Bradlee Heckmann: "The pandemic has opened the medical comunity´s eyes to and ignored disease: chronic fatigue syndrome"

Bradlee L. Heckmann is an American biologist and neuroimmunologist who works at the Byrd Alzheimer’s Center and the University of South Florida’s Health Neuroscience Institute (USF), he is also Assistant Professor of molecular medicine at Morsani College of Medicine (USF). Dr. Bradlee Heckmann’s current research focuses on modulating neuroinflammation as therapeutic targeting to treat neurodegenerative diseases, including Alzheimer’s and the role of the machinery of autophagy in this context. In addition to his academic positions, Heckmann is co-founder and CSO of Asha Therapeutics, a biotech pharmaceutical company, based in Tampa (Florida) that explores novel therapies for neurodegeneration and neuro-oncology for a variety of diseases including Parkinson’s, Alzheimer’s and myalgic encephalomyelitis/chronic fatigue syndrome/long COVID.

What is the current state of neuroimmunology?

What my laboratory is interested in, and we are fascinated by, is the functioning of the neuroimmune system. In reality, in terms of human diseases, we know that inflammation may be beneficial: it protects our body against the invasion of pathogens, infections. It is even possible that the central nervous system (CNS) defends us from things like amyloid protein plaques in Alzheimer’s disease, against ischaemia and a stroke.

But my laboratory is really interested in broadening knowledge about how this process is mechanistically controlled. The last ten years have seen the interest in neuroimmunology begin to bear fruits in science and medicine, and it has brought us round us to thinking that immunity in the brain and functioning of the immune system are regulated by a cell called microglia.

But now, with the work of a series of researchers, we are learning that the brain’s immune system is not what we used to think, and it is not so separate from the rest of the body as we believed. We have seen that there is a great deal of interaction between the peripheral immune system and our central nervous system, which implies a real change in our understanding of how we see regulation of immune responses in the brain.

Our laboratory, and of course many others worldwide, are really interested in understanding the details of how immunity is regulated in different scenarios, different stages of disease and in normal physiology, in the hope of being able to design future therapeutic approaches for diseases ranging from neurodegeneration to others like a stroke.

And also, Alzheimer’s?

Our laboratory has the resources necessary to study a variety of pathologies or disease models and to be at the pinnacle where basic science and research meet, thanks to being part of the USF Neuroscience Institute.

Alzheimer’s disease has been our daily bread. Collaborating with other groups, we have identified and characterised an LC3-associated endocytosis pathway.

As well as Alzheimer’s, more recently we have been working in other areas, like the functional context of strokes, and on the resolution of bacterial and viral infections.

And, forced to some extent by the pandemic, we have begun to research the mechanisms connected with COVID, particularly long COVID or persistent COVID, and how they affect the brain.

Over 70% of patients infected by SARS-CoV-2 who lived through the disease experience prolonged symptoms or have had a sporadic reappearance of symptoms over the last months or years. In many cases, this has become what is known as long COVID, whose symptoms range from continuous muscle pain, brain fog, difficulties in logical function and, of course, fatigue. We want to know why this is happening, and what mechanisms are involved if, in the majority of cases, no infection exists.

We are learning that the brain’s immune system is not what we once thought it was, it is not so separated from the rest of the body as we thought. We have seen that there is a great deal of interaction between the peripheral immune system and our central nervous system, which implies a real change in our understanding of how we see the regulation of immune responses in the brain

Talking of Alzheimer’s, do you think it will be possible to have preventive vaccines to avoid the progression of the disease, particularly for the people most at risk?

I think there are two answers to that question The first is with regard to genetic risk. We know that APO E4 is the most predominant risk factor for what we typically refer to as sporadic Alzheimer, which arises in later stages of life. Over 80% of patients with Alzheimer’s disease suffer sporadic Alzheimer’s.

In this sense, the advent of gene-editing technologies like CRISPR CAS 9 and other similar technologies, as they develop and begin to tackle the ethical questions related to gene modulation, make it quite likely that in the next 10 to 20 years there could be a viable approach to repairing genetic deficiencies or single nucleotide polymorphisms, mutations that increase the risk factors, not only in APO E4 but also in genes that are related to this disease.

Holistically, I consider that in the next 10 to 20 years we will find an approach to tackle the disease before it appears.

Another aspect of this question is the fact that there are so many variables, especially in the neuropathology of Alzheimer’s disease and its pathogenesis, it is difficult to know if we need to selectively target these mutations; for instance, will it really diminish the risk? Because 50% of the people with amyloid plaques never develop the disease.

But many other factors are involved in Alzheimer’s, as well as amyloid beta deposition or other aspects like phosphorylation or neurofibrillary tangles. The truth is that there has been a long debate within the Alzheimer community about the amyloid hypothesis as the cause of the disease. For instance, the tau protein hypothesis states that amyloids are irrelevant and that they only trigger the process, whereas tau is what really generates the disease.

In my opinion, the solution would be to combine the two hypotheses and probably add new ones, because there are many aspects involved.

One of the reasons why so much attention has finally been paid to this subject in recent years is the approval of drugs produced by large pharmaceutical companies like Biogen; however, their effectiveness and success have been very limited. In principle, it was a great idea, but what we can see now is that even if you administer these drugs to a patient, they have limited effectiveness.

Because we are a neuroimmunology laboratory, we focus on inflammation. We have shown, in very early pre-clinical models, that if we target specific inflammatory mediators and if we block the complex that produces certain cytokines that are responsible for inflammation, such as interleukin 1 beta, we can significantly limit the pathogenesis of the disease in mouse models.

This suggests, and is what we believe, that there is a bridge between amyloid pathology, tau pathology and neurodegeneration, and that inflammation is a central element in this mechanical process.

So, we believe that, if we are capable of treating something like neuroinflammation, this could translate into to a very effective approach to treating diseases, not just Alzheimer’s, but others where the same cytokines are active, like Parkinson’s and ALS, or even strokes and other diseases.

Our idea is that there could almost be a unified treatment plan that would, in essence, strike against each of these diseases using neuroinflammation, which would give effectiveness.

Do you think we might see a future revolution in neuroimmunology like the one we have seen in cancer with immunotherapy?

That is exactly the idea. I think that the advent of blocking checkpoints for the treatment of cancer has meant a particularly beneficial development for people who would have died of the disease and are now surviving; that is absolutely incredible.

The idea would be for us to see the same revolution in the field of neurology over the next 20 years, not only for Alzheimer’s disease but, we hope, for many other things.

If we are capable of treating something like neuroinflammation, this could translate into to a very effective approach to treating diseases, not just Alzheimer’s, but others where the same cytokines are active, like Parkinson’s and ALS, or even strokes and other diseases

You mentioned that you are interested in how SARS-CoV-2 affects the brain…

SARS-CoV-2 is without a doubt, one of the great areas of research we have come across, particularly for us as neuroimmunologists. At the start of the pandemic, we researched what was happening in post-mortem samples of brain tissue from patients who had died of COVID. And one of the most singular things we started to see at the onset of the pandemic was that not all people had a measurable amount of the virus in their brain, whereas in other cases they did.

We had many questions: Is this only because we are analysing these levels in people who have, unfortunately, died of the disease? What amount of virus really reaches the brain? What mechanisms govern this process?

One of the aspects that really interests us about SARS-CoV-2 and why it is so special, is that there is a condition called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that has basically been ignored by the medical and scientific community for years due to the fact that from a clinical perspective it was practically impossible to diagnose.

All of the patients who complain of chronic fatigue, headache, brain fog, etc, these are symptoms that are very similar to long COVID.

They said: “I was sick, I got better, a few months later I started to feel awful again and again,” and the process perpetuated.

Many of them have lived through medical torment: blood tests, CT scans of the brain, MRIs etc., and the results show nothing bad in their brains, but the patients continue to be sick, and the doctors end up diagnosing a mental health problem. For most physicians, these patients are, to all intents and purposes, crazy.

The curious thing is that while the pandemic has been devastating for many people, for them it has meant that the medical community has opened its eyes to a disease that they have been struggling with for the last eight years: chronic fatigue syndrome.

The similarities between ME/CFS and long COVID are so surprising that we are learning a lot, and we, like many other groups, are discovering that there are similarities between certain virus that are believed to cause these diseases, like the human herpes virus 6, in particular, and SARS-CoV-2.

We think that it is plausible that, studying chronic fatigue syndrome and the virus that are associated with the typical pathogenesis of CFS, we might find out a lot about coronavirus and vice versa.

How many people are there in the world with this syndrome?

Calculations for the UK alone are approximately 3 million people with this syndrome and another 3 or 4 million in the USA. These are very conservative figures, so it affects many more people, although they don’t even realise it.

It seems that the pandemic has been good for some people, has it for science?

During the first days of the pandemic, we didn’t really know what we were up against. I think it is the first time in our history that we have had an outbreak of a disease at that level.

There have been other outbreaks, like MERS or the original SARS outbreak, but they were limited to geographical regions, and there have even been outbreaks of Ebola in Africa, limited to geographical regions, whereas the USA and most of Europe were not affected by them.

But with COVID we are speaking of millions of people all over the world who were affected.

I think this has stimulated interest in science and demonstrated that if we face a scenario in which we have to do something immediately, academic science, business -obviously- or the pharmaceutical and biotech industries are capable of responding.

You only have to remember, for instance, that the flu vaccine took decades before it had advanced enough for use in clinical practice.

With COVID, everything went a lot faster, although it could be argued that in some cases, it went too fast.

Because, faced with a new virus that nobody knew anything about, many laboratories got to work on it, trying to find a vaccine or a therapy or simply trying to understand the basic biology of the virus. Obviously, there are going to be data that are not exact. And it should also be known that fake data has been a great problem recently in the scientific community.

At the same time, the pandemic has been detrimental for other areas of research, and much of this is due to the urgency of finding a solution to the world pandemic.

Maybe one of the most important aspects has been the fact of sharing scientific information in almost real time...

Yes, and I think that this is one of the most important things to have come out of the pandemic. The process of peer review that we normally undergo, which is very strict in most cases, implies a delay in the publication of articles, but with the hurry to publish data about the pandemic we had almost instant access to what were mostly very good articles, but also to others that were more than questionable in terms of scientific validity. But, in the end, the fact of publishing information quickly is something that is good for the scientific community.

Bradlee Heckmann presented the seminar “The good, the bad, the ugly: the diverse roles of Rubicon in the CNS,” at the invitation of M. Ángeles Moro.