Awad Lab: Predicting and preventing strokes and brain bleeds

Editor’s Note: This is part of a series called Inside the Lab, which gives audiences a first-hand look at the research laboratories at the University of Chicago and the scholars who are tackling some of the world’s most complex problems.

Strokes and genetic conditions that cause brain bleeds are among the leading causes of disability and death worldwide.

By the time University of Chicago neurosurgeon Issam Awad sees these patients, their brains have already been damaged. That’s why he has made it a mission to understand the causes and mechanisms behind this bleeding—to predict and avert these bleeds before they happen. 

Using specialized MRIs and tests that provide precise measurements of molecules in the blood, his lab has transformed our knowledge of these conditions.

He and his team can now use biomarkers in the blood to predict brain bleeds while also testing new therapies to both prevent and treat bleeding.

To learn more, we spoke to Awad, who is the John Harper Seeley Professor of Neurological Sciences and Neurological Surgery at UChicago, along with two graduate students who conduct research in his lab: Abhinav Srinath, an MD/Ph.D student, and Aditya Jhaveri, an MD student.

Why is studying brain bleeding important?

Awad: The brain has about 20 to 50 times more blood vessels in it than any other organ in the body. Hundreds of miles of blood vessels are coiled inside the human brain. It's the distance from Los Angeles to San Francisco. 

It is extremely rich with blood vessels because the brain is a supercomputer, and it needs a lot of energy. And that blood is extremely regulated. Blood vessels take blood to areas of the brain that are active, and they take it away from areas that are not active.

Bleeding causes damage to the brain, and it prevents blood from getting to the right area of the brain. It deprives areas of the brain from getting circulation, which can lead to brain cell damage or death.

Jhaveri: Brain bleeding can have devastating consequences for patients, leading to neurological deficits, long-term disability and even death. 

How does bleeding in the brain happen?

Awad: Strokes or bleeding in the brain happen because the blood vessels of the brain weaken over time, and then eventually break down and ooze into the brain.

There are some risks related to smoking and drug use, blood thinners and stents. Amphetamines like Adderall can cause you to bleed in the brain because they cause a rush of blood. Also, some sex hormones and bodybuilding hormones can increase your risk.

All of those can contribute to bleeding. But some people get it, and some people don't. We want to know who is predisposed. We want to be able to tell who is at much higher risk so we can monitor that risk.

Srinath: If we can understand some of the changes that happen prior to brain bleeds, we can help patients make lifestyle changes or take certain therapeutics that can help prevent brain bleeding from happening.

Aditya Jhaveri, MD student

How do you study new treatments for brain bleeds?

Awad: There is a huge opportunity to understand how this weakening in blood vessels occurs so we can stabilize it and ultimately prevent the bleeding.

We have many different procedures. We work with mice who have genes or variations that could make them bleed or protect them from bleeding. And we use scans of their brains to assess how much bleeding there is in the brain with various treatments. That allows us to understand what things help the bleeding and what things promote the bleeding.

We also scan the brains of human patients to see abnormalities or early hemorrhages, and whether this is more or less over time in association with treatments and with these blood tests.

How does your research help predict brain bleeds?

Awad: We also study molecular signals in the blood that show us a propensity to bleed. The blood has myriads of molecules, and these molecules include proteins, fragments of proteins, even fragments of our DNA and RNA and various genes of our body. 

We have some extremely precise tests to measure molecular levels and very advanced computing to find proteins that reflect the brain's reaction to bleeding. They could be inflammation. They could be the signals of a broken blood vessel. And they can also be signals of the genes that make us bleed. And we detect those signals, called biomarkers.

Abhinav Srinath, MD/PhD student

Srinath: Microbleeds—small bleeds in the brain—are caused by a mix of environmental and genetic factors. A patient with a microbleed has a 10 times higher risk of having a hemorrhagic stroke. If we understand the mechanisms behind how these bleeds happen, perhaps it could help us prevent that small bleed from turning into a stroke. 

I studied autopsy tissue to understand how the brain responds to bleeding, and studied potential gene changes that might have been the cause or a result of this bleeding. When we identify biomarkers, it helps patients. Rather than having invasive imaging, patients could get a blood test to determine whether they have had a microbleed.

Awad: We have also identified some signals that actually predict a bleed in the following year, so that you know that the blood vessel is weakening but hasn't yet gotten to the point of bleeding.

What about bleeding caused by genetic diseases?

Awad: There are also very rare diseases where you inherit the gene that actually makes you more prone to bleed, even at a young age. The study of these genetic diseases gives us a window into how these things form and bleed so that we can help the population at large.

My clinic has become a magnet for people who have these genetic conditions that most doctors don't even know about. And for those patients, we're able to give them very, very good answers because we understand what that gene does and doesn't do. For some people with rare bleeding conditions, we can make a big difference in their lives. We're identifying commonly used drugs that stabilize the blood vessel and prevent it from becoming brittle. 

How can your research be used to treat patients?

Awad: The very special part of the team that I've built over the years is the ability to go from very basic research all the way to the bedside and to treatments that are delivered to patients.

It comes down to blood tests for biomarkers. Eventually we can test an individual before they get on a blood thinner and tell them their risk for brain bleeding is two times the average person, or half the average person. It's individualized medicine.

The biggest thing we deal with is people who have had a little signal in their brain of some bleeding, whether it is a micro bleed or a tiny, abnormal blood vessel. It was found on MRI because they have a headache. They ask: “What's going to happen to me? Is this thing going to cause me to be paralyzed or dead in five years? Or can I forget about this?”

And this is where we really need to be able to tell one group of people that they are safe and another group that they are not. Those who are not, we can give them some medications that target these “switches” that make you bleed. We want to understand those switches and target them.

 Jhaveri: The goal is precision medicine that emphasizes non-invasive therapies and diagnostics that helps reduce risk wherever possible. 

Why is this work important to you?

Awad: In addition to being a researcher, I'm a regular neurosurgeon. I deal with families devastated by disease. I deal with people who are now having to go to rehab or be let go because their brain is so damaged. That is the tragedy. And so the other half of my life that is related to research is to try to understand why this happens and how we can alter it so that a person is much more likely to avoid that outcome.

 I think that's the privilege that we have if we're physician-scientists. To actually touch the patient's hand and get them through the illness and to try to explain what this whole thing is about and maybe try to prevent it or create a better way to deal with the problem.

Srinath: We can see the direct impact that the work we do in Dr. Awad’s lab has on patient care in the clinic. I always dreamt of going into neurology, even in high school, but seeing how this work impacts patients and could ultimately help prevent stroke is exciting.

Jhaveri: I left finance consulting and moved to medicine to have more impact. The work being done in Dr. Awad’s lab shows how rapid innovation in neurosurgery can directly translate to improved patient care. His career is inspiring; he’s a physician-scientist who has integrated research and clinical excellence in a way that I hope to emulate. If you’re working on a project and are putting in long hours, you can expect him to match you step for step.

How does the University of Chicago pave the way for this work?

Awad: I’ve worked at many institutions during my career, and many of the great institutions have opportunities for people to be physician-scientists. But what is quite unique here is we are small enough to be interconnected, yet extremely deep and strong in almost every area.

The micro-CT scan that I do on mouse brains is quite unique in the country, and it is actually housed in the neighboring Department of Organismal Biology and Anatomy. It's something that they study insect fossils with. I've adapted that scan to study bleeding in the brain. That couldn't be done anywhere other than the University of Chicago.

Jhaveri: It’s one of the reasons I came here as a student. I get to work closely with pathologists, geneticists, and immunologists, and they are all well established and driving innovation. 

Srinath: Science is at a state now where one person cannot contribute everything. You need collaboration, and the University of Chicago’s collaborative nature is essential to creating a new knowledge base that can have a real impact on patient care.