Editor’s note: The following is a letter written by Nobel Laureate Craig Mello to President George W. Bush on February 21, 2007. For more on the letter and its fate see this post.
Dear Governor Patrick:
It is a pleasure to write in response to your recent note. In a year in which I have had so many wonderful things happen, I want to thank you for your excellent description of RNAi at our celebration in Worcester on January 26 and for your recent invitation to share my thoughts about the possibility of some funding in your upcoming capital budget for our efforts at UMass to advance this exciting science.
I know that you have been in discussion with University of Massachusetts President Jack Wilson about similar investments in the University. It is my understanding that he forwarded to you a draft report done by a panel of faculty from Amherst and the Medical School identifying the opportunity to build a program in Stem Cell Research and Developmental Biology. The report responded to the requests of the University’s Science and Technology Committee of the Board of Trustees as well as provisions in the Stem Cell legislation passed in 2005.
The recent report forwarded by President Wilson builds on the many strengths within the University and includes resources for important shared technology hubs that would enhance the work of University scientist and student researchers. We could not overstate the importance to all our research of the $12 million investment proposed for these vital cores, which include a Gene Silencing Core, a Proteomics and Protein Fractionation Core, a Microarray Core, a Sequencing and Synthesis Core, a Chemical Biology Core and a Bioinformatics and Computational Biology Core.
While embedded in the proposal around Stem Cell Research and developmental Biology, the ‘Cores’ President Wilson is proposing provide essential tools to our research initiatives in RNAi.
More specifically, however, over more recent months, those of us working on RNAi based gene silencing have been developing a proposal to capitalize on our preeminent position and expertise and create an RNAi Therapeutic Center (RTC) here at the Medical School.
If Small Molecules were the therapeutic modality of the 1950’s and 1960’s (with over 1000 approved products and over $175 billion in sales); and Proteins and Antibodies became the modality of the last decade (now with over 200 approved products and over $40 billion in sales); we believe the next great modality will be RNAi.
Our RTC will provide key reagents and expertise for RNAi-based screens and discovery of novel proteins that function in cellular processes and human diseases. The RTC will also develop new technology for increasing the effectiveness of RNAi in gene silencing, both in cell systems and in intact animals. The vision for this Center emphasizes facilitating and promoting clinical and translational research by application of RNAi to testing hypotheses on underlying mechanisms of disease processes and ultimately to developing the next generation of powerful drugs to treat a broad range of diseases including cancers, Alzheimer’s, diabetes and heart disease.
RNAi has become a premier research tool across the entire range of biological fields, based on its specificity and potency in silencing gene expression in both primary and cultured cell systems. Its utility is being increasingly enhanced by further innovations and applications. Furthermore, RNAi has now been shown to be effective in silencing genes in intact animals and is being tested in humans. Importantly, this technology will greatly facilitate the development of the next generation of medicines for a broad range of human diseases.
The Medical School has amply exploited its unique position at the forefront of the RNAi. World-class scientific advances in the field from our scientists include: a.) discoveries of novel components and mechanisms that promote RNAi function in gene silencing, b.) the development of novel chemistries to stabilize and deliver RNAi to target cells, c.) the application of RNAi to alter gene expression in primary tissues of the body and d.) the use of RNAi to screen for genes that function in a variety of cell processes and disease states such as cancer and diabetes.
UMMS scientists are at the cutting edge of research in all these RNAi fields and represent a critical mass of talent and expertise that can be mobilized to further develop powerful RNAi technologies and to make them available to all scientists at the Medical School and beyond.
We seek to build an RTC with the following concentrations:
Screening and Target discovery. RNAi screening is a powerful approach to discover genes that function in specific cellular processes that can be assayed in single cell or high throughput format. The Center will procure and be a repository for RNAi reagents (libraries of silencing RNAs) that facilitate the knockdown of every gene in the human genome. The center will prepare these RNAi libraries in forms (retroviral and lentiviral vectors) that permit the delivery of silencing RNA to a variety of cell types commonly utilized in the laboratory. These libraries can then be applied by investigators to diverse systems in target discovery programs.
The RTC will need to constantly acquire the equipment and technology that is as cutting edge as is our science. To maintain our preeminent position, we will need to be THE place that has the latest, fastest most accurate tools to do the science and push it along the development pipeline towards therapeutic products. The inability of individual scientists from their grant funds—or even groups of scientists pooling their resources to create self financing ‘cores’—to purchase and/or access technology where the leaps in speed and accuracy is matched only by leaps in expense is holding us back from reaping the full rewards of the genomic revolution. The RTC hopes to provide resources to unlock these opportunities.
The Center will also provide expertise in design, processing and quality control for these RNAi libraries in order to facilitate their widespread use. Expertise in assessing off target effects of RNAi involving such confounding issues as interferon or toll receptor responses will also be available. Already several Medical School laboratories have had major success with RNAi screening in discovery of novel proteins that function in cancer cell metastasis and cell signaling pathways. These discoveries have high relevance to potential therapeutic approaches to such diseases as cancer, diabetes and degenerative diseases of the central nervous system like Alzheimer’s and ALS (Lou Gehrig’s Disease).
RNAi chemistries for stabilization and delivery: UMMS scientists have already discovered exciting new ways of prolonging the lifetime of RNAi in serum and in tissues—thus extending the time and extent of gene silencing. The Center will build on this novel technology to further improve RNAi stability. Center scientists will test these improvements in animal models. Similarly, UMMS scientists have invented ways of using nanotechnology to enhance the delivery of RNAi to specific tumors and organs. The use of nanoparticles and nanotubules in conjunction with stabilized siRNA will pave the way for the therapeutic use of RNAi in humans. A key goal of the Center will be to further innovate in the field of RNAi chemistry and retain the cutting edge position that the Medical School enjoys in this field.
RNAi-based gene silencing in human diseases: A major goal of the Center is to engage clinical and translational scientists at UMMS and elsewhere to promote their research. Researchers with disease models and hypotheses to be tested with respect to specific genes of interest will be supported in their efforts to silence such genes in vivo. Acquisition of gene-specific siRNA and appropriate co-factors (e.g., nanoparticles) will be facilitated by the Center in support of clinical researchers’ projects. GMP quality siRNA will be generated with quality control methods to assure purity and efficacy. Delivery methods will be tailored to the needs of the investigator. Importantly, the Center will employ scientists who are expert in the handling of animals and the delivery of RNAi in vivo. This expertise will be invaluable to both clinical and basic researchers who wish to test important hypotheses within whole body conditions. The Center envisions its expertise being extended to delivery of RNAi for gene silencing to primates and humans in the near future.
Resource needs
We are early yet in the evolution of our plans. As you can imagine, the more we think about the opportunity the more we think we can do and the more resources we will need. At this juncture, however, we have identified some of the building blocks—what we might term ‘Phase One’. In addition to the $12 million for research cores embedded within the University’s Stem Cell and Developmental biology initiative, our RNAi Therapeutic initiative will be looking for resources to meet the following initial needs:
• $20 million to develop laboratory and support space that may need Good Manufacturing Practices/Good Laboratory Practices (FDA standards of operations) capability to produce RNAi for use in animals and humans; instrumentation for siRNA synthesis, etc;
• $13 million capital investment in equipment, laboratory technology and supplies (siRNA reagents for animal and human studies; chemicals for nanoparticle synthesis and preparations; emerging laboratory technologies; computing and informatics); and
• $1.5 million in annual operating support for the high end technology programs supporting this effort to develop our science into therapeutic products (RNAi Synthesis Core: synthesis and animal work; shRNA Library Core; RNAi stability and delivery technologies)
I know that the leadership at the President’s Office and at the Medical School can work with your staff as necessary to match our needs to your budgetary processes.
Thanks again for your continuing interest in our science and your strong support for the University of Massachusetts.
Sincerely,
Craig C. Mello
Blais University Chair in Molecular Medicine
