I believed its cost would limit its use to the military. But the target price requirements set by DoD have come down substantially, to less than $500 per device. If we can achieve the price goals that DARPA has placed on both the instrument and cost per assay, everybody should be able to afford this. It’s the type of device that could eventually be placed in every doctor’s office, even in school nurses’ offices.
What is the target date for completing a workable, functioning handheld device?
By the end of Phase 3—probably in about a year—we should have a prototype device in place for field testing. The government will decide how long testing will occur before a device is released.
Public concern about bioterrorism has settled down somewhat since 2001, but I don’t think anybody has forgotten about it. Quite the opposite. The government has put out a number of solicitations to develop these types of detection devices. But you can’t rush to put something out that might create false-positive results and generate a panic. So, I think the government is taking it slowly. As a result, what comes out of its programs will be sensitive, specific, adaptable devices that could be around for a long time.
New Opportunities
What would you suggest to IVD companies interested in working with the government on biodefense?
There are really two approaches, depending on the state of a company’s technology. Small companies that have an idea, but not much preliminary data, can start by looking for SBIR grants. These generally allow you to achieve proof of principle. After this, a company can apply for a Phase 2 grant to develop its technology.
On the other hand, if the technology is a bit further along and ready to be applied to a device or detection method, then the company should pay attention to the broad agency announcements (BAAs) that are released by nearly all of the relevant government agencies. It’s important to actively search the information being posted on DHS’s and DoD’s Web sites. When these BAAs are released, the response turnaround time is typically very short.
Another thing that I would suggest to companies considering these BAAs is to attend the bidders’ conference, where you can go and meet the program managers and ask specific questions. When funding agencies issue BAAs, they have very specific goals in mind. A company is wasting its time bidding on a project that it can’t complete within the set specifications. And this is the kind of information you can get by attending bidders’ conferences.
I’ve had a wonderful experience with the government, but it’s important to remember that these projects do take time. And government processes take time as well.
Does Ribomed have plans to get involved in other testing areas?
With our homeland security contract, we’ve already begun moving into the food testing area. The device we’re working on right now will eventually be used to test both liquid and food supplies.
What I’d like to do is to develop the test for some of the original applications we had in mind—to diagnose and monitor cancer and other human diseases. We already have a technology that can detect different types of biomarkers with one enzyme and one set of reagents.
It’s been great having the government support so much of the early development of our protein and RNA detection tests. We definitely plan to take advantage of the opportunity and return to our clinical-testing roots.
