ALS Alert Newsletter | May

New ALS Human Cell Cultures Underway

A handful of this country's stem-cell pioneers are meeting to change the face of research with the first large-scale batches of human cells with ALS.

It’s happening with more than a little help from our friends

This spring, a consortium of scientists from Johns Hopkins, Harvard and Columbia universities began work on the first national ALS stem cell bank --- a resource with more than two dozen lines of human ALS cells, in cultures made easily available to anyone.

According to an aggressive, industry-style schedule with built-in project management and progress deadlines, the researchers plan to have the cells ready in two years.

The idea of having a plentiful supply of motor neurons and other cells derived from actual patients is energizing ALS scientists. Packard and other investigators have long made do with animal models of the disease — good as they are --- to search for its cause and effects.

Using human cell cultures to explore ALS biology, screen possible drugs or run early drug safety or even efficacy tests has been something of a holy grail.

Recently, because of a recent $3.7 million NIH Grand Opportunities (GO) grant awarded to Johns Hopkins, Packard director Jeffrey Rothstein — also a Hopkins neuroscientist/neurologist — was able to set up this consortium of academic and industry stem cell biologists and others to produce the cells. (The government’s stipulated two-year deadline, he says, drives the work.)

The new cell cultures center on iPS cell biology. “Discovered” several years ago, induced pluripotent stem cells are cousins to headline-making embryonic stem cells in that both can likely form any cell type. Unlike ES cells, though, many different body tissues can serve as their source. Still, researchers now most commonly derive iPS cells from adult skin cells that have been biopsied, then biochemically nudged into a less-mature, stem cell state.

For ALS, the value of iPS cells lies in their ability to form motor neurons and astrocytes, the disease’s two key nervous system cells. Also, iPS cells are likely able to grow indefinitely and consistently in culture. That makes them low-maintenance — and more probable for researchers everywhere to use.

Who’s on Board

“Generating the cells from a single patient is something many labs could do,” says Rothstein, “but methods differ from lab to lab, which can make slight, but perhaps crucial differences in the final cultures.

“And the real challenge lies in the ability to produce large numbers of cells from many different ALS patients. Just validating each cell line biochemically, for example —that’s something like a certificate of authenticity — involves brand-new science.

“Right now, the only way to have the large scale production we need is with a really coordinated approach, with experts locked in at each step,” says Rothstein —hence the consortium.

In addition to four other stem cell scientists at Hopkins, experts at Harvard and Columbia University are on board. They include Kevin Eggan and Chris Henderson, whose labs were the first to create iPS cells from ALS patients and then show the cells could form motor neurons. And world-respected molecular biologist Tom Maniatis offers necessary expertise in the sort of genetic studies the new cells will require.

While it’s rare to have national pioneers in iPS biology work together, the consortium is also unique in its depth of industry involvement. In this case, iPierian, a biopharmaceutical company in San Francisco, is a key part of the project. The company leads in creating iPS cells on a large scale from skin samples.

In return for its help, iPierian will be able to advance its own studies to find therapeutics for ALS, using the cell cultures. “We collect the skin cells along with patient consents to allow industry to use them,” says Rothstein.

The reason for that is strong. “Keep iPS cells only within academia and you’ll quickly see some really neat, useful studies. But universities aren’t set up, large scale, to ready drugs or other therapies for clinical trials. Because we think these cells will be optimum for drug discovery, we need to encourage industry’s help.”

Jumping a Hurdle

One large hurdle, surprisingly, is getting the skin samples. The sampling itself isn’t difficult; biopsies are small and almost painless. The challenge is finding familial ALS patients. At least nine different genes cause fALS, each with different mutations. To help patients and science alike, all varieties are needed. That translates to an unprecedented number of willing people with a rare disease.

Because time is short — it’s always short without a cure, but it’s especially so for this study — the scientists need help.

The Plan

The Packard-originated effort begins with the skin biopsies at Johns Hopkins and at collaborating clinics at Massachusetts General and Emory University hospitals. After an interim step, tissue goes to iPierian to generate iPS cells. These resulting stem cells are shipped to motor neuron experts at Columbia University to prompt into motor neurons, or to the Packard/Hopkins group. The latter oversees transforming iPS cells into astrocytes — the spinal cord cells that advance and spread ALS.

“At the end,” says Rothstein, “some 30 new cell lines will go into a national resource bank that the NIH will set up, where anyone can use them.” And even before that, plans are snapping into place to analyze each of the new cell lines, to compare which genes are active, which not.

It’s a whole new picture-window into ALS.