Developing Low Cost Diagnostics for Infectious Disease – Strategies and Advice

Mana Chandhok:
Hi, everyone. Welcome to this podcast from Cambridge Healthtech Institute for the Next Generation Diagnostic Summit, which runs August 20th to the 24th in Washington, DC.

I'm Mana Chandhok, an Associate Producer. We have with us today, our speaker Dr. Paul Yager, a Professor Bioengineering at the University of Washington. Dr. Yager will be speaking at the Enabling Point-of-Care Diagnostics and the Microfluidics and Lab-on-a-Chip Devices for point-of-care testing tracks this year.

Paul, thank you for joining us.

Paul Yager:
Thank you very much for having me.

Mana Chandhok:
Can out you outline what you consider to be some of the greatest obstacles to developing NAAT testing and low cost diagnostics for infectious diseases?

Paul Yager:
It's a very complex multifactorial problem in many ways. One of them, which has been prominent, certainly is cost. The cost per test and/or the cost of adopting a particular mechanism that you want to use for testing. Initial setup costs, if you like. There are many, I'd say all of the models that are out there right now, are instrumented models, where there is essential instrument, which has an ill-defined cost. I think that's a problem for some people, who might be adopters.

On the other hand, it might be worth it, and is worth it apparently, for some of the companies to give away the instrument, and then as usual, make their money on the per test devices. But I think defining a platform, and a mechanism will depend on the very specific adopters of the test, and that's, I think, still evolving, as we speak. Simplicity is really, really important. If we're going to go with low cost diagnostics for point-of-care use, making sure that you don't need to have a well-trained technician involved to run it is critical. And then not needing laboratory equipment per se, is also critical. So simplicity of function.

Sample prep is another critical issue, so determining what has to happen between the collection of the sample and when it's ready to be tested is something that's great, having it done entirely inside a disposable is much, much, much better than forcing the end user to go through a multi-step protocol prior to using a single instrument. So I would say for low cost, the cost itself is an issue. But it's a cost, not just of the test, but the cost of the person who has to run it. So if the end user is going to buy the test directly and use it him or herself, simplicity becomes really critical.

So in terms of an obstacle to developing them, it's understanding who's going to adopt it, when the adoption's going to occur, what the requirements are for that kind of adoption, and then, as we all know, there's regulatory issues and reimbursement. And you can't really think it all the way through to an end use until you've thought through those issues.

Mana Chandhok:
Can you describe your approach and what is unique about it?

Paul Yager:
Our particular approach I'll be speaking about was developed thanks to DARPA and I really want to give thanks where thanks is due there. We got five years of support for a project we called Multiplexable Autonomous Disposable Nucleic Acid Amplification Test. And that's a big set of words. Let's just say Nucleic Acid Amplification Test. It's a NAAT test and that was a given. Multiplexable, meaning we wanted to be able to have a single test event that allowed us to monitor multiple targets. So pick up certain targets and amplify them, and get multiple answers, so that it could go after a symptomatic analysis.

Let's say you have someone with an upper-respiratory infection, something you could look at, at least a few targets that would identify which pathogen was responsible. Autonomous, we wanted it to not require an instrument. So from the very beginning we said, "We wanted to go instrument-free." And a natural consequence of that is not just instrument-free, but something that's so inexpensive that you can afford to throw it away. You could say the reasons to throw away NAAT test because you don't want contamination if you've amplified something with the next sample going through.

So [inaudible 00:03:51], use it once and clean it, and reuse it, but something where the whole instrument got thrown. We wanted that partially to be different from the majority of approaches to NAAT tests, which are instrumented with perhaps an inexpensive disposable. Sometimes they're very expensive disposable. We wanted to have everything in the disposable. So what we have is something that can be in a pouch, a foil pouch typically, where we would include the sampling tool, as well as the test device itself. And then a mechanism for reading that out, whether by eye or with a cell phone.

We wanted this to be useful, for example, for [inaudible 00:04:23] for a war fighter in a far forward sight, or a person at home, or at work, simply wanting to check up their health, or that of a family member. The device itself starts with sampling. We focused a lot of nasal swabs, but it could be an environmental swab. We also worked on blood sampling and urine sampling to enable one to start with a variety of sample types and focus them into the final device. Most of the effort we put into the swab, but we worked on the others, as well.

We do sample prep because the sample will include, let's say human cells, as well as pathogens and other materials. We found that a bacterial mixture called Achromopeptidase, combined with heat was really very effective in taking a sample and reducing it to something that could be amplified downstream without terribly much interference at all.

We combined that with heat, typically heating to about 95 degrees for a couple of minutes. Either with a chemical heating method, or a resistance wire. The chemical heating method, which was fun to develop with our colleagues at Path, was using the Meals Ready to Eat metal particles. You add saltwater to them, and they will boil. So it's a fabulous source of a lot of energy, packed in a small space at a ridiculously low cost.

The amplification method we used was an isothermal one, so we had to hit one temperature. In this case our temperature is 50 degrees C, plus or minus about one degree. So there was a bit of engineering to figure out how to do that. The amplification method is an isothermal method. We chose one from our partners at ELITech, here in the Seattle area. It's called ISDA or Isothermal Strand Displacement Amplification. We like it because it is sensitive down to single copy and tube. Rapid in that you get your first indication of amplification at around seven minutes. And it can be compete in 15, even at low copy numbers.

We spent a lot of time on the heating system, using this chemical heating, as well as electrical heating systems. The detection method is one that we also got from ELITech initially, which is lateral flow detection. Essentially taking the amplicons and building a sandwich between something that will bind specifically to a spot on a lateral flow strip on paper, and at the other end, a binder that will bind the amplicon and attach it to a colored particle. So essentially, we used lateral flow detection to see the product of the nucleic acid amplification test.

So in addition to lateral flow that's readable by eye, we've also looked at the fact that, to save time, we can do real time fluorescence detection using fluorescence probes. So we've done everything from sampling, direct swabs into noses, out to real time fluorescence and lateral flow detection. We originally built a box that was about the size of a couple of packs of cigarettes, standing one on top of the other. And some of our initial investment partners looked at it said, "Does it have to be so big? And how much does it cost?"

So we have, in the last year or so, been reducing the size of that down to something which is in the same form factor as a pregnancy test. We originally had batteries for the electrical version of this thing. We've now thrown away the batteries and have the USB port, so the whole device can be plugged into a USB power source. Whether it's your laptop, your phone, or for that matter, a wall charger. Or, even a battery pack. So now single disposable in a pack, but in the same form factor as a pregnancy test.

Mana Chandhok:
What advice do you have for people developing and introducing low cost tests?

Paul Yager:
The simplest answer I can give to many people I've seen get into this primarily from the academic side, is know your clinical market early. Identify what that is and work to solve the principle problems in that market. I think many of us make the mistake of starting out with a technology platform, and assuming it will solve all problems. That's the hammer in search of the nail problem. Typically, the answer is to find the nail first and then go see if you can make a hammer for it. Knowing the market is the single biggest advice I can give people.

And once you know the clinical market, you have to decide whether you want to fit into that clinical market. Are you better than somebody else by a large factor? Are you one-tenth of the price? Are you 100th the price? What would it take to displace the people currently on that market? So I think definition of markets, defining whether you want to broad platform versus a single disease solution, or critical issues, and then finding the partners who are willing to pay for it. And to take it to market.

Mana Chandhok:
What are some of the most exciting new developments emerging for rapid diagnostics and how has your work changed as a result?

Paul Yager:
Well, I've actually said for a long time, that the advances of cellular phone technology, and what we will now all call Smartphones, are probably the single most important thing that's been available to diagnostics. Because one, it allows one to think about bringing a sophisticated diagnostics test out of a central life laboratory. So for me, the single biggest issue is, this enabling technology that lets us get there.

I mean, the phone has every conceivable kind of transducer you can imagine, and a very sophisticated computer, and the ability to send data, either in raw form, or predigested, to health provider network. So the healthcare providers can provide feedback, can analyze the data, look at the data in context of medical records, and decide what particular therapy needs to be applied to the patient. So that an appropriate therapeutic regimen can be applied, or in fact, in certain cases, no therapeutic regimen, if that's not warranted.

But the Smartphone and data connectivity allows the healthcare providers to extend their reach out to their patients wherever they are, and I would say the changing perception on the part of the public, that getting as much as possible health information on your phone yourself, all the time is a good idea. There are a lot of people now who are willing to buy a variety of apps that will allow them to stay healthier and avoid illness.

And that perception has, I think, opened the door to technologies that address that particular kind of desire on the part of the end user. Frankly, most exiting in a certain way is interest on the part of some of the centralized lab companies in preparing themselves for a point-of-care and home test market.

Mana Chandhok:
Dr. Yager, thank you for your time and insights today.

Paul Yager:
You're very, very welcome.

Mana Chandhok:
That was Dr. Paul Yager from the University of Washington. Dr. Yager will be speaking at the Enabling Point-of-Care Diagnostics and the Microfluidics and Lab-on-a-Chip Devices for point-of-care testing tracks at the upcoming Next Generation Diagnostic Summit that is held from August 20th to the 24th in Washington, DC.

I'm Mana Chandhok. Thank you for listening.