History and Philosophy

The Silver group has followed many different scientific paths over the years so I thought I would provide a little history and perspective here. Most of our success can be attributed to the numerous students and fellows who have travelled through the lab over the years.

The group began around my original discovery of one of the first nuclear localization signals – short peptides that target proteins to the nucleus. Following on this, the focus was on the organization of the nucleus and movement of molecules between the cytoplasm and the nucleus. In the course of this work, we developed and confirmed some of the models of nuclear transport, developed a systems-wide approach to the problem and people extended this work as they departed to establish their own groups. The lab was continuously funded by the NIH including with a MERIT award and was located for many years in the Dana Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. We made a number of contributions to development of anti-cancer therapies – including a small molecule screen, which resulted in a novel cancer therapeutic now FDA approved by Karyopharm Therapeutics as well as pioneering some of the first uses of GFP to track molecules within cells.

Some years ago, I had the good fortune to meet a group of computer scientists and bio-engineers who formed the Synthetic Biology Working Group at MIT. My group became increasingly engaged in developing the fields of Systems and Synthetic Biology and we are now recognized as leaders in efforts to engineer biological systems to perform useful tasks. As a result of these efforts, I became one of the founding members of the Department of Systems Biology at Harvard Medical School. This was a good fit because Synthetic Biology seeks to provide a computational framework to make the engineering of biological systems faster and more predictable. I participated in formulating the first definitive report on Synthetic Biology for the US government, which helped set the international agenda for the field.

We have enjoyed a number of successes including the rational engineering of genetic circuits in both eukaryotes and prokaryotes, metabolic engineering to re-route carbon metabolism and the application of modularity in cell engineering and the design of organisms to report on states within animals. The development of the Bionic Leaf and natural gut bacteria that sense prior drug exposure to animals illustrate many of our approaches.

Our group has a very informal atmosphere. We encourage people to work on interesting, unsolved problems that might have broad implications. We also encourage collaborations and forays into completely new areas. For example, we are working with Neri Oxman at MIT on photosynthetic wearables and Dan Nocera on the Bionic Leaf. I also believe in the empowerment of young researchers as they are the future of science. The engineering of biology is the technology of this century. To paraphrase a certain rock band of the last century – ‘it’s going to be a long strange trip.’

Here I summarize some of our accomplishments over the years.

1. Nuclear organization and transport. During my postdoctoral work, I independently conceived of and discovered one of the first NLs and early work from my own lab therefore focused on factors required for nuclear protein and RNA transport. This led to identification of receptors for nuclear protein transport and the elucidation of the role of various nuclear pore proteins. We were among the first to move from a ‘single factor’ analysis to a more systems-based approach. We used novel imaging techniques to map interactions between transport factors and the nuclear pore. We were also among the first to investigate the interactions between the genome and nuclear transport. In doing so, we found that some activated genes moved to the nuclear pore upon activation in yeast. We extended these studies to mammalian cells including genome-wide mapping of binding of key transcription and transport factors. This work has laid the foundation for work in many labs and establishes our ability to image spatio-temporal events in living cells. It also led to the discovery of novel molecules that trap tumor suppressors in the nucleus and thereby reverse the tumorigenic phenotype. These molecules are now in successful clinical trials for a number of different types of cancer.

2. RNA processing and transport. Our early studies of nuclear transport used a novel genetic screen in yeast. This led to the discovery of a number of key factors including RNA binding proteins that also control other aspects of mRNA processing indicating a close interplay between these processes. We determined the relative specificity for mRNAs for these factors using a genome-wide approach. We were also among the first to use GFP to show the kinetics of shuttling of these RNA transport factors between the nucleus and the cytoplasm. In subsequent studies, we translated this work to mammalian cells where mRNA splicing and transport is key to some genetic diseases.

3. Gene Regulation. In the course of our studies of nuclear transport, we found an intimate connection between nuclear transport and gene regulation. One of our key discoveries was the identification of the first arginine methyltransferase, which not only plays a role in chromatin function but is also important in the movement of RNA binding proteins between the nucleus and the cytoplasm. In addition, we made a surprising discovery that not all ribosomes are created equal; there is a unique previously undescribed specificity for the matching between ribosomes and translation of mRNAs. This finding continues to have implications including in cancer cells as reported by others. We also used our knowledge of synthetic switching to build unique sensors for silent regions in mammalian cells.

4. Photosynthesis and carbon fixation. Dave Savage, now a Professor at UC Berkeley brought the study of the photosynthetic cyanobacteria to the laboratory. Many people worked and continue to work on these fascinating organisms with great potential. We characterized the behavior of the major carbon-fixing unit, termed the carboxysome. We also engineered them to be commodity producing factories and showed how one might improve their photosynthetic efficiency. This has led to a general interest in intracellular compartments and their engineering.

5. Synthetic biology. For about the past ten years, much of my lab has focused on the building of predictable genetic circuits and new chromosomes with a goal of using the power of biology to enable real world applications. In brief, this includes the design of predictable circuits that can remember past events in both prokaryotes and eukaryotes, including the construction of mammalian cells that remember the amount of radiation to which they were exposed. This has implications medically and for space travel and was of interest to NASA. More recently, we engineered natural gut bacteria that can remember exposure to antibiotics in the context of whole animals (mice) and can ‘count’ the number of generations since exposure. These programmable sensors have potential as probiotics for treating inflammation and for diagnostics particularly in the livestock industry. They also tell us more about various cell population behaviors. And lastly, together with Dan Nocera we have developed the bionic leaf that is the first bioengineered system to beat photosynthesis.