[Correction: 3:15 pm PT] You can learn a lot about a potential human being if you can get your hands on a few red blood cells from a developing fetus.
The thing is, these cells are fragile and hard to obtain. More than 50 companies have tried and failed to create a reliable, noninvasive way to get these precious cells, and extract all kinds of genetic information from them for diagnostic purposes.
Newark, CA-based Cellscape is betting it is zeroing in on a way to do it.
Cellscape has raised a little less than $20 million since it was founded five years ago by Karen Drexler, Bhairavi Parikh, and James Stone. It isn’t yet ready to take its proprietary test to the market, but Cellscape made a preliminary move in that direction this summer by hiring an experienced commercial diagnostic CEO in Ted Snelgrove, formerly of Crescendo Bioscience.
Already, a group of four companies—Sequenom, Illumina’s Verinata Health unit, Ariosa Diagnostics, and Natera—have made progress in the past year building a new market for noninvasive prenatal tests, which extract information from small amounts of fetal DNA circulating in a mother’s blood. But those tests aren’t perfect, as they are limited mainly to looking for chromosomal abnormalities like Down syndrome, and sometimes yield inconclusive or false positive results. Cellscape seeks to raise the bar by getting a richer source of information than trace DNA from the mom’s blood—whole fetal cells that still have an intact nucleus. Those are the type of cells that physicians today can obtain through procedures known as CVS or amniocentesis, but those tests are invasive, come with a risk of miscarriage, and generally aren’t done unless the physician has a strong reason to believe something’s wrong.
The ultimate prize for Cellscape would be to come up with a test that’s reliable enough to become a standard first-trimester diagnostic tool like ultrasound, in a country where 4 million children are born every year. If the company can nail down a reliable diagnostic test over the next couple years, it could make it possible for doctors and patients to discover genetic abnormalities in fetuses that can’t be spotted through today’s noninvasive means.
“There’s a strong emphasis in understanding the genetics at the front end of life, and it’s a harbinger of change that’s coming,” says Cellscape CEO Ted Snelgrove. “The power of the information is strong.”
Gautam Kollu, a former vice president of marketing at Natera, a non-invasive prenatal testing company currently on the U.S. market, said he was impressed by Cellscape’s addition of Snelgrove. But he says the company still has a lot to prove. “Very interesting technology indeed, if it turns out to be real. There are a lot of hurdles to still overcome,” he said.
The technical hurdles were immediately apparent to Cellscape’s founding team in 2008, but they also saw a lot of lessons in what didn’t work, and a challenge that didn’t seem impossible. Technology was getting sensitive enough to detect circulating tumor cells (CTCs) in blood, even when there’s only one present out of 1 billion cells. So they reasoned that similar platforms could be used to find the fetal red blood cells floating around in a mom’s bloodstream, which are just as rare. “We spent the first year studying what other people had done, and had a lot of knowledge of what not to do,” says Drexler, the company’s executive chair.
Cellscape, which also went by other names like Saryna Medical and Abraza Medical in its early days, raised its first $800,000 in May 2009 from XSeed Capital Management and angel investors. It was a small miracle, given those were some of the darker days of the recession, and Cellscape hadn’t even begun developing a technology. “We had an approach in mind,” Drexler says.
There are several reasons why it’s hard to get fetal cells in a noninvasive procedure.
For starters, they’re rare. That means if you want to make sure to get enough cells to analyze, you have to draw a lot of blood from the patient.
They’re also fragile, and likely to die when handled by rough instruments, unlike tumor cells, which are hardy by the standards of ordinary cells. This is where a lot of other companies stumbled, Drexler says, noting that procedures which work for capturing circulating tumor cells—such as magnetic cell separators—are too harsh for fetal cells.
Plus, there’s a narrow window of opportunity to capture the right kind of cells. Cellscape has focused on fetal red blood cells with intact nuclei, because there’s no way those cells can live on in the mom’s bloodstream from a previous pregnancy, and therefore set off false signals about the current fetus. The trouble with nucleated fetal red blood cells, though, is that they live in a different environment in the womb, with different oxygen and acidity levels, and they are thought to live only a few days when they enter the mom’s bloodstream, Drexler says.
Given those basic parameters, here’s what Cellscape does: It starts with about 16-17 milliliters of blood from the mom, which has about 100 billion cells of all different types, Drexler says. The company runs a physical process to filter out the red blood cells, separating the ones that don’t have a nucleus, leaving about 1 billion cells.
Other companies at this point have used chemical or magnetic processes to separate out cells of interest, which have been too harsh for fetal cells, Drexler says. So Cellscape uses what it calls “optical enrichment” which uses a stain to highlight the nucleus under fluorescent lighting, in a high-resolution manner. This method is gentler, and allows the company to whittle down the sample down from 1 billion cells to about 1,000 cells for analysis, Drexler says.
And that’s not the end. The fetal cells still need to be identified as distinct from the mother’s. Cellscape does that by looking for a protein that is more heavily expressed in maternal cells, which it says is a core part of its intellectual property. Once they are sure they have “tens to hundreds” of cells from the fetus, and not the mom, then they go through the final steps. The DNA gets taken out for amplification through standard PCR methods, and the amplified DNA from the fetal cells is hybridized on a chromosomal microarray. The results are analyzed on an array scanner from Agilent Technologies. [Correction 3:15 pm PT: An earlier version said gene expression patterns are analyzed.]
By looking at certain targeted regions of the fetus’s genome, Cellscape believes this method will be able to detect not only the chromosomal abnormalities that today’s DNA-based methods spot, but also another 20-30 “microdeletion” syndromes in which a small stretch of DNA is missing or defective, Drexler says. (DiGeorge Syndrome is one example). Results from the sample should take about one week to send back to the doctor, Drexler says.
Cellscape has spent the past few years trying to nail down this process. It has run some blood samples through its system, but hasn’t yet published the big kind of controlled clinical trial in a medical journal that would show its test is ready for prime time.
The stakes are about as high as it gets in medicine, as people make life-altering decisions based on prenatal diagnostic information. “We want to be 100 percent sure that the cells we say are fetal are actually fetal,” Snelgrove says. Not only that, but you can be sure that physicians are going to want to double-check the results they get from a Cellscape analysis with another analysis that comes from a traditional invasive procedure, like CVS or amniocentesis, where there’s no doubt about what kind of cells you’re analyzing. “It’s important to have a way to confirm the result,” Drexler says.
Cellscape doesn’t have traditional venture capital backing, but its investor group does include RA Capital, a Boston-based hedge fund. The company, still in R&D mode, has grown to 36 employees.
The next phase of growth for Cellscape is about gathering convincing data. The clinical trials that it develops to test its process will go a long way toward determining what kind of price it can command, and whether it can persuade insurers to pay for its product. If things move fast, Cellscape could hit the market by late 2014, but it is likely shooting for early 2015, Snelgrove says.
The day will come when Cellscape will want to tout its offering, but it’s not ready yet. There’s still a lot of work to do.
“51 companies failed to do this for a reason. It’s hard to do,” Snelgrove said. “It’s hard for us to do. We want to make sure we have this nailed before we go forward.”
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