Growing Diseases In A Dish

A new kind of stem cell could vastly improve drug development.

Inside a laboratory at Ipierian in South San Francisco, Calif. a stunning transformation is taking place. Using viruses, scientists insert four genes into the genome of skin cells taken from patients with a rare, often fatal disease called spinal muscular atrophy. During three weeks of tending the researchers induce a fraction of a percent of the cells to morph into embryonic-like stem cells. But they don’t use a single embryo.

Ipierian, a sapling with only 35 employees, then coaxes these “induced pluripotent stem cells” into becoming neurons and brain cells known as astrocytes. Over the past 18 months university researchers have transformed such cells into beating heart cells, liver cells, kidney cells and others. Several companies and hundreds of academic labs in the U.S., Japan and Europe are also creating these newfangled stem cells.

The goal, at Ipierian and many academic labs, is to get the cells to show signs of diseases such as spinal muscular atrophy or Parkinson’s–essentially, to grow a disease in a petri dish. If Ipierian can do that, it can test vast numbers of potential drugs against several neurodegenerative diseases. This would speed up the search and maybe lead to drugs that would otherwise never have been found.

In the past few years work on stem-cell technology has inspired sci-fi visions of renewable body parts. That remains a fantasy. So far only a few labs have gotten the new kind of stem cells to exhibit symptoms of diseases. But that achievement, coming only three years after induced pluripotent cells were discovered using mice skin cells, is itself phenomenal.

“It feels like we’re on the cusp of a revolution,” says Dr. George Daley, associate director of the Stem Cell Institute at Children’s Hospital Boston and cochairman of Ipierian’s scientific advisory board. “This is a breakthrough–to take human cells and use them to make the tissue involved in the disease.”

Part of the reason so many drug candidates flop is that they are first tested in animals such as mice or rats, not always great stand-ins for people. Some diseases, like Alzheimer’s, are not easily reproduced in animals. The result: Eight out of every nine drugs in human trials fail.

Starting with cells from patients with spinal muscular atrophy, predicts Ipierian Chief Executive John Walker, will enable his scientists to test potential drugs against far more relevant cells than have been used before. “It’s like a clinical trial in the lab,” says Walker, who has spent two decades as chief executive at a handful of small biotech companies.

But the science around the new stem cells is still raw. It was only in late 2007 that James Thompson of the University of Wisconsin at Madison and Shinya Yamanaka of Kyoto University independently published results showing that their labs had reprogrammed human skin cells this way. One of the genes used to alter the cells is known to be cancerous, which might lead to cancer tumors growing in the stem cells. To eliminate that risk, researchers around the world are coming up with ways to create the stem cells without using genes or viruses. Instead they are inserting bits of DNA or other organic compounds, or reprogramming the cells without inserting foreign DNA into the genome.

The technology is so new that researchers are mostly brewing their own cells rather than relying on a vendor. Typically only one in a thousand skin cells will convert into a stem cell over 20 days; it’s unclear what makes this process successful. It takes another month to convert one of these stem cells into, say, a neuron, and that process is technically challenging. “They require a huge amount of gardening,” says Thomas Maniatis, a molecular biology professor at Harvard whose lab is using patient-derived IPS cells to study amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease).

Then there’s that matter of growing a disease in a petri dish. “We don’t know at this stage what part of [ALS] we can recapitulate in a dish,” admits Ipierian Chief Technology Officer Berta Strulovici. Ipierian will study Parkinson’s as well as spinal muscular atrophy and hopes to develop drugs for all three diseases.

But diseases that in humans develop over decades–such as Parkinson’s or Alzheimer’s–may be very difficult to reproduce in the lab in a much shorter time. “Can a disease with a long latency like Parkinson’s grow in a dish of culture over a few weeks?” ponders Rudolf Jaenisch, a biology professor at MIT whose lab took patients’ skin cells and produced neurons involved in Parkinson’s disease.

“There is still an awful lot of art in inducing IPS cells,” says Ipierian’s Walker, but he insists that his scientists are aiming to industrialize the process of reprogramming cells. Ipierian (“Pierian” refers to the spring of wisdom in Greek mythology) was formed in July through the merger of two young stem-cell companies, Izumi Bio and Pierian. Together they have raised a total of $31 million from venture capital firms including Kleiner Perkins Caufield & Byers and MPM Capital. During a visit in early August shelves in some of the company’s labs were bursting with cardboard boxes holding recently purchased microscopes and other lab equipment.

Cellular Dynamics International, situated in Madison, Wis. and founded by stem-cell pioneer James Thompson and three university colleagues, inked a deal in March 2008 to supply Roche with beating heart cells for toxicity testing in drug development. In the fall of 2008 Cellular Dynamics began using induced pluripotent stem cells instead of embryonic stem cells to make the heart cells. Using IPS cells both avoids the ethically charged issue of using embryos and can provide more genetic and clinical information about the donor that may help drug development. Chief Commercial Officer Christopher Kendrick-Parker says the company is “delivering hundreds of millions of cells” to Roche and other customers.

In June Cellular Dynamics said it had reprogrammed human blood cells into IPS cells. “Most people would rather give blood than a chunk of skin from their arm” (in a “punch biopsy”), which is how skin cells are now collected, says Kendrick-Parker. “I’ve had it done. It hurts.”

Stanford researchers published results in early September showing that they had reprogrammed human fat cells left over from liposuction into the new stem cells.

In San Diego biotech Fate Therapeutics is collaborating with biotech toolmaker Stemgent to form Catalyst, a venture to make IPS cells for other firms that join them in a consortium. So far no company has signed up. Fate also aims to use IPS cells to learn about the role of stem-cell biology in areas like bone regeneration and to create drugs that turn on adult stem cells in the body for healing purposes.

The commercial rumblings around IPS cells call to mind the mid-1970s excitement about monoclonal antibodies, when researchers hoped to vastly improve cancer treatment with disease-fighting antibodies that would bind to specific targets on cells. It took two decades for the first wave of antibody drugs to be approved.

It might just be too early to pursue IPS cell science in a commercial setting. Says MIT professor Jaenisch, who is also the scientific cofounder of Fate: “You can wait until everything is settled, and then you miss the boat. Or you go early, and there’s some risk–and you participate in the development of the science.”


Growing Diseases In A Dish
Kerry A. Dolan – 16 August 2009
Forbes Magazine – 5 October  2009