Diagnostics
failure and death,” explains Donald Ingber, founding director of Harvard University’s Wyss Institute for Biologically Inspired Engineering. According to the WHO, sepsis is responsible for one in five deaths worldwide. What makes the disease so deadly is the rate at which it progresses, coupled with the time it takes to diagnose and treat it, with studies estimating that the chance of sepsis progressing to severe sepsis and septic shock, causing death, rises by 4% to 9% for every hour treatment is delayed. “It’s caused by infection, but you often don’t know what the cause of that infection is,” says Ingber. This, he adds, is because the way in which most pathogens are detected is using the “75-year old technology” that is blood cultures, which means “it takes days before you get results”. Molecular diagnostic methods like PCR and mass spectrometry can identify pathogens more quickly, but Ingber says these are expensive for hospitals and they can still take “a day or so” because the pathogen must be multiplied for detection to be accurate, which is too long when every hour brings patients closer to death.
For reasons still unknown to the world of medical research, the progression of sepsis happens even quicker in children, with 40% of all sepsis deaths occurring in children under five years old, according to the WHO. The current standard of care tends to be the use of broad- spectrum antibiotics but, in many cases, the pathogen is never detected and so they miss the target. That’s why Ingber and his colleague Michael Super, senior staff scientist at the Wyss Institute, have been on a journey spanning more than a decade to create a new technology designed to shorten the time from diagnosis to treatment dramatically through broad-spectrum pathogen capture.
Creating FcMBL
The technology evolved from experiments performed by Ingber using microfluidics about a decade and a half earlier. “These were tiny devices with hollow channels, and what’s interesting about them is that you can have two little channels coming together like two tributaries into a river,” he says. “If you have a red and yellow dye, they go right by each other. That made me think ‘well, maybe we could have blood and sterile saline and figure out a way to pull pathogens from them, discard them, and cleansed blood would go back to the patient like with a dialysis machine’.” He put it to the test using magnetic beads coated with different antibodies and very quickly figured out what didn’t work, but was still on the hunt for an antibody that did, which is where Super came into the equation. “During my
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PhD thesis I co-discovered what we now call human mannose binding lectin, or MBL,” says Super. “MBL is a key component of the innate immune system, which is the immediate early response to infection.”
Super explains that, in essence, MBL is the
body’s way of determining what is host and what is foreign and determining how to prevent the foreign invader from coming into the body, or if it does, how best to attack it. It does this by binding to the sugars on the surface of pathogens and releasing chemical signals that start “a feedback loop of amplification” which results in “a massive shower” of MBL on the pathogen, explains Super, which is what phagocytes, a type of white blood cell designed to engulf and kill invaders, use to identify them as foreign.
“During my PhD thesis I co-discovered what we now call human mannose binding lectin. It is a key component of the innate immune system, which is the immediate early response to infection.” Michael Super, senior staff scientist at the Wyss Institute
To make MBL a viable choice for pathogen capture, Super and Ingber first had to overcome two challenges: producing it at a low enough cost that it was viable in the clinic, and preventing it from activating the immune system in a way that was known to cause cardiovascular inflammation. Super tackled both by creating FcMBL, a fusion of the tail region of the human IgG1 antibody with MBL. Tests comparing the binding behaviours of both MBL and FcMBL showed no difference between the two, other than the fact that FcMBL had to be applied to magnetic beads like in Ingber’s earlier experiments.
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FcMBL is created by fusing of the tail region of the human IgG1 antibody with MBL.
Wyss Institute at Harvard University
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