Advances in medical research are happening faster than ever, constantly resulting in better or new treatments. But where does this progress come from? You’ll probably think of the pharmaceutical industry or hard-working researchers in their labs. While these agents are of course very influential and responsible for researching and refining promising medicines, the roots of many medicines is often found in the nature around us – for example, the precursor to aspirin (which you can find in your painkiller pill) originated from tree bark Salix alba (willow tree), and penicillin (an antibiotic you may have been given if you’ve been sick with a bacterial infection) was detected in the fungus Penicillium notatum. But how do you find out that the bark of a tree can cure your headache (whose idea was it to eat bark when you’re sick?). Often, discoveries can be attributed to vigilant individuals, coincidence, luck – or a combination of all three.

One such vigilant individual was John Eng, who in the 1990s was employed at a hospital in The Bronx, New York, where he worked on developing tests to identify unknown hormones and their function. In his daily work at the hospital, he met many patients with diabetes, a disease that causes high blood sugar levels if not treated properly. As prolonged high blood sugar can cause many serious side effects, the body normally produces the hormone insulin in the pancreas to transport glucose into the cells. Diabetes can have two causes. Either the cells of the body’s respond less to insulin or alternatively the production of insulin is impaired.

John Eng was reading a study done in the 80s by the National Institutes of Health. This study found that the venom of some snakes and lizards overstimulated the pancreas. Later he became interested in one particular venomous lizard – The Gila Monster, one of only two venomous lizard species. John Eng’s curiosity was sparked when he found that the lizard could maintain a constant blood sugar level even after long periods without food – a trait that would be ideal for diabetic patients. He found himself in a intriguing position; he had experience with diabetic patients, he had knowledge of an animal whose venom affected the pancreas, where insulin is produced, and he had developed an experiment that enabled him to investigate the unknown hormones in the venom that caused the pancreatic effect.

Figure 26. The Gila Monster (heloderma suspectum)

It turned out that one hormone in the venom, called exendin-4, was particularly interesting. It was very similar to another hormone, glucagon-like peptide 1 (GLP-1), which is normally released in the human gut after we eat. GLP-1 has a number of functions. Among other things, it reduces our appetite when we’ve eaten enough. When our blood sugar is high, it stimulates the natural production of insulin. However, it does not stimulate the production of insulin when blood sugar levels are low, making it easier for the body to hit the correct dose compared to the use of pure insulin. The correct dose is the amount of medicine you need to take to achieve the desired effect. If you take too little medicine, it has no effect, but too much is usually dangerous. Good medicines should ideally have a large window between the two points, so that the risk of accidental overdose is as low as possible, while still ensuring an effect. Having a drug that only induces the production of insulin when needed will make it much easier to control blood sugar levels. This is in contrast to the use of pure insulin, which, if overdosed, will result in the opposite condition called hypoglycemia – dangerously low blood sugar.

Other researchers had already had their eye on GLP-1 in diabetes treatment, but unfortunately, GLP-1 is very quickly broken down in the blood by the enzyme dipeptidyl peptidase IV. This meant that the half-life (the time it takes for the body to halve the available amount of the drug) was only around 2 minutes, and patients needed very frequent injections or an IV drop of the hormone to achieve a lasting effect. Thus it was promising when exendin-4 was shown to have virtually the same effect as GLP-1 while being far more resistant to degradation by enzymes, giving it a half-life of 2.4 hours. This allowed for 2 injections per day, which is much more convenient for use as a drug.

From something as exotic as a lizard’s venom, John Eng now had a drug, that he believed could help millions of people. However, it can cost billions to develop, test, and get approval to sell a drug, not to mention years of hard work – something that wasn’t possible for one person. He patented the idea to protect it and started looking for a pharmaceutical company that found the project attractive enough to invest in it. As it turned out, it would take a full 3 years before he found a company, Amylin Pharmaceuticals, willing to take a chance with him in 1996. In 2005, the US Food and Drug Administration (FDA) approved the hormone exendin-4, sold under the name Byetta, for the treatment of diabetes, more than 13 years after its original discovery.

Since Byetta came on the market, another version of the medication, called Bydureon, has been approved, which only needs to be injected once a week, again a huge improvement from both Byetta and GLP-1. The possibility of using Byetta to treat other conditions is also being explored. In this context, a number of clinical studies have been initiated for indications such as Alzheimer’s and Parkinson’s. In this way, Byetta is a prime example of how a seemingly crazy idea can end up in multiple versions of a drug. Even now, – almost 30 years after its discovery! – the drug is still improving the lives of millions of people and opening the doors to new potential applications.

Working questions

1. Consider how Byetta differs from regular insulin What are the pros and cons of the different treatments?

2. Why are larger companies primarily interested in patented or patentable products?

3. Can you think of other sources in nature where new medicines could potentially be found and would you expect them to be used for a specific disease?

Answer

1. examples:

– Byetta only induces insulin production when needed, making it easier to dose than pure insulin, which can be overdosed.

– Byetta has a slower onset of action than insulin as it must first affect the release of insulin, whereas a dose of insulin will have an immediate effect

– Byetta does not work for the treatment of type 1 diabetics, as type 1 diabetics do not have functional beta cells.

2. Without patents, companies risk doing all the hard and expensive work to get a drug approved for use in humans, leaving other companies to simply copy the product and sell it. This is one of the things patents protect against.

3. Examples:

– Hemotoxic venom could have potential beneficial effects against diseases affecting the human circulatory system

– Neurotoxic venom can be used to target certain ion channels, as in the Maxion case

– Cone snail venom is incredibly complex and also affects ion transport

Most answers are good as long as they are argued for well

Discussion questions

1. Drug development is traditionally very expensive. This can be a problem for patients with rare diseases, as the market is often not big enough to guarantee that companies can make enough money from a drug to make it worthwhile for them. Research and provide examples of what is being done to encourage companies to focus on developing drugs for serious but rare diseases (so-called “orphan drugs”), and provide your own examples of additional actions that could be taken.

2. A disease that, like diabetes, affects millions of people every year is breast cancer. Imagine you found out that people bitten by a certain snake were much less likely to develop breast cancer. Outline in general terms how you would develop it into a potential drug.