Precision Tinkering of Cells, Genes & Microbes: The Big Idea Finalists
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ammonia made in the body. Ammonia is normally removed from the blood and excreted as urea in the urine but people with urea cycle disorders can’t do this well. Kaleido’s lead drug is designed to drive down the microbiome’s production of ammonia in people with these disorders.
Kaleido’s experimental drugs belong to a broad class of sugar-based molecules called glycans. Glycans can be found as ingredients in food and are considered as “Generally Recognized as Safe” (GRAS). This FDA designation allows Kaleido to move its glycan drugs into early human testing without going through the application process with the FDA to start clinical trials, as biotech companies typically need to do.
This translates into faster and less costly clinical development up to the Phase 2 stage of human testing, says Alison Lawton, Kaleido’s president and chief operating officer. If those early tests show promise, the company would seek FDA approval to continue clinical testing using the traditional process, starting at the Phase 2 stage, Lawton adds. Kaleido’s lead drug, for a type of urea cycle disorder called hyperammonemia, will be tested in patients starting this fall, with the hope of getting the FDA green light to start Phase 2 testing next year.
To find their glycan drugs, Kaleido studies human microbiomes from stool samples donated by healthy volunteers and patients. It has also designed more than 700 different glycans. The startup tests the effect of the glycans on the microbiomes, in hopes of finding the ones with the best therapeutic effect.
The startup has secured about $165 million in investment. Lawton says its second drug, for a liver disease, should enter Phase 2 testing later next year.
David Liu, Broad Institute & Harvard University – High-Precision Gene Editing
CRISPR-Cas9 gene editing has been touted as a precise way to edit the genome, but “editing” is bit of a misnomer. The classical CRISPR system breaks both strands of DNA and leaves it up to the cell to repair it—this often results in the insertion or deletion of bits of DNA in ways that can be hard to predict.
That’s why there’s growing interest in a CRISPR 2.0 approach called base-editing, invented by the lab of David Liu. Base editing is a lot closer to what you might think of as actual editing: it allows scientists to replace single “letters” of the DNA code with another, with a lower chance of unintentionally introducing other kinds of mutations than CRISPR-Cas9 editing. In key papers published in 2016 and 2017, Liu’s team described their CRISPR-based “base editors,” which don’t make the double-stranded DNA breaks that some gene-editing experts have said should be avoided to achieve more precise editing.
Earlier this year, Liu, along with Feng Zhang of the Broad Institute and Keith Joung of Massachusetts General Hospital, co-founded Beam Therapeutics with $87 million in investment to turn base editing into human medicines. Joung has been working to make base editing even more precise, and Zhang (nominated this year as Discoverer of the Year) has developed a base editor for RNA.
Travera – A Scale for Single Cells
Cancer cells arise with a striking amount of genetic diversity, carrying any number of a wide range of different mutations that drive their relentless growth. But one thing the cells have in common: when they die, they lose weight. Measuring the rate of that miniscule change in mass of individual cancer cells is what Travera, a Cambridge, MA-based startup is trying to commercialize, as a way for oncologists to better tailor treatments for patients.
Oncologists have relatively few ways to accurately predict which cancer drug will work best for a patient. So Travera’s vision is to take cancer cells from a patient, expose them to different drugs, and see which one successfully kills the cells. If a cell starts to rapidly lose weight, that’s a sign that the cell is dying in response to a drug, says Scott Manalis, an MIT professor and Travera co-founder.
Travera, which started earlier this year and recently secured more than $5 million in Series A funding, has built equipment that can measure the rate of change in cellular mass. Manalis says what makes his technology stand out is its precision: Travera’s machines can detect a change in mass as small as 0.1 picogram (A picogram is one-trillionth of a gram. A human white blood cell typically weighs about 100 picograms.).
The core part of the technology is a microfluidic device with tiny vibrating platforms (think mini diving boards) that contain small channels that cells flow through. A cell that’s losing weight while inside the platform will change how frequently the platform vibrates. Trevera’s machine measures this frequency change and then calculates the rate of mass loss.
Manalis’s research group published a paper last year showing that this technology, by analyzing bone marrow samples from nine patients with multiple myeloma (a type of blood cancer), could predict how those patients responded to certain drugs.
Manalis says his company will soon start a clinical trial enrolling at least 100 multiple myeloma patients to see how accurately his technology can predict the patients’ sensitivity to drugs.
This is the fifth in a series of articles profiling the 2018 Xconomy Award finalists. See the stories about finalists in the CEO, Startup, Digital Trailblazer, and Innovation at the Intersection categories, as well as the winner of the Lifetime Achievement award.