In fact, the target-recognition of MACis far more complicated than referred above, in which a lot of molecules are related. So it is much difficult to mimic the whole system, leading us to take a simple synthetic biological approach.
In fact, the target-recognition of far more complicated than referred above, in which a lot of molecules are related. So it is much difficult to mimic the whole system, leading us to take a simple synthetic biological approach.
Cancer is one of the most common diseases in the world. Cancer cells divide abnormally and grow uncontrollably, resulting in the formation of malignant tumors, and invading human body. Cancer causes about 13 percent of the all human deaths worldwide (WHO 2007).
Chemotherapy is a popular medical treatments for the cancer, however, it often attacks normal cells in addition to the cancer cells, damaging normal tissue and organs, which cause severe side effects. According to the American cancer society, these side effects include pain, vomiting, limphedemia, sexual decline and various symptoms, which seriously decrease quality of life.
To improve cancer-specificity, drug delivery system (DDS) has developed, but it is difficult to optimize a delivery system for each drug.
Team Todai nanORFEVRE are trying to make cancer-specific drug which doesn’t need delivery system(DDS).
To achieve a cancer-cell-killing system with high specificity, we first took attention to a mechanism in the human immune system called membrane attack complex (MAC), which operates when bacteria infect our body. In the system of MAC, subunits penetrate the membrane, oligomerize, and form a pore into the bacteria membrane. Then the subunits disrupt the lipid bilayer, inducing targeted cells lysis and death. The point of this system is that the subunits show citotoxity only after forming a pore. MAC do not kill the cell simply by penetration, as molecules on the surface of harmless cells prevent MAC from sticking in (and forming pores). Therefore, MAC will only show citotoxity to foreign cells such as bacteria.
In fact, the target-recognition of MAC is far more complicated than referred above, in which a lot of molecules are related. So it is much difficult to mimic the whole system, leading us to take a simple synthetic biological approach.
In the previous study, Rausch et al. used peptides to develop pore-forming proteins like MAC ,but in that research they could not recognize the specific cells. To achieve the recognition system, we thought about to use DNA. Recently, in situ computation by DNA was reported (Maria Rudchenko et al. (2013)). In that study, DNA was used as logic circuits: using surface antigens as inputs and generating DNA strands as outputs. Rudchenko et al. said that it may be possible to use their logic circuit for other self assembling systems and DNA machinery. We, therefore, thought that it might be possible to make cancer-recognition system using DNA.
Our general idea is explained as follows. 1) Subunits stick in normal and cancer cells nonspecifically. 2) In case of cancer-specific antigens are existed, DNA computing circuit puts out certain DNA strand. 3) And this strand triggers oligomerization of the subunits (e.g. connecting subunits by hybridization), and cytotoxicity is induced to the cancer cell. Overall, our subunits may oligomerize only on the cancer cells and kill only cancer cells.
DNA itself has information embedded in the sequence. Using DNA computation and DNA-protein hybrid system, in which multiple molecules coordinate, we believe that our “Oligomeric Cell Killer" has the potential to treat cancer and other diseases like infection.
Our general idea can be divided into two steps, cancer-recognition and killing. Since DNA computing circuit for recognition has already reported, we set our summer goal of the biomod 2013 to develop pore-forming DNA origami for the killing system. To achieve this goal, we thought about biomolecular robotic system named as “Oligomeric Cell Killer" explained in
the Design page
We can divide the project goal into following five steps.
DNA strands assemble to form designed structures.
The formed subunits oligomerize in solution.
Subunits stick in the membrane.
Subunits oligomerize on the membrane.
Subunits form the pore and kill the cell.
As a first step toward our goal, we started with simple DNA origami structure: Cylinder in Barrel.