In the past year, the work of our Center has become focused on the construct that we call the functional protocell or, more frequently, just protocell.
How is the protocell like a biological cell? Like a biological cell, it is surrounded by a membrane that contains lipids and proteins. Like a biological cell, it contains a solution inside comprised of water and solutes, which may be ions or molecules. By varying the contents of the protocell interior, and by varying the chemical composition of the surface membrane, the protocell may acquire a great variety of properties, just as biological cells have various properties based on the same kind of variation.
Up to now, practically all biophysical membrane studies have been on unsupported membranes. The membranes in our protocells, on the other hand, are supported on a nanoporous solid that mimics the crowded interior milieu of a living cell. Our studies show that supported membranes behave very differently from unsupported ones in many ways, such as the induction of targeted endocytosis (their ability to induce another cell to "swallow" it).
How is a protocell different from a biological cell? For the protocells we make, there are two major ways; 1) it can not replicate itself, and 2) it can not change its shape.
Our protocells come in two major forms. One is the delivery protocell, which is designed to enter living cells and deliver materials. The other is the decoy protocell, which is designed to have some interesting interaction on its surface, such as the inactivation of viruses.
Scientists in our center have been able to design delivery protocells for effectiveness, efficiency, specificity, and non-immunogenecity. They have made a protocell that will enter liver cancer cells but leave healthy liver cells alone.
Not only will it enter the liver cells, but it will also kill them when loaded with the right drug. These experiments are in cell cultures, so we do not know yet how the protocell will work in an animal or, ultimately, a human. There are a lot of issues in animals that do not arise in cell culture. For example, could the protocell provoke a destructive immune response in the host animal? We think we know how to prevent that from happening, but that remains to be shown. Tissue specificity is another iissue. We know that the protocells will not enter normal liver cells in culture, but could they enter some other nomal cell type? So many questions must be answered before our protocells can be enlisted to fight cancer, but we are confident that these issues will be resolved.
Our decoy protocells have shown interesting results against viruses in culture medium. We coat the surface of the protocell with a human receptor protein. In the human cell the virus uses this protein to gain entry. This protein on the surface of the protocell tricks the virus. The virus senses the human protein, thinks it has found a new cell home, and deploys a fusion protein to force its way into the cell interior. But it cannot get inside the protocell, because the interior of the protocell is silica, the scientific name for glass. Not only is the virus prevented from entering the protocell, but as it attempts to break in, the protocell actually disables the very fusion protein that allows the virus to get into human cells. As with the delivery protocell, we may be years from using a construct like this in human antiviral therapy, but what we are seeing this year is a promising start.
While some of our scientists are working with the protocells, other members of our team are trying to understand the molecular details of how the protocells work---and why some protocell designs don’t work. We are trying to understand the protocell-living cell interaction in enough detail that we can design a protocell in a computer and know what it will do. The big advances in the past year have been in the development of an integrated multiscale environment for the simulation of membranes. We do simulations at five different levels of detail: 1) quantum, 2) atomically detailed, 3) coarse grained, 4) continuum, and 5) whole cell. The bulk of our efforts are devoted to understanding how the different levels of detail fit together, so that we can pass information from the more detailed calculations to less detailed ones. The goal is to use the information from these more detailed calculations to improve the accuracy of less detailed but more efficient ones, so that our calculations can be both fast and accurate.
Our Center's broad goals are:
Please see the research section for current research plans.
Our core team is supported by the NIH Roadmap grant, but we are not functionally limited by this particular funded project. We welcome collaborations with all workers with relevant technologies and skills, and aligned interests. These collaborations can be in the form of studies conducted with existing resources, or collaborative grant proposals for new projects aligned with the mission of our Center.
For general scientific and technical issues about the Center, please contact the Director, . For other general issues about the Center, please contact the Programs Coordinator, . To find particular scientific expertise and contact information about other Center participants, please go to People.