ALS Research Update from New York Genome Center Scientific Director and CEO – Dr. Tom Maniatis

From donations raised through the ALS Ice Bucket Challenge, The ALS Association, in partnership with the Greater New York Chapter, made a $2.5 million commitment to the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center (NYGC). This commitment, combined with a matching gift from the Tow Foundation, was one of the driving forces supporting the NYGC’s ALS research program in 2014. Three years later, the NYGC’s CGND has made enormous headway in the ALS genetics space and has become one of the major leaders in the field. Their accomplishments are broad in that they have sequenced and analyzed hundreds of ALS DNA samples, while pairing this information with patient clinical history and more. We are pleased to note that Tom Maniatis, PhD, one of the NYGC’s original founders and renowned ALS researcher, was recently appointed Scientific Director and Chief Executive Officer of the NYGC.

For part II of our NYGC progress update, today we sat down with Dr. Maniatis to learn how ALS Association donations impacted the NYGC over the years and his vision for the Center’s future.

Thank you Dr. Maniatis, for taking the time to sit down with us today and congratulations on your new position as Scientific Director and CEO of the NYGC. I know you have a long history with The ALS Association. Can you tell us about that and how you got involved in ALS research?

Over 20 years ago, my sister was diagnosed with ALS. Soon after her diagnosis, I was approached by Robert Abendroth, one of the original founders of The ALS Association, about the possibility of chairing a committee whose objective was to attract scientists doing basic research, like myself, into ALS research. At the time, ALS research was dominated by clinicians, which is important, but there was an element of basic cutting-edge research that was missing from The ALS Association research program. I came onboard and chaired the committee with Robert. Together, we brought in basic research scientists, and ideas emerged, programs were generated, and funds were provided. Things really started moving. However, it became clear that in order for this program to become successful, it required a full-time scientific research administrator. That was when Dr. Lucie Bruijn was recruited to help run The ALS Association research program. I worked closely with her over many years to develop and expand The ALS Association’s research committee and programs. The earliest advance was to focus on ALS genetics, which clearly influenced my decisions about helping to establish the NYGC later.

How did ALS research get established at the NYGC?

When I first came to New York in 2010, I had already worked on trying to understand the interactions between astrocytes (i.e. neuron support cells) and neurons, which was funded by The ALS Association. We were working on mouse stem cell differentiation into motor neurons and then later human stem cells. We also studied how gene mutations affected transcription and gene expression. This is an area where I worked much of my life. At that time, the genomic methods were just being developed. It became clear the infrastructure needed for this type of work did not yet exist in New York, so there was relatively little activity in genomics. I reached out to the scientific leadership in New York and was pleased that everyone had the same concern and a common desire to establish a robust genome center in New York City. Our institutional founding members, comprised of the top academic leaders, came together in 2011. The institutional founding members of the genome center provided startup financial support and an agreement to serve on the NYGC Board of Directors. That is how we got started. It was a consequence, in a very direct way, of my interest in ALS.

How has ALS Association funding support impacted the NYGC?

The ALS Association contribution of $2.5 million and the matching grant from Leonard Tow and the Tow Foundation made it possible for the NYGC to create the infrastructure to establish a unique global ALS Consortium. This landmark initiative is defined by data sharing, having common Internal Review Board procedures, including patient consent forms, and an agreement to collaborate in generating and analyzing ALS genomic data. Lucie recently commented on how unusual it was to see something this vibrant and internationally connected come together so quickly. That was really our goal.

Do you have a message for our donors that made this support to the NYGC possible?

I believe that the approach we are taking is fundamentally important for ALS research, as it provides the infrastructure for ultimately developing effective treatments for ALS. We got this important initiative off the ground, but it, of course, requires continued funding. The more patients we can sequence, the more information we are going to have. The cost for each patient for whole genome sequencing is significant. Supporting the framework and infrastructure that allows us to continue this is very important. We must continue to raise funds to keep this initiative going. There is always a threat of not being able to fund it, and as a result, lose the momentum in this program. So, that is the message – to emphasize the importance of the continuity of financial support for the NYGC’s work in ALS research. The ALS Association’s investment in this research will help fulfill our joint mission to better understand the mechanisms of this devastating disease and discover new therapies and therapeutics to improve the lives of ALS patients.

Sequencers_1
Sequencers at the New York Genome Center

What do you see as the future of the NYGC?

There are three main areas that we are currently focusing on: ALS, cancer genetics, and autism. There is actually some symmetry in these three research programs. The one you know about is in ALS, which is a consortium-based effort to collect genomic data of ALS patients, along with their clinical data. The goal is to harmonize this information in a way that one can explore the nature of the effects of ALS mutations. Dr. Hemali Phatnani leads this program. Her NYGC laboratory and the Center for Genomics of Neurodegenerative Disease, reflect our primary objective – to have consortium based aggregation of clinical and genomic data. We use this data to better understand ALS disease pathways utilizing cutting-edge genomic technology and disease models. That is our major effort at the NYGC.

There is also a symmetric effort going on at the NYGC in cancer genetics. Here we are working with Drs. Harold Varmus, Charles Sawyers, and all of the institutional members of the NYGC, with the goal of establishing a large-scale, shared database of genomic and clinical cancer data. The NYGC excels at generating data and one of our real strengths has been in genome sequencing. I think we are recognized as one of the major players in the whole genome sequencing. Because of our unique expertise, we were awarded a prestigious Center for Common Disease Genomics grant from the National Institutes of Health. Obtaining this award was significant, considering we were only in operation for two years at the time.

This grant supports our research program in autism. Because of the cooperation with the Simons Foundation and two of the top geneticists in autism – Drs. Evan Eichler and Michael Wigler – this is a major program at the NYGC. We are also in discussion with various neurologists in the city about establishing a similar program in other neurodegenerative diseases. Our overall objective is to be an intellectual and data center for these major disease areas and enable the New York scientific community to use genomic approaches to study disease pathways, which we obviously feel is required to develop drugs to treat these diseases.

Thank you for taking the time to sit down with us today to share the NYGC story and your vision for its future. We look forward to hearing the many more great successes targeting ALS coming out of the NYGC!

Read part I of our interview on October 6, 2017 featuring NYGC CGND Director, Dr. Hemali Phatnani.

For more information about the New York Genome Center, click here and here.

Article originally written by the ALSA National Office

The ALS Association and Target ALS Partner to Uncover the Connection Between Ancient Retroviruses and ALS

research news banner 2015In partnership with Target ALS, The ALS Association is using part of its original investment in the Center for Genomics of Neurodegenerative Disease (CGND) at the New York Genome Center (NYGC) to create a valuable resource of RNA sequence data generated from tissue samples and induced pluripotent stem cells (iPSCs). This resource will help advance a project examining how Human Endogenous Retrovirus (HERV) RNA sequences may play an important role in a proportion of ALS cases. Leading this project are Hemali Phatnani, Ph.D., Director of the CGND, Robert Darnell, M.D., Ph.D., Founding Director and CEO of NYGC, Avindra Nath, M.D., NIH/NINDS and Lyle Ostrow, M.D., Ph.D., Johns Hopkins University.

In October 2014, The ALS Association announced a total commitment of $2.5 million to support the New York Genome Center’s Consortium for Genomics of Neurodegenerative Disease (NYGC CGND). The Greater New York Chapter contributed $1.25MM of those funds from money directly raised through the ALS Ice Bucket Challenge. The ALS Associations funding matched a $2.5 million leadership gift from the Tow Foundation to establish this program.

Retroviruses are a type of virus that carries viral RNA that infects cells and converts its RNA into DNA that is then incorporated into the host cell’s genetic code (i.e. genetic sequence). Human Endogenous Retroviruses (HERVS) are remnants from retroviral infections that occurred in our ancestors over millions of years and became incorporated into our DNA, passed down from one generation to the next. In the human genome, there exist upwards of 800,000 regions representing some form of integrated HERV sequence. This is important because recent research studies by Dr. Avindra Nath’s laboratory (published in Science Translational Medicine in the Sept. 30, 2015 issue) have demonstrated that the expression of a specific HERV, called HERV-K, is activated in a proportion of ALS cases, and expression of a HERV-K protein in transgenic mice caused progressive motor neuron degeneration as is seen in ALS.

Elevated amounts of a retroviral enzyme called reverse transcriptase can be detected in the blood and spinal fluid of a portion of patients with ALS. The suggested involvement of HERV-K in ALS begs the question of whether the expression of HERV sequences correlate with severity of ALS disease, and furthermore, whether reverse transcriptase levels in the blood or spinal fluid might identify this cohort of patients and may be useful as a biomarker to track disease progression and response to therapy. The ALS Association is committed to understand ALS disease mechanisms like the involvement of HERV RNA sequences in ALS.

Target ALS has established a multicenter ALS post-mortem tissue core, directed by Dr. Ostrow, and The ALS Association has partnered to expand this resource to collect fluid samples from people living with ALS. The current partnership to fund a study at NYGC’s CGND to sequence HERVs read from samples taken from people living with ALS compared to healthy people (i.e. controls) will exploit these resources.

The advanced technology and tools that the NYGC CGND possesses allows for accurate mapping of HERV sequences to characterize the HERV “expressome” (i.e. a complete picture of HERV sequences in a person) and to uncover the connection between ALS severity and the presence of HERV sequences. To accomplish this, researchers will use a method called RNA-Seq, which reads RNA sequences and at the same time reveals the quantity of RNA in a sample at any given time. RNA-Seq will be performed on multiple brain and spinal cord regions from each case to compare expression patterns in areas involved in ALS with ones that are spared. A portion of the funds from the previously commitment from The Association to NYGC’s CGND is dedicated to this study.

“We are excited to follow up on the interesting findings published by Dr. Avi Nath and to exploit both the tools that are being developed at NYGC and the tissues being collected to explore the possible connection between ALS and the presence of HERV sequences,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist of The ALS Association.

The CGND’s ALS consortium is a collaboration between numerous U.S. universities and academic medical centers capable of generating and analyzing thousands of DNA sequences from people with ALS. The goal is to discover new genetic contributors of ALS to translate into clinical solutions for ALS. “Target ALS is excited to partner in this effort to make an unprecedented resource of RNA-seq, whole genome sequencing, detailed clinical and neuropathological dataset as well as the corresponding tissue and biofluid samples immediately available to ALS researchers worldwide,” said Target ALS Foundation President, Manish Raisinghani, MBBS, Ph.D.

About Target ALS

Target ALS Foundation (www.targetals.org) is a non-profit organization with the overall goal of accelerating development of new treatments for ALS. We drive emergence of novel ALS drug discovery programs in industry by funding collaborative consortia focused on development of novel therapeutic targets. To ensure that all new ideas get tested, we make essential tools and resources openly available to all – especially young investigators – with no embargo or strings attached.

About the New York Genome Center

The New York Genome Center (NYGC) is an independent nonprofit at the forefront of transforming biomedical research and clinical care with the mission of saving lives. As a consortium of renowned academic, medical and industry leaders across the globe, NYGC focuses on translating genomic research into clinical solutions for serious diseases. Our member organizations and partners are united in this unprecedented collaboration of technology, science, and medicine. We harness the power of innovation and discoveries to improve people’s lives — ethically, equitably, and urgently. Member institutions include: Albert Einstein College of Medicine, American Museum of Natural History, Cold Spring Harbor Laboratory, Columbia University, Cornell University/Weill Cornell Medicine, Hospital for Special Surgery, The Jackson Laboratory, Memorial Sloan Kettering Cancer Center, Icahn School of Medicine at Mount Sinai, NewYork-Presbyterian Hospital, The New York Stem Cell Foundation, New York University, Northwell Health (formerly North Shore-LIJ), The Rockefeller University, Roswell Park Cancer Institute, Stony Brook University and IBM.