Abby: From the campus of Harvard Medical School, this is ThinkResearch, a podcast devoted to the stories behind clinical research. I'm Abby.

Brendan: And I'm Brendan. And we're your hosts. ThinkResearch is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.

Abby: And by NCATS-- the National Center for Advancing Translational Sciences

Brendan: Diagnostics provide us with information that is critical for effectively treating disease and for overall public health efforts. Mara Aspinall is a leader in understanding diagnostics, including their implementation, effectiveness, and importance. On today's episode, Mara discusses her career in biotech, why diagnostics is actually a data business, and looks ahead to the future of COVID testing. Mara Aspinall is a professor of practice and co-founder of the Biomedical Diagnostics Program at Arizona State University college of health solutions.

Mara Aspinall, thank you for joining us, and welcome to ThinkResearch.

Mara Aspinall: Great to be here.

Brendan: So you're an expert in diagnostics. Can you tell us when you became interested in diagnostics?

Mara Aspinall: Yeah, it was about 30 years ago, and I was at Genzyme, and they had a large diagnostics division. And it was very clear that despite all of the great therapeutics and treatments in this world, if you don't know the disease the patient has, even the best of drugs and the best of doctors and the best of treatments do not work. There was a study around that time that showed one third of people at autopsy were being treated for a disease that they did not have. And as soon as I heard that, I realized that diagnostics is critical to every part of health care, but particularly at the beginning.

Brendan: How have you seen the field of diagnostics change? Since you started at Genzyme and now at Arizona State, you run a school or a program focused on diagnostics.

Mara Aspinall: Over these last 30 years, diagnostics has gone from-- I guess I would say, the little leagues to the big league. It has often been in the shadow, thought about as a nice-to-have but a need-to-have, and that has been true during the COVID pandemic. At the beginning of the pandemic, there was a conscious effort to not focus on diagnostics. Then we had vaccines, and we thought that vaccines alone would create a cure and end the pandemic. And time after time, we find that without an accurate diagnosis, you can't deal with a public health crisis or an individual health crisis. So diagnostics are key.

The other thing that happened-- I don't know, probably about 25 years ago-- is that through some very interesting analysis, doctors rely on diagnostic tests for about 70% of the decisions that they make. So if you look at those standard tests that you get, from blood tests to urine tests to even just a day-to-day physical, it's all about the data they get from the lab. And that's often taken for granted and not respected, as much as a silver bullet or the exciting treatment.

Brendan: I was listening to this podcast you did a few months ago. And you mentioned a story of-- maybe it was when you were at Genzyme-- but somebody said, why are we worrying about diagnostics. There's no margin, and you can't scale the business. And you had a really interesting response. Can you tell the listeners a little bit about that?

Mara Aspinall: Sure. For me, the response was that diagnostics is a data business with a wet lab on the side. Diagnostics is about the information you learn from the test. There's a lot of debate about which technology do I use, even in COVID, do I use a PCR, do I use antigen tests. For most people, it really doesn't matter. It's all about the information that it gives you. And it's that information that brings power.

The power to choose how to go forward. The power to know whether you're sick or not. The power to choose the best treatment. And that is a mind shift. So much of the last decade, and more, has been talking about the subtleties of which kind of technology and which sort of reagents. The question we need to be asking ourselves-- as non-laboratorians, just the rest of the world using these tests-- are, so what will this test tell me, and how will that change my health care?

Brendan: So we're talking about diagnostics. You mentioned COVID testing, which is top of everybody's mind these days. One area that diagnostics have really changed is cancer. We know so much more about cancer than just the example of breast cancer. There are many different types of breast cancer, and this diagnostic-- or genetic test will tell you which type of cancer you have, and that dictates the treatment. So maybe you could talk a little bit about how diagnostics have improved cancer treatment and how they work-- like how that diagnostic treatment interface has grown or improved.

Mara Aspinall: Sure. What I would say is pre-pandemic, the most fundamental change in diagnostics has been the advent of personalized medicine-- precision medicine-- it's called a lot of different things. But it's all about the fact that we have far more diseases than we think. Breast cancer is a great example, and cancer broadly, particularly solid tumors, was all about the size of the tumor. And if it was big, it was bad, and if it was small, it was better. The reality is it's just not true. It's all about the genotypic, a little bit of phenotypic, but all about the genetic basis of that tumor. And there could be a very small tumor that is highly, highly aggressive. And there could be a large tumor that could sit there for years and years and years and never affect your life.

So what happened with breast cancer, with blood cancers, in particular? We used to think about it as leukemia and lymphoma. And they were all cancers of the blood of some sort. Today, there are more than 120 different types of leukemias and lymphomas. And what's the so what here? We went from probably a 10% cure rate-- I mean, this is several generations ago-- to a 50% cure rate, and now close to an 80-85% cure rate. And it's all because we recognize we can't just treat all lymphomas the same way or all leukemias the same way. We need to be thinking about them in that personalized way. Would this have happened without diagnostics? I'm going to say no. Would it have happened alone? No. It has to be the combination of the diagnostics, get a more precise diagnosis, and that allows drugs to be used more effectively.

Brendan: And developed in a more targeted way too.

Mara Aspinall: Exactly. And there's a great story about Herceptin, which, as many people know, is an extraordinary drug for what's called HER2-positive breast cancer. It was tried on a large clinical trial, a breast cancer, and it failed according to the traditional ways that you look at a clinical trial. I think it was something like 15% of the patients did better, and 85% did not, and it failed. They were going to just kill the drug. But what they did instead was the beginning of personalized medicine. They said, wait a second. What is the same about those positive 15%? When we found they had an elevated HER2 level-- Herceptin-related level-- and then from there, that gave us the opportunity to create the test and only give the drug to those who are most likely to improve.

Brendan: Wow. So your work in diagnostics went from Genzyme to Roche Pharmaceuticals. You spent about a year at Dana-Farber Harvard Medical School in between there. And you also started a program at Arizona State devoted to teaching master's-level students about diagnostics. How did that opportunity come up, and who were the types of people that you teach in this program?

Mara Aspinall: Sure, and let me just describe a little bit more about that-- when I spend a year-- I took a sabbatical from Genzyme, and I had the privilege to work and learn at Harvard Medical School and Dana-Farber. I happened to be on the board of Dana-Farber at the time, but I didn't really understand how doctors think. How do they make a cancer diagnosis? How do they choose from options? There were fewer than there are now. How are they educated? What role does Medical School play in teaching diagnostics? And after the huge privilege of being able to do a sabbatical, it gave me the idea that we don't have anywhere near enough information for how to best use diagnostics. And that many physicians hearken back to their Medical School years, on average many years ago, and we're never really taught that diagnostics is an art. It's a science, independent of the rest of biotech or medicine.

And so, from there, I met Dr. Michael Crow, the president of Arizona State University. And we said, how could we make an impact on health care? How can we improve that? And from my bias and history and diagnostics, I said, we need to educate on the value of diagnostics, when are they used, when are they not used. And we started a program with five aspects-- the science of diagnostics, the technology, the finance, the policy, and the application.

The students in the program-- so far, their first degree is a master's degree-- are people who are typically mid-career. Who want to go from a small company to a bigger role at the small company or a large company. Somebody who's regionally head of quality, who wants to become the national or international head of quality. We also have about 20% of our students who just graduated and who want to apply to Med School but are not ready to do it. This gives them that great basis of a key part of the medical continuum.

Brendan: We talked a little bit about the importance of diagnostics. Why have diagnostics been taken for granted, do you think?

Mara Aspinall: Well, for a long time, diagnostics were pretty generic. The tools and techniques were available at every lab. There was very little intellectual property-- and I'm talking 30, 40, 50 years ago-- but the techniques didn't change. The taking of blood and doing what's called a CBC-- a Complete Blood Count and analysis of blood had remained stagnant for a long time. It was automated, but only partly. And what happened-- I'd say really beginning 30 or 40 years ago. I'm not that old, but somewhat coincidentally, my journey of the industry-- is we started to see real entrepreneurship in the industry. We started to-- well, I shouldn't say it was just the industry.

What it also was is the Human Genome Project, which happened more recently. And people started understanding that we can use bodily fluid, bodily tissues to understand a whole lot more than presence or absence of numbers. So we were able to analyze amniotic fluid in a way that was much more aggressive. We were able to look at DNA and later RNA for pregnant women to predict diseases. We were able to do PCR, which is probably the single biggest innovation, until we came to NGS or sequencing. And as we put those together, we saw the diagnostics could go-- orders of magnitude, more information, more useful, and more data than we ever had before. That's been the revolution over the last 30 years.

Brendan: It goes back to doctors who went to Medical School many years ago, before all of these innovations, before the genome sequenced-- not to say that doctors who went to Medical School before X date are out of touch or anything-- but it seems like a huge shift in the way that you think about what is possible in terms of diagnosing disease.

Mara Aspinall: It absolutely has been a huge shift, but you bring up a good point. And I will make a maybe controversial statement here. But one of the ways that doctors continue to learn, regardless of how many years out of Medical School, is that they have continuing education requirements. We need to make diagnostics, genetics, and genomics, a required piece of continuing medical education. And that has not happened in all states. A lot of places have not changed that. The majority of medical schools are not teaching diagnostics, genetics, and genomics, maybe some genetics, but very little genomics. And that needs to change for doctors to be best equipped to use all the tools they will find in practice.

Brendan: Let's shift to COVID testing, the thing that everybody is worried about. So today is January 18, just for a little context, so it seems like COVID testing has been a struggle through the entire pandemic. Why has testing been so challenging during the pandemic?

Mara Aspinall: Why is testing been so challenging? There are really three reasons. Number one is testing was taken for granted. At the beginning of the pandemic, with the last administration, it was despised. It was thought of as just an excuse to show the numbers of people. The Biden administration has focused much more on testing, about $23 billion, before the free testing program-- announced this month-- but it was still secondary to vaccines. It was still a focus on vaccines are going to cure this disease. They're going to rid us of the pandemic. And what we found out is that's not true.

Secondly, there has been a culture in the US of not doing home testing. Many of us expected 5 years ago, 10 years ago, that our industry would move much more to self-testing and home testing, and that never happened, a little bit in HIV testing, pregnancy testing, but otherwise, there were so many interesting tests. The FDA was slow to approve them. And Americans-- even with COVID in April and May when the first home test came out-- were not eager to take them off the shelves. They were happy with the current system. So what happened with COVID is they got sick and tired of it, didn't want to wait three days, didn't want to wait in line, and wanted to take the power into their own hands.

I think lastly, we had a different-- we have a different philosophy than Europe for test authorizations. Today, we have 12 manufacturers with at-home tests. In Europe, with CE IVD marks, there are 46. Now, I don't know that one is fundamentally better approach than the other. But I do wonder if the FDA was appropriately staffed to move authorizations for diagnostic tests quickly through the system. We've seen year after year-- and in my experience-- the FDA is understaffed in the area of diagnostics, and it's a small group within the device agency. We need to have diagnostics be front and center, not only for COVID but for other diseases going forward. So I do think it's those three issues-- both top-down in terms of the FDA and number of tests and the government's approach to it. But also bottom-up, the Americans were not willing to do a test at home until very recently.

Brendan: Yeah. I think you mentioned-- when we spoke previously-- that something like 20% to 40% or 20% to 50% of people are asymptomatic. And that's where the importance of testing comes in, too, right?

Mara Aspinall: Yeah. Well, it's kind of a different question is, why is testing so important? If I look at why testing is so important, it's critical for so many diseases, as we talked about. But it has a unique role in COVID, where at least 20% and some epidemiologists would say closer to 40% or 50% of people with COVID have zero symptoms. That is kind of mind-blowing. We don't have many diseases where you could transmit to others, and even be super spreaders, and have no symptoms yourself. It's a sad commentary, but I've used the phrase that the three most dangerous words in the COVID era are, "I feel fine." Because if you feel fine, you feel like you can't possibly be sick, and that is unfortunately wrong. And it is only tests that can tell you whether you have an infectious case of COVID.

Brendan: So now we have this free testing program that's going out. People can order four tests per household. What is your thought on what the government's doing with covidtests.gov, with sending people four tests per household? How do you see this as a response?

Mara Aspinall: I think it is a great first step. It acknowledges the importance of tests and testing on a regular basis. Is it enough? Probably not. But it is a great start to move forward. For so many people, they've never tested at home even though there's a huge amount of demand. And once you do it first and realize how easy and simple it is. I believe people would be much, much more comfortable to test going forward. What we need to do is ensure that people are using the test correctly. So that what is still in limited supply can be used to best impact.

Brendan: And you mentioned in Europe, they have 40-something different tests, and in the US, we have 12. And just personally, I've noticed that I have a cabinet full of tests, and each one is different. And they all have different instructions. And you just mentioned using them correctly. So how do you fix that? Is the idea just to get one test and everybody uses that one, or everybody makes the test the same way? How do you fix the user error problem?

Mara Aspinall: Well, in a perfect world, everybody would have the choice of their favorite test. And they could keep buying that test, and only that test. Unfortunately, we don't live in that world. It is true-- and I've tried most of the tests once-- that they are a little bit different, but fundamentally not very different. The sample taking is virtually identical, but the form factor is different. This is not a time for creativity. So it is important that people read the instructions. The advantage to our systems today is the instructions are almost always in English and in Spanish, and on video. So if you're not one to read the instruction-- because the FDA does require the manufacturers to put it in some detail-- go to YouTube. Look up the test that you have, and then just watch somebody do it.

The other option that people have for testing is that several of the manufacturers, unfortunately not all, have a QR code on their test box. You can scan that code and get the video of how to use it. You can scan that code and have them send you a confirmation of whether you're negative or positive. And I think Brendan, that brings up a bigger issue here-- which is the data that comes from home or self-tests. Well, I think that this is a key issue that we need to talk about, in terms of what a lot of people are very concerned about. So many of these tests are going unrecorded.

Brendan: Right, so let's talk about that. So you have case counts and positivity rates, and that's based on PCR tests that people get in hospitals or at some kind of health care facility, which is not counting the antigen tests that people do at home. So why is that a problem?

Mara Aspinall: Well, it's a problem for public health. And when you think about COVID, I think about it at two levels. One is a public health, and the other is individual health. This program-- the Biden Administration Program-- and any home testing helps with individual health. So I know whether I'm sick and I can go visit my grandson. But it doesn't help very much from a public health basis. The public health professionals are often flying blind.

In my estimates, there are at least twice, if not now, three times as many home tests being done as there are lab tests being done. And we don't know the positive rate for those tests. So it's critical that even if it's, unfortunately not for this pandemic, we need to embrace, I believe, a technology-based system where people can report the results of their test-- negative or positive-- in a private way. Because that's part of the reason people want to do it at home by themselves. But we're feeding that information into public health authorities, so they know that the positive rate in my ZIP Code is three times the positive rate in your ZIP Code. And without the visibility from these tests, we don't know that.

Brendan: From there, what does that mean for public health? Can't you just say, well, we think it's two or three times more. Or we wrote a computer model based on estimates, and we just say, it's probably this. Why is that an issue?

Mara Aspinall: Yeah, so why does public health need the data? Well, this is an example of something that they could write a model. They could have a computer program to estimate it. But in a new disease-- even though the pandemic is two years old-- we don't really know the pattern that it provides. And I'll use the example here of opioids. One of the ways that we got public health data from opioids-- opioid abuse-- is in wastewater. And quite frankly, there was a lot of discussion that opioids was an inner city problem. Opioids was only for certain ZIP Codes. And we found out that lo and behold, when we looked at public health data-- in this case from wastewater-- we found that, nope, opioid was an issue across the entire country. We also found out in communities where doctors were prescribing a ton of opioids. Lo and behold, that community didn't have a lot of opioids in their wastewater, that they must be selling them to other communities. You learn a lot-- back to data-- from the data that comes out of public health systems.

So on COVID, if we found that the positive rate was very high in a particular county, a particular ZIP Code, we could put more education there that says that. We could increase the number of tests in that district's schools. We could take proactive actions to keep people safe. We could tell a nursing home that you might want to test visitors because 90% of your residents' families live in this ZIP Code. So there are a lot of actions-- that with information-- we can take to protect the public's health, which is why they're there.

Brendan: I thought it was interesting-- maybe we could talk about some numbers-- you mentioned in September that there were 75 million tests a month happening. Has that number gone up, or what is the testing right now?

Mara Aspinall: Wow. No, it's gone up very materially. Let me just pull up my numbers. If we look at the home or self-test-- which are the focus of a lot of discussion now-- right before Thanksgiving, we had about 140 million tests capacity in the US. In January, it's risen almost 100% to 260 million tests available. And I believe by the end of February, another two months from now, it will double to more than 520 million tests. So the programs to expand the number of tests available is working. Would it have been better if it were earlier? It absolutely would have. But the pandemic-- despite the mildness of Omicron-- is not yet over. And I believe we will be and should be testing for many months. Hopefully, not years, but many months to come.

Brendan: Well, why not, though, just have it as part of your medicine cabinet. We talked about how we have a problem with home testing. I know there's colon cancer screenings that people do at home, which requires a stool sample, and like that's a separate issue. But why not have just COVID tests in your medicine cabinet?

Mara Aspinall: You bring up a great point. I hesitate because I actually don't want people to worry and/or be depressed about the fact that this is going to be with us forever. But I think you're right. That in some way-- I believe relatively soon in 2022-- we will see COVID become like the flu. It will be endemic, seemingly more contagious. Usually, viruses, as they progress, become more and more contagious. And what has been challenging about COVID is-- unlike the flu or the seasonal flu-- it has no season.

We thought it was going to go away the first summer. It didn't. Then we thought maybe it would go away the first winter. It didn't. So you were probably more realistic here that in some way, shape, or form, we're going to be testing for COVID. And testing to show the difference between COVID and flu. But I hope with higher and higher, either true vaccination or, I quote, "vaccination through infection," which is not as effective but still useful. That we will become less afraid of COVID, and we will resume our-- what I call BCV, Before COVID-- life. But with the reality, just like AIDS, it's a disease that didn't exist some generations ago and is not going away.

Brendan: Right. And the mitigation measures will probably be-- I mean, it's impossible to predict-- but there will be probably some form of mask-wearing. Or people will have a different concept of what they need to do in certain spaces, probably for many years.

Mara Aspinall: Yeah, I think that's right. I mean, this is not something that any of us are going to forget, from five-year-olds to 95-year-olds. But I do think that our mitigation efforts change, particularly in diagnostics. I do think we move much more to wastewater testing and then outbreak control. I hope we would have an effective air monitoring system. We'll move to programs that maybe are less sensitive, i.e., more false negatives, but we're catching super-spreaders. So again, it's all about outbreaks and slowing spread, not eliminating spread. And that helps us get our economy back, and most importantly, keep kids in school at all ages. So we can keep education going forward.

Brendan: Well, Mara Aspinall, from Arizona State University, and many other projects. Thank you very much for joining us. It was a pleasure to have this conversation with you.

Mara Aspinall: Great to be with you. Stay well, everyone.

Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes, and help us spread the word about the amazing research taking place across the Harvard community.

Abby: To learn more about the guests on this episode, visit our website-- catalyst.harvard.edu/thinkresearch.