It seemed that a consistent story was developing, because experiments in mice seemed to confirm a role for this gene in control of body weight. Mice that were genetically manipulated so that they over-expressed this gene were overweight, and developed type 2 diabetes symptoms when they ate a high-fat diet.{301} When this gene was knocked out in mice, the animals had less fat tissue and a leaner body type than control mice. Even when the knockout mice ate a lot, they burnt loads of calories, even though they weren’t particularly active.{302}
This created a lot of excitement. It implied that if scientists could find a way to inhibit the activity of this gene in humans, they might be able to develop an anti-obesity drug. There was still a problem because we aren’t altogether sure what the candidate gene does in cells, and that makes it difficult to create good drugs. But at least we had a starting point. Both the human and mouse data implied that the gene coded for an important protein in obesity and metabolism. This was coupled with the reasonable assumption that the variant base pair associated with obesity affected the expression of the gene itself.
But in the immortal words of Mitch Henessey, the character played by Samuel L. Jackson in The Long Kiss Goodnight, ‘Assumption makes an ass out of “u” and … “umption”.’ Of course, hindsight is always 20/20 and there’s no reason to feel condescending to the scientists who were exploring the role of the protein. It’s just that nature seems to have a way of tripping us up.
Here’s the real reason why that single base pair variation makes a difference to human physiology. There’s another protein-coding gene half a million base pairs away from the key single base pair change described above.[49] The junk region of the original gene interacts with the promoter of the second gene, altering its expression patterns. Essentially, the junk region acts as an enhancer. The effect is seen in humans, mice and fish, suggesting it is an ancient and important interaction.
The investigators looked at the expression levels of this second gene in over 150 human brain samples. There was a clear correlation between the base pair variant in the junk/enhancer region and the expression levels of the second gene. But there was no correlation between the base pair variant and the expression levels of the original candidate, the gene that actually contains the variation.
When the researchers knocked out expression of the second gene in mice they found that, compared with control animals, the mice were lean, had low adipose tissues and increased baseline metabolic rate. This was in fact the first time anyone realised that the second gene was involved in metabolism at all.{303}
What we have here is a model very similar to the one we have already encountered for human pigmentation and for pancreatic agenesis. There are in fact a number of different variant base pairs in the junk region of the original obesity-associated gene. Many of these have been associated with obesity. This suggests that all of these variants probably have the same effect, i.e. they change the activity of the enhancer, and thereby alter the expression levels of the target gene, half a million base pairs away.
Of course, the mouse data suggest that the original gene, the one that contains the variations in its junk DNA, may also play a role in obesity and metabolism. So we could ask if, in practical terms, it really matters how the single base pair changes bring about their effects. But there is a way in which this matters a lot, and that’s in the field of drug discovery.
One of the many problems in developing new drugs is that frequently some patients will respond to a drug and others won’t. This adds a lot of additional expense. It means that pharmaceutical companies have to run very large clinical trials to see if their drug works, because they have to test it in all-comers. It also means that it’s expensive to use the drug in clinical practice, because the doctor will give it to all patients with the relevant condition, but it will only work in some of them.
These days, pharmaceutical companies are all trying to create something called ‘personalised medicine’. This means that they try to develop drugs for situations where they know very early on which patients they want to treat, usually based on their genetic background. This can be very effective. It means drugs cost less money to develop, are usually licensed faster, and are only given to patients who are likely to benefit. This is an advantage for the health care providers because they aren’t wasting money treating people who won’t respond. It’s also potentially better for the patients, as all drugs have possible side effects, and there’s no point having the risk of side effects if there is very little likelihood of receiving benefit.{304} There have been real successes in this approach, most notably in drugs for breast cancer,{305} a blood cancer{306} and most recently lung cancer.{307}
The critical step in developing personalised medicines is to identify a reliable biomarker. The biomarker tells you which of your potential patients should respond to your drug. Ideally, you want a situation where 100 per cent of people with the relevant biomarker will respond to the drug. The problems start if you have the right biomarker for the disease, but you link it with the wrong target. You will create a drug and then be stuck wondering why patients who ‘should’ respond, don’t. It will be because there is a break in the circle of relationships, as shown in Figure 15.3.
Figure 15.3 On the left-hand side there is a perfect relationship between the biomarker, target and disease. On the right-hand side there is no relationship between the target and the presence or absence of the particular biomarker. Under these conditions the biomarker is useless for predicting which patients with the disease will respond to a drug developed against the target.
The potential market for obesity drugs is, with no pun intended, huge. It’s likely some companies had already started drug discovery programmes against the original target, which they will now be either terminating, or trying to find a way to salvage. In the meantime, portion control and a bit of exercise remain our best bet.
16. Lost in Untranslation
There are few crimes lower than deliberately hurting a child. In many countries, staff in emergency departments are trained to look for patterns of unexplained injuries including fractures in babies and toddlers. Often such a medical history will result in children being taken into care, little or no parental access, and ultimately prosecution and possibly imprisonment of one or both parents.
Protection of a child is of course paramount. But imagine the nightmare for parents if this happens to them and they are entirely innocent, because the fractures are due to an undetected medical condition.{308} Although the number of such miscarriages of justice is small compared with genuine cases of child abuse, the effects for the family are devastating. Loss of liberty, marital breakdown, social exclusion and, most heartbreakingly, the loss of parent — child contact.
A genetic condition can and has led to this misdiagnosis of child battery on more than one occasion. The disorder is called osteogenesis imperfecta, but it’s more commonly known as brittle bone disease.{309} Patients with brittle bone disease suffer fractures very easily, sometimes from mild traumas that might not even cause much of a bruise in a healthy child. The same bones may break repeatedly, and they may heal imperfectly, so that the affected person becomes increasingly disabled over time.