Provoking Our Inner Stem Cells

A startup aims to spur the body's native stem cells to heal disease.

By Lauren Gravitz

Fate Therapeutics, a startup based in La Jolla, CA, aims to harness the body's ability to heal itself by developing drugs that stimulate resident stem cells. Rather than developing cell transplants to replace diseased or damaged tissue, which is the focus of a great deal of stem-cell research, Fate is searching for molecules that can control the behavior of adult stem cells in different parts of the body. The two-year-old company began its first clinical trial in May of a novel molecule that could make cord-blood transplants more effective by enhancing the activity of the stem cells that create the blood and the immune system.

Caspar the Fish: By creating a transparent zebrafish, Harvard researcher Leonard Zon could watch fluorescently labeled hematopoietic stem cells from a donor fish repopulate the bone marrow of the recipient. The transparent mutant zebrafish, dubbed Caspar, provided a means for studying the effects of FT1050, an experimental drug now in clinical trials to boost the effectiveness of cord-blood transplants. Credit: Cell Stem Cell

The human body is full of adult stem cells--small populations of tissue-specific stem cells that are capable only of developing into the cells of their resident tissue, and whose job is to help maintain and repair that tissue. While they lack the flexible fate of embryo-derived stem cells, adult stem cells come in a variety of flavors, including those capable of making liver cells and immune and blood cells, among others. Fate Therapeutics believes that, with a little pharmaceutical prompting, these cells can be nudged to repair tissue and organ systems, or even fight back against cancer.

"[Adult stem cells] can be induced to proliferate, they can be induced to differentiate into the cell type they were destined to become, or potentially even induced to become something they weren't destined for that might be therapeutically relevant," says Paul Grayson, Fate's president and CEO.

To better understand how to activate and command adult stem cells, Fate has focused much of its research on induced pluripotent stem (iPS) cells, adult cells that have been reprogrammed back to an embryonic state and have the same flexible developmental potential as embryonic stem cells. Rather than trying to use these iPS cells to treat disease, Fate is using them as a discovery tool to learn more about which pathways are important for activating or inhibiting stem-cell development.

"Fate's strategy is to try and take advantage of what we're learning about stem-cell biology to develop methods of using drugs to turn on or turn off stem cells," says David Scadden, one of the company's founders and director of the Center for Regenerative Medicine at Massachusetts General Hospital. Scadden and other top investigators from regenerative-medicine institutes across the country--including MIT, Scripps, and Stanford--were brought together by a group of venture capitalists who saw Fate Therapeutics as a way to quickly take their research to the forefront of stem-cell science.

Fate has raised $25 million in capital and is backed by three venture-capital groups. The company has been building its intellectual-property portfolio by licensing technology from different universities, focusing in part on iPS cell technology, as well as patenting the stem-cell discoveries of its founders and in-house scientists.

Fate's first clinical trial focuses on a molecule known as FT1050. The molecule appears to stimulate proliferation of hematopoietic stem cells--which give rise to blood and immune cells--and helps guide them to the bone marrow. If successful, the drug could become an invaluable companion treatment to bone-marrow transplants and cord-blood transfusions used to treat cancer and blood diseases.

Treatment for leukemia or lymphoma, for example, kills off most of a patient's hematopoietic stem cells, and the best way to repopulate them is through bone marrow transplanted from a matched donor. When a bone-marrow donor match is unavailable, oncologists turn to umbilical-cord blood, which is rich in stem cells and requires only a partial tissue-type match. However, cord blood is also incredibly expensive, costing upwards of $30,000 or more per unit, and blood from a single cord is often insufficient to treat an adult.

"It becomes very difficult to find a unit large enough to sufficiently large enough for a full-grown adult," says Dennis Confer, chief medical officer of the National Marrow Donor Program. Physicians can sometimes use blood from two cords, but this is even more expensive and requires that both cord samples match the donor. "If someone could come up with an expansion strategy that was more cost-effective, that could gain wide acceptance," he says.

In an early-stage clinical trial, Fate Therapeutics is testing FT1050 in 12 patients who've undergone chemotherapy for lymphoma. The patients will each receive two units of cord blood: one that's been treated with the stem-cell-modulating drug, and another that's been left alone. The trial is primarily a safety study, but because the two units were harvested from two different newborns, researchers can use the genetic differences to track the cells and determine if FT1050-treated stem cells can more efficiently take hold and prosper in bone marrow.

Fate believes that multiple conditions can be treated this way, using small molecules to control adult stem-cell activity. The company is even pursuing the same strategy for cancer treatments, with the hope that they can disrupt the uncontrolled growth of cancer cells by forcing them into a more differentiated, less malignant state.

http://www.technologyreview.com/business/23017/

The Big Smart Grid Challenges

Regulations, privacy and security concerns, and other issues could hold back developments.

By Kevin Bullis

A smarter electricity grid could fundamentally change the way people pay for and manage their electricity use. In theory, the technology could help reduce demand, save money, and improve reliability and efficiency. But implementing the necessary changes will be difficult, according to experts attending a symposium on the smart grid at GE Global Research in Niskayuna, NY, this week. They expect resistance from regulators and consumers alike, citing the complexity of the proposed system as well as concerns about privacy and security.

Smarter meter: Possible strategies for reducing energy consumption rely on devices that can send and receive information from utilities and communicate wirelessly with appliances. Credit: Kevin Bullis, Technology Review

Multimedia See how the smart grid works.

The smart grid will incorporate new networking technology, including sensors and controls that make it possible to monitor electricity use in real time and make automatic changes that reduce energy waste. Furthermore, grid operators should be able to instantly detect problems that could lead to cascading outages, like the ones that cut power to the northeastern United States in 2003. And the technology ought to allow energy companies to incorporate more intermittent, renewable sources of electricity, such as wind turbines, by keeping the grid stable in the face of minute-by-minute changes in output.

For consumers, the smart grid could also mean radical changes in the way they pay for electricity. Instead of a flat rate, they could be charged much more at times of high demand, encouraging them to reduce their energy use during these periods. Companies such as GE are developing refrigerators, dryers, and other appliances that can automatically respond to signals from the utility, shutting off or reducing energy consumption to allow consumers to avoid paying the peak prices. Such strategies could allow utilities to put off building new transmission lines and generators to meet peak demand--savings that could be important as proposed regulations on carbon dioxide emissions force them to switch to more expensive sources of electricity.

But the necessary changes could prove difficult for consumers to adjust to, says Garry Brown, chairman of the New York State Public Service Commission, a utility regulator. Industrial and commercial electricity customers already have variable electricity rates that change with the time of day, but "they have the ability and expertise and wherewithal to figure out what to do with this," Brown says. "They have a manager that spends their life trying to react to it." Ordinary consumers don't have that advantage. Indeed, in the 1990s the New York state legislature blocked mandatory variable pricing amid concerns about the impact it could have on customers who couldn't avoid peak prices, such as people who must use electric-powered medical equipment around the clock. We have to be "slow and cautious," about introducing the technology, Brown says.

The grid upgrade may also face resistance from regulators because some of the benefits are difficult to measure. Regulators are responsible for ensuring that utilities make wise investments that restrain the price of electricity. But improved efficiency and reliability can't easily be quantified, says Bryan Olnick, a senior director at the major utility Florida Power and Light. He says that regulators need to start considering long-term societal benefits in addition to electricity costs. Ultimately, regulators will need proof that the systems can deliver the promised benefits, which is why there are now smart-grid demonstration projects in places including Boulder, CO; Maui; and Miami.

Beyond the challenge of measuring results, the smart grid raises questions about national security, says Bob Gilligan, GE's vice president for transmission and distribution. "We hear a lot of concerns about cyberterrorism and attacks on our energy infrastructure," he says. "As we talk about bringing more technology into the grid, providing more connections to the energy infrastructure, there are escalating concerns about protecting that infrastructure."

Gilligan adds that the technology raises serious privacy concerns as well. "The major concern is that folks don't want to be inundated with telemarketing calls associated with their usage behavior," he says. "There's also some concern about what they're doing being known minute by minute."

The massive amount of data generated by smart-grid technology could itself pose a practical problem. Right now, a utility with five million meters has about 30,000 devices for monitoring the grid. As the smart grid develops, that number could increase a thousandfold, with each device conveying a thousand times as much information as one of its counterparts does now, says Erik Udstuen, a general manager at GE Fanuc Intelligent Platforms. Though so much data may be difficult to process, it could also create opportunities for entrepreneurs to develop new monitoring applications, especially if open standards are developed.

Consumers needn't brace themselves for changes right away; it could take a decade to implement variable pricing. Meanwhile, the grid can be improved in ways that won't affect customers directly, such as reducing the amount of energy wasted in getting power from generators to consumers: 7 to 10 percent is often lost, and that figure can reach 20 or 30 percent during periods of peak demand. Meanwhile, smart meters and appliances that allow variable pricing will cost billions to develop and could take a decade to install.

Eventually, however, the smart grid could make the supply of electricity more efficient and reliable, and it could help reduce greenhouse-gas emissions by promoting renewable technologies and reducing overall power consumption. "In the long run," says James Gallagher, a senior vice president at the New York City Development Corp, "it will lead to lower rates."

http://www.technologyreview.com/energy/23015/

Data Overload on Dating Sites

The information overload caused by too much choice could have lessons for other websites.

By Andrew Schrock

Consumers can find more of what they want on the Web, but that may not always be such a good thing. New research about online dating sites shows that users presented with too many choices experience "cognitive overload" and make poorer decisions as a result. The findings could have implications for other kinds of websites, although new technologies and approaches could help address the problem, researchers suggest.

Credit: Technology Review

Dating sites are big business. According to a survey conducted in 2006 by the Pew Center for Internet and American Life, over 37% of all single Web users have tried them. Dating sites frequently resemble e-commerce sites such as Amazon.com; users enter search criteria such as height, appearance, and religion and are presented with a set of matches.

Pai-Lu Wu from Cheng Shiu University and Wen-Bin Chiou from the National Sun Yat-Sen University in Taiwan performed an experiment that involved giving online date-seekers varying numbers of search results to their queries on dating sites. Their study, published last month in the journal Cyberpsychology and Behavior, shows that having more search results leads to a less careful partner choice.

Chiou calls this a "double-edged sword," since people desire a wider selection, but then devote less time to evaluating each prospect. Wu and Chiou conclude that "more search options lead to less selective processing by reducing users' cognitive resources, distracting them with irrelevant information, and reducing their ability to screen out inferior options." In other words, when faced with cognitive overload, date-seekers evaluated as many matches as possible, even ones that weren't a good fit, and they were less able to distinguish a good option from a bad one.

Michael Norton, an assistant professor at Harvard Business School, coauthored a study published in the Journal of Interactive Marketing last year that suggests that this kind of cognitive overload is common on dating sites. His study found that the average date-seeker typically spends nearly 12 hours a week searching online and emailing for a payoff of less than two hours of offline dating. Norton says that date seekers "evaluate each person only superficially, never investing the time and energy to explore whether a match might work." Having too many options raises our expectations of potential matches too high, leading to an "often fruitless search for an ideal person who may not exist." Incessant browsing for Mr. or Ms. Right may be exactly the wrong decision, Norton says.

The problem clearly extends well beyond dating sites. "Anytime you get on the Web, there is the danger of cognitive overload," says Nicole Ellison, a professor at Michigan State University who studies online relationships and dating. Ellison believes that the sheer amount of information online presents a challenge to users, although search engines such like Google have proven effective for sorting through the simplest types of information. "Google already has a pretty sophisticated algorithm," she says. "We know that few people go past the first page of results when searching."

When searching for more complex, subjective information, such as the ideal holiday destination, however, Web users may experience similar cognitive overload and make equally rushed choices.

As for dating sites, Chiou suggests a few technical solutions that could help. Users could be reminded of the number of profiles they have reviewed already, and told how closely a profile matches their own. Ellison's research suggests that collecting more interview data also helps refine searches and produce more relevant results. "Including different kinds of questions in the profile would be helpful--questions that allow individuals to highlight unique aspects of their personality," Ellison says.

Norton goes further, suggesting that prospective dates should not be searched for "as though they were shoes online." Simple demographic variables such as height and religion have poor relevance to whether a romantic pairing will be successful, he says. Better predictors of relationship success are concepts such as humor and rapport. Unfortunately, these are highly subjective--one person's joke can be another's bad taste.

A startup called Omnidate hopes to profit from technologies that help users gather and evaluate this kind of subjective information. The company's solution is an add-on for existing dating sites that allows users to interact as avatars in a 3-D virtual space. Rather than waste time with pages of matches with meaningless information, users can evaluate qualities that are only revealed during a meeting.

"As people chat, their characters respond naturally, providing a realistic dating experience," says Omnidate's president Igor Kotlyar. He adds that women are particularly pleased with the virtual experience. They comprise 60% of the site's registrations (twice that of a typical dating site) and prefer virtual dates to email exchanges.

http://www.technologyreview.com/web/23016/

Who's Typing Your Password?

By watching how passwords are entered, a company hopes to make log-ins more secure.

By Erica Naone

Passwords can be one of the weakest links in online security. Users too often choose one that's easily guessed or poorly protected; even strong passwords may need to be combined with additional measures, such as a smart card or a fingerprint scan, for extra protection.

Credit: Technology Review

Delfigo Security, a startup based in Boston, has a simpler solution to bolstering password security. By looking at how a user types each character and by collecting other subtle clues as to her identity, the company's software creates an additional layer of security without the need for extra equipment or user actions.

The software, called DSGateway, can be combined with an existing authentication process. As a user enters her name and password, JavaScript records her typing pattern along with other information, such as her system configuration and geographic location. When the user clicks "submit," her data is sent to the Web server and, provided that the username and password are correct, the additional information is passed on to Delfigo. The company's system then evaluates how well this information matches the behavior patterns of the appropriate authorized user.

Delfigo's algorithms build up a profile of each user during a short training period, combing 14 different factors. The company's president and CEO, Ralph Rodriguez, developed the necessary algorithms while working as a research fellow at MIT. Rodriguez notes that recording multiple factors is crucial to keeping the system secure without making it unusable. If the user types a password with one hand, for example, while holding coffee in the other, the system must turn to other factors to decide how to interpret the variation, he says. If she does this every morning, the system will learn to expect to see this behavior at that time of day.

The idea that a password should completely succeed or completely fail "is an old paradigm that should go away," says Rodriguez. Even if the system sees something strange about the way that a user enters her password, for example, it just assigns a confidence level to that log-in attempt. Access levels can be configured depending on this confidence level. For example, if a user logs in from an odd location, lowering the system's confidence, it might allow her to see her account balance but restrict the funds that she is able to transfer. If the user needs to increase her confidence factor at that moment, Rodriguez says, she could answer additional security questions or have a one-time password sent to her mobile phone or via e-mail.

Trying to strengthen authentication without forcing users to change their behavior is a promising approach, says Bill Nagel, an analyst at Forrester Research, who covers security and risk management. "People want ease of use without losing any security, and that's a tough balance for a lot of IT departments," he says.

Ben Adida, a fellow at Harvard University's Center for Research on Computation and Society, who studies security and privacy, notes that other companies have tried to find ways to improve authentication without inconveniencing users. Some banks, for example, install a cookie in a user's browser after he answers several security questions correctly. The cookie serves as another identifying token. "That's easier than having a physical token, but it's also not as secure," Adida says, since the attacker could trick the user into giving up the information needed to recreate the cookie..

Adida adds that the strength of Delfigo's product will depend on how hard it is for an attacker to re-create the additional factors that it uses. For example, an attacker may be able to trick a user into typing her username and password into a dummy site, in order to collect keystroke patterns and other information, Adida says.

http://www.technologyreview.com/computing/23008/

Artificial Knees Made to Order

A startup company uses medical imaging and rapid prototyping to create customized knee implants.

By Courtney Humphries

A startup company is taking a customized approach to knee replacement surgery, creating knee implants on demand that exactly match a patient's anatomy. The company, ConforMIS, based in Burlington, MA, is bringing the technology of rapid prototyping, which converts a three-dimensional computer design into a physical object, into the field of orthopedics. The company believes that such custom-made implants can make knee replacement surgery faster, more accurate, and less traumatic to the patient.

Customized knees: A depiction of a knee implant designed to cover one part of the knee joint. Credit: ConforMIS

Multimedia Watch how a customized knee implant is made.

Knee replacement surgery repairs damage and relieves pain in patients with severe osteoarthritis or knee injury. Total knee replacement involves removing diseased cartilage and bone from the surfaces of the knee joint--the thigh bone, shin bone, and kneecap--and replacing them with an artificial joint made from a combination of metal and plastic. A partial knee replacement can also be performed on one part of the joint.

Typically, a surgeon chooses an artificial joint from several options of different sizes. ConforMIS, however, creates a custom implant based on imaging data of a patient's knee joint, a technology that the company calls iFit. ConforMIS transforms images from CT or MRI scans into a three-dimensional computer model using computer-aided design (CAD) software, which serves as a template for manufacturing the implant.

Philipp Lang, president and CEO of ConforMIS, says that typically, surgeons must shape the patient's bone to fit the implant. Because the bone-facing side of ConforMIS's implant is matched to the patient's anatomy, it can reduce the amount of bone that the surgeon must cut. On the joint-facing side of the implant, Lang says, "we want to re-create the geometry that the patient had before he or she developed arthritis." He says that the ability to fit the implant to the patient without removing excess bone will speed recovery time and lessen pain.

Andrew Freiberg, an orthopedic surgeon who heads the joint replacement services at Massachusetts General Hospital and is not involved with the company, says that ConforMIS is an early example of an approach that has the potential to be important in the orthopedic field. However, he adds, "I'm not aware of any study that shows that custom-made implants give a better outcome" than traditional ones do. Lang says that the company is working with medical centers to conduct studies that will gather data about their outcomes.

Precise localization: In addition to creating knee implants, ConforMIS uses CT data to create personalized, single-use guides that help surgeons determine the exact placement of the implants. Credit: ConforMIS

Freiberg says that the ability to model what a knee replacement would look like before it's performed could have advantages, although he notes that many surgeons prefer to actually see and measure the patient's anatomy before making decisions. He says that replacing a knee properly is a geometrically complex task that requires a great deal of precision, and companies have been looking for ways to eliminate guesswork with technology.

Along with the implants, ConforMIS also creates customized instruments, called iJig, which assist surgeons in placing the implant. Because the knee joint must be precisely aligned to function properly, surgeons use cutting and placement guides to ensure that any cuts to the bone are made at the correct angles so that the implant is placed in proper alignment. ConforMIS uses the imaging data from the patient to create disposable instruments that are calibrated to the patient's specific implant and anatomy. Lang says that the instrumentation will enable surgeons to perform the operation more quickly and easily, and it will also reduce time spent sterilizing reusable equipment.

ConforMIS announced today that it has raised $50 million in funding from investors worldwide in its latest round of fund-raising. Currently, the company has released three products for partial knee replacements, along with instrumentation, and it plans to make an implant available for a total knee replacement in 2010. Lang says that it takes about six weeks to create the implant, from imaging to shipping, and ConforMIS hopes to reduce that time to four weeks.

One concern about such a customized approach is the cost. As volume grows, the company hopes to provide its customized products at the same price as that of a standard implant.

http://www.technologyreview.com/biomedicine/22988/

Hints of How Google's OS Will Work

Google isn't saying how its new operating system will function, but the clues lie in its browser.

By Erica Naone

Soon after Google announced plans for its own operating system (OS), called Google Chrome OS, on Tuesday night, the Web giant clammed up about technical details, saying that the project is still at too early a stage. The first netbook devices running Chrome OS won't be released until the second half of 2010, so most users will have to wait until then to find out precisely how the software will work. But that doesn't mean there aren't hints out there already, and the biggest clues can be found in Google's Chrome browser, which the company says will be a key part of the new OS.

Credit: Technology Review

According to a post written by Sundar Pichai, a vice president of product management at Google, and Linus Upson, the company's engineering director, the open-source Chrome OS will consist of a Linux kernel with the Google Chrome browser running on top inside an entirely new desktop environment.

The Chrome browser was released nine months ago and is Google's effort to reinvent the browser completely: it's designed from scratch with Web applications in mind and is meant to be the only application that a Web-savvy user needs on her computer.

In an interview in March, Darin Fisher, an engineer on the Google Chrome team, said that in early sessions, the engineers decided to "take a page out of the operating system book" when they built the browser. Notably, the Chrome team decided to treat the browser as a launchpad from which the user can start different Web applications. Each application operates independently so that if one crashes, it doesn't affect the others. OSes, Fisher said, had to take the same approach to allow a single application to crash without requiring a user to reboot the whole system. This change in browser design helps give Web applications the stability that desktop applications enjoy.

The concept is easily extended back to the OS. Provided that the user relies on Web applications, such as Gmail, Google Docs, and the like, this simplifies the OS a great deal. It vastly reduces the number of applications that need to be installed and the amount of data that must be stored and processed on the computer itself.

With Chrome OS, Google will blur the line between the browser and the OS completely, says Ramesh Iyer, head of worldwide business development for mobile computing at Texas Instruments, which is one of Google's partners on the project. "The browser is your operating system," Iyer says. "The browser is your user interface. The browser is the mechanism from which you launch applications."

Streamlining the OS to focus on the Web, Iyer says, will allow devices to run more powerful programs with less powerful processors. By keeping processor requirements low, new devices could use less battery power and stay lighter. Texas Instruments, for example, is working with Google to integrate the Chrome OS software with its OMAP 3 multimedia applications processors, creating a system that could be easily installed in netbooks and other devices.

Giving Web applications deeper access to the underlying kernel could make it easier for Web developers to provide better functionality and a better user experience, says Jared Spool, founding principal of User Interface Engineering, a consulting firm based in North Andover, MA. When Web applications such as Gmail and Google Maps first appeared, Spool says, the software engineers who built them had to do a lot of hacking to create the appropriate levels of interaction. "When we went from the desktop to the browser, we took a huge step backward," Spool says.

With an OS tied closely to the Web, Google can introduce sophisticated resource management tools that will allow Web applications to run much more smoothly. A major role for the OS is allocating memory to applications and adjusting it as their needs change. A big problem with interactive Web applications to date has been that browsers didn't have efficient ways to adjust the memory assigned to different Web pages. The Chrome browser has already improved the situation, Spool says, and he expects the OS to go even farther. He says that this will allow more powerful Web applications that run more smoothly on the new OS.

But building the Chrome OS won't be as simple as sticking a browser on top of the Linux kernel, Spool says. The browser version of Chrome relies on the underlying OS's user interface, for example. Features such as scrollbars come from the OS, not the browser, so Google will need to build all of this from scratch, and even simple things will require significant time and effort.

The Chrome browser also lacks the drivers needed to power any external devices, such as printers or iPods. Texas Instruments' Iyer envisions a new way that Chrome OS could address this problem. "Wouldn't you rather have a printer connected in the cloud?" he says. As more devices, including cameras, printers, GPSes, and so on, become able to connect to the Internet in their own right, the concept of a Web interface between a user's computer and the device comes closer to reality. "This is the holy grail of the Internet," Iyer says.

Pichai and Upson have also said that Chrome OS will support all Web-based applications automatically, and that new applications written for Chrome OS will run "on any standards-based browser on Windows, Mac, and Linux." While Web application development has exploded in recent years, this might also introduce limitations, preventing the user from accessing interesting applications developed in programming languages not intended for the Web.

However, Google may have a solution for that too. The company is working on an experimental project called Google Native Client that would allow code written in non-Web languages such as C and C++ to run securely in the browser.

Chris Rohlf, a senior security consultant for Matasano Security, which has been involved in testing the implementation of Native Client, says, "It could be Google's secret weapon when it comes to Chrome OS, because it would allow developers to extend that platform with things like video and graphics without having to wait for Google to implement any of that."

http://www.technologyreview.com/web/22987/