Challenge 7: Biological Macromolecules

In recent years, scientists have been experimenting with using large molecules called ‘macromolecules’ to target and destroy tumour cells. These macromolecules can disrupt the processes that cancer cells use to survive – for example by stopping them from growing or by flagging their presence to the body’s immune system.

This approach works very well on cancer cells in the laboratory, but unlike conventional ‘small molecule’ treatments like aspirin, it’s really difficult to deliver these molecules to, and then into, the cells where they need to act.

If we could work out ways of delivering these macromolecules to any and every cell in the body, it would not only create a totally new way to treat cancer but would have a huge impact on other diseases too.

Biological macromolecules such as proteins, DNA, RNA, siRNA, and antibodies have already been shown to have huge therapeutic potential in cancer and other diseases. They can be engineered to be far more specific and active than current small-molecule therapies.

The challenge is to deliver these macromolecules to, and into, cells in the body, because their size and properties make it difficult to deliver them into the right cells in an active form.

Existing research mostly focuses on targeting the macromolecule to the tissue of interest. We want to look at an alternative approach: delivering a macromolecular drug to all cells, but ensuring that it is only toxic to cancer cells.

Our Grand Challenge is to make what is true today of small molecule drugs into something that also applies to macromolecules: in other words, to develop a macromolecular drug that can be taken as a pill or similar, such that every cell in the body experiences the drug, but only certain cells are killed.

The focus of this challenge is on delivery mechanisms; designing macromolecules so that they can be taken up by a cell’s normal import mechanisms. This strategy of universal delivery is how the cancer drug Gleevec works – it’s a small molecule drug, in tablet form, and although it does affect normal tissue, its major effect is to kill cells carrying the BCR–ABL fusion protein which is exclusively expressed in tumours.

This is an extraordinarily large challenge, as there are many unresolved components of the delivery problem. These include: establishing the optimal delivery method; crossing endothelial barriers (including the blood–brain barrier); pharmacokinetic issues, and a deepened understanding of cell membrane transport mechanisms.

Progress in any or all of these areas will take us closer to overcoming the most important barrier to efficient drug delivery.