The cell factory: James Thomson (above) and Junying Yu
first transformed adult cells into stem cells called iPS cells
 in 2007.   Credit: Kevin Miyazaki

James Thompson
(Cellular Dynamics) Engineered stem cells could revolutionize drug discovery

OTHERS WORKING ON ENGINEERED STEM CELLS
Fate Therapeutics, San Diego, CA
iPierian, South San Francisco, CA
George Daley, Children’s Hospital Boston, Boston, MA
Shinya Yamanaka, Kyoto University, Kyoto, Japan

Mimicking human disease in a dish

 

 

This article is part of an annual list of what we (MIT TR) believe are the 10 most important emerging technologies.

 

 

MIT Technology Review, May/June 2010, by Emily Singer  –  The small plastic vial in James ­Thomson’s hand contains more than 1.5 billion carefully coddled heart cells grown at Cellular Dynamics, a startup based in Madison, WI. They are derived from a new type of stem cell that ­Thomson, a cofounder of the company, hopes will improve our models of human diseases and transform the way drugs are developed and tested.

Thomson, director of regenerative biology at the Morgridge Institute at the University of Wisconsin, first isolated human embryonic stem cells in 1998. Isolating these cells, which are capable of maturing into any other type of cell, marked a landmark in biology–but a controversial one, since the process destroys a human embryo. A decade later, ­Thomson and Junying Yu, then a Wisconsin postdoc, reached another milestone: they developed a way to make stem cells from adult cells by adding just four genes that are normally active only in embryos. (Japanese researcher Shinya Yamanaka simultaneously published a similar approach.) Dubbed induced pluripotent stem cells (iPS cells), they have the two defining characteristics of embryonic stem cells: they can reproduce themselves many times over, and they can develop into any cell type in the human body. Because no human embryos are used to create them, iPS cells solve two problems that had long plagued researchers: political protest and shortages of material.

Much of the excitement over iPS cells, and stem cells in general, arises from the possibility that they could replace damaged or diseased tissue. But Thomson thinks their most important contribution will be to provide an unprecedented window on human development and disease. Scientists can create stem cells from the adult cells of people with different disorders, such as diabetes, and induce them to differentiate into the types of cells damaged by the disease. This could allow researchers to watch the disease as it unfolds and trace the molecular processes that have gone awry.

In the nearer term, iPS cells may revolutionize toxicity testing for drugs. The cells are “the first unlimited source of any type of human tissue,” says Thomson, who founded Cellular Dynamics to put stem cells to practical use. The company sells heart muscle cells derived from its iPS cells to pharmaceutical giants such as Roche, which are using them to screen experimental drugs for harmful side effects. Thomson hopes those cells will help uncover problems early in the drug development process, saving billions of dollars on research and testing. For instance, since the iPS-derived heart cells will beat in a dish, scientists should be able to detect which drugs alter the heart’s rhythm. Scientists can also use the cells to study how the heart functions at a molecular level. And the company is developing other cell types, including brain and liver cells. The latter are of particular interest to pharmaceutical researchers, since drug toxicity often shows up in the liver. “Having a model that would predict toxicity before going into humans is incredibly valuable,” says Chris Parker, vice president and chief commercial officer of Cellular Dynamics.

By generating iPS cells from people with diverse ethnic backgrounds and genetic conditions, and from those who have reacted poorly to certain drugs, scientists can also gain a better picture of how compounds will affect different people. Thomson and others have already created iPS cells from people with ALS, Down syndrome, and spinal muscular atrophy, among other disorders. While it’s not yet clear how well those cells reflect the specific diseases, early research is promising. If it succeeds, researchers hope to use iPS cells to study other disorders and develop drugs to treat them. “That’s the thing that would fundamentally change the way drug development happens,” says Kyle Kolaja, director of early safety and investigative toxicology at Roche, which has partnered with Cellular Dynamics.

The last decade brought many difficult years for Thomson. His work on embryonic stem cells was a breakthrough, but it also brought intense controversy and media attention, turning him somewhat reclusive. With the rise of iPS cells and Cellular Dynamics, Thomson is beginning to come back to the limelight. “I think the legacy of embryonic stem cells will be that they gave rise to iPS cells,” he says. “These cells will be used in creative ways we can’t even imagine.” 

MIT Technology Review Editors, May/June 2010  –  Doctors who perform in vitro fertilization typically rely on a visual assessment of the embryos when deciding which ones to transfer into the uterus, but two-thirds of such embryos fail to implant. A new test analyzes the proteins and small-molecule metabolites in the fluid surrounding each embryo and compares the resulting metabolic profile with that of a healthy embryo. The test improves implantation rates up to 30 percent. That means doctors can transfer fewer embryos, reducing the chances of an undesired multiple pregnancy.

 

Courtesy of Molecular Biometrics

Product: ViaMetrics-E

Cost: $30,000 to $50,000 for the testing system in the U.S. market. (Tests will not add appreciably to the typical cost of $12,000 to $15,000 for an IVF treatment.)

Availability: Now in the U.K., Australia, Japan, Ireland, and Greece; seeking FDA approval in the U.S.

Source: www.molecularbiometrics.com

Company: Molecular Biometrics

The vast data housed in electronic records and genomics databases could reveal new insights

MIT Technology Review, April 22, 2010, by Emily Singer  –  When the stimulus bill passed last year–allocating $20 billion to help doctors and hospitals adopt electronic medical records (EMRs)–many scientists were excited about the possibilities for medical research. EMRs provide vast amounts of medical information that can be combed automatically and used to ask questions that are too expensive or perhaps unethical to study in traditional clinical trials, such as whether newer, more expensive treatments are more effective than older ones.

“There is a lot of federal funding right now supporting the development of the infrastructure to do that kind of work, as well as to look at comparative effectiveness research using databases,” says Richard Tannen, a physician at the University of Pennsylvania, in Philadelphia. “But it’s a complex and difficult problem, in some ways more difficult than people appreciate.”

While the idea of using electronic medical records for research has been around for more than a decade, it’s only recently started to take off. Scientists and physicians are now scouring the growing number of electronic medical records and genomic databases to figure out how to use this vast medical resource to answer a number of questions in medicine, such as why patients can respond so variably to treatment, and how genetics or other factors might contribute to this.

It has been necessary to invent new analysis methods to glean useful data from often disparate databases, and to make sure that the results produced aren’t biased. Studies based on data from EMRs are subject to the same concerns as observational studies, in which scientists look for links between an individual’s natural behavior and their health. It was observational study that suggested that hormone replacement in postmenopausal women reduced risk of heart attack, while subsequent clinical trials found that the treatment increased risk of heart disease and stroke.

Dan Roden, a clinical pharmacologist at Vanderbilt University, in Nashville, TN, is beginning to address some of those challenges in a pilot project linking EMRs to genomics databases. While he ultimately wants to use EMRs to better understand why different patients can react so differently to the same drug, the project is starting with the most basic questions. “We wanted to ask what genetic information would you want to access to take care of someone, what are the informatics challenges, and what are the ethical challenges in storing people’s information?” says Roden.

His team began by building a DNA database in 2007, extracting DNA from clinical samples collected for other research projects. (Thanks to the way the Vanderbilt medical system is organized, researchers can use such samples for multiple purposes and link that information to the patient’s medical record, while the patient’s identity remains hidden.) The team analyzed DNA from 10,000 people, searching for 21 specific single-letter variations that had been previously linked to different diseases. Using a technique called natural language processing–a sophisticated way of analyzing information–researchers developed a method to reliably identify patients with specific diseases solely from their medical records. The task is more challenging than one might expect; for example, someone may see a rheumatologist for evaluation without actually having rheumatoid arthritis.

By searching for genetic variations that are more common in people with specific diseases, the team confirmed a number of previously identified gene-disease links. The findings, published last week in the American Journal of Human Genetics, show that this type of research can yield useful results.

The team has now expanded the database to 81,000 samples and plans to use it to ask more complex questions. Roden will to try to find genetic predictors of drug response–specific variations that predict whether a patient is unlikely to respond to a specific drug, or more likely to suffer a dangerous or debilitating side effect. “The outcome will be a set of genetic variants that we think will be important to incorporate into medical record,” says Roden. “We want to be able to say, ‘Here’s a person who won’t respond to beta blocker, so they should get a diuretic.’ ”

According to Penn’s Tannen, it will likely take years to build up the databases needed to conduct broader clinical research. He estimates that a database of about 50 million people is necessary to ask the types of questions he is most interested in, such as whether patients older than 75 react the same way to a particular therapy as do those who are in their 40s. “That’s the potential great power of database studies,” he says. 

Science may consider fundamentalism a threat, but our study shows that most scientists are spiritual—suggesting both sides may have more in common than they think

The-Scientist.com, April 2010, by Elaine Howard Ecklund and Conrad Hackett  –   When President Barack Obama appointed Francis Collins, a geneticist and evangelical Christian, to head the National Institutes of Health in 2009, a cry went up. The problem? Collins is a theist. A religious believer, the critics said, was not the right choice for the public face of science.1

While the majority of scientists are not evangelicals, there are several well-known scientists—like Ken Miller, John Polkinghorne, and Freeman Dyson—who are engaged in public efforts to persuade believers that they do not have to choose between their faith and science.

What do the country’s leading scientists really think about religion? Scientists have investigated the question, but have asked only a small number of narrow survey questions about religion.

To get a more definitive answer, we reviewed responses from 744 tenured and tenure-track scientists (chemists, biologists, and physicists) working and teaching at the top 21 US research universities, according to the University of Florida’s “Top American Research Universities” report. The data were collected between 2005 and 2007 as part of the Religion Among Academic Scientists study (RAAS), which uses extensive state-of-the-art measures of religious identity, practice, spirituality, and belief, and can compare the answers to those given by the general public.

Not surprisingly, scientists differed from the general public in several key ways. Compared with 34% of all Americans, only two of the natural scientists we surveyed agreed that “the Bible is the actual word of God and it should be interpreted literally.” When it comes to belief in God, 63% of the general public agrees with the statement, “I know that God exists.” Yet only 5% of physicists, 7% of biologists, and 10% of chemists say the same. On the flip side, 39% of biologists, 36% of physicists, and 24% of chemists say they do not believe in God, while only 2% of the general population identifies as atheist.

But our findings also uncover surprising areas of common ground. Eighty percent of scientists who teach and do research at top US research universities were raised in a religious home and 55% were raised in a home where religion was important. Scientists show the most overlap with the general public in the realm of spirituality, with 62% of scientists considering themselves spiritual. A surprising 38% of atheist scientists say they are somewhat spiritual, as do 61% of agnostic scientists. Nearly half of all surveyed scientists say they attended religious services at least once in the last year.

Although scientists who work at elite universities are less religiously conservative—and less committed to organized religion generally—than the public at large, most scientists think religion has some degree of truth. Many individual scientists have a positive attitude toward the idea of religious truth and think their colleagues have a positive or neutral attitude toward religion. Only a minority believes there is an irreconcilable conflict between religious knowledge and scientific knowledge. Since a majority of scientists are interested in spirituality, this may be an area where they will find fruitful terrain for talking about issues of science and faith with the public.

Awareness that many scientists are not hostile to religion and emphasizing areas of overlap between scientists and the general religious population might help to advance constructive engagement between science and faith, lessening the threat factors on both sides.

Ecklund is a faculty member in the sociology department at Rice University, where she is also associate director of the Center on Race, Religion and Urban Life.

Hackett is a National Institute of Child Health and Human Development Postdoctoral Research Fellow in the Population Research Center at the University of Texas at Austin.

References

1. S. Harris, “Science is in the details,” The New York Times, July 26, 2009.