Since my last post, I have spent most of my time by the Bulgarian beach, frankly – doing nothing. Recharging, especially in the few days before starting my life’s biggest challenge so far (a PhD!), is alfa and omega. I could be better at it, though. In the end, a combination of my passion for science and eager to be on top of everything always brings me back to scrolling through hot-off-the-press papers, checking my emails, making arrangements and preparing for the two vivas waiting for me back in Cambridge. In the paradoxical setting of beach bars and girls in monokinies, my hobby of a job hardly ever escapes my mind, and yet the past month did allow me to regain some lost mental strength in anticipation of the 3-year-long roller coaster ahead of me. You ask if I’m terrified? “No” would be a lie. If I’m excited? A hell of a yes.
So what am I actually going to do? Hardly any research is interesting to anyone but the scientist behind it, unless its relevance is demonstrated and explained to the wider public. Looking around me, the beach is full of different people. Different facial features, different voices, short, tall, thin, fat. Fat. Fat. Fat. Notably many people, from toddlers to elderly, are bulging outwards. Rather than being a random Bulgarian anomaly, “the fat human” is becoming a global citizen, causing an unprecedented surge in Type 2 diabetes cases and a whole range of other obesity-associated complications. The strong tie between fat and Type 2 diabetes is insulin, a key hormone important for blood sugar regulation as well as growth, development and appetite. When the capacity of our body’s fat stores is exceeded, additional calories can no longer find a safe home in specialised fat cells; instead, those extra pizza slices lead to fat deposition in blood vessels, muscle, pancreas and liver, causing damage and dysfunction. Outcome: officially en route to developing insulin resistance, a term describing an impaired ability of certain cells to respond to insulin by taking up sugar from the blood, requiring ever increasing insulin levels to trigger an appropriate lowering of blood sugar levels. Insulin is also important for the ability of our fat cells to do their job: store fat. Yet, the intricacies of the molecular network controlling the ability of fat cells to be fat cells and respond to different insulin levels remains incompletely characterised. How is the insulin signal encoded and decoded within the fat cells? This perplexing question has now taken us half way through the reasoning behind my PhD.
Let’s zoom out again. Our next stop is another group of “big” people. Yet, they are far from a common sight. These people suffer from a rare genetic defect that causes pathological overgrowth. The overgrowth may be local, such as a single finger, but it may also be generalised with additional complications, such as aberrant blood vessel formation, brain damage and substantial skeletal abnormalities. The molecular defect is often found in one of several genes whose protein products work together to enhance cell survival, growth and nutrient uptake/storage. Similar to an electronic circuit, aberrations in either one of these critical components disrupts the function of the system. This growth circuit is activated in response to several growth signals circulating in the body, including insulin. Indeed, the circuit is required for insulin-induced sugar uptake into muscle and fat cells; in other words, the appropriate storage of excess calories. One key component of this circuit is an enzyme termed p110alpha (I know, a very creative name, indeed!). This enzyme is part of a protein complex, PI3K, which acts as the main switch of the aforementioned growth pathway (again, think about this as an electronic circuit!). Hence, PI3K dysfunction corrupts the whole network, which may become autonomous and independent of growth-regulating signals. Therefore, it is no surprise that the PI3K growth pathway is commonly hijacked in cancer. It is, for instance, hyperactivated in 30-40% of all breast cancers, most commonly due to mutations in the aforementioned enzyme component: p110alpha. The same p110alpha mutations are also frequently found in people with early-onset overgrowth. Indeed, my supervisor’s lab was one of the first to identify that mutant p110alpha was the culprit behind the severe overgrowth of the famous lady with the big leg, Mandy Sellars.
One would think that the same mutant protein (p110alpha in this case) would generate pretty much the same symptoms in different people; yet patients with p110alpha mutations may present with severe anomalies such as life-threatening brain overgrowth, or just a single finger that is disproportionately big. How is that possible? The simple answer is that the defect arose during different developmental windows – perhaps very early in the development of one person, thus leading to widespread malformations, and quite late in the developmental trajectory of another person, affecting a very localised area of the body.
This explanation falls short in patients with equally widespread presence of different p110alpha mutations, who nonetheless exhibit a wide range of symptoms. What is going on? Let me bring in another analogy: a broken car. A car may be broken in many different ways, and not all of them will render it completely useless. We know that some p110alpha mutations only result in subtle hyperactivation of the growth circuit, whereas others leave it glowing. So despite being equally prevalent in the body, they may yield dramatically different symptoms. Clearly, the cell must have ways of sensing the different levels of p110alpha activation, and this would explain the conundrum. But what are these ways? This is the main question that I want to answer. I want to decipher the code used by this intricate circuit, which is present in all of us. Think about it like AM vs FM signal transmission when tuning the radio. Understanding if and how different magnitudes (AM) and frequencies (FM) of p110alpha activation control distinct cellular responses may promote the development of personalised therapies for patients with overgrowth, with high specificity and minimal toxicity because such treatments will be guided by the molecular knowledge about each individual p110alpha mutation.
Moreover, studies of rare genetic defects offer crucial insight into the normal biological function of the affected gene. Because fat expansion is such a common feature in patients with overgrowth, a detailed understanding of p110alpha – and thus PI3K – signalling dynamics may yield novel insight into fat development and subsequent growth, bringing us back to the urgent need to deal with the current obesity and T2D pandemics. A need that can only be met with improved biological knowledge.
Answering these questions won’t be trivial, it will be hard. But I am determined to give it a try! My future posts will be a mixture of science discussions, insights into my day-to-day life in the lab and some lay explanations of some really cool techniques. Stay tuned!