Creating a Celiac-Safe Wheat: Part 1

The treatment for celiac disease sounds simple — stop eating wheat — but it makes life very complicated. The diagnosis means no more tasty, nutritious wheat foods, constant vigilance for ingredients and never-ending requests to avoid cross contamination.

What would it take for celiacs to be able to have their wheat — and eat it too?

Until now, much of the research on celiac disease has focused on the human element of the disorder, in which a person cannot tolerate gluten — a protein matrix formed by gliadin and glutenin, present in wheat, rye and barley — which causes damage to the lining of the small intestine and prevents the absorption of nutrients. The best way to stop the symptoms is to stop consuming gluten — and hence the gluten-free movement.

Instead, what if researchers could find a way to fix the gluten itself so that it would cause a more mild reaction or even no reaction at all?

That is what researcher Dr. Chris Miller is hoping to find in two-year project funded by Kansas wheat farmers through the Kansas Wheat Commission.

Too Big to Tackle?

Miller is a biochemist working on cereal proteins, a very specific field, but one that makes him uniquely qualified to tackle this monumental task. That’s why folks from the Kansas Wheat Commission and Kansas State University approached him time and again, asking what it would take to create a celiac-safe wheat. Miller initially rebuffed their requests.

“The project seemed so intangible, too big to try and tackle,” he said.

Eventually, however, Miller explained he sat down to “think about the problem honestly” and penciled out a checklist of what exactly was needed to find a celiac-safe wheat — and one that could still make a great-tasting, good-looking loaf of bread.

The answer, he discovered was nothing more than “straight-forward biochemistry.” To find a celiac-safe wheat, a researcher needed to first identify the spectrum of celiac disease reactivity present in the wheat grown by Kansas farmers.

“To create a celiac-safe wheat variety, we need to understand the natural variation in reactivity among our existing germplasm,” Miller said. “Identifying a cultivar with naturally low levels of reactivity will provide ideal starting material for further reduction through breeding and biotechnology.”

In 2014, Miller submitted a research proposal to the Kansas Wheat Commission. With $112,000 of funding in hand, he commenced his work.

Racking and Stacking Varieties

In the first phase of Miller’s research, he is working to identify the level of celiac disease reactivity in four different categories: currently planted Kansas wheat varieties, historically popular wheat varieties dating back to the early 1900s, new experimental wheat lines and wild wheat relatives.

To start, Miller is working with Dr. Allan Fritz, leader of Kansas State University’s wheat breeding programs. Fritz can draw from the vast seed bank of the Wheat Genetics Resource Center  — in which more than 2,500 wheat species are housed just down the hall from Miller’s office and lab space at the Kansas Wheat Innovation Center — to select around 300 cultivars, short for samples of a cultivated variety that is more pure than a naturally occurring relative.

Miller will literally put these samples to the test to see what level of celiac disease reaction each causes.

Antibody and Protein: A Natural Pairing

To understand how the 300 different samples will be tested, one first has to understand the biological reaction of a celiac to a wheat protein.

Each human immune system builds a unique arsenal of antibodies over time. Each antibody is programmed to recognize a specific agent as a threat — an allergen, a virus, etc. When the antibody spots its target, it attacks, sticks to it like glue and does not let go — all the way through the human body. This is how the human body fights off disease.

What makes celiac disease tricky is that it is a spectrum disorder. That means that every celiac sufferer’s sensitivity to gluten is a little different, which is why some celiacs just get an upset stomach and others end up in the hospital after consuming gluten.

From the wheat side, this means that there is not one antibody that reacts to one protein. Instead, an array of human antibodies and their variations react to potentially hundreds of different wheat proteins — or even just fragments of proteins.

Researchers have identified two main human celiac disease antibodies, known as HLA-DQ2 and HLA-DQ8. However, there are numerous variations of these two antibodies that are not always included in research as scientists are still working to identify them.

For Miller’s project, he has gained access to an extremely comprehensive, proprietary anti-body pool for human celiac disease — one that goes into far more detail than just the two main antibodies. Armed with a larger pool of human antibodies to test against wheat proteins than a typical researcher, he can take a deeper look into the wheat proteins that cause the celiac disease reaction.

Making a Rainbow Protein JELL-O Salad

To match wheat proteins with the custom-made human antibodies with which they react, Miller will use a process called anti-body staining.

In this process, Miller will take all of the individual proteins from one wheat variety and stick them in a gel — think like pieces of fruit in Grandma’s prize JELL-O salad. The human antibodies are then washed with a colored stain and then mixed into the gel. If the human antibody finds its wheat protein target – they stick together and show up as a colored band. Proteins without an attached antibody remain invisible, and unmatched antibodies simply wash away. The more dense the color, the more antibodies that reacted, or the higher level of reactivity for that specific wheat variety to human celiac disease.

With this information, Miller can rank each of the 300 cultivars for their level of reaction for human celiac disease — information which does not currently exist.

Breeding a Better Wheat for Celiacs

Wheat breeders, like Fritz at Kansas State University, can use Miller’s rack-and-stack to screen new and upcoming varieties and even target those varieties that have a lower naturally occurring level of reaction for human celiac disease.

Scientists generally recognize that lower levels of reactive proteins will mean less severe reactions for celiacs — think potentially a tummy ache instead of a trip to the hospital. Mild celiacs may not even have a reaction at all.

That result is still years away, but Miller said categorizing existing wheat varieties and their reaction for human celiac disease is a giant first step.

His research proposal stated, “Using wheat varieties with naturally low reactivity will decrease the number of proteins that must be genetically removed or altered to meet our long-term goal of developing a truly celiac-safe wheat variety.”  

For the rest of the story, read about the second phase of Miller’s research.

by Julia Debes

Phase II Summary

The second phase of Miller’s research will identify any wheat protein fragment that could potentially react to any one person’s antibodies and create a celiac reaction. Whereas the first phase of his research tested 300 different cultivars, this second phase will examine only a single sample.