Treating SCD before it hurts

Daniel sits down with Dr. Patrick Hines, the founder and CEO at Functional Fluidics and the leading Sickle Cell Disease (SCD) researcher at Wayne State University in Detroit, where he set up a transformational study on defining the health of red blood cells — membrane stability, abnormalities, stickiness, and more. Dr. Hines also introduces us to exciting new therapies — recently approved — and the importance of being proactive with SCD.

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Dr. Patrick Hines:
We've underestimated the value of science education in this country, how a virus is transmitted, how you can carry a virus but maybe not manifest disease, how these vaccines work and why there aren't sort of manipulating your genetics, so to speak. These concepts are really difficult when you're trying to convey them to a population where we have not invested the appropriate amount of resources in science education.

Danny:
Welcome to Healthy Conversations. Today we're lucky to be in healthy conversation with Dr. Patrick Hines. He's an associate professor of pediatric critical care medicine at Wayne State School of Medicine and the founder and CEO of Functional Fluidics, and I'm lucky to be a friend and colleague of Patrick as we're both part of the inaugural class of the Aspen Institute Health Innovations Fellowship. So great to see you, Patrick. Thanks for joining us.

Dr. Patrick Hines:
It's a pleasure to be able to hang out with you and talk about some really cool stuff, so, glad to be here.

Danny:
You're like what I think of one of those sort of multi-threats. You're an amazing clinician in the ICU. You've been in the trenches during covid. You're been a bench stop researcher now you're actually an entrepreneur helping take some of the technologies you've developed to address some of the challenges in the red blood cell space, the sickle cell space particularly. Maybe just tell us a little bit about your journey.

Dr. Patrick Hines:
Growing up, I didn't know much about science or research, certainly not innovation. I did my undergraduate degree in chemistry at Hampton University and I knew I wanted to apply my science background to some area of medicine. I wasn't sure what, but I caught the research bug at the same time, so I decided to do an MD PhD at the University of North Carolina Chapel Hill and it was there through my PhD training with Leslie Parise, we began to think about red blood cells, much like her lab thought about platelets, as these cells that didn't have a nucleus but did a lot of really cool things and responded to a lot of signals that the body created, particularly in response to stress. We found some really cool applications of sickle cell disease and I thought I was going to be a pediatric hematologist until I realized that outpatient medicine wasn't quite my thing, but I really loved the ICU and so I became a pediatric cardiac critical care physician in terms of my clinical role.
I never lost my passion for sickle cell disease throughout this though. I would continue to see individuals with sickle cell disease in the ICU with really bad complications. During that time we also began to have a lot more activity in the therapeutic space where drug companies were developing therapeutics that modified the health, the red blood cells as a strategy for keeping people with sickle cell disease healthier. That's when I founded Functional Fluidics as a professor of pediatric critical care at Wayne State University. That's a little bit about how I got to where I am right now.
We tend to think about sickle cell as a disease where you realize people are sick when they come into the emergency department because they have something called a pain crisis, which is caused by a red blood cell mediated blockage of blood flow in the small blood vessels. Those blood vessels can lead to the bone and that can cause significant amount of bone pain, it can be in the brain where it can lead to strokes, in the lungs where it can lead to acute chest.
The big one-on-one that I would give with sickle cell disease, however, is waiting for someone to have a pain crisis or a stroke is like waiting for someone to have a myocardial infarction or a heart attack before we intervene to try to prevent those things from happening. That's really been the standard by which we've cared for individuals with sickle cell disease for decades. We've really been committed to how can we leverage biomarkers to understand when red blood cells are starting to function abnormally and intervene in that point.

Danny:
That gives an opportunity also to measure what could be a therapy before it fails or-

Dr. Patrick Hines:
Exactly.

Danny:
... how to optimize this dosing, whether that's hydroxyurea or some of the new monoclonal antibodies.

Dr. Patrick Hines:
Yeah, and you've now really touched on one of the reasons why we jumped into this field to begin with. People were developing these drugs that were supposed to help people with sickle cell disease and prevent problems, but they were using pain as an endpoint, so we were waiting until the patient had pain to say that something was wrong and looking for the absence of pain to say that we were actually improving their situation, as opposed to looking at a marker that was much more upstream of that. The whole idea is let's intentionally measure aspects of red blood cell health and make that an endpoint, but to do that we've got to provide a reliable, scalable tool that's broadly accessible and we've got to have a standard for measuring that.

Danny:
Yeah, I'm thinking of an analogy might be measuring the TIMI flow in someone's coronary arteries instead of waiting for them to have a heart attack.

Dr. Patrick Hines:
Exactly.

Danny:
Give us a little of a visual picture of the technology developed, maybe how you invented it and what does it do to actually measure what happens in terms of the physiology of a red cell?

Dr. Patrick Hines:
Sure, sure. A normal healthy red blood cell should not do much at all besides delivering oxygen and removing carbon dioxide from working tissues and cells in the body and it should flow easily, get back to the lungs, pick up more oxygen, and do the whole thing all over again. Well, one of the properties of red blood cells that are sick are that the membranes become abnormal. One of those things that it can do is become sticky. It can actually stick to components of the blood vessel wall and that can contribute to the slowing of the transit of red blood cells from the body back to the lungs.
In addition to that, it can completely block the flow of blood and that can stop the flow of oxygen to working cells and organs that need it. We specifically have designed tests that are able to measure at what level does a patient become in danger of having one of these problems develop based on the stickiness properties of their red blood cells? Normal red blood cells survive in a circulation about 90 to 120 days, but in patients with sickle cell disease, they can survive as short of a time as two weeks, which means there's a lot of turnover. The bone marrow's working really hard and these byproducts that happen such as hemoglobin are very toxic to the body. They cause inflammation, they can cause clotting as well, and so we are able to measure the likelihood that a red blood cell will be stable and survive, but we measure this in intact red blood cells.
When I'm in the ICU and I have a patient that has a problem with red blood cell stability because they're on dialysis or because they're on a bypass circuit or a heart lung bypass or ECMO, we don't know that there's red blood cell problems until those red blood cells have been destroyed. Well, with this test, we can measure the stability of the intact red blood cell non-invasively at a point where they can actually intervene.

Danny:
And this requires a drop or two of blood or can this be done with other sensors?

Dr. Patrick Hines:
We do this in standard sodium citrate tubes. It doesn't require a lot of blood, 30 to 50 microliters for the stickiness or the adhesion assays, and about a half a CC or 500 microliters in the case of mechanical fragility.

Danny:
Are there differences about where you sample in terms of measuring red cell fragility?

Dr. Patrick Hines:
That's a great question and we have noticed differences if you measure these from arterial lines or if you measure them from finger pokes because there's a lot of collagen and things that the blood gets exposed to before you actually collect it in the tube. Right now all of the tests are standardized to be measured via venipuncture.

Danny:
So is this sort of in its use today or into the future, something limited to sort of an ER and ICU or ...

Dr. Patrick Hines:
Right now we do have a pilot program where we are making the test available to select medical centers across the US. Generally they're patients who are in steady state, they're coming into clinic two to four times a year just to assess how they're doing. That patient's either in a lower high risk strata for having a pain event. For folks that they're interested in starting therapy on, they'll get these tests before they initiate therapy as an immediate baseline of red blood cell health.

Danny:
This technology can really partner with big pharma or small pharma developing new molecules or approaches to sort of see how you're doing, again proactively, and get us to this idea of precision, personalized, proactive sickle cell management or other red cell diseases.

Dr. Patrick Hines:
That's exactly what we're hoping for and so we're looking at applications in various aspects of cardiovascular disease, in the context of diabetes where we know high blood sugar levels can glycosylate red blood cells, which can make them stickier. We've looked at some interesting data in the context of post-COVID patients where we see these patients having issues with fatigue and shortness of breath, and we've demonstrated that in a subset of these patients, they have elevated stickiness levels that we think can contribute to inadequate oxygen delivery, which we believe can contribute to some of these symptoms, and we're partnering with some of our pharma partners to determine whether we can use these tests and potentially direct the right therapy to those individuals with these abnormal properties.

Danny:
Really exciting. Can you catch us up on what's the state of the art on managing sickle cell patients both proactively and then in the maybe acute crisis setting?

Dr. Patrick Hines:
In terms of proactive approaches, the area where I think we've been the most successful in sickle cell disease is in the context of stroke, where we have a predictive surrogate endpoint, which is transcranial doppler, and that's measuring the velocity of blood flow in the brain and individual sickle cell disease because we know that as that velocity increases, that directly correlates to cerebral vascular narrowing, which can happen in individuals with sickle cell disease. The issue there is that you're talking about having to develop vasculopathy that's detectable by an ultrasound measurement before you intervene, and so with blood-based biomarkers, we think we have the opportunity to intervene much earlier before the patients develop something as severe as vasculopathy that's measured on a transcranial doppler. Particularly in kids, the therapies that are currently FDA approved and are in the pipeline are really exciting.
One of the areas our monoclonal antibodies against P-selectin and P-selectin is expressed on platelets and white blood cells and it mediates an adhesive interaction between some of the inflammatory cells with the vascular wall. This FDA-approved version called Adakveo, which is produced by Novartis, disrupts this interaction and is given as a monthly infusion and is found to be particularly effective at reducing the frequency of pain events in individuals with sickle cell disease.
Another really exciting drug target is hemoglobin modification. We all know from early medical school days that one of the ways that problems are initiated in sickle cell patients is that the hemoglobin inside of the red blood cell sticks together, forms these chains when it polymerizes, and that damage the red blood cell over time. With something like Oxbryta, which is a hemoglobin modifying drug produced by Global Blood Therapeutics, by increasing that oxygen and affinity for hemoglobin, you prevent that polymerization from happening from the very beginning, which should ultimately keep patients healthier.
The third drug that's approved by the FDA is something called in Endari, and that's an L-glutamine analog, and what that's believed to do is to reduce the oxidative stress inside of the red blood cell. There's a lot of other ones that are in the pipeline. Having other options is really important. Even patients on hydroxyurea have been shown to have other complications in sickle cell disease, and so having multiple ways to attack the problem are going to be critical.

Danny:
It's exciting to have a lot more sort of bullets in our armamentarium. Everyone's now aware of some of the exciting early studies, essentially curing sickle cell with a variety gene therapy approaches. What's your take on that and what might be the barriers to adoption or what might accelerate it?

Dr. Patrick Hines:
Obviously, there have been folks that have been doing work with bone marrow transplantation, stem cell transplantation in sickle cell disease for many years, but they're obviously the problems that you see with stem cell transplantation in patients and finding appropriate matched donors for these patients. Looking at technology like CRISPR and gene editing have been really exciting in the context of sickle cell disease. Those therapies are in the research phase still, but I think they have a lot of promise, particularly in higher resource settings, for offering an option to actually cure the disease and not just treat chronically over time.

Danny:
You're relatively unique, super active as a clinician in the ICU, also develop benchtop tools and solutions and diagnostics. Tell us a bit about your challenges and the pathway to now take this from an idea that worked in the bench and really commercialize it.

Dr. Patrick Hines:
The road can be long and with a lot of twists and turns, and so as you know, Danny, you've seen a lot of technologies from conception to application. One of the sort of fundamental challenges is just getting people to sort of change their mindset about what's possible. As physicians, we're very comfortable with our practice and comfortable with our approach to managing patients, and many of these sort of new innovative approaches require a very different way of thinking. They're barriers in terms of trying to get funding for this type of work, particularly in a rare disease population that has been traditionally underserved. Sickle cell disease affects, in United States, primarily African Americans and folks from sub-Saharan African descent or from areas in which malaria is endemic. It's a huge problem in the developing world and as a result of that, historically, even though it was the first single gene disorder to be diagnosed in terms of its molecular underpinnings in 1949 by Linus Pauling, it was one of the last to receive a lot of the funding and advancements that have led to what we appreciate now is a significant upsurge in the availability of therapeutic options and curative options for these patients. These things have been available with other similar genetic diseases for decades before they became available in sickle cell disease.
Just getting people, when you're trying to do this on an innovation level, to fund this type of work is a challenge, but one thing I've learned through the process is that there are a lot of investors that really believe in trying to do well by doing good, and ultimately the investments that we make here are going to help in many other areas as well.

Danny:
Maybe tell me a bit more of your personal arc about what it's like to start a company, get it funded, get it through trials, get pharma partners.

Dr. Patrick Hines:
The first thing I would say is you have to be comfortable with being uncomfortable. You have to be comfortable stepping out of the comfort zone in which you practice because by definition, if you're innovating in medicine, you're identifying something that we do that you strongly believe that we can do better and that we should do a better job at. That's going to require you to stand out, so to speak, and to not accept the status quo and the solutions that are available, but to really try to stretch and think creatively and outside of the box.
For me, I really felt that at the time when we were transitioning from this being a lab-based, exclusively research-based tool into something that could have applications in the clinical world, the perspective that I brought to the table was really important to convince people, particularly investors, across a number of different types of stakeholders, but there was a lot of things I didn't know that I had to learn, and you need to surround yourself with some really smart people that can teach you things that you don't know.

Danny:
What are some of the challenges you've seen particularly related to, let's say, your work in the ICU and sickle cell disease that our listeners should sort of be aware of and how might we start to address those challenges?

Dr. Patrick Hines:
Particularly when I talk to trainees, when folks sort of rotate through the wards, emergency medicine residents and surgical residents and a lot of folks from different disciplines also to converging in ICU, when you hear them talk about sickle cell patients, there's a lot of assumptions that people make. You hear, "They're coming in with pain again, and should we even believe that they're in pain? Are they just drug seeking?" A lot of these beliefs that were really prominent years and years ago, we see them propagated even till today. Understanding how to treat people from economically disadvantaged backgrounds, how to think about unconscious bias that we bring to make sure that they aren't negatively influencing the care that we provide or that we don't provide for these patients. I think that's absolutely one of the reasons why it's been acceptable to see these patients having this excruciating pain as an endpoint. Having the tools to help these patients stay healthy and to treat them when they're ill is definitely going to make a difference, but I think it's going to take more than that. It's going to take a culture change, a mindset change, in how we deal with this population, and a lot of great work is happening to reverse that.

Danny:
Not to get too political, but you live in a pretty purple state, lots of divisions. There's definitely an infodemic at play and still the pandemic of the unvaccinated. Any learnings on how to better communicate and bridge that divide, whether it's political, educational, anti-science, pro-science?

Dr. Patrick Hines:
Danny, we could be here all day talking about this one. This is such an enormous issue. Our ability as scientists, healthcare providers, to communicate and relate to patients, to gain the trust of the broader community, I think is something that many of us as providers and people in science have taken for granted, and I think COVID has put into stark focus how that is an extremely dangerous attitude to take because ultimately we're only as good as the public trusts us to be because they have to adopt the things that we try to apply to improve their health. If we have over generations created a culture of mistrust, particularly in communities of color and communities that have been historically mistreated by institutional medicine, these are things that are extremely important. We've underestimated the value of science education in this country, how a virus is transmitted, how you can carry a virus, but maybe not manifest disease, how these vaccines work and why they aren't sort of manipulating your genetics, so to speak. These concepts are really difficult when you're trying to convey them to a population where we have not invested the appropriate amount of resources in science education. I think those are huge opportunities that I hope coming out of this pandemic we don't miss this opportunity to improve upon.

Danny:
Amen to that.

Dr. Patrick Hines:
Daniel, you, as always, do a great job at starting the conversation and asking the right questions.

Danny:
Well, my friend, Dr. Patrick Hines, thank you so much for joining us on Healthy Conversations and godspeed on what you can do next with Functional Fluidics and beyond and all your work in health care. Thanks.

Dr. Patrick Hines:
I appreciate it. Thanks so much.