Blood-type conversion process informed by crystallography now in pre-clinical trials

Application of a discovery that was aided in part by the Canadian Light Source (CLS) at the University of Saskatchewan has advanced to pre-clinical trials and is now the basis of a dynamic new startup.

In 2019 Dr. Stephen Withers and colleagues at the University of British Columbia identified a series of enzymes that can be used to modify the chemical structure of a sugar antigen on the surface of blood cells, thereby converting a Type A blood cell to a Type O blood cell — the universal donor type. The team used crystallography on the CMCF beamline at the CLS to better understand how the enzymes cause this change.

These same antigens are also present on the surface of solid organs, and Withers and colleagues have demonstrated that the enzymes they discovered are very efficient at making this conversion both on the surface of red blood cells and on the surface of donated human organs such as lungs or kidneys.

Avivo – the company launched to bring this technology to the marketplace – is now busy finetuning both applications. If successful, this exciting advance would be a huge step forward in addressing shortages in blood and organ supply here in Canada and around the world. “The idea is that we could broaden the supply considerably,” says Withers, a professor in the Departments of Chemistry and Biochemistry and the Michael Smith Laboratories at UBC. “It would remove the need to worry about blood type in transfusions (and organ donations).”

John Barclay, VP of business development with Avivo says the company is focusing first on applying their approach to organ donations because it’s considerably more straightforward to remove the conversion enzymes prior to transplantation than it is to remove them before transfusing blood.

When a donor organ is harvested, it will often be placed on a perfusion device that continuously pumps a preservation solution, or perfusate, through it to maintain the tissue’s viability. The enzymes discovered by the Withers team can be added to the fluid mixture, where they essentially convert the blood type of the organ to the universal blood type. After that conversion, the solution – including the enzymes — is essentially “rinsed” out of the organ as part of the existing transplant process. Removing the enzymes from red blood cells or whole blood is considerably more challenging, says Barclay.

The Avivo team has demonstrated the process works using a set of human lungs that were deemed not viable for transplanting into a patient. “We’ve shown that we can remove those antigens and convert an A type lung to an O type lung quite readily,” says Withers. “We’re working on kidneys at the moment…so that’s very exciting.”

This application of their technique is in pre-clinical trials now; they’re hoping to move on to clinical trials (i.e., in human patients) in 2024.

How the Canadian Light Source contributed

“The information we learned from it (crystallography) was very supportive in knowing exactly the structure of the enzymes we’re adding,” says Withers. This information, he says, will be very useful if they need to modify the structure of the enzyme.

It will also be valuable when they seek regulatory approval, to be able to present the complete structure of the enzymes. “We’ve learned a lot more through having that information, which may be useful in the future,” says Withers.

Read more on the CLS website

Image: Steve Withers, John Barclay, and John Coleman.

The mechanism of the most commonly used antimalarial drugs unveiled

For centuries, quinoline has been an effective compound in antimalarial drugs, although no one knew its mode of action in vivo.

Today, a team led by the Weizmann Institute has discovered its mechanism in infected red blood cells in near-native conditions, by using the ESRF, Alba Synchrotron and BESSY. They publish their results in PNAS.

Malaria remains one of the biggest killers in low-income countries. Estimates of the number of deaths each year range from 450,000 to 720,000, with the majority of deaths happening in Africa. In the last two decades, the malaria parasite has evolved into drug-resistant strains. “Recently, the increasing geographical spread of the species, as well as resistant strains has concerned the scientific community, and in order to improve antimalarial drugs we need to know how they work precisely”, explains Sergey Kapishnikov, from the University of Copenhagen, in Denmark, and the Weizmann Institute, in Israel, and leader of the study.

Plasmodium parasite, when infecting a human, invades a red blood cell, where it ingests hemoglobin to grow and multiply. Hemoglobin releases then iron-containing heme molecules, which are toxic to the parasite. However, these molecules crystallise into hemozoin, a disposal product formed from the digestion of blood by the parasite that makes the molecules inert. For the parasite to survive, the rate at which the heme molecules are liberated must be slower or the same as the rate of hemozoin crystallization. Otherwise there would be an accumulation of the toxic heme within the parasite.

>Read more on the ESRF website

Image (taken from BESSY II article): The image shows details such as the vacuole of the parasites (colored in blue and green) inside an infected blood cell.
Credit:
S. Kapishnikov

Two other institutes, BESSY II at HZB and ALBA Synchrotron, have participated in this research. Please find here their published articles:

> X-ray microscopy at BESSY II reveal how antimalaria-drugs might work

> The mechanism of the most commonly used antimlalarial drugs in near- native conditions unveiled

Scienstists make breakthrough in creating universal blood type

Enzymes in the human gut can convert A blood type into O.

Half of all Canadians will either need blood or know someone who needs it in their lifetime. Researchers from the University of British Columbia have made a breakthrough in their technique for converting A and B type blood into universal O, the type that is most needed by blood services and hospitals because anyone can receive it.
In a paper published in Nature Microbiology, Stephen Withers and a multidisciplinary team of researchers from the University of British Columbia show how they successfully converted a whole unit of A type blood to O type using their system.  They were able to remove the sugars from the surface of the red blood cells with help from a pair of enzymes that were isolated from the gut microbiome of an AB+ donor.
The Canadian Light Source (CLS) at the University of Saskatchewan (UofS) played a critical role in understanding the structure of a previously unknown enzyme that was part of this pair. The researchers were unable to identify what this unique enzyme looked like from the gene sequence they had.  Crystallography, done at the CLS, was crucial for the researchers to understand how this enzyme works and why it had a particular affinity for the A type blood.

>Read more on the Canadian Light Source website