Mother's milk as a source for COVID-19 antibodies: Interview with Kelly Dingess
Mother’s milk is a marvelous mix of nutritional and bioactive components. Among its myriad qualities, the transference of a mother’s immune system to the infant through antibodies is perhaps the most spectacular. The antibodies in human milk provide the infant protection against pathogens the mother has previously encountered, including the new coronavirus SARS-CoV-2. In the search for active antibodies that can be used to treat COVID-19, the disease caused by the virus, researchers are now turning to these immunological qualities of mother’s milk.
Antibodies derived from human milk may provide a [more] potent therapeutic against SARS-CoV2
“Antibodies found in human milk potentially have different functions than those found in blood serum,” explains Kelly Dingess, human milk researcher at Utrecht University and the Utrecht Molecular Immunology Hub. In an interdisciplinary project, Dingess has joined forces with other researchers in the life sciences community to study these antibodies. “Antibodies derived from human milk may provide a [more] potent therapeutic against SARS-CoV2,” she adds. Small wonder the spotlight is on human milk research.
As a nutritional chemist, Dingess has studied human milk for most of her academic career. She is interested in the components of human milk. “Human milk is unlike any other biofluids such as serum or plasma,“ she starts. Aware of the importance of human milk, she is determined to study components of the substance at the molecular level. “To analyse human milk, you have to develop new experimental methods and really think things through,” that is what appeals to Dingess who is now in the final year of her PhD and describes herself as mass spectrometry specialist. Much is known about the nutritional and bioactive content of human milk, from academic research but also from formula companies that want to replicate human milk as closely as possible. “One thing formula cannot replace are the antibodies that mothers pass to their infants,” Dingess notes. While antibodies were initially only part of her research, they are now her central focus. Interdisciplinarity is encouraged in the Utrecht Life Sciences community and through the Molecular immunology Hub she is now working with researchers in various groups to study the SARS-CoV-2 antibodies. “Of course, with the COVID-19 pandemic, these antibodies receive special interest” she notes, which put her research efforts into the spotlight. In a project with the Dutch human milk bank, Wageningen University, Amsterdam University Medical Center, Viroclinics and Sanquin she is now working solely on immunology. “The shared maternal-infant environment is a great system to protect infants. It’s fun to study,” she adds.
Moms can get excited about their milk, they do something really cool: they make the perfect product for their baby
Human Milk Research
The human milk research community is surprisingly small for such an important substance. Yet these all-important antibodies, which cannot be reproduced in the lab, are extremely vital for infant immune responses. “Moms can get excited about their milk, they do something really cool: they make the perfect product for their baby,” she adds. “We have a big picture overview of the composition of milk, so what we focus mostly on now is functionality of the three major components: carbohydrates, fats and proteins. Human milk oligosaccharides, for instance, are unique carbohydrates only found in human milk. “And there are hundreds of those,” Dingess exclaims. Their function is an active field of research. “Even identifying all of them is quite complex. Add to that the fact that milk constantly changes in constitution, from birth until the infant is about 2 years of age. Relative concentrations of components affect functionality and so on. “You could spend a lifetime studying that alone,” says Dingess. Enter antibodies: these complex proteins exist in hundreds of billions of configurations and are unique to each individual. “If we’d study the antibodies in my blood and compare them to yours, we’d hardly have any overlap,” explains Dingess. The same goes for antibodies in milk: no two mothers produce the same milk, even without considering genetic components. Still, milk from one mother can be used to feed another’s infant, so there is compatibility. The antibody makeup of milk may differ, but the universal quality of milk does not.
We already identified specific antibodies in human milk that respond to SARS-CoV-2.
The interdisciplinary work on COVID-19 antibodies truly shows how the research community has come together to study the newly emerged virus. “In Amsterdam, researchers use an ELISA plate-based method to test the functionality and activity of SARS-CoV-2-specific antibodies, which is great because it sheds light on the exact workings of antigens. In Utrecht, we are looking at more fundamental questions, unraveling the complexity and diversity of antibodies.” The research is complementary and shows open science at its best. “Antibodies are more complex than people think, perhaps that’s because it’s one word that describes a whole set of molecules,” sighs Dingess. Antibodies are complex protein structures derived from B-cells, which can exist in hundreds of billions of variations. The Y-shaped molecule has a variable region in the tips of the Y attached to a constant region at the base. The variable region recognises different bacteria, viruses or even specific cell-surfaces and marks it friend or foe.
“We have developed a way to identify different variations of antibody based on their mass. This allows us to compare antibodies across different biofluids, for instance milk and serum,” Dingess explains. Mass spectrometry can detect minute differences in mass, which in turn are correlated with retention times to distinguish between antibody variations. “We’ve measured hundreds of variations so far, and while that only scratches the surface of the total number of variations, we already identified specific antibodies in human milk that respond to SARS-CoV-2. We use a technique similar to the one used in Amsterdam, by testing how the antibodies we isolate react to the SARS-derived spike proteins.” The group Dingess works in uses a top-down approach to identify antibodies. This means that, rather than cutting the protein up, identifying the parts and extrapolating the original from that, the group isolates a simi-intact protein and identifies it through exact measurements. “It’s a bit like how electron microscopy allows you to take a picture of a protein: mass spectrometry gives you the information you need to take that picture, and bioinformatics does the rest. “Bioinformatics is hugely important in my work, although I personally prefer to focus on the molecular stuff,” says Dingess, who has always been fascinated by the molecular workings of life.
From peptide profiling to antibody research
Originally from the US, Dingess did an internship at Wageningen University and moved to Utrecht for her PhD. “The PhD was in line with my research in Wageningen so it was easy for me to transition. This was a good thing, because I still had a lot to learn about mass spectrometry and other molecular analyses and Albert Heck’s lab has an amazing variety of equipment for that,” she recalls fondly. Her PhD focused on profiling endogenous peptides in human milk. “Endogenous peptides are peptides that are broken up by specific enzymes in the mammalian glands, to increase their functionality in infants, who do not have these enzymes. Profiling both endogenous peptides and protein composition allowed her to gain a complete picture of this system. “It was really interesting to find out what changes these proteins undergo before they are assimilated into the milk,” Dingess says. While her group was already studying proteins in human milk, it was a relatively small step to focus on one specific protein (antibodies) when the COVID-19 pandemic hit.
You have the antibodies which already have the right structure to recognise the virus at the location where they’re needed most!
Human milk antibodies are different from human blood antibodies
Antibodies in human milk are structurally different than those found in blood serum. They are more similar to the antibodies found at epithelial cell surfaces of the upper respiratory tract, the predominant point of entry for the SARS-CoV-2 virus. “What is very interesting is that antibodies in human milk more closely resemble the IgA antibodies that are secreted by the mucus layer that coats our airways. This class of antibodies is thought to be more effective than the type that circulates in our blood.” The secreted form is our first-line defense at recognising pathogens and getting rid of them. “So maybe milk could even be a better form of therapeutic than blood serum because you have these potentially more active antibodies against SARS-CoV-2.” That’s what Dingess is interested in: elucidating the difference in structure between secreted antibodies and those found in serum. “It would be a major thing if you could pinpoint that difference.”
While Dingess and her colleagues are working hard on these fundamental questions, the Dutch milk bank is already putting the human milk antibodies to action. “Ice cubes made from donor milk are given to people vulnerable to the virus. That’s a great idea: as you are sucking the ice cubes, they slowly coat the lining of your respiratory tract, which is most vulnerable. So you have the antibodies which already have the right structure to recognise the virus at the location where they’re needed most! That’s beautiful in its simplicity and effectiveness. “It’s not rocket science, but it’s equally cool,” says Dingess.
Why the IgA antibodies in milk are more effective than those in serum is not really known. “It could be that the difference is already in the B-cells they come from. That idea has merit but then the question is: why do these B-cells differ. It’s also possible that it’s a function of being secreted. It is known that when the antibody travels through the epithelium it picks up another protein in the process, becoming more complex, which may give it different function.” Dingess is fascinated by all these questions, which require an interdisciplinary approach to answer. “Working together with so many researchers to answer the big questions is a thrill. It’s by no means a solo effort. Dozens of researchers from various disciplines, dedicated lab technicians and support staff and not to forget the thousands of breastfeeding moms who donated their milk to an equally important team of people that collected all that milk for our research. With the end of her PhD in sight and things neatly wrapped up, Dingess is looking forward to bigger things.