Boğaziçi University’s Neurodegeneration Research Laboratory (NDAL) is representing Turkey in Project MinE, which has brought together teams from 16 causescountries aiming to discover the causes of ALS (Amyotrophic Lateral Sclerosis), a disease related to loss of motor neuron cells, and to develop effective treatments. Project MinE is the first, biggest, and most comprehensive research study on ALS conducted internationally, after the Human Genome Project initiated in the 1990s to identify and map human DNA. The project is expected to provide a revolutionary breakthrough in ALS research and determine the molecular causes of the disease.
The Neurodegeneration Research Laboratory (NDAL) was established at Boğaziçi University’s Department of Microbiology and Genetics with the objective of enhancing the neurosciences in Turkey and contributing to neurodegenerative disease biology. The lab is supported by the prestigious Suna and İnan Kıraç Foundation.
Celebrating the 10th anniversary of its establishment this year, NDAL is the only laboratory from Turkey participating in Project MinE. NDAL is located on the premises of Boğaziçi University and has several collaboration agreements with the University of Massachusetts, and Harvard, Yale and Brown Universities. Boğaziçi University aims to become the center of excellence in the Neurosciences.
We talked with Prof. Nazlı Başak, the director of NDAL, about Project MinE and other studies conducted within the framework of NDAL. Prof. Başak explained that Project MinE is an unprecedented, multinational research project established to investigate the causes of ALS.
What is a neurodegenerative disease? How do we define it?
Neurons are the nerve cells in the brain and spinal cord. Neurodegeneration is the progressive loss of the structure or functions of these nerve cells, i.e., neurons. Thus, neurodegenerative diseases are those that result from damage to the cells of the nervous system, such as Alzheimer’s, Parkinson’s, ALS, and ataxias. All of these diseases fall under the umbrella of neurodegenerative diseases because the fundamental mechanisms that lead to the degeneration of neurons are similar, and overlap to a great extent. Yet they are considered as separate diseases because each disease targets neurons in a different region of the brain. For example, in Alzheimer’s, neurons in the cerebral cortex and hippocampus are affected, whereas in Parkinson’s, it is the dopaminergic neurons in the substantia nigra region; in ALS, it is the upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord; and in ataxias, the Purkinje cells in the cerebellum. The cause of this authentic neuron death referred to as “selective vulnerability” remains unknown. Since the type of cell and the region of the brain affected are different in each disease, the impacts of each of these diseases on a person are also different. For example, in Alzheimer’s the degenerating neurons cause loss of memory and massive forgetfulness; in Parkinson’s they cause a movement disorder. In ALS, the loss of motor neurons that move the muscles leads to infirmity, spasticity, and ultimately total paralysis due to muscular atrophy, which negatively affects not only walking, but also speaking, swallowing, and breathing abilities.
Genes of approximately 22,500 individuals around the world are being studied
Project MinE is a large-scale international research project that aims to map the DNA profiles of at least 15,000 ALS patients worldwide, and to find the genetic causes of the disease. As Director of NDAL at Boğaziçi University, you are responsible for the Turkish leg of this project. First, can we talk about the stage the project is at today and the daily data that have been collected (on both the global and local levels)?
MinE is a giant, revolutionary, research project; it is a consortium of ALS laboratories in 16 countries.
Project MinE is the biggest and most ambitious project related to ALS today. Such large-scale genetic research into the origins of ALS is unprecedented; there is no project on other neurological diseases (including the more common Alzheimer’s and Parkinson’s) that even comes close to the scale of MinE; therefore, it is a first. The work is expected to become a breakthrough in ALS research and in understanding the molecular causes of the disease. That is the departure point of Project MinE.
The project was initiated by two young and enterprising ALS patients, in collaboration with the Utrecht Brain Research Center (Director: Prof. Leonard van den Berg) and the Dutch ALS Association, based on the idea that understanding all effective mechanisms of the disease is crucial is solving ALS. And this is not a job that can be dealt with by a single lab. Because of the number of samples, the sophisticated techniques, genome analyses, and bioinformatics assessments as well as the funding involved, such a giant project on ALS and biology cannot succeed without an international and very powerful consortium.
Let’s use a simple comparison. MinE involves the application of the Human Genome Project to 22,500 individuals: The Human Genome Project mapped the genome sequencing of one single individual with international effort in a 15-year period, at a cost of 3 billion USD. This first human genome map has changed biological paradigms and rendered biology the science of the 21st century. Project MinE is the application of human genome mapping to 22,500 individuals by using the large-scale, highly efficient, fully automated procedures referred to as “the golden standard” of the genome age and by effective giant data analyses in a period as short as 2 to 3 years.
The NDAL lab has established itself in the international ALS community not only with its wealth of samples, but also with its recent publications and its performances in ALS conferences. The name and strong support of the prestigious Kıraç Foundation has had a significant role as well. Being invited to the official inauguration of the project MinE in Amsterdam in September 2014 to represent Turkey, and being commended on the importance and necessity of our contribution to the project are indications of the prestigious position we have in the ALS world.
We have been preparing the bioinformatics infrastructure required for this project for nearly a year. For that purpose, we have added a new post-doctoral researcher to our staff this summer to work on bioinformatics. At the moment, three of our students (two graduate and one undergraduate) are being trained in the lab of Leonard van den Berg, the coordinator of Project MinE.
A total of 500 ALS samples from Turkey and a similar number of healthy control genomes will be studied within the context of this project. Genome analysis (wet lab), the first stage of the experiments, is quite costly. We will be able to meet a large part of the cost with the funding we have received and will continue to receive from the Kıraç Foundation. The second stage of the project is the assessment of the analysis results, which involves analyzing large amounts of data (“big data”) by bioinformatics procedures on the computer. Assuming that the genome of each individual comprises 200 gigabytes of data, a capacity of 100 terabytes will be needed for 500 people. And for that, we will need a substantial computer infrastructure, and several computer technicians and bioinformatics specialists.
Participating in Project MinE will bring even more respectability to NDAL and the results to be obtained from the lab’s wealth of samples will increase the lab’s visibility in the international ALS community. Our success in the project depends on the performance of our personnel and equipment infrastructure besides many other factors. To be competitive in such an ambitious project, the Kıraç Foundation added an extra budget to the funds allotted to the project in 2016-17; I would like to extend our heartfelt thanks for that here.
What are the unknowns that will be clarified when the genes causing ALS are discovered? How will the world of science benefit from this research?
We have realized in recent years that ALS is much more complex than we ever envisaged. The genes that are known to cause ALS are now more than 35. With every new gene that is identified, the phenotypes included in ALS increase and the clinical picture we refer to as ALS changes. Today, we know that every new gene and every mutation has its own authentic signature and to understand the mechanisms, it is imperative to define all of the genes responsible for ALS.
You have stated that the ALS genes that we know today explain nearly 60% of European societies. You have also said that we face more heterogeneity in Turkey and the fundamental ALS genes identified so far can barely define 45% of Turkish society. How do you interpret the data collected in Turkey? In terms of susceptibility to ALS, what are the differences between Turkey and Europe?
Obviously, Turkey is genetically much more heterogeneous than European societies because of its unique geographic location and its wealthy historical background. One factor that simplifies this heterogeneity in one sense is the frequency of consanguineous marriages in Turkey. On the other hand, children born in these consanguineous marriages carry a 25% risk of recessively transmitted diseases, which is a very high rate. The predisposition to ALS in Turkey is no different than in other societies; however, the recessively transmitted ALS that we observe in Turkey and Middle Eastern countries does not exist in Europe, and this is an important difference.
We know that there is no cure for ALS. In accordance with the information you have given, we know that over 400,000 individuals are suffering from ALS. In other words, every 90 minutes, one person is diagnosed with ALS. The life expectancy of an individual diagnosed with this progressively degenerative disease is only three years. Does Project MinE aim to reach more solid information towards the treatment of the disease? In this sense, what other targets does the project have besides ALS?
Although ALS is defined as an orphan disease and consequently is not found exciting enough by pharmaceutical companies, the risk of being diagnosed with the disease during one’s lifetime is 1/400, even for individuals with no ALS cases in their families. This is a rather high rate. Therefore, ALS is the third most frequently observed neurodegenerative disease after Alzheimer’s and Parkinson’s, and it is the most frequently encountered motor neuron disease. Certainly the most important and final objective is finding ways of treating this as yet incurable disease. Unfortunately, in these diseases which have only symptomatic treatment, neuronal death occurs so fast that treatments fall short and the disease progresses very quickly. The development of effective treatment methods is not possible without understanding the mechanisms of the disease. Until recently, neurological diseases that were believed to have had only one mechanism and thus only one cure proved to be more complex that we thought. The disease is caused by not one but several mechanisms, which means that there will not be only one type of treatment or one miracle drug. In defining the genes that cause the disease, Project MinE aims to define the different mechanisms that lead to the disease, with the ultimate goal of developing effective treatments.
Can you tell us about other ongoing studies at the Boğaziçi University NDAL lab? Are there studies that focus on all neurodegenerative diseases rather than on ALS alone?
Although neurodegenerative diseases have proved to be much more complex than we ever estimated, the cellular mechanisms that cause them overlap, and the degeneration and death of neurons stem from similar mechanisms. Therefore, we believe some traits are common to all of them, and that grouping and studying them under the same roof is correct. Particularly recent studies have shown that these diseases overlap at many points, not only clinically but on the molecular level as well. For example, a mutation observed in ALS causes fronto-temporal dementia, which brings these two diseases closer to each other. Similarly, it has been shown that SCA Type 2, one of our important topics of research, is the biggest risk factor for ALS. In other words, the borders between these diseases are losing their prominence on the molecular level. Among our research topics are ataxias as well as Parkinson’s, an important neurodegenerative movement disorder. Big families with many children where genetic transmission is very conspicuous have an important part in our achievements. For example, one of my students is writing his Ph.D. dissertation on the early indicators of Parkinson’s disease; biomarkers are of vital importance in early diagnoses of diseases which have no cure yet.
The only specialized lab in Turkey
Can we say that this is the first lab of its kind in Turkey that has been accepted by the international ALS community? Are there others in Turkey?
Without doubt, NDAL is the first, and in my opinion, the only lab in Turkey that has been accepted by the international ALS community. NDAL is a very well-equipped laboratory which has very strong international connections; it has hosted the highly prestigious biannual Suna Kıraç conferences, and thereby has proved its worth to high level labs. There is no other ALS lab in Turkey that can match this. Similarly, there are no other labs where such intense research on neurodegenerative diseases is being conducted, or that are equally specialized and have an equally strong infrastructure. I can safely say that we have been the authority on neurodegenerative diseases in Turkey for the last 10 years.
With its professionally designed infrastructure, dynamic and well-trained team, stimulating atmosphere, and rich and well-equipped scientific environment, NDAL has assumed the mission of obtaining patient samples and latest technologies through interdisciplinary and national-international collaboration. That is the only way mechanisms underlying neurodegenerative diseases can be globally investigated and long-awaited treatments can be developed.
You have a patient network of around 5000. How do you reach the patients whose genes are preserved in NDAL? How does the process work for each patient?
We have a DNA bank of 5000 patient samples and over 2000 healthy control samples. Patients reach us in a variety of ways. We reach most of our patients through the strong associations we have built across the country, and through clinics and hospitals, our longstanding collaborators. We have a good clinician network; specialized clinicians all across the country refer patients to us. Our comprehensive webpage is another important source of patients; some patients find us on the Internet or through our webpage. Associations such as the Turkish ALS Association or the Muscular Diseases Association also refer patients to us. I can safely say patients are pouring in.
“A laboratory is like a symphony orchestra; research is either a symphony or a concerto”
Could you introduce your lab team to us? At what point do students contribute to NDAL?
Our team is composed of undergraduate and graduate students, researchers with Ph.D. degrees, specialists, technicians, and lab administrators. While they all contribute to the work in different areas, their contributions complement each other. Each student is a part of the ongoing research; they carry out the experiments in the lab. The instructors plan the work to be done with them, supervise, coordinate, and verify their work. The people who personally do the experiment, those who receive the samples to be studied, those who process the samples, those who isolate the DNA in the samples, those who draw the family tree, those who gather and upload patient information, those who procure the needed equipment at the right time so that the work is not interrupted, those who make sure that the infrastructure necessary for the routine work cycle is functioning at all times, they are all equally important in the lab. The instructor is the one who coordinates the work; tries to find the needed funds; applies for projects; does whatever is necessary for the theses of the students to have a certain quality and are completed on time; establishes external relations; talks with patients, their families, and their clinicians; and tries to be a role model to the students not just to train them to become scientists, but to lead them to internalize academic values. Every person in the lab is a link in the chain. No one’s job is more or less important than another’s. Success comes when everyone works very hard and in harmony.
A laboratory is just like a symphony orchestra. There is a soloist, there are the first violins, members of the orchestra, different instruments, a conductor and a composer. The research gains meaning and succeeds with the harmony and coordination among them, with intensive team work – just like a classical music piece. Every stage of this process allows the lab worker to experience all kinds of positive and negative emotions. The dominating emotions are, without doubt, the great curiosity, dissatisfaction with the results, hard work and disappointments on the way to understanding and learning the unknown; and ultimately, the immense, the really extensive, pleasure upon reaching a solution. The presentation of the results in prestigious professional meetings and their publication in international journals is the crowning of the work. (*)
For information about NDAL: http://www.alsturkiye.org/
(*) Articles titled “NEK1 variants confer susceptibility to amyotrophic lateral sclerosis,” co-authored by Prof. Nazlı Başak; and “Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis,” by Prof. Nazlı Başak, Ceren Tunca and Hamid Hamzeiy from NDAL have been published as the first products of Project MinE in the 25 July 2016 issue of Nature Genetics, one of the most prestigious scientific journals.
Links to the articles:
(*) The name MinE is derived from “Data Mining Engineering,” and related to the slogan of the project: “Make it Yours”: MINE!
Interview: Süveyda Ece Çil and Duygu Durgun Köseoğlu, Office of Corporate Communications