This year’s Lindau Nobel Laureate Meeting is dedicated to Physiology/Medicine, so there was a wealth of topics on health and diseases; from rare diseases to those that often make the headlines.
One Missing Protein
On Monday, Nobel Laureate Sir John E. Walker took to the stage at the Main Hall in Lindau’s Inselhalle to explain the science behind a little-known disease: citrin deficiency. Walker was awarded a Nobel Prize in Chemistry in 1997 for establishing the structure of the enzyme ATP synthase, which links two molecules together−adenosine diphosphate (ADP) and inorganic phosphate to form adenosine triphosphate (ATP). ATP is the molecule that carries energy in any type of living cell; those belonging to humans, plants, or microorganisms. There are many different proteins that supply energy to cells and one of them is citrin, which transports energy to liver cells. Citrin has other important functions, such as breaking down carbohydrates and making aspartate available for the urea system, helping to clear ammonia out of the body.
A rare mutation of the SLC25A13 gene causes citrin deficiency (CD), an autosomal recessive metabolism disorder. As Walker explained, the disease is quite often missed in infants. “There’s a big problem with failure to diagnose this condition early in life,” he said. Childhood is the silent period of the disease, which usually manifests in a preference for protein-rich foods and an aversion of sugar, as well as hypoglycemia, short stature, and a high amount of lipids in the blood (dyslipedemia). As ammonia isn’t sufficiently cleared from the system, symptoms of hyperammonemia begin to surface in adolescents and adults, and the condition worsens over time, eventually leading to liver failure. The only chance of recovery is liver transplantation.
Only at the Starting Line
At the moment, whole genome sequencing is advocated as a primary diagnostic tool, but this still isn’t accessible to the wider population. The scientific basis of CD isn’t sufficiently understood. “We need cell-based models, we need animal models, we have to get the infrastructure in place,” said Walker, “At the moment, we’re still at the starting line really.” This is just one type of rare disease, which could someday benefit from gene therapy.
Next Gen Science: Microbiology in Health and Disease
“Drug resistance is a major challenge in the control of tuberculosis,” said Nabila Ismail from Stellenbosch University.
Although the disease is well-known, the treatment success rate is 50-60%, with treatment options limited to oral drugs. Ismail and her colleagues looked at how some particular genetic variants of Mycobacterium tuberculosis, the bacteria responsible for tuberculosis, are resistant to bedaquiline and clofazimine.
Viral illnesses weren’t omitted in this session. Etori Aguiar Moreira, from the University of Bern, has been working on a live-attenuated vaccine for SARS-CoV-2. The intra-nasal vaccine was injected into mice and compared to the mRNA vaccine. Not only did the live-attenuated vaccine clear the virus from infected lung tissue faster than the mRNA vaccine, it also promoted a faster resolution of inflammatory responses.
The Long Road to A Cure For Hepatitis C
The last lecture on Thursday was given by Charles M. Rice, who won the Nobel Prize in Physiology or Medicine in 2020, with Harvey J. Alter and Michael Houghton, “for the discovery of hepatitis C virus.” Each of the Laureates was responsible for a different piece of the puzzle in the discovery, and it took decades to identify and clone the virus, as well as prove that the virus alone could cause hepatitis C. “For the students, I think it’s a story of persistence,“ said Rice.
Hepatitis C is a blood-borne disease, with millions of people infected with the virus each year. It’s a silent virus, causing few symptoms until the symptoms of cirrhosis, or liver damage, begin to surface. In the 1970s, soon after the discovery of hepatitis A and B, it was found that blood screened for these diseases still caused hepatitis in patients after a blood transfusion (10% of transfusion patients developed hepatitis). Harvey Alter demonstrated that the illness was caused by a virus and several years later, Michael Houghton isolated a single immunoreactive clone from a library of DNA fragments found in the blood of an infected chimpanzee. But could the cloned virus cause hepatitis C on its own?
Rice faced many years of setbacks trying to demonstrate that this was so. The problem was the variability of the viral genome, poor replication in cell cultures, as well as the lack of a mouse model. Evidence of infection in chimpanzees with an infectious clone of the hepatitis C virus (HCV) was achieved in 1997. Once it was demonstrated that HCV could replicate in cells in the laboratory, Rice and his team created self-replicating RNAs from the virus, and identified adaptive mutations. This led to the creation of a complete RNA replication system for HCV. “HCV is now one of the best studied RNA positive strand viruses,” said Rice.
Fortunately, the decades of research have led to effective therapeutics for the disease. In 2011, hepatitis C had a 75% cure rate, but it was treated with protease inhibitors, which had many side effects. Only four years later, the cure rate was 95%; an effect of direct acting antivirals. These remarkable new treatments have few side effects and can eliminate HCV from the body in 8-12 weeks. “What we don’t have, and it’s kind of embarrassing, is a vaccine for hepatitis C,” admitted Rice. Despite the progress, there is still work to be done. “We’re still not out of the woods yet,” said Rice, “Many people don’t know they’re infected.” Testing for hepatitis C is still a challenge in many parts of the world.
Rice concluded his lecture with a favourite quote from medical researcher Lewis Thomas, “Scientific research works, it is the only way to get at the underlying mechanisms of disease, and the only way to learn what to do about them.”