Seeing the “Zebras” Among the Horses

With rare diseases, their designation suggests a scarcity in the human population. In reality, this couldn’t be more misleading. Although they affect seemingly small groups of people, according to the National Institutes of Health (NIH), there are around 10,000 rare diseases in the United States alone, with over 30 million affected people. That’s only accounting for those that have been identified and diagnosed. For many of these diseases causes remain unidentified, but the majority are thought to be caused by genetic mutations.

One of the genes involved in rare disease manifestations is PIK3CA, responsible for phosphatidylinositol 3-kinase (PI3K) production, with the collective term describing this group of disorders as PIK3CA-related overgrowth syndromes (PROS). To understand the mechanism a bit better, let’s go back to the basics - cellular signaling. Signal transduction inbetween cells is facilitated by receptors activated upon a signal, passing the message further along to other receptors. Receptors and messengers downstream can be thought of as the post delivery service - passing the message along so that, ultimately, a cell will receive its long-awaited parcel and react! With the PIK3CA gene, what happens when it mutates and the product it gives is not exactly what we want it to be? Due to it’s involvement in many cellular processes, including growth and survival, it has many detrimental effects.

As CLOVES Syndrome Community describes it, CLOVES, one of the disorders belonging to the PROS group, can be explained as:

• Congenital - trait you are born with

• Lipomatous - concerned with soft fatty tissue, often seen in patients

• Overgrowth - showcasing accelerated tissue growth

• Vascular Malformationsaffecting the circulatory system

• Epidermal Neuvs - skin lesions

• Spinal/Skeletal Anomalies or Scoliosis - affecting skeleton formation

This acronym showcases well just how varied the symptoms can be and how many systems the PIK3A gene regulates, be it directly or indirectly.

What about treatment? When it comes to finding a cure, treatments where the PIK3CA gene is targeted are available and there is keen interest in developing therapies like this, not only for PROS but also cancer. The problem with this approach is that shutting off the entire gene will ultimately lead to losing the beneficial “signals” it’s producing as well. While this may work well for some, for the majority it will cause a plethora of undesirable side effects, not fixing the issue entirely. That is why the current research focus is on mapping the PIK3CA signal pathways and understanding how they interact. This will allow for understanding discrete interactions while also looking at the bigger picture. The reason why this is key is due to the aforementioned diversity when it comes to gene mutations.

In the long run, the answer to not only PROS, but possibly most rare diseases is the personalized healthcare model. No one person is the same, but for people living with rare conditions especially, this could open a door of possibilities in terms of management or even curing their conditions. Good understanding of biology, supplemented by other disciplines such as mathematics and physics, will undoubtedly be of great benefit when designing strategies suitable for each patient’s treatment. What is crucial for this approach is the individual assessment and tailoring of treatments. Although seemingly futuristic, many companies today are already introducing a personalized approach, and there is no shortage of research and development in this area. In fact, the School of Medicine at the University of Dundee is already involved in tailored therapeutic approaches catered to individuals sharing similar characteristics by implementing bioinformatics - focusing particularly on genome-wide association studies (GWAS), as well as proteomics and RNAseq analysis, which has the potential to further tailor healthcare.

But what has led to many breakthroughs in this research has been the unwavering support and contributions of PIK3CA-related conditions communities worldwide.

When raising awareness of rare diseases, such as these, it’s important to highlight the amazing people involved in making it happen.

CLOVES Syndrome Community and GoPI3Ks are both charities that are great examples of that. Another community, CaRAVAN, advocating for vascular anomaly research has also contributed greatly to the cause. These are not only great spaces to go for seeking support and help for individuals and their families but also for taking action and seeking improved healthcare for those affected. The most effective way to find a cure for PROS remains to invest in research and understand the underlying pathways to target. Therefore, raising awareness and contributing to these collective efforts are greatly appreciated and could be life-changing to many. And finally, this article would not be possible without the guidance of Dr Ralitsa Madsen, a researcher and advocate for open science and public engagement, who has made a massive impact within the PROS community and tirelessly continues to contribute her time and expertise towards this cause.

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Phoebe Wilman & Livvie Baird

Issue #100 Cover is by our previous Creative Directors: Phoebe

Wilman & Livvie Baird. Thank you both so much for all the work you've done this year and good luck for after Uni!! ❤