C. difficile had Meg Newman's number; it had struck her 18 different times beginning in 1985. The bacterial infection takes over the gut bringing explosive diarrhea, dehydration, weight loss, and at its worst depletes blood platelets. It causes nearly 30,000 deaths each year in the U.S. alone.
"I was one sick puppy as that point and literally three days after the transplant I was doing pretty well, day four even better."
Meg knew these statistics not just from personal experience but also because she was a doctor at San Francisco General Hospital. Antibiotics had sometimes helped to treat the infection, but it never quite seemed to go away. Now, "It felt like part of my colon was sort of sliding off as I had the bowel movement." On her worst day she counted 33 bowel movements. It was 2005 and she knew she was at the end of her rope.
Medical training had taught Meg to look at the data. So when antibiotics failed, she searched the literature for other options. One was a seemingly off-the-wall treatment called fecal transplants, which essentially gives poop from a healthy person to one who is sick.
Its roots stretch back to "yellow soup" used to treat dysentery in China nearly two thousand years ago, in which ancient Chinese treaters would combine stool with liquid, mash it up, and administer it. The approach also is commonly used in veterinary medicine today. However, there were only about three papers on its use in humans in the medical literature at that time, she recalls. Still, the logic of the intervention appealed to her.
The gut microbiome as a concept and even a word were not widely known fifteen years ago. But the idea that the microbial community in her gut was in disarray, and a transplant of organisms from a healthy gut might help restore a more normal ecology made sense. And besides, the failure of standard medicine left her few options.
Meg spoke with a colleague, gastroenterologist Neil Stollman, about a possible fecal microbial transplant (FMT). Only a handful of doctors in the U.S. had ever done the procedure; Stollman had tried it just once before. After conversation with Newman, he agreed to do it.
They decided on Meg's partner Sherry as the donor. "I try very hard to use intimate sexual partners as the donor," explains Stollman. The reason is to reduce disease risk: "The logic there is pretty straightforward. If you have unprotected sex with this individual, in a monogamous way for a period of time, you have assumed pretty much any infectious risk," like hepatitis, HIV, and syphilis, he says. Other donors would be screened using the same criteria used to screen blood donations, plus screening for parasites that can live in stool but not blood.
Martini aficionados fall into two camps, fans of shaken or stirred. In the early days the options for producing of fecal transplants were a blender or hand shaken. Stollman took the hands-on approach, mixing Sherry's fecal donation with saline to create "a milkshake in essence." He filtered it several times through gauze to get out the lumps.
Then he inserted a colonoscope, a long flexible tube, through the anus into Meg's colon. Generally a camera goes through the tube to look for polyps and cancers, while other tools can snip off polyps and retrieve tissue samples. Today he used it to insert the fecal "milkshake" as high up the colon as he could go. Imodium and bed rest were the final pieces. It works about 90 percent of the time today.
Meg went home with fingers crossed. "And within about two weeks things just slowed down; the diarrhea just stopped. I felt better so my appetite was better." The tide had turned, though it would take months to slowly repair the toll taken on her body from disease and antibiotics.
Then in 2011 another serious medical challenge required heavy use of antibiotics and Meg's C. difficile came roaring back; she needed a second FMT. Sherry had a bad sinus infection and had been on antibiotics, so that ruled her out as a donor. Red, Meg's godson, volunteered. He was twenty-one and had little or no exposure to antibiotics, which can harm friendly bacteria living in the gut.
"I was one sick puppy as that point," Meg recalls, "and literally three days after the transplant [from Red] I was doing pretty well, day four even better. It was unbelievable." It illustrated that donors are not the same, and that while an intimate partner may be the safest option, it also may not be the most efficacious donation in terms of providing missing parts of the microbial ecosystem.
By then, FMTs were starting to come out of the shadows as more than just a medical oddity. One gigantic milestone in changing perceptions was a Dutch study on using the procedure to treat C. difficile that was published in January 2013 in the New England Journal of Medicine. "That was the first trial where people said, look this isn't voodoo. This wasn't made up; it really worked," says Colleen Kelly, another pioneer in using FMTs to treat C. difficile and a researcher at Brown University. A single dose was successful more than 80 percent of the time in resolving disease in patients who had failed multiple regimens of antibiotics.
Charlatans pounced on the growing interest in the microbiome, promoting FMT as a cure for all sorts of ailments for which there was no scientific evidence. The FDA stepped in, announcing it would regulate the procedure as a drug, and essentially banned use of FMTs until it wrote regulations. But the outcry from physicians and patients was so great it was forced to retreat and has allowed continued use in treating C. difficile albeit on an interim regulatory basis that has continued since 2013.
Another major change was the emergence of stool banks, modeled on blood banks. The most widely know is OpenBiome, established in 2012 as a nonprofit by young researchers at Harvard and MIT. It aimed to standardize donation of stool and screening for disease, and package them in frozen form for colonoscopic delivery, or pill form. It greatly simplified the process and more doctors became willing to use FMTs to treat C. difficile. Today, some gastroenterologists specialize in administering the transplants as a feature of their practice.
To be sure, there have been some setbacks, including a transplant between family members where the recipient became obese, likely in part because of bacteria in the material she received. The same thing has occurred in studies in mice. And last year, an elderly man died from a toxic strain of E. coli that was in material provided by a stool bank. That caused the FDA to add that pathogen to the list of those one must screen for in products designed for use as fecal transplants.
Cost remains an issue. OpenBiome charges $1500-$2000 per transplant dose, depending on whether a frozen or pill form of the product is used. And that is likely to go up as the FDA increases the number of diseases that must be screened for, such as the virus that causes COVID-19, which is present in feces and likely can be transmitted through feces. Most insurance companies do not cover FMTs because no product has been formally approved for use by the FDA.
One of the greatest treatment challenges is making the correct diagnosis, says physician Robin Patel, who initially treated patients at the Mayo Clinic in Rochester, Minnesota but now spends most of her time there developing new diagnostics. Many things can cause diarrhea and the simple presence of the organism does not mean that C. difficile is causing it. In addition, many people are colonized with the bug but never develop symptoms of the disease.
Patel used the expensive tool of whole genome sequencing to look in great detail at C. difficile in patients who were treated with antibiotics for the infection and had recurrent diarrhea. "Some of them, as you might predict, were getting their symptoms with the same exact strain [of C. difficile] but others were not, it was a different strain," suggesting that they had been reinfected.
If it is a different strain, you might want to try antibiotics, she says, but if the same strain is present, then you might want to try a different approach such as FMT. Whole genome sequencing is still too slow and expensive to use in regularly treating patients today, but Patel hopes to develop a rapid, cost-effective test to help doctors make those types of decisions.
Biotech companies are trying to develop alternatives to poop as a source for transplant to treat C. difficile. They are picking and choosing different bacteria that they can grow and then combine into a product, to varying degrees of success, but none have yet crossed the finish line of FDA approval.
"I think [the future of FMTs] is going to be targeted, even custom-made."
The FDA would like such a product because it is used to dealing with small molecule drugs that are standardized and produced in batches. Companies are pursing it because, as Kelly says, they are like sharks "smelling money in the water." Approval of such a product might cause the FDA to shut down existing stool banks that now exist in a regulatory limbo, leaving the company with a monopoly of exclusive rights to the treatment.
Back when Meg received her first fecal transplant, the procedure was so obscure that the guidelines for treating C. difficile put out by the American College of Gastroenterology didn't even mention FMT. The procedure crept into the 2013 revision of those guidelines as a treatment of last resort. Guidance under review for release later this year or early next year will ease use further but stop short of making it a first option.
Stollman imagines a future holy grail in treating C. difficile: "You give me a stool specimen and I run it through a scanner that tells me you have too much of this and too little of that. I have a sense of what normal [microbial composition of the gut] should be and add some of this and subtract some of that. Maybe I even give you some antibiotics to get rid of some of the bad guys, give you some probiotics. I think it is going to be targeted, even custom-made."
His complete vision for treating C. difficile won't arrive tomorrow, but given how rapidly FMTs have become part of medicine, it is likely to arrive in pieces and more quickly than one might think.
About five years ago Meg discovered she had an antibody deficiency that contributed to her health problems, including vulnerability to C. difficile. She began supplementation with immunoglobulin and "that has made a huge difference in my health. It is just unbelievable how much better I am." She is grateful that fecal transplants gave her the time to figure that out. She believes "there's every reason to consider it [FMT] as a first-line treatment and do the studies, ASAP."
When David M. Kurtz was doing his clinical fellowship at Stanford University Medical Center in 2009, specializing in lymphoma treatments, he found himself grappling with a question no one could answer. A typical regimen for these blood cancers prescribed six cycles of chemotherapy, but no one knew why. "The number seemed to be drawn out of a hat," Kurtz says. Some patients felt much better after just two doses, but had to endure the toxic effects of the entire course. For some elderly patients, the side effects of chemo are so harsh, they alone can kill. Others appeared to be cancer-free on the CT scans after the requisite six but then succumbed to it months later.
"Anecdotally, one patient decided to stop therapy after one dose because he felt it was so toxic that he opted for hospice instead," says Kurtz, now an oncologist at the center. "Five years down the road, he was alive and well. For him, just one dose was enough." Others would return for their one-year check up and find that their tumors grew back. Kurtz felt that while CT scans and MRIs were powerful tools, they weren't perfect ones. They couldn't tell him if there were any cancer cells left, stealthily waiting to germinate again. The scans only showed the tumor once it was back.
Blood cancers claim about 68,000 people a year, with a new diagnosis made about every three minutes, according to the Leukemia Research Foundation. For patients with B-cell lymphoma, which Kurtz focuses on, the survival chances are better than for some others. About 60 percent are cured, but the remaining 40 percent will relapse—possibly because they will have a negative CT scan, but still harbor malignant cells. "You can't see this on imaging," says Michael Green, who also treats blood cancers at University of Texas MD Anderson Medical Center.
The new blood test is sensitive enough to spot one cancerous perpetrator amongst one million other DNA molecules.
Kurtz wanted a better diagnostic tool, so he started working on a blood test that could capture the circulating tumor DNA or ctDNA. For that, he needed to identify the specific mutations typical for B-cell lymphomas. Working together with another fellow PhD student Jake Chabon, Kurtz finally zeroed-in on the tumor's genetic "appearance" in 2017—a pair of specific mutations sitting in close proximity to each other—a rare and telling sign. The human genome contains about 3 billion base pairs of nucleotides—molecules that compose genes—and in case of the B-cell lymphoma cells these two mutations were only a few base pairs apart. "That was the moment when the light bulb went on," Kurtz says.
The duo formed a company named Foresight Diagnostics, focusing on taking the blood test to the clinic. But knowing the tumor's mutational signature was only half the process. The other was fishing the tumor's DNA out of patients' bloodstream that contains millions of other DNA molecules, explains Chabon, now Foresight's CEO. It would be like looking for an escaped criminal in a large crowd. Kurtz and Chabon solved the problem by taking the tumor's "mug shot" first. Doctors would take the biopsy pre-treatment and sequence the tumor, as if taking the criminal's photo. After treatments, they would match the "mug shot" to all DNA molecules derived from the patient's blood sample to see if any molecular criminals managed to escape the chemo.
Foresight isn't the only company working on blood-based tumor detection tests, which are dubbed liquid biopsies—other companies such as Natera or ArcherDx developed their own. But in a recent study, the Foresight team showed that their method is significantly more sensitive in "fishing out" the cancer molecules than existing tests. Chabon says that this test can detect circulating tumor DNA in concentrations that are nearly 100 times lower than other methods. Put another way, it's sensitive enough to spot one cancerous perpetrator amongst one million other DNA molecules.
"It increases the sensitivity of detection and really catches most patients who are going to progress," says Green, the University of Texas oncologist who wasn't involved in the study, but is familiar with the method. It would also allow monitoring patients during treatment and making better-informed decisions about which therapy regimens would be most effective. "It's a minimally invasive test," Green says, and "it gives you a very high confidence about what's going on."
Having shown that the test works well, Kurtz and Chabon are planning a new trial in which oncologists would rely on their method to decide when to stop or continue chemo. They also aim to extend their test to detect other malignancies such as lung, breast or colorectal cancers. The latest genome sequencing technologies have sequenced and catalogued over 2,500 different tumor types, says Chabon, which gives the team the opportunity to create more molecular "mug shots."
The team hopes that that their blood cancer test will become available to patients within about five years, making doctors' job easier, and not only at the biological level. "When I tell patients, "good news, your cancer is in remission', they ask me, 'does it mean I'm cured?'" Kurtz says. "Right now I can't answer this question because I don't know—but I would like to." His company's test, he hopes, will enable him to reply with certainty. He'd very much like to have the power of that foresight.
The white two-seater car that rolls down the street in the Sorrento Valley of San Diego looks like a futuristic batmobile, with its long aerodynamic tail and curved underbelly. Called 'Sol' (Spanish for "sun"), it runs solely on solar and could be the future of green cars. Its maker, the California startup Aptera, has announced the production of Sol, the world's first mass-produced solar vehicle, by the end of this year. Aptera co-founder Chris Anthony points to the sky as he says, "On this sunny California day, there is ample fuel. You never need to charge the car."
If you live in a sunny state like California or Florida, you might never need to plug in the streamlined Sol because the solar panels recharge while driving and parked. Its 60-mile range is more than the average commuter needs. For cloudy weather, battery packs can be recharged electronically for a range of up to 1,000 miles. The ultra-aerodynamic shape made of lightweight materials such as carbon, Kevlar, and hemp makes the Sol four times more energy-efficient than a Tesla, according to Aptera. "The material is seven times stronger than steel and even survives hail or an angry ex-girlfriend," Anthony promises.
Co-founder Steve Fambro opens the Sol's white doors that fly upwards like wings and I get inside for a test drive. Two dozen square solar panels, each the size of a large square coaster, on the roof, front, and tail power the car. The white interior is spartan; monitors have replaced mirrors and the dashboard. An engineer sits in the driver's seat, hits the pedal, and the low-drag two-seater zooms from 0 to 60 in 3.5 seconds.
It feels like sitting in a race car because the two-seater is so low to the ground but the car is built to go no faster than 100 or 110 mph. The finished car will weigh less than 1,800 pounds, about half of the smallest Tesla. The average car, by comparison, weighs more than double that. "We've built it primarily for energy efficiency," Steve Fambro says, explaining why the Sol has only three wheels. It's technically an "auto-cycle," a hybrid between a motorcycle and a car, but Aptera's designers are also working to design a four-seater.
There has never been a lack of grand visions for the future of the automobile, but until these solar cars actually hit the streets, nobody knows how the promises will hold up.
Transportation is currently the biggest source of greenhouse gases. Developing an efficient solar car that does not burden the grid has been the dream of innovators for decades. Every other year, dozens of innovators race their self-built solar cars 2,000 miles through the Australian desert.
More effective solar panels are finally making the dream mass-compatible, but just like other innovative car ideas, Aptera's vision has been plagued with money problems. Anthony and Fambro were part of the original crew that founded Aptera in 2006 and worked on the first prototype around the same time Tesla built its first roadster, but Aptera went bankrupt in 2011. Anthony and Fambro left a year before the bankruptcy and went on to start other companies. Among other projects, Fambro developed the first USDA organic vertical farm in the United Arab Emirates, and Anthony built a lithium battery company, before the two decided to buy Aptera back. Without a billionaire such as Elon Musk bankrolling the risky process of establishing a whole new car production system from scratch, the huge production costs are almost insurmountable.
But Aptera's founders believe they have found solutions for the entire production process as well as the car design. Most parts of the Sol's body can be made by 3D printers and assembled like a Lego kit. If this makes you think of a toy car, Anthony assures potential buyers that the car aced stress tests and claims it's safer than any vehicle on the market, "because the interior is shaped like an egg and if there is an impact, the pressure gets distributed equally." However, Aptera has yet to release crash test safety data so outside experts cannot evaluate their claims.
Instead of building a huge production facility, Anthony and Fambro envision "micro-factories," each less than 10,000 square feet, where a small crew can assemble cars on demand wherever the orders are highest, be it in California, Canada, or China.
If a part of the Sol breaks, Aptera promises to send replacement parts to any corner of the world within 24 hours, with instructions. So a mechanic in a rural corner in Arkansas or China who never worked on a solar car before simply needs to download the instructions and replace the broken part. At least that's the idea. "The material does not rust nor fatigue," Fambro promises. "You can pass the car onto your grandchildren. When more efficient solar panels hit the market, we simply replace them."
More than 11,000 potential buyers have already signed up; the cheapest model costs around $26,000 USD and Aptera expects the first cars to ship by the end of the year.
Two other solar carmakers are vying for the pole position in the race to be the first to market: The German startup Sono has also announced it will also produce its first solar car by the end of this year. The price tag for the basic model is also around $26,000, but its concept is very different. From the outside, the Sion looks like a conservative minivan for a family; only a closer look reveals that the dark exterior is made of solar panels. Sono, too, nearly went bankrupt a few years ago and was saved through a crowdfunding campaign by enthusiastic fans.
Meanwhile, Norwegian company Lightyear wants to produce a sleek solar-powered luxury sedan by the end of the year, but its price of around $180,000 makes it unaffordable for most buyers.
There has never been a lack of grand visions for the future of the automobile, but until these solar cars actually hit the streets, nobody knows how the promises will hold up. How often will the cars need to be repaired? What happens when snow and ice cover the solar panels? Also, you can't park the car in a garage if you need the sun to charge it.
Critics, including students at the Solar Car team at the University of Michigan, say that mounting solar panels on a moving vehicle will never yield the most efficient results compared to static panels. Also, they are quick to point out that no company has managed to overcome the production hurdles yet. Others in the field also wonder how well the solar panels will actually work.
"It's important to realize that the solar mileage claims by these companies are likely the theoretical best case scenario but in the real world, solar range will be significantly less when you factor in shading, parking in garages, and geographies with lower solar irradiance," says Evan Stumpges, the team coordinator for the American Solar Challenge, a competition in which enthusiasts build and race solar-powered cars. "The encouraging thing is that I have seen videos of real working prototypes for each of these vehicles which is a key accomplishment. That said, I believe the biggest hurdle these companies have yet to face is successfully ramping up to volume production and understanding what their profitability point will be for selling the vehicles once production has stabilized."
Professor Daniel M. Kammen, the founding director of the Renewable and Appropriate Energy Laboratory at the University of California, Berkeley, and one of the world's foremost experts on renewable energy, believes that the technical challenges have been solved, and that solar cars have real advantages over electric vehicles.
"This is the right time to be bullish. Cutting out the charging is a natural solution for long rides," he says. "These vehicles are essentially solar panels and batteries on wheels. These are now record low-cost and can be built from sustainable materials." Apart from Aptera's no-charge technology, he appreciates the move toward no-conflict materials. "Not only is the time ripe but the youth movement is pushing toward conflict-free material and reducing resource waste....A low-cost solar fleet could be really interesting in relieving burden on the grid, or you could easily imagine a city buying a bunch of them and connecting them with mass transit." While he has followed all three new solar companies with interest, he has already ordered an Aptera car for himself, "because it's American and it looks the most different."
After taking a spin in the Sol, it is startling to switch back into a regular four-seater. Rolling out of Aptera's parking lot onto the freeway next to all the oversized gas guzzlers that need to stop every couple of hundreds of miles to fill up, one can't help but think: We've just taken a trip into the future.