Futurism, Medicine, Neuroscience, Parkinson's, Science
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Interview with Biochemical Neuroscientist Prof. Hilal Lashuel (Part 1)

Dr. Hilal A. Lashuel received his B.Sc. degree in chemistry from the City University of New York in 1994 and completed his doctoral studies at Texas A&M University and the Scripps Research Institute in 2000. After obtaining his doctoral degree, he joined the Picower Institute for Medical Research in Long Island New York as a research. In 2001, he moved to Harvard Medical School and the Brigham and Women’s Hospital as a research fellow in the Center for Neurologic Diseases and was later promoted to an instructor in neurology at Harvard Medical School. In 2005 Dr. Lashuel moved Switzerland to join the Brain Mind Institute at the Swiss Federal Institute of Technology Lausanne (École polytechnique fédérale de Lausanne, EPFL) as a tenure-track assistant professor in neurosciences. Currently, Dr. Lashuel is an associate professor of life sciences and the director of the laboratory of molecular and chemical biology of neurodegeneration. (http://lashuel-lab.epfl.ch/). He also served as the executive director of Qatar Biomedical Research Institute from 2014-2016.

The following has been paraphrased from an interview with Prof. Hilal Lashuel on August 2nd, 2018.


 

Could you talk about your trip to meet Huntington’s disease patients and the impact it has had on your work? 

I had an experience last year that was truly an eye-opener for me and which really motivated me to move towards a more patient centered-approach to my science. It was an event called HDdennomore (Hidden no more) that was organized by two colleagues from the HD research community (Prof. Elena Cattaneo and Dr. Ignacio Munoz) along with other HD advocates and hosted by the Vatican. About 300 Huntington’s disease patients and their families attended the meeting where Pope Francis also spoke against the stigma associated with HD and called for more support for HD patients and their families. It was my first time really being in a room filled with HD patients. One observation that was really transformative for me was the heterogeneity of the disease. I looked around and couldn’t find two patients that exhibited the same set of symptoms.

One question really struck me coming out of that experience – how can we as researchers trying to understand this disease be so focused on one molecule, or a few molecular mechanisms, in a disease that is so heterogeneous? Researchers often talk of pathology as if it is one thing, but just looking at the real disease in people we see that it is very different from person to person. I also recently went to Colombia where I, along with a group of humanitarian HD scientists and physicians, organized a conference on HD (LAHD2018) where we spent a week together with HD patients and their families. These interactions with patients have transformed how I think about my research. I took to heart the lesson that we must truly embrace the complexity and heterogeneity of these diseases and engage with more patients if we are going to develop the right scientific foundation for developing effective therapies.

Unfortunately, the focus and investment in scientific research does not always address what is important to patients. We are so focused on finding a cure that we forget what the disease is all about. When setting research priorities, there needs to be some redistribution of efforts to allow for more research into helping people cope with the symptomatic aspects of these diseases while we work towards addressing the underlying causes. In the field we downplay the symptoms because they are not the cause of the disease, but for the patients, the symptoms are the disease. That is what they deal with every day.

We must also acknowledge that many of the current values, practices and incentives in academia represent major barriers to advancing the type of collaborative and team-based research that is necessary to make transformative discoveries and address these major health challenges. Open science, timely sharing of information and tools, along with healthy discussions and debates of competing ideas should be the norm, not the exception.

Patients and their families are the beneficiaries, and often the funders, of our research and they must be at the center of what we do. We need a more patient-centered, rather than publication and grants-centered, approach to advancing research and therapies for neurodegenerative diseases. The great majorities of the thousands of scientists working in neurodegenerative diseases have never even met patients and have never seen the human face of the diseases they work on. I didn’t until last year and deeply regret not doing so when I started working in this field.

 

What do you think researchers studying the basic biology of neurodegenerative diseases gain from interacting with people living with the disease?

Today, researchers rely on clinicians and pathologists to tell us how these diseases affect people, we are then left to our own devices to connect what they tell us with what we see in the lab. Adding to the problem is that we are preoccupied with reductionist approaches that take us away from the true complexity of these diseases.

When I came back from the HDdenomore event in the Vatican, I began to question what we know about the human pathology and whether our current understanding truly reflects what happens in the human brain. Could the clinical heterogeneity be explained by a pathological diversity that we are not able to capture?

It quickly became clear to me that we know very little about what is actually happening in the brains of people with these diseases and that there is an urgent need to revisit and reconsider our simplistic and reductionist view of the pathology of neurodegenerative diseases, which does not take into account the large biochemical, structural and morphological diversity of the pathology in different patients and in different regions of the brain.

For example, if you were to ask someone to define Lewy Bodies (a hallmark of Parkinson’s disease), nobody can tell you what they are, other than to say that they are rich in aggregated alpha-synuclein and a large number of other proteins. We don’t understand, at the basic level, the true biochemical and structural features of the pathologies that characterize these diseases, their mechanisms of formation and how they contribute to disease progression.  Despite the fact that it has been decades since the discovery of Lewy Bodies and awareness of their complexity, we are still using primitive tools to assess the pathology. Some neurodegenerative diseases are classified into different types just on the basis of using limited set of antibodies against 3-7 proteins.

In synuclein pathologies, the alpha-synuclein protein comes in many different shapes, but we don’t know if they are distinct entities or a continuum of the same thing, nor do we know what makes them change shape. These questions ultimately have significant implications in designing strategies to model the disease, and in our approaches to developing novel therapies and diagnostic tool.  Recent data from our group suggests that some of the most commonly used tools to monitor and quantify alpha-synuclein pathology only detect a subset of the alpha-synuclein aggregates due to the fact that these aggregates are subjected to post-translational modifications (for more on these PTMs seem part 2 of this interview) that occur after aggregate formation.

I ask myself, how can we succeed in developing cellular and animal models that reproduce the human pathology if we don’t even fully understand what we are trying to model.  This also leads us to judge animal models on the basis of a limited view of the human pathology.  Perhaps if we gain a deeper understanding of the human pathology, we would realize that the different models we have generated are not as bad as we thought. We might also discover that the different models reproduce different features or stages of the human pathology.

Over the past two years, our group has been working actively to develop a comprehensive set of tools and standard reagents that would enable us to capture all the different normal and pathological forms of alpha-synuclein.  We are currently working with neuropathologists in the US, UK and Sweden to validate these tools in human tissues as a first step towards launching an international collaboration focused on redefining alpha-synuclein pathology and how it spreads in the brain at the biochemical and structural levels.

 

What do you think it would take to get the field to adopt a patient-centered approach to research?

It begins with the realization that the patients are not just a source of data. They are the Real Experts. If we want to truly understand and find cures to treat these devastating diseases, we must start by taking the time to meet and learn about the disease from the REAL experts, the patients & their families.

When science and research funding are under threat, scientists are encouraged and called on to be more proactive in engaging the public to communicate the importance and impact of their work. This is viewed as important to ensuring sustainable support and funding for research.  We see the public and patients in this case solely as the funders of research and forget that they are the Real Experts and have much more to offer to our research than giving their data, samples or simply participating in clinical trials.

I personally believe that more effective interactions and collaborations between scientists and clinicians with patients and their families is crucial to understanding the complexity of neurodegenerative diseases and accelerating the translation of research from bench to clinic to novel therapies. My experience has been that such interactions inform and inspire new research directions and priorities that are aligned with patient’s needs. This has led my lab to draft our own manifesto of open and collaborative science.

But in getting to real patient-centered research we will need these interactions to be a two-way street. There are a lot of problems with academic research that too often lead to science being done for scientists rather than for society and patients. There I see a role for patient advocacy in changing the incentive structure that drives science and innovation. The way it is set up now, the currency of researchers is secrecy, and in some cases monopoly of data and tools. For example, if I find a promising new target for Alzheimer’s disease, which could be a new enzyme that is involved in the processing of APP (precursor to beta amyloid), I could publish my findings today in an open access journal, or I could wait three years to do all validation in complex animal models along with all the other work needed to get it into “a high-impact journal”. If you ask people in the field which approach they would recommend, the great majority would say the latter because, unfortunately, that is what will get you tenure, promotion or grants. In an academic setting, it is very easy to defend such an answer, but if one is asked the same question in front of tax payers and patients, none of us would be able to defend this reasoning.

Most of my colleagues would agree that there is a need to reflect and reassess how we define success and evaluate research in academia today, but there is no sense of urgency to have an open and honest debate about these issues. I believe that the patients and patient advocacy group could help catalyze this process and inspire changes that encourage patient-centered research approaches in academia.  By no means does this suggests that we put more emphasis and focus on applied research. The opposite is true, we need to invest more in basic research, but we need to do so while ensuring that our practices and policies encourage the rapid dissemination of the knowledge and tools generated and their application to developing novel treatments and cures.

As Lord Porter, former president of the Royal Society once said “There are two kinds of research—applied research and not-yet-applied research.”

 

These systemic problems often seem insurmountable, any advice as to how to actually push forward with these changes?

I think we need to create a platform where we can bring these issues up and ask – do the incentive structures we have today promote innovation and solutions to society’s problems or not? But we shouldn’t criticize, we need to do this in a positive and constructive way. These discussions should take place in every institution and with active engagement from the next generation of scientists, e.g.,  current PhD students and post-docs.

We can start by stressing the importance of sharing information and tools and encouraging and rewarding individuals that practice openscience and contribute to advancing reproducible science. People don’t want to share because they don’t want to let others know what they are doing. They are forced to do this, because of the increasing competition to secure funding. It would be a big step forward if the funding agencies and foundations would just demanded that once a grant is completed all the data and tools from that grant must be made available to everyone and deposited in central repositories such as Addgene.  If we would only share what we can today without “compromising their competitive positioning” that would be great as a starting point. This would also reduce the time wasted in reinventing the wheel and inspire scientists from other disciplines to join our quest to find cures for these diseases.

Also, the presence of patients at all of the meetings and conferences would change the dynamics of the conversations there. Academics just talk with each other about papers and grants, but when we bring patients into the mix it forces people to answer why what they are working on matters and why how we do it also matters. Their presence could also sensitize the scientific community to why there is a sense of urgency to advance science and find cures for these devastating diseases and help them realize the impact of certain practices that stifle progress on people’s lives and well being. I now always tell myself, if I can’t defend my actions in front of tax payers and patients then something is wrong. That is my litmus test.

As researchers, we are lucky that society has blind trust in us, there is no accountability, apart from showing our publications. All scientists have good intentions and have committed to this profession for the right reasons, but we get trapped into this wheel that creates science for scientists rather than science for society.  Yes, the solutions to many of the challenges I mentioned are not easy, but we must start to discuss and debate the different options, for the sake of our profession and for the sake of society.

 

What do you think can be done to improve how we educate and train new scientists?

First, we need more interactions with patients and their families, not as people we are trying to serve, but as equal partners in our journey and search for cures. If it was up to me, I would not grant any degree to a student working in a human disease if they had not interacted with individuals that are affected by the diseases they work on. Perhaps structured interactions under the supervision of clinicians could be integrated into the curriculum and training of our students. Indeed, we are starting to work on a program for PhD students where they would spend a period of 2-3 weeks working with patient advocacy/support groups in South America, as volunteers. As part of this experience, they will also spend a few days in the clinic-observing physicians while they care for HD patient groups. Myself, I have made arrangements to spend at least two days a year in the clinic with physicians who see HD and PD patients in Germany and Italy.

Second, changing the value system. Redefining success and changing the criteria for hiring and promoting based on one’s contributions and impact to both advancing and translating their science for the benefit of society.  If the incentive is not there, why would people do it? I believe that if we had more patient-research interactions it would force scientists and the leaders of academic and research organizations to rethink how we incentivize research in diseases, and the problems surrounding them, on a more human level and influence more of us to act in the best interest of society.

Third, realizing that transformative discoveries will only come through interdisciplinary and collaborative team-based research. For us to realize the full potential of such collaborations, we need to develop new mechanisms that not only encourage, but also recognize and reward team-based research. We have succeeded in the first, but not the latter two.  Although we encourage scientists to work together, when it comes to evaluating their contributions or success, they are still being evaluated on the basis of their individual contributions and successes. This pushes scientists to retreat and gives rise to collaborations that lead to incremental rather than transformative discoveries.

Finally, we need new models of collaborations between academia and industry where we can leverage and combine the strengths, expertise and resources of both side to accelerate the path to cures and treatments that improve day-to-day life of patients. At the end of the day, translational research done just in companies and academic institutions do not have the expertise and resources to push molecules to the clinic. Therefore, collaboration with industry is a win-win situation and must start early. The industry also has a wealth of know-how and research reagents and tools that end up in locked storage facilities without anyone using them. Such tools and reagents are desperately needed to advance basic and translational research in academia.  We need to reach out more to the industry and develop new models of open and collaborative science at the individual and institutional levels.

I always tell students in my lab, when you die you are not going to take your CV with you. Scientists work extremely hard, our success comes at the price of our health and our families. At the end, one needs to pause and ask, why am I doing this? The answer for me is to have an impact on society beyond my own lifetime.  We are able to enjoy life today because others made sacrifices for us and we need to do the same for the sake of our children and the next generations.

The second part again comes back to the patients. 65% of my lab funding comes from patients-funded organizations. These people trust me with resources and I need to show they are used responsibly and are directed towards advancing the science while accelerating the path to better diagnostics and treatments. The challenge is that a lot of work that needs to be done to advance translational research does not lead to publications or immediate returns. Only a few groups are privileged enough to be able to engage in such work. Our situation in Switzerland, along with the generous support we get from the EPFL and the Swiss people, gives us this privilege and this is why we feel obligated to get involved and contribute to such efforts.

 

 

Click here to read part 2 of my interview with Prof. Hilal Lashuel on the Need to Embrace Complexity and Revisit the Pathology of Neurodegenerative Diseases

2 Comments

  1. gavinmogan says

    I have a new favorite neuroscientist! Actually never thought I could have a favorite neuroscientist. But Dr. Lashuel is one of new favorite people, period! Kudos on your compassion, perspective, and courage! I hope your message gets the attention it richly deserves. Great piece, Benjamin. All are valuable, but really struck gold here.

    Like

  2. Pingback: Tomorrow Edition - Interview with Biochemical Neuroscientist Prof. Hilal Lashuel (Part 2)

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