Poisoned Bodies

Frida was one-and-a-half years old when she began to suffer symptoms. One day, she suddenly vomited and lost consciousness on the way to see a pediatrician. Her life was saved at the last moment in intensive care. Frida was diagnosed as having a disease with the unwieldy name methylmalonic aciduria (MMA) – a rare, inherited metabolic disorder. 

Her body lacks an enzyme that it needs to break down certain proteins. As a consequence, toxic substances build up in her body and damage the brain in particular and the kidneys over a long period of time. In the years after Frida was diagnosed, she also experienced the symptoms typically associated with this disease. She suffered from delayed physical development, only learned to talk at a later age, and needs a wheelchair and rolling walker.

Across Switzerland, there are only around 30 people with the same diagnosis as Frida – which is why MMA is classified as a rare disease. Around 8,000 of these rare diseases are currently known. They’re diseases that affect fewer than one in every 2,000 people. Most of these diseases are caused by an inherited defect in a single gene. They often manifest during childhood, though this is not always the case. 

In Switzerland, there are around half a million people with a rare disease. So they’re not that rare overall, but each individual disease is rare in its own right, which is why physicians rarely encounter these diseases. It’s no wonder, then, that for many sufferers the journey to getting a diagnosis often resembles an odyssey. “On average, it takes five years for a person with a rare disease to get the correct diagnosis,” says Olivier Devuyst. The professor of physiology at UZH specializes in kidney disorders and co-chairs the University Research Priority Program ITINERARE at the University of Zurich, which focuses on rare diseases and looks for new treatments.

Methylmalonic aciduria is a typical and atypical rare disease at the same time. It’s atypical because the disease can be diagnosed quickly and easily with a blood and urine test – and this is what happened in Frida’s case. Most sufferers are fortunately spared a multiyear odyssey. In contrast, MMA is typical in that, like many rare diseases, it affects the metabolism and results in slow poisoning of the body. “Rare diseases are extreme manifestations of more common diseases,” says Devuyst. For example, there are rare kidney disorders, rare forms of diabetes or high blood pressure. They’re extreme because the diseases are often more pronounced and occur at an earlier stage in life than other diseases.

That’s why research into rare diseases can also help teach us more about common diseases – and vice versa. But the researchers face particular challenges. As the diseases are by their very nature rare, there are only a very small number of patients but also few experts in the specific disease. This is why international cooperation is essential, but complicated because different countries have different healthcare systems. 

Funding is also a big problem: pharmaceutical companies are less interested in rare diseases because of the small number of treatments, and research into these diseases is underfunded as a result. “That’s why for around 90 percent of rare diseases, there’s still no therapy that targets the causes,” says Matthias Baumgartner, Head of the Division of Metabolic Diseases at University Children’s Hospital Zurich. But in most cases, the symptoms could be treated. “Depending on how feasible this is, patients will also enjoy a more or less decent quality of life.” 

Baumgartner together with Olivier Devuyst and the geneticist Janine Reichenbach are the directors of ITINERARE. The program comprises 21 research groups. They explore not just medical, but also economic, ethical and social questions in relation to rare diseases. Disciplines as varied as medicine, informatics, pharmacology, psychology, ethics and law all work together here. “This broad interdisciplinary approach probably makes us unique in Europe,” says Baumgartner.

The research groups focus on diseases in which people already have expertise in Zurich. Depending on the disease, there are even traditions stretching back decades – certain rare diseases were actually discovered at the University Children’s Hospital Zurich, for example. The fact that the hospitals, UZH and ETH Zurich are located in close proximity is a huge advantage for the interdisciplinary approach of ITINERARE. The aim of the group is to make Zurich a world-renowned center for researching and treating rare diseases, including for patients from abroad.

“In recent decades, research has made huge strides in understanding rare diseases,” says Olivier Devuyst. This has been made possible in particular thanks to advancements in genome analysis. For example, the underlying change in the genetic material is known for most rare diseases today. It’s now all about understanding the mechanisms that this triggers, and then developing suitable therapies.

Artificial intelligence can also help with this. “AI enables us to speed up the search for active ingredients and develop even more precise disease models,” says Devuyst. This is also where rare diseases also have an upside: “Unlike common diseases, a rare disease is generally triggered by just a single gene, which is why the chance of finding an effective treatment is higher.”

When it comes to looking for new therapies, there are essentially two approaches. Either the genetic defect can be repaired using gene therapy, or its impacts can be minimized. In this latter context, the researchers hope that existing drugs will also prove to be effective in treating rare diseases. This is because the drug approval process is much more straightforward when drugs are repurposed.

The researchers in Zurich are also very keen to focus more on developing nutritional therapies that have an effect on the metabolism. They’re also a key tool in treating MMA. It’s why Frida will need to follow a low-protein diet and nutritional supplements for the rest of her life. Nutritional advice plays an important role in her treatment and care. But Baumgartner and Devuyst hope that in future, drugs might also be able to help break down the toxins in the body or gene therapy might be able to correct the genetic defect.

ITINERARE was launched in 2021. Three clinical studies are already underway – and more are set to be added in the next few years. The patients who have rare diseases are extremely motivated to take part. “As each disease has so few patients, they’re much more interconnected and are highly motivated,” says Baumgartner, based on his experience. With rare diseases in particular, patients are very much involved in the process, for example when it comes to deciding on what aspects should be the focus for research or what kind of treatment will be beneficial for them.

Psychological and ethical questions also play a key role in the program. Patients who have rare diseases face a very specific situation, because they’ll often have to live with their disease for their whole lives. Thanks to improvements to treatments in recent decades, the life expectancy of many patients has in some cases been significantly extended. This is why it’s now so important to consider the situations these people will face in adulthood and as they grow older.

For example, as part of the URPP, psychologists are examining the questions of what restrictions patients have to live with or what support they require. It’s become apparent that children are often amazingly good at dealing with their disease – better than their closest relatives. For their parents, the odyssey of getting a diagnosis and the lack of prospects of any cure are a great burden. Sometimes they’re also plagued by feelings of guilt because they’ve passed on a disease to their child. This is why psychological support is also increasingly being offered at the treatment centers.

In terms of structure, the treatment of rare diseases has come on leaps and bounds. Following a national action plan, nine diagnostic centers have now been created at major hospitals across Switzerland. One of them is the Center For Rare Diseases Zurich, which is an interdisciplinary collaboration between the University Children’s Hospital Zurich, the University Hospital Zurich, Balgrist University Hospital and the Institute of Medical Genetics at UZH.

Once a diagnosis has been made, treatment will then be provided at one of 36 reference laboratories for rare diseases across Switzerland. They are currently being set up, as is a register of rare diseases. According to Baumgartner and Devuyst, the fact that there will soon be legislation in place to make it a requirement to register rare diseases is also a big step forward. 

The two researchers would also like to see the process of accessing genetic diagnostics made easier in Switzerland. “These would be vital steps in making sure that patients can get a diagnosis earlier in future and thus access the right treatment sooner,” says Baumgartner. The University Research Priority Program ITINERARE wants to play a big part in helping to make this reality and continue to improve the life prospects for patients like Frida.