Your Disease In A Dish

When you read about biomedical discoveries in the press, odds are you’re reading about experiments done in cells, grown in laboratories. They float, disembodied, in flasks of red liquid, so it’s easy to forget that they originally came from people. The most commonly used human cells, known as HeLa, came from a woman called Henrietta Lacks. MCF-7 cells came from the breast tumour of a 69-year-old woman named Frances Mallon. Jurkat cells originated within a 14-year-old boy with leukaemia.

These individuals, along with hundreds of others, have acted as stand-ins for the rest of humanity. Their immortal cell lines provided scientists with a ready supply of cells for experiments, and fuelled countless discoveries that benefited the rest of us. But our command of cell biology is growing to a point where we may no longer need proxies.

Here’s a vision of the future. You’re diagnosed with a rare genetic disorder. Your doctors take a sample of your cells and grow them, creating cell lines, tissues and even mini-organs—little model versions of you, complete with all the genetic faults that are responsible your disease. The doctors use these models to work out what these mutations are doing, and to test the safety and effectiveness of different drugs. Based on these tests, they decide on the most appropriate treatment—one that’s intimately tailored to your biology.

We’re not quite there yet, but we’re making good progress. Consider what Kathrin Meyer and Brian Kaspar from the Nationwide Children’s Hospital in Ohio, USA have just done.

They study amyotrophic lateral sclerosis (ALS)—the fatal disease that affects physicist Stephen Hawking, and that affected baseball player Lou Gehrig. It’s caused by some combination of genetic mutations that gradually kill motor neurons—the ones that control our muscles. As they die, muscles weaken and waste away. Patients lose their ability to walk, move their arms, speak, swallow, and breathe.

Recently, a few teams of scientists have shown that other cells in the brain—glial cells—help to show the motor neurons to death’s door. Glial cells normally provide support, nutrition and protection to neurons. But if they carry ALS-causing mutations, they can selectively kill motor neurons instead. The protectors become assassins.

To study these turncoats, the team took skin cells from their seven patients and reprogrammed them into neural precursors, which can produce the various cells within our brains and nervous systems. It took just four genes to trigger the transformation, and around a month to grow healthy batches of cells. With different growth factors, the team could coax these precursors into becoming neurons (including motor neurons specifically) and astrocytes (a star-shaped type of glial cell).

On their own, the motor neurons lasted for weeks. But Meyer found that they quickly died when exposed to the astrocytes. Within five days, up to 80 percent of them were dead, and the survivors were left with just a few, short branches. The ALS astrocytes were the only ones that did this; those from healthy patients had no such murderous effects.

Four of the patients that the team worked with have familial ALS—a kind that accounts for 10 percent of cases, and is caused by inherited mutations in genes such as SOD1 and C9orf72. Three of the patients had sporadic ALS—the most common variety, which is caused by typically unknown mutations that spontaneously appear in people with no family history. The team found that astrocytes from all of these patients are toxic to motor neurons. This suggests that both the SOD1 and C9orf72 mutations are probably turning astrocytes into killers through the same route—one that also applies to whatever unknown mutations are behind the sporadic cases.

The details are still unclear, but the team hope to uncover them through their powerful new tool—their quick and consistent technique for generating an endless supply of neurons and astrocytes, which are personalised versions of a single patient’s cells. They also think they might be able to test different drugs on these cells, to work out the most promising treatments for individual people with ALS during their lifetimes.

If that seems a long way away, it’s worth remembering how far this line of research has come in a very short time. In 2006, Shinya Yamanka found a way of reprogramming cells from adult mice into a stem-like state, from which they could be coaxed into a number of different fates. Take a skin cell, and you could eventually end up with a neuron. Other scientists accomplished the same feat with human cells in 2007, and with cells from a woman with ALS in 2008 (which were then converted back into motor neurons).

In 2010, a Stanford group skipped the intermediate stage altogether and just converted skin cells directly into neurons. As before, the mouse cells came first, then human cells a year later. Meanwhile, another team converted mouse skin cells into neural progenitors, which can produce glia as well as neurons. And now, Meyer and Kaspar have repeated the same trick for human neural progenitors.

When the press covers these discoveries, they normally talk about creating supplies of new cells to bolster the ones that are lost through diseases like ALS. Such applications are a long way off, with many safety issues to address and open questions to answer. In the meantime, they have enormous potential as research tool.

As I wrote in 2008, “it’s a godsend for ALS research. Progress in understanding the disease has been relatively slow, mainly because it has been nigh impossible to obtain a decent supply of living motor neurons affected by the condition. Now, researchers can culture large colonies of both motor neurons and glia that carry genetic defects associated with ALS. That gives them free reign to investigate the causes of the disorder, the environmental conditions that interact with these genes, and the way the affected neurons interact with other types of cell. It also provides them with neurons to use for screening and testing potential drugs.”

Reference: Meyer, Ferraiuoloa, Miranda, Likhite, McElroy, Renusch, Ditsworth, Lagier-Tourenne, Smith, Ravits, Burghes, Shaw, Cleveland, Kolb & Kaspar. 2013. Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. PNAS http://dx.doi.org/10.1073/pnas.1314085111