Have you ever wondered why with all the research going on, there are no treatments that completely eradicate the effects of Alzheimer’s disease and a treatment for Parkinson’s disease that is five decades old? This is part 2 of my attempt to answer this question. Today I will try to explain why no one before us discovered the signaling network in the brain that is involved in the control of motion and cognition.

The short answer is because of the types of experimental systems used to conduct research on neurodegenerative disorders.

THE INVISIBLE TRAP OF Xenopus OOCYTES & TUMOR CELL LINES

There is a standard path that most scientists follow when trying to understand a disease. They try to find a causative agent. This process resembles finding a needle in hay stack. For the neurodegenerative disorders, the search usually begins with a family or cluster of families affected by the same disorder generation after generation. Then the scientists comb through the genome of the affected family until they find a single gene or a group of genes responsible for the disease. Most often, even when a single gene is identified, only a small percentage of the people afflicted by the same disease carry the mutated (defective) gene. For example, a small percentage of Parkinson’s patients have a mutation in the LARK2 gene. After the gene had been identified, the scientists began the long process of characterization of the protein encoded by this gene and its function in the cell. This characterization, however, takes place in artificial experimental systems. Most frequently, the gene is introduced either in the eggs of an African frog (the scientific term is Xenopus laevis oocytes) or in rapidly dividing tumor cell lines. These artificial systems can rapidly produce large amounts of the new protein and can accelerate the pace of research. This protein, however, is not incorporated in the correct context of the cell content because the frog eggs and tumor cell lines are wired for functions different from the functions of the cells in the brain and in the heart.     

When we first discovered the signaling network in the heart, we attempted to reproduce it in tumor cell lines and in Xenopus oocytes by introducing the gene that encodes for a major component of the network. Even when the critical component of the network was overproduced in the foreign cell environments, the signaling network did not form. The individual components were present - these components, however, did not assemble into signaling network. The take-home message is that no scientific effort can discover something that is fundamentally lacking in the artificial experimental systems routinely used to study neurodegenerative disorders.   
THE RESPONSE OF A NETWORK IS MORE THAN THE SUM OF THE INDIVIDUAL RESPONSES.

Different cell types in the human body use the same building blocks to achieve very different functional outcomes. Yet, scientists most frequently focus on a single building block and ignore its connection to the cell environment.  For this reason, every year, hundreds of scientific papers are published promising the next breakthrough in treatment of different conditions only to fail the test of clinical trials.  In a recent interview, M. J. Fox elaborated that his foundation has funded research on more than a hundred different targets but new treatments have been notoriously difficult to discover. What everyone was overlooking was that anytime a signaling element is taken out of its normal environment, the properties of this element change. This is where the method we developed is so different from what everybody else is doing and why it has the enormous potential in discovery of new treatments and even cures for neurodegenerative disorders.  This method allows us to isolate the brain signaling network and to monitor the activity of each individual building block in real time, as well the live interactions between different components. Furthermore, the test of a candidate drug takes a week from start to finish. Imagine the possibilities for drug discovery if the efficiency of candidate drugs can be tested within a week instead of years.  This is what your support of Cognistrata Inc. can accomplish.

Tatyana Ivanova-Nikolova, Ph.D. 

Today I would like to begin answering this question based on my own personal experiences. I would also like to initiate dialog with people whose lives have been affected by these disorders and people who have actively searched for answers to this question.

I became a biophysicist because I wanted to define the magic of life with mathematical models. Finding treatments for diseases was not something I had ever given much serious thought to. Then, within a few years, several eye-opening events took place and changed my views on what was important in my work. Early on, I lost a young colleague to a heart condition. My colleague’s death was a devastating loss not only for me but for everyone who knew him. It was an even more devastating loss for his family, because he was the fourth of five brothers succumbing to the same heart ailment. I, however, was certain that modern medicine had done everything it could do to save my colleague’s life. After all, my colleague had three heart surgeries and several devices implanted. Furthermore, his father was a physician, and I was positive he had uncovered all medical treatments that could save his son’s life. A few years had gone by, and I hadn’t given much thought to my colleague’s heart condition. Then, as I was settling into a new position, preparing my lectures for medical students, I came across some astonishing information. One of the topics I was assigned to cover was channelopathies. Channelopathies are disorders caused by defects in the structure and function of different ion channels. The ion channels are signaling molecules in the cell membrane that allow neighboring cells to communicate with each other. As I was reviewing the scientific literature, I came across studies that had identified my colleague’s heart condition. Had the cardiologists who treated my colleague read the same studies, they would have known that some of the devices they implanted did not benefit my colleague, but rather that they contributed to his death. At this point, I realized that what I do and learn as a biophysicist can translate into effective treatments for some of the most devastating disorders. At the same time, I recognized the presence of the dangerous gap between scientific research and current medicine even when the two target the same medical condition. One cannot help but wonder how many lives are lost in this gap. One thing for sure, I constantly wondered about the toll this gap had on many human lives.

Therefore three years ago when we discovered a vast signaling network in the brain that controls motion and cognition, we went into overdrive to characterize this network. We established that current medications that slow the progression of Alzheimer’s disease work through this same network. Furthermore, we found ways to enhance the effects of such medications. Finally, we established that the progression of Parkinson’s disease and the escalation of L-DOPA induced dyskinesia are results of the deterioration of this brain network. However, when I tried to publish the results of our work and make this knowledge available to the entire scientific community, I was stopped by anonymous reviewers of our work. Scientific publishing is a difficult process – every scientist is well aware of this fact. My initial reaction was to provide all additional data requested by the reviewers in order to have our discovery published so that the floodgates of development of new treatments for Alzheimer’s and Parkinson’s diseases would open. Two years later, I realized that our critics would never be satisfied with our data because our work has nothing to do with the established theory of neurodegeneration and formation of amyloid plaques in the brain. In response, I formed Cognistrata Inc. (www.cognistrata.org) with the mission to translate our scientific discovery into new treatments for neurodegenerative disorders. I also decided to turn directly for financial help to the families whose lives are affected by Alzheimer’s disease and other neurodegenerative disorders.

In my next blog entry I will explain why no one was able to discover this brain network before we stumbled upon it. But first, I would like to initiate a dialog and hear directly from you. Does it matter to you who will develop effective treatments for Alzheimer’s disease?  Would you support a woman biophysicist in her quest to find such treatments? Does it matter to you that most of the work that enabled us to discover the brain network was done in the heart? Or you would rather support the road well-traveled and the $400 million a year money pit focused on amyloid plaques research? I would like to hear your voice and your thoughts publicly or privately (just press CONTACT US).

Thank you.

Tatyana Ivanova-Nikolova, Ph.D.

Principal Investigator and President of Cognistrata Inc.