Nature's drug database

This article originally appeared in the first print issue of Works in Progress, which subscribers received last week. Subscribe to get six full-color editions sent bimonthly, plus invitations to our subscriber-only events.

Clinical trials for new drugs are expensive and uncertain. More than nine out of every ten drugs that enter human trials fail because of harmful side effects or a lack of efficacy. Safety and effectiveness in animals often fail to translate to humans. Imperfect as animal trials are, though, we need to know what happens when we block or boost certain biological pathways with drugs.

But there is another source of this data that we are beginning to draw on. Nature has already done lots of the trials we want to run, through random genetic mutations and natural selection. Since the first full mapping of the human genome in 2003, and the rise of technologies to sequence human DNA, we now can study the genetic mutations in nature that do the same thing as the drugs we want to test. For the first time, we are starting to peer into nature’s laboratory and learn from the millions of years of experiments it has done.

Trials and errors

On 13th March 2006, eight healthy young men began a clinical trial at Northwick Park Hospital in North London. A new drug called theralizumab was being tested on humans for the first time.

Theralizumab is a monoclonal antibody, a lab-made protein that mimics the body’s immune system antibodies. It is engineered to activate a type of immune cell in the blood called T cells. Normally, these cells are activated only when two proteins on their surface make a signal. These proteins are called the T-cell receptor and CD28.1 Theralizumab can circumvent this ‘two-factor authentication’ and activate the T cell directly through CD28 alone.

In early animal studies, the drug appeared to have many medical benefits, such as killing cancerous leukemia cells and dampening autoimmune responses in rheumatoid arthritis. Injecting the drug into crab-eating macaque monkeys, which are commonly used in drug testing because their physiology and immune systems closely resemble those of humans, suggested it could be safe even in higher doses than researchers planned to ever use. The UK’s Medicines and Healthcare products Regulatory Agency allowed TeGenero, the company developing the drug, to use it in human trials.

Volunteers were randomly assigned into either receiving theralizumab or a placebo, ...