By analysing specific proteins in the blood, researchers can identify haemoglobin variants linked to serious inherited blood disorders such as sickle cell anaemia or beta thalassaemia in just minutes. The method could replace slow specialist analyses and give families answers while a pregnancy is still at a stage at which decisions can be made.
For many expectant families, the wait for answers can feel like the longest week of their lives.
Today, families often have to wait up to a week for a final answer as to whether a child has a serious inherited haemoglobin disorder – in which the blood’s ability to carry oxygen is impaired, such as sickle cell anaemia or beta thalassaemia.
“For disorders of the red blood cells during pregnancy, it is crucial to find out quickly whether the child is at risk,” says Professor and Chief Physician Nicolai J. Wewer Albrechtsen from the Department of Clinical Biochemistry and the Copenhagen Center for Translational Research at Bispebjerg and Frederiksberg Hospital, Denmark. “If there is a risk, further diagnostic work-up, genetic counselling and, if necessary, preparation for the birth need to begin.”
Researchers have now found a way to dramatically reduce this waiting time. Instead of relying on genetic analysis, they can use advanced protein analysis to determine within minutes whether the child’s haemoglobin is functioning normally – or shows signs of serious disease.
Tasting the cake instead of reading a baking recipe
Sickle cell anaemia and beta thalassaemia cause problems in different ways.
In beta thalassaemia, genetic mutations mean that the body does not produce enough haemoglobin to transport oxygen around the body. In sickle cell anaemia, by contrast, the haemoglobin itself is deformed and does not function properly.
Under current practice, these disorders are typically investigated by first analysing the red blood cells biochemically, followed by genetic screening for errors in the genes that control the body’s haemoglobin production. This approach, carried out in specialised hospital laboratories, is thorough but also slow and resource‑intensive.
“We have been using this approach for many years,” explains Nicolai J. Wewer Albrechtsen. “Reading genetics is somewhat like reading a baking recipe to work out whether a cake has the right tastes. Simply tasting the cake is often easier – and that is exactly what we do when we look directly at the protein composition.”
Faster, biologically accurate and ready for routine use
Instead of analysing DNA, Nicolai J. Wewer Albrechtsen and colleagues have developed a method that examines the haemoglobin in the blood itself.
Haemoglobin is a protein, and proteins can be analysed using mass spectrometry, in which researchers measure their mass and chemical composition. With the help of machine learning, characteristic patterns in these protein measurements can be recognised and matched to known disorder-associated variants of haemoglobin.
This is known as proteomics – studying which proteins are present in the body and how they function.
If a protein weighs slightly more or less than expected, this reflects changes in its amino-acid composition, which are a direct consequence of genetic variation. Such changes can alter the structure of haemoglobin and, in turn, its ability to transport oxygen. With sufficiently detailed analysis, researchers can even work backwards from the protein and infer which errors are present in the underlying genetic code.
“DNA does not tell you whether you are ill or not,” says Nicolai J. Wewer Albrechtsen. “That information lies in the proteins, which carry the biological function. That is why examining the proteins rather than the DNA can be more informative in determining whether someone has these blood disorders. This is what we can now demonstrate in practice, by performing a fully automated mass‑spectrometry analysis in just 21 minutes.”
The new analysis is therefore fast enough to be included in routine diagnostics on the same day the blood sample is taken. According to the researchers, the test costs around DKK 200 – a price point that makes the technology realistic as a standard hospital analysis.
The clinical applicability of the method is supported by close collaboration with clinicians at Rigshospitalet, including haematologist Andreas Glenthøj, who contributed to the clinical validation of the approach. The research has been published in HemaSphere.
When proteins reveal disease before genetics do
According to Nicolai J. Wewer Albrechtsen, the study also points to a method that could prove important for investigating a range of other childhood diseases – including disorders affecting the heart, brain and liver.
“If a disease is caused by a protein that is not functioning properly, measuring the protein directly makes more sense,” he says.
The approach effectively works like a blood test 2.0, picking up diseases caused by genetic defects that produce faulty proteins very rapidly.
The technology therefore offers a very precise way of determining whether children, in particular, have certain haemoglobin disorders.
Conversely, focusing solely on genes means analysing the recipe rather than the finished protein that actually has to do the work in the body.
A genetic defect does not always have real biological consequences. Both genes and proteins are often cut, folded and modified before proteins reach their final form. In some cases, errors may be removed or corrected along the way.
For many years, the dogma has been that congenital diseases should be investigated by examining DNA,” says Nicolai J. Wewer Albrechtsen. “But perhaps our attention should shift to the proteins that do the biological work. This is like tasting the cake to determine whether it is right instead of trying to guess from the recipe.”
If the approach gains wider acceptance, it could change how congenital diseases are diagnosed – by tasting first and reading the recipe afterwards.
