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Cells That Don’t Belong

Several years ago, biologist Thea Tlsty’s team at the University of California, San Francisco, was studying wound cells in breast tissue. These are adult cells that divide furiously in response to injury, helping to replace those that were damaged. The typical wound cell in the breast has the ability to turn into different kinds of breast cells, each specialized for a different role in the tissue, such as producing milk. But Tlsty’s team stumbled on a subset of repair cells that could do much, much more.

This tiny subset, making up just 1 out of every 10,000 cells in the breast, are pluripotent, meaning that they can be chemically coaxed to turn into a wide range of other cells. “Cells that we could get in the breast, they can make neurons, they can make beating heart cells, they can make bone, cartilage, fat, blood vessel cells — it was amazing,” Tlsty says.

Tlsty published these findings earlier this year, and I just wrote about them for Smithsonian Magazine. The work is exciting because the new stem cells could be used as therapies for a host of diseases, from diabetes to Parkinson’s. But it hasn’t been replicated yet, and until that happens, many scientists aren’t ready to believe it. Why? Because if the study is true, it means that one of biology’s central dogmas is wrong.

“Everybody thought that pluripotency was a condition that went away after you formed your whole body,” Tlsty says. “Because otherwise, why wouldn’t you have an eyeball forming in the middle of your back, right? Or a toenail growing out of your forehead?”

Good point. As it turns out, though, there have been a handful of examples of cells cropping up in tissues where they don’t belong. Tlsty cited a few medical case reports in her paper, and I looked them up. I don’t know if they necessarily bolster her argument, but they’re certainly weird and fascinating.

One of the most common examples of misplaced cells seems to be livers. They grow all over the place. The first reported case, in 1922, described a liver growing on a gallbladder. Since then doctors have found other livers in gallbladders (like the one pictured above), as well as in the thoracic cavity, pancreas, esophagus, and on adrenal glands sitting atop the kidneys. A recent review finds 74 so-called ectopic livers reported in the medical literature, and offers no explanation.

Then there are the errant bones. Take a 2005 report of an 85-year-old woman in the U.K. who went to the doctor for bowel troubles. For a month, she had experienced alternating diarrhea and constipation. The doctors had no idea what it could be, so they peered inside her large intestine. They found a 1.5-centimeter pale brown polyp and sent it to the lab for testing. And what was that polyp? A piece of bone. In her colon. Why was it there? Unclear. Similarly, last year, researchers from India described a 16-year-old girl who couldn’t see out of her right eye. The vision loss had started six years earlier, when she suffered “accidental trauma by fist of hand.” Surgeons removed the eye and, a few weeks later, gave her an artificial one. When they analyzed the damaged eye in the lab, they found pieces of adult bone, with marrow and all.

Just one more and then I’ll stop, promise. In 2007, researchers from Japan reported the case of an 11-year-old girl with a brain tumor. She had had the mass since birth and her doctors had been watching it closely throughout her childhood. By age 11, she needed surgery to remove it. Later, researchers analyzed the dissected tissue. And it was totally weird. As one study put it: “The initial histological analysis demonstrated a tumor growing out of what appeared to be nearly normal looking pancreas.” Pancreas. In her brain.

“Pathologists have known for a long time that sometimes the body makes mistakes,” Tlsty says. Her newly discovered stem cells might explain why, or they might not. Either way, it makes me wonder about my own eyes and gut and brain, and all of the misfit cells that may be lurking inside.

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Grow new organs, or get them from animals?

We don’t have enough organs. Due to our ageing population and the rising burden of chronic diseases, the organs of living people are failing. Meanwhile, those of the recently dead continue to be in short supply, despite well-funded initiatives to increase donation. So what can we do?

In a new feature for The Scientist, I explore two very different solutions to the organ shortage: transplanting them from animals, and growing them afresh. Both approaches have been chugging along for many years, and proponents of both think that they’re on the cusp of something big. I go into a fair bit of detail about the history behind both routes, where they are now, and where they might reasonably get to in the future.

This isn’t an easy piece to structure – it’s almost like two mini-features. But I was struck at how people who work on both approaches were drawn into the field by their frustration at being able to save terminally ill patients but just not having the replacement parts to do it. Do have a read. Here’s the first act, to whet your appetite:

For Joseph Vacanti, the quest to build new organs began after watching the death of yet another child. In 1983, the young surgeon was put in charge of a liver transplantation program at Boston Children’s Hospital in Massachusetts. His first operation was a success, but other patients died without ever being touched by a scalpel. “In the mid-80s, kids who were waiting for organs had to wait for a child of the same size to die,” says Vacanti. “Many patients became sicker and sicker before my eyes, and I couldn’t provide them with what they needed. We had the team, the expertise, and the intensive care units. We knew how to do it. But we had to wait.”

On the other side of the Atlantic, David Cooper was having the same problem. Having taken part in the first successful series of heart transplants in the United Kingdom, he had moved to South Africa to run a transplantation program at the University of Cape Town Medical School. At the time, people had a 50/50 chance of surviving such a procedure, but Cooper recalls that most of his patients were killed by a lengthy wait. “We just didn’t have enough donors,” he says.

Today, the organ shortage is an even bigger problem than it was in the 1980s. In the United States alone, more than 114,000 people are on transplant lists, waiting for an act of tragedy or charity. Meanwhile, just 14,000 deceased and living donors give up organs for transplants each year. The supply has stagnated despite well-funded attempts to encourage donations, and demand is growing, especially as the organs of a longer-lived population wear out.

Faced with this common problem, Vacanti and Cooper have championed very different solutions. Cooper thinks that the best hope of providing more organs lies in xenotransplantation—the act of replacing a human organ with an animal one. From his time in Cape Town to his current position at the University of Pittsburgh, he has been trying to solve the many problems that occur when pig organs enter human bodies, from immune rejection to blood clots. Vacanti, now at Massachusetts General Hospital, has instead been developing technology to create genetically tailored organs out of a patient’s own cells, abolishing compatibility issues. “I said to myself: why can’t we just make an organ?” he recalls.

In the race to solve the organ shortage, xenotransplantation is like the slow and steady tortoise, still taking small steps after a long run-up, while organ engineering is more like a sprinting hare, racing towards a still-distant finish line. Most of those betting on the race are backing the hare. Industry support has dried up for xenotransplantation after years of slow progress, leaving public funders to pick up the expensive tab. Stem cells, meanwhile, continue to draw attention and investment. But both fields have made important advances in recent years, and the likely winner of their race—or whether it will result in a draw—is far from clear.

Photo by Socialisbetter

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Scientists correct the typo behind a genetic liver disease

Every year, thousands of people die because of typos in their genes. There’s a long list of debilitating or fatal genetic diseases that are caused by a single incorrect DNA letter among the three billion in our genome. It’s the equivalent of pulping an entire encyclopaedia on the basis of a single typo. But hope is at hand. We are fast approaching the point when we can proofread these errors out of our genes.

Kosuke Yusa  and Tamir Rashid have taken the latest step towards this goal, by developing a more efficient and less risky way of correcting genetic errors. They took cells from patients with a genetic liver disease, edited the gene responsible, and grew corrected liver cells that successfully treated mice with the same disease.

The disease in question is called alpha 1-antitrypsin deficiency (or alpha-1 for short). It affects 1 in every 2,000 Europeans and is caused by a single typo in the A1AT gene. The error stops people from making enough of the A1AT protein. The little they do make builds up in their liver, overloading it and leading to cirrhosis. At the moment, the only treatment is a liver transplant, and donors are hard to come by.

Yusa and Rashid fixed this problem in three steps: they took skin cells from alpha-1 patients with two bad copies of the A1AT gene; reprogrammed them into stem cells; fixed the error in both copies of the broken gene; and used the corrected stem cells to produce liver cells. This is the first time that anyone has corrected a faulty gene in stem cells derived from a human patient.

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The genetic sergeants that keep stem cells stemmy

Stem cells are bursting with potential. They can produce every type of cell in the human body. Small clumps of them can generate entire individuals. But this ability, known as pluripotency, is hard won. So stem cells must constantly repress genetic programmes that threaten to send them down specific routes, and rob them of their limitless potential. “Imagine you’re a stem cell,” says Mitchell Guttman from the Broad Institute of MIT and Harvard. “The worst thing that could happen is that you accidentally turn on, say, neural genes and become a brain cell.”

Now, Guttman has found that stem cells keep themselves ‘stemmy’ with a group of genes called lincRNAs. His discovery not only assigns an important role to these mysterious genes, it opens up a new potential way of precisely controlling what goes on inside a cell.

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Scientists transform skin cells directly into neurons

It’s difficult for people to change their identities or careers, but it can be done. We don’t have to be stuck with one particular fate; with a bit of effort, we can become different people. The same is true for the cells that we’re made of. They come in different types, from brain cells to skin cells to muscle cells. Stem cells can produce all of these types, but once a cell commit to a particular role, it’s largely stuck there.

But not always. Scientists can convert one type of cell into another with the right cocktail of molecules – a process known as transdifferentiation. It’s a cellular makeover. The hope is that this technique will allow doctors to grow bespoke tissues and organs. If someone suffers from a disease that destroys their nervous system, like Alzheimer’s, you could theoretically take their skin cells, and transform them into a fresh supply of genetically identical neurons.

To do this, you need to work out the right recipe. Many groups are working on this. They’ve managed to change pancreatic cells into liver cells, skin cells into heart cells, and more. But no one has been able to transform other types of cells into human neurons. That is, until now. Zhiping Pang, Nan Yang and Thomas Vierbuchen from Stanford University have identified a quartet of proteins that can change human skin cells into working neurons.

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An entire flatworm regenerated from a single adult cell

In a lab in MIT, a flatworm is dying. It’s a planarian – a simple animal that is normally very difficult to kill. Planarians are masters of regeneration; whole animals can be reborn from small clumps of tissue. If you cut one in half, it will simply grow into two planarians. But this animal has been bombarded with high doses of radiation that have wiped out its ability to regenerate. Slowly, its cells are bursting apart. With no new ones to replace them, the planarian has a few weeks to live.

But Daniel Wagner and Irving Wang are about to save it, in a fashion. They transplant one special cell from a donor planarian into the terminal individual’s tail. The cell starts to divide. It produces skin, guts, nerves, muscle, eyes and a mouth.

As the planarian dies from the head backwards, the transplanted cells spread from the tail upwards. At its worst, the animal is a stunted mass with no discernible head. But two weeks after the transplant, it has completely regenerated. A new planarian has risen, phoenix-like, from the ashes. Its entire body is now genetically identical to the single transplanted cell. (more…)

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Breast cells naturally transform into stem cells

Our bodies are rife with disappearing potential. We come from stem cells, which can give rise to all the diverse types of cells in the human body. They can produce neurons, muscle cells, skin cells and more. As their daughters become more and more specialised, they lose this ability and become stuck with a specific fate.

That’s the standard story – a one-way street of lost potential.

The story is wrong.

According to a provocative new study from Christine Chaffer at the Whitehead Institute for Biomedical Research, some specialised cells can spontaneously revert back to a stem-like state. The one-way street actually works two ways.

It’s a very surprising result. Until now, no one thought that these reversions were possible, and scientists have spent a lot of effort finding ways of artificially reprogramming specialised cells into a stem-like state. Now it turns out that cells can naturally do the same thing. It’s like suddenly discovering that the people you pass every day in the street have been secretly gaining superpowers under your nose.

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Worrying genetic changes in reprogrammed stem cells

As we age, we lose potential. The options for a child seem limitless but as adults, our careers, opinions and relationships are constrained by the choices we made. And as we become more specialised, so do the cells in our bodies. As early embryos, we contain a core of stem cells that have the potential to become all the types of cells in an adult body – skin, nerves, muscle, and more. As our cells divide, they become increasingly specialised and they lose this limitless potential. But over the past five years, scientists have found ways of turning back the clock.

We can now reprogram adult cells into a stem-like state, where they once again have the potential to produce a variety of different types. These “induced pluripotent stem cells” or iPSCs are one of the most important advances of the last decade. They herald the promise of creating personalised treatments for diseases, or even new body parts, all tailored to a person’s own genome. This field of research is frenetic, exciting and optimistic (see the interactive timeline below for more).

But these cells aren’t ready for the big time yet. In recent months, several scientists have sounded a note of caution. Since iPSCs were first created in 2006, there was always reason to suspect that they weren’t quite the same as genuine embryonic stem cells (ESCs). And the scope of those differences is becoming clearer all the time.

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Research into reprogrammed stem cells: an interactive timeline

Our bodies are made up of hundreds of different types of cells, but stem cells can become all of them. Over the last five years, scientists have made great advances in reprogramming specialised adult cells back into a stem-like state, turning back the clock and restoring their lost potential. These “induced pluripotent stem cells” or iPSCs could be used to create personalised treatments for diseases, or even new body parts, which are tailored to an individual’s genome.

The journal Science named iPSCs as its Breakthrough of the Year in 2008. Since their discovery in 2006, research on these cells has rocketed ahead and this timeline charts the progress of this exciting field, right up to today’s latest discovery. For readers who are using Readers or phones and cannot see the timeline, all of its content is available as text below.

This timeline was inspired by John Rennie’s manifesto on how to improve science journalism, by looking at the stories that lead up to new discoveries, rather than focusing on every new paper in isolation.

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Reprogrammed stem cells are loaded with errors

This is an updated version of another post, edited to meld together a brand-new discovery with an intimately related one from last year.

Imagine trying to rewind the clock and start your life anew, perhaps by moving to a new country or starting a new career. You would still be constrained by your past experiences and your existing biases, skills and knowledge. History is difficult to shake off, and lost potential is not easily regained. This is a lesson that applies not just to our life choices, but to stem cell research too.

Over the last four years, scientists have made great advances in reprogramming specialised adult cells into stem-like ones. By turning back the clock, they can once again imbue the potential to produce any of the various cells in the human body. It’s the equivalent of erasing a person’s past and having them start life again.

But two groups of scientists – one led by Kitai Kim, and the other by Ryan Lister and Mattia Pelizzola – have found a big catch. They showed that these reprogrammed cells, formally known as “induced pluripotent stem cells” or iPSCs, still carry a memory of their past specialities. A blood cell, for example, can be reverted back into a stem cell, but it keeps a record of its history that constrains its future. It would be easier to turn this “stem cell” back into a blood cell than, say, a brain cell.

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Reprogrammed stem cells carry a memory of their past identities

Embryonic-stem-cells

Imagine trying to rewind the clock and start your life anew, perhaps by moving to a new country or starting a new career. You would still be constrained by your past experiences and your existing biases, skills and knowledge. History is difficult to shake off, and lost potential is not easily regained. This is a lesson that applies not just to our life choices, but to stem cell research too.

Over the last four years, scientists have made great advances in reprogramming specialised adult cells into stem-like ones, giving them the potential to produce any of the various cells in the human body. It’s the equivalent of erasing a person’s past and having them start life again.

But a large group of American scientists led by Kitai Kim have found a big catch. Working in mice, they showed that these reprogrammed cells, formally known as “induced pluripotent stem cells” or iPSCs, still retain a memory of their past specialities. A blood cell, for example, can be reverted back into a stem cell, but it carries a record of its history that constrains its future. It would be easier to turn this converted stem cell back into a blood cell than, say, a brain cell.

The history of iPSCs is written in molecular marks that annotate its DNA. These ‘epigenetic’ changes can alter the way a gene behaves even though its DNA sequence is still the same. It’s the equivalent of sticking Post-It notes in a book to tell a reader which parts to read or ignore, without actually editing the underlying text. Epigenetic marks separate different types of cells from one another, influencing which genes are switched on and which are inactivated. And according to Kim, they’re not easy to remove, even when the cell has apparently been reprogrammed into a stem-like state.

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