This article was taken from the December issue of Wired magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content by subscribing online
To be in the company of Chris Calhoun is to encounter breasts, and encounter the damn things anytime, anywhere -- including over a plate of spaghetti in a bustling Manhattan restaurant.
On this spring afternoon, the 44-year-old CEO of San Diego-based
biotech company Cytori Therapeutics pulls out his laptop, launches a PowerPoint presentation, and there they are: conical and cantaloupy, As to Ds, beige and pink and taupe and tan, more breasts than you might see in a women's locker room, never mind at a lunch table.
A passing waiter does a double take at this lively slide show, but Calhoun is oblivious. He's talking excitedly about how these women's bodies led him and his team of scientists to a discovery in tissue engineering, a process that could well be one of the most momentous advances of the 21st century: the use of stem cells -- specifically stem-cell enriched adipose (fat) tissue -- to enhance and rebuild injured or damaged organs. A few taps on his laptop reveal the unsettling "before" images of these seemingly normal breasts.
There: a breast with a plum size divot taken out from a lumpectomy.
There: a chest as flat as a mat from a double mastectomy. There: one so misshapen after a partial mastectomy, it's possible to see what it is only because of its healthy companion. "We realised that for these women there was a huge unmet need for a disruptive change in technology," Calhoun says of the work that has consumed his team of researchers and surgeons for the past eight years. "It's the first practical cell therapy." He pauses. "And it's breasts." Which means cancer victims with breasts mutilated by surgery, as well as women who are simply unhappy with their natural shape, can now grow a new pair with raw materials harvested from their own body fat.
But breast augmentation is just one development in the company's more ambitious plan: to introduce stem-cell medicine to the mass market -- and not using the ethically fraught kind of stem cells from human embryos. Instead, based on almost a decade of trials that Cytori and its academic partners have performed on cell cultures, lab rodents and humans, they believe their engineered flab cells can treat many different organs. Chronic heart disease?
Check.
In human studies released in May, the cells improved patients' aerobic capacity and shrank the size of the infarct (tissue killed by lack of blood). Heart attack? Check. A human clinical trial, also reported in May, found that the cells increased both the blood supply to damaged heart muscle and the volume of blood that the heart pumped. Kidney injury as a result of cancer therapy? Check. In recent rat studies, the cells improved kidney function. Incontinence after prostatectomy? Check.
Another recent study reported that, by 12 weeks after injection, the cells had decreased the amount of urine male volunteers were leaking by 89 per cent. If Calhoun and his scientists succeed, they won't just create more cleavage. They'll make practical a whole new field, one that visionaries have dreamed of: regenerative medicine.
It makes sense to apply Cytori's technology to enhance breasts instead of, say, repair urinary sphincters as away to move the patented technology out of rats and into people as soon as possible. Hearts, kidneys, and even sphincters have to work in order for us to survive. But we can live just fine without breast tissue, and, beyond feeding offspring, breasts don't have to do much. Breasts simply aren't as necessary as other organs. The scientific and regulatory hurdles to getting Cytori's cells into clinical use will be easier to clear for breasts than for other tissue. It's also a booming market. In 2009, US women forked out more than $964 million (£600 million) for breast augmentation, which edges out nose jobs as the most commonly performed plastic surgery in the country.
More is driving that trend than just media hyped views of beauty. Breast cancer is a major factor. In the UK, incidence of the disease has risen from77per 100,000womenin 1978 to 120 per 100,000 in 2007 (the latest official figures available), and the survival rate has increased: around 50 per cent of women diagnosed in 1975 lived at least five moreyears,comparedwith80percentdiagnosedin2005. That means more women will live more years after a lumpectomy or mastectomy. Most of these survivors would just as soon live those years with something that resembles what they had before. There is also demand from a burgeoning demographic no one would have predicted 15 years ago: young women choosing bilateral prophylactic mastectomy after testing positive for mutations in genes -- known as BRCA1 and BRCA2 -- that increase the risk of breast cancer by a factor of five.
Others are diagnosed with cancer in one breast, have a mastectomy, and decide to have the healthy breast removed as well.
In a 2009 study of women undergoing all forms of surgery for breast cancer, published in Annals of Surgical Oncology by researchers led by surgical oncologist Todd Tuttle of the University of Minnesota, 29 per cent opted for this. Among just mastectomy patients (that is, excluding those who had a lumpectomy or other breast sparing surgery), the rate of taking out the good with the bad was an astounding 56 per cent -- even though studies find no survival advantage in removing the healthy breast. Yet Tuttle hears it all the time: I never want to go through this again. "Younger and more educated women are the ones choosing to go this route," he says. And despite the improvements in silicone implants, they're still vulnerable to ruptures and may eventually need to be replaced. What's more, inserting a single implant after cancer surgery can leave a woman a symmetric: it stays put while the surviving breast sags. It's no wonder that women all over the world are desperate for a better option.
Here's the weird thing about breasts: they are a point of obsession, vulnerable to the mercurial whims of mass culture. But one thing remains constant: in every era, a lot of women are convinced they have the wrong kind. For better or for worse (mostly worse), science -- or a rudimentary facsimile thereof -- has always been eager to help. European women of the 16th century applied a cumin-seed paste with a cloth soaked in water and vinegar to their breasts to keep them small and firm. In the late 1800s, the Princess Bust Developer consisted of a cream and a nifty device resembling a toilet plunger to increase cup size. Starting in the 1940s pinup era, there were liquid silicone-oil injections for breast enlargement (bad idea: leakage, inflammation, granulomas) followed, in 1962, by silicone-filled implants.
Given this history of far-fetched augmentation schemes, it's not unfathomable that a plastic surgeon would one day realise the secret to enhanced breasts was hidden in a pair of love handles. In 1999, Marc Hedrick then an assistant professor of surgery at UCLA, was doing yet another liposuction, and not a little suck-out-a-bit-around-my-thighs please- doctor procedure, either.
He vacuumed eight litres of fat from his patient. Scientists had long wondered whether fat tissue might contain stem cells. "If it does, then here we are, stupid plastic surgeons, doing the stupidest procedure on the face of the Earth," says Hedrick, 48, now sitting in the La Jolla, California, offices of Cytori, which he cofounded in 2002. "I'd just taken eight litres out of some woman and dumped it in the trash. I asked myself, are there really stem cells in there?" Meanwhile, a postdoctoral fellow named Min Zhu had become bored with the rheumatology research she was doing.
She joined Hedrick's lab in spring of 1999, and he set her to the task of finding out once and for all whether there were stem cells in fat. Determining the qualities of a stem cell (versus a regular one) requires proving that it can differentiate into many cells, but Zhu hit a brick wall even before she could attempt that. After she isolated candidate stem cells from fat, the things refused to grow, let alone differentiate.
Her breakthrough came when she decided to use blood rather than the standard fibroblasts as feeder cells. "She just brute-forced it," Hedrick says. "She was forging her own trail -- with a machete." Zhu managed to induce them to differentiate into three lineages: first bone and cartilage, then muscle, then neuron. She walked into Hedrick's office and said, "I think I have something." In April 2001, the scientists published in the journal Tissue Engineering their discovery that adipose tissue is chock-full of stem cells.
As Zhu was making her breakthrough, Cytori's Calhoun was running a medical device company called MacroPore Biosurgery, and one of his salespeople told him about a plastic surgeon at UCLA named Marc Hedrick, who was doing some interesting work. Curious, Calhoun arranged a meeting. After some pleasantries, the surgeon dropped his bombshell: we've found stem cells in fat tissue. And it's the mother lode. The cells are in the padding around hips, thighs, abdomen and flabby upper arms in such quantity that it isn't even necessary to grow and proliferate them in lab dishes to harvest an abundant supply. There is roughly one adipose stem cell per 100 fat cells. (By comparison, bone marrow contains one per 250,000 to 400,000 cells.) "Marc said, 'We can get these cells out, it has nothing to do with embryos, and their potential is enormous',"
Calhoun recalls. "I loved him the moment I met him." That love was worth $1 million, the amount of MacroPore's money that Calhoun invested in the company Hedrick was starting, called StemSource.
By 2002, Calhoun had persuaded Macro- Pore's board to sell a division of the company to Medtronic, the medical-device maker, for $21 million, which Calhoun used to buy StemSource, inking the deal in October 2002. (MacroPore changed its name to Cytori Therapeutics in July2005.) Although StemSource's original plan had been to bank stem cells, once it had been acquired by MacroPore, the focus switched to therapeutic uses for adipose stem cells. Since Hedrick's surgical practice focused on children with facial defects, he thought the cells could be coaxed to make bone in kids with a cleft palate. But as he and his UCLA team did more studies, Hedrick says, "we realised that although the cells could make bone, what they were really good at was making a new blood supply. We felt like if we could target that, it would be the key to every ischaemic disease," in which tissue dies for want of an adequate blood supply, and therefore oxygen. "That led us to reconfigure the company to investigate using the cells for heart-attack patients."
As he and his team conducted rodent studies for heart disease, Hedrick thought if adipose stem cells could restore blood flow to heart tissue, maybe the cells could also keep other tissue healthy.
The radiation that women typically undergo after lumpectomy or mastectomy, for instance, damages surviving tissue and destroys the local blood supply. "The tissue gets hard, and that makes it difficult to reconstruct or put an implant in," Calhoun says. And thus the idea of using adipose stem cells to reconstruct the breast was born.
By2003, Hedrick and Calhoun were pushing ahead with research on using their stem cells to repair hearts damaged by heart attack or chronic disease. At the same time, they were grappling with the challenge of repairing patients after partial mastectomy and lumpectomy. It's always been a problem for surgeons. Building only part of a breast with conventional methods is more difficult than constructing a whole new one, because it requires what UCLA's McGuire delicately calls "local tissue rearrangement and/or flaps rather than implants". In other words, the doctor squeezes and moves tissue to fill in divots and missing quadrants and, with luck, turns what might have been reduced to an A cup during a cancer operation into a match for the B or C on the healthy side.
The result, alas, can be "very much less than optimal," McGuire admits. "It's difficult to recreate the shape."
Ironically, given how grateful most breast-cancer patients are if they can have a lumpectomy rather than a total mastectomy, such breast-sparing surgery can leave a woman with an aesthetically irreparable breast. With tumours smaller than two centimetres across, lumpectomy leaves a gouge of up to twice that size, says surgeon Jan Vranckx of Leuven University Hospitals in Belgium: "Breast-conserving surgery is good at keeping the cancer from returning only if it is followed by radiotherapy, but that leaves scars and rigid, badly healing tissue. Yet the defects are often regarded as too small to do a full reconstruction."
Calhoun and Hedrick wanted to test their cells on damaged breasts that other doctors couldn't be bothered with. But Hedrick knew that bringing adipose stem cells into the clinic required more than biology. It also required technology. When Hedrick originally outlined his vision for Calhoun in 2000, he showed him drawings of a device to isolate the stem cells from liposuctioned fat en masse. "We were thinking a box," Hedrick says. "We need some kind of box."
After $200 million in R&D, the "box" became the Celution System. It looks like a souped-up photocopier, but instead of taking in originals and spitting out replicas, it turns liposuctioned fat into breast-making gold. The process to fix a lumpectomy divot begins when a surgeon pierces a patient's tummy with a syringe and sucks out about 360cc of fat. Each syringe takes about five minutes to fill; to treat an average divot requires eight to ten syringes' worth. The fat is squirted into the Celution device. A proprietary mix of enzymes digests the scaffolding that holds the tissue together, freeing the cells; the centrifuge separates the adipose tissue from the stem cells, which form a pellet at the bottom of the tube. Those cells are then combined with some of the remaining liposuctioned fat-tissue cells. The result, now a pale pink suspension containing millions of the stem and regenerative cells, is ready to go. The whole process takes about two hours.
It's worth pausing here to ask just what, exactly, these magic cells are. Cytori calls them adipose-derived stem cells, or adipose derived stem and regenerative cells, or adipose- derived progenitor cells. "These things have gone through the wringer in choosing a name," says biomechanical engineer Kent Leach of UC Davis, who has used whatever they are to treat bone cysts in racehorses.
A stem cell, by definition, is able to differentiate into any of the 200-plus kinds of cells in the human body, just as the cells of a days-old embryo can (and do). Cytori's are unlikely ever to show that range of differentiation. But they can differentiate into fat, bone and muscle -- among other tissues -- depending on which signalling molecules they are exposed to. In a Petri dish, the scientists provide those "this is what you will be when you grownup" molecules.
Now that they had the box, the Cytori team faced one more hurdle: finding suitable subjects. "There aren't good animal models for breast reconstruction after cancer," Hedrick says. "That's why we went to humans so soon." They found their humans in Japan, where the company had connections to surgeons. But Japan made sense for another reason: there, the disfigurement of a mastectomy or lumpectomy is tantamount to social banishment. Much of a traditional woman's social life centres on public baths, and those whose breast cancer has left them deformed seldom go.
When Keizo Sugimachi, a surgeon and president of Kyushu Central Hospital in Fukuoka, learned what Cytori was developing, he launched an investigator-initiated (as opposed to Cytori-sponsored) trial, dubbed Restore 1. Over the course of six months in 2006, he treated 20 women who'd had a partial mastectomy two to five years before. It was also the first clinical use of Cytori's Celution System. Hedrick assisted on nearly all of the procedures and helped orchestrate how each would progress.
They used a lot of guesswork. How much fat do you extract? How many cells do you add back into the mix? How do you combine the liposuctioned fat with enzymes and growth factors and the other magic potions (all trade secrets) in the Celution machine? Do you over treat, giving a woman more cell-enhanced tissue than you think is needed in case some of it doesn't take? Where do you make the incision in the breast to inject the cells? How do you deal with scarring from the radiation most mastectomy patients get after surgery? "I think we just guessed right," Hedrick says. "We solved a lot of the problems in the first operation. If it didn't work, it was because we put too much in, or didn't treat the scar, or didn't prepare the tissue bed right." They got better with each case, improving the protocol as they went. In December 2007, Sugimachi told the San Antonio Breast Cancer Symposium that all 20 of the women in Restore 1 tolerated the procedure fine, none had an immune response, and 79 per cent were satisfied with the outcome.
There was no significant loss of breast size between one month and the final assessment 12 months later. That was a crucial barometer, given what happens when plastic surgeons inject fat alone, which was a popular cosmetic-surgery technique in the 80s and 90s. The injected fat tended to vanish into the surrounding tissue several weeks later like butter into hot toast. (Women who opted for this method were encouraged to think of breast enhancement like a dye job -- once the effect fades, go back for another session.) But Cytori's adipose stem cells stuck around.
This is because Cytori's cells are not becoming breast tissue, as you might assume if you heard that someone was using stem cells for boob jobs. You don't sprinkle the cells in Petri dishes and come back in a few weeks to find a crop of breasts Instead, the fat cells in the Celution mixture provide the volume, filling the divot in the lumpectomy, the missing quadrant in the quadrantectomy, or the empty skin pouch in the mastectomy. Think of them as the big dumb grunts of the battalion. The regenerative cells in the mixture encourage the growth of a blood supply. They're the clever engineers who provide the supply lines that the grunts need to survive.
And that combination is what promises to distinguish the breasts built with adi Instead, the fat cells in the Celution mixture provide the volume, filling the divot in the lumpectomy, the missing quadrant in the quadrantectomy, or the empty skin pouch in the mastectomy. Think of them as the big dumb grunts of the battalion. The regenerative cells in the mixture encourage the growth of a blood supply. They're the clever engineers who provide the supply lines that the grunts need to survive.
And that combination is what promises to distinguish the breasts built with adipose regenerative cells from those built with fat injections alone. "If you give the tissue blood, it will survive and not be reabsorbed," Leuven University's Vranckx says. Sensation is about as good as before because the relevant nerves are in the skin and muscle (and, with lumpectomies, the nipple remains intact).
It's the cells' ability to induce the formation of blood vessels, however, that makes them attractive as therapy for ischaemic heart disease. Although some researchers have claimed that adipose regenerative cells can differentiate into epithelial cells, which can form capillaries and other blood vessels, the evidence is pointing to something more modest but no less useful.
The cells churn out proteins, among them vascular endothelial growth factor, that induce surrounding cells to form blood vessels.
As a result, cells that had been starved of blood and therefore oxygen are suddenly awash with both. If the science part was working out how to process the fat in the box, the art comes in doing the injections. You don't take a big syringe full of the stuff from the Celution machine and cram it into the breast as if you were filling a doughnut. You meticulously inject hundreds of tiny dollops, like a patissier piping rosettes on a cake. To accomplish that, Cytori created the Celbrush It has a blunt tip to make tiny cuts that break the scar tissue, transforming it into a biological mesh. As the Celbrush is moved, the surgeon turns a wheel, which releases the tissue 0.5cc at a time. "You do that hundreds of times and you create a lattice with stem cells,"
Hedrick says. Adds Calhoun, "It's really as close to sculpture as anything done in plastic surgery today."
The injection area is not painful afterward, and the liposuction site is only slightly sore. Patients go home that day. A clinical trial in Europe in 2008 and 2009, called Restore 2, used the next generation of the Celution machines, also with tantalising results.
It studied women who'd had a partial mastectomy, including Irene MacKenzie, 51, who works for the NHS in Scotland. She was diagnosed with breast cancer six years ago, and after a partial mastectomy was told by her surgeons that reconstruction wasn't necessary, or even possible. MacKenzie had heard about a surgeon, Eva Weiler-Mithoff of the Glasgow Royal Infirmary, who might be able to help.
MacKenzie sought her out and, in spring 2008, Weiler-Mithoff rang and told her about the Restore 2 trial, for which Weiler-Mithoff was a lead investigator. MacKenzie signed on. She liked the results but in January 2009 returned to Weiler-Mithoff for another go. "She told me maybe we should have put more cells in, so I went back," says MacKenzie, who now pronounces herself delighted with her new breast. In December 2009,Weiler-Mithoff told the San Antonio Breast Cancer Symposium that the procedure improved breast deformity in most of the 31 patients who were assessed, with the new breasts holding up for the six to 12 months that the women had been followed. How the new breast felt and moved on the chest wall kept improving. "One of the most striking aspects of the trial was how happy the patients were" with their new breast, says Weiler-Mithoff. The women, she says, "felt whole again".
MacKenzie's need for a touch-up, however, shows that not everyone gets the desired results the first time. In fact, all but one of Vranckx's post-mastectomy patients needed at least two procedures.
The Celbrush, after all, is the instrument of an artist. "So far, we've been able to repair defects that we couldn't before,"
Vranckx says. "But it can take eight hours to do two breasts -- eight hours bringing one droplet after another to the breast. It's sculpting, and not everyone can be a sculptor." Restore 1 showed that Cytori's cells could rebuild breasts lost to cancer. The next logical step was trying them out for breast augmentation. Perhaps not surprisingly, once again this happened in Japan. The country has a strong cultural prejudice against putting anything foreign into one's body; organ transplants were slow to be adopted in Japan and remain rare. But if that ick factor is the immovable object, the Western-inspired desire for bigger breasts is the irresistible force.
In late 2007, cosmetic surgeon Tatsuro Kamakura of Cosmetic Surgery Seishin, a chain of surgical clinics in large Japanese cities such as Tokyo and Osaka, began a study of the Celution System for breast augmentation, eventually enrolling 20 women.
In 2008 he told the Congress of the Japan Society of Aesthetic Surgery that the first three patients kept their new volume and that the tissue remained soft and natural. He had injected an average of 160cc of stem cell- loaded fat droplets, boosting breast circumference an average of four centimetres (1.6 cup sizes). In commercial use, a new breast could run to about $2,000 to $2,800 (£1,259 to £1,750). "It's probably a $1 billion market," Calhoun says.
But the possibilities aren't boundless. "It's not a substitute for implants for women who want to look, um, unnaturally large,"
Hedrick says. "You can't take a flat-chested woman and make her look like a dancer at a strip club. We're not targeting that market. If they don't care about looking natural, let them do silicone. The goal of this is a natural, soft-tissue feeling. Plus, there is a whole new market of women who would love another 100cc to 200cc but would never have an implant. I think that's bigger than the current breast-implant market." That is, women who wouldn't consider a silicone implant but who would be intrigued by the chance to have their breasts plumped with cells from their own bodies while reducing the fat in their hips and abdomen to boot.
Typically, experimental medical treatments go through years of
testing in animals before they reach people. Although regulators in Europe and Japan were satisfied with the animal and human studies that Cytori submitted for approval of the Celution machine, the US Food and Drug Administration has yet to weigh in.
And as women in Japan were being treated with Cytori's cells, the company was still conducting studies on animals to assess the safety of the procedure. As recently as 2007, Cytori's principal scientist, John Fraser, was performing key experiments on mice. The problem is that the reason adipose regenerative cells work -- inducing the formation of blood vessels -- is also the reason they might be dangerous, especially to cancer survivors. Such angiogenesis, after all, is what allows metastatic tumours to thrive. But Fraser's experiment showed that in mice, the adipose regenerative cells did not trigger the formation of breast tumours, promote their growth or cause them to metastasise to the lungs.
The human trials have not followed the women for very long, so it is still possible that a dangerous side effect like cancer will emerge. "People do challenge me: 'Why are we moving so fast?'"
Fraser says, standing in a corridor adorned with posters of results he and his colleagues have presented at conferences. Hedrick jumps in: "It's because we think like doctors taking care of patients. We have a lot of doctors working here. When we felt there was clear sailing, we hit the gas pedal. Where we felt there were obstacles, we slowed down."
Adds Fraser, "We're not cowboys." They might find themselves in an industry shoot-out, however, as the allure of adipose-derived stem cells has drawn other companies to the field. The most flamboyant is AdiStem, based in Hong Kong. Its process, like Cytori's, begins with liposuction. The fat is mixed with enzymes and centrifuged, then the precipitated cells are centrifuged again.
That, however, is where the similarity ends. AdiStem next mixes its cells with plasma and exposes them to laser light, the company claims, to photoactivate stem cell functionality. CEO Vasilis Paspaliaris says the resulting cells can then potentially be used to treat autism, idiopathic pulmonary fibrosis, osteoarthritis of the knee and hip, type 2 diabetes, acne scarring and hair loss, as well as in cosmetic reconstruction.
Although Paspaliaris says all the results seem promising, he believes "the most convincing" are those for the face. Some Los Angeles cosmetic surgeons are already using the AdiStem process with face-lifts. These claims have raised eyebrows. It hasn't helped that AdiStem posts videos of its autism "treatments" on YouTube or that there are no peer-reviewed scientific papers on the use of photoactivation to increase stem-cell functionality. Calhoun says: "At the right time, we will protect our markets and enforce our patents, but at present it seems to be a potential waste of capital, resources and energy."Cytori's bigger concern is that although these companies may pose no competitive threat, they are a PR disaster waiting to happen.
There is one other key feature that the next-generation Celution machine shares with a photocopier, as Calhoun demonstrates. Just as the latter has a touch screen control panel that displays options (paper size, number of copies, magnification), so does the Celution -- only here, the options are organs. "See? There's a picture of a breast, a heart, a disc in the back," he says. "You push that and the machine loads different software, which adds the right drugs," reagents and other biochemicals to the liposuctioned fat cells. He envisions an iPhone like business model, with individual doctors devising apps to repair different organs with the perfect slurry of adipose regenerative cells. If it works, the breasts on his laptop will have plenty of company.
This article was originally published by WIRED UK
