image006.gifUntil recently, the ability of bacteria to communicate with one another was considered an anomaly that occurred only among a few marine bacteria. It is now clear that group talk is the norm in the bacterial world, and understanding this process is important for fighting deadly strains of bacteria and for understanding communication between cells in the human body.

Bonnie Bassler has discovered that bacteria communicate with a chemical language. This process, called quorum sensing, allows bacteria to count their numbers, determine when they have reached a critical mass, and then change their behavior in unison to carry out processes that require many cells acting together to be effective.

For example, one process commonly controlled by quorum sensing is virulence. Virulent bacteria do not want to begin secreting toxins too soon, or the host’s immune system will quickly eliminate the nascent infection. Instead, Bassler explained, using quorum sensing, the bacteria count themselves and when they reach a sufficiently high number, they all launch their attack simultaneously. This way, the bacteria are more likely to overpower the immune system. Quorum sensing, Bassler says, allows bacteria to act like enormous multicellular organisms. She has shown that this same basic mechanism of communication exists in some of the world’s most virulent microbes, including those responsible for cholera and plague.

Working with Vibrio harveyi, a harmless marine bacterium that glows in the dark, Bassler and her colleagues discovered that this bacterium communicates with multiple chemical signaling molecules called autoinducers (AIs). Some of these molecules allow V. harveyi to talk to its own kind, while one molecule—called AI-2—allows the bacterium to talk to other bacterial species in its vicinity. Bassler showed that a gene called luxS is required for production of AI-2, and that hundreds of species of bacteria have this gene and use AI-2 to communicate. This work suggests that bacteria have a universal chemical language, a type of “bacterial Esperanto” that they use to talk between species.

Bassler’s research opens up the possibility for new strategies for combating important world health problems. Her team is currently working to find ways to disrupt the LuxS/AI-2 discourse so the bacteria either cannot talk or cannot listen to one another. Such strategies have potential use as new antimicrobial therapies.

Her interest in bacterial communication grew from her curiosity about how information flows among cells in the human body, and she is convinced she will find parallels between the bacterial systems and those in higher organisms. “We have a chance to learn something fundamental in bacteria about chemical communication,” Bassler said. “If we can understand the rules or paradigms governing the process in bacteria, what we learn could hold true in higher organisms.”

Bassler won a 2002 MacArthur Fellowship, which she said provided tremendous validation for her group’s research, recognizing that they are working on a problem that is much larger than a glow-in-the-dark bacterium. She was also chosen as the 2004 Inventor of the Year by the New York Intellectual Property Law Association for her idea that interfering with the AI-2 language could form the basis of a new type of broad-spectrum antibiotic. “The fantasy is to make one pill that works against all kinds of bacteria,” she said.

Dr. Bassler is also Squibb Professor and Director of Graduate Studies in the Department of Molecular Biology at Princeton University.


Bonnie Bassler studies the molecular mechanisms that bacteria use to communicate with one another, and her aims include combating deadly bacterial diseases and understanding cell signaling in higher organisms.

Stanford University School of Medicine

* B.S., biochemistry, Tulane University
* Ph.D., biophysics, The Johns Hopkins University School of Medicine

The molecular mechanisms that a cell uses to monitor and relay information about its environment to its interior are not well understood. Cell surface receptors are the gateways through which this information is relayed. The activation of receptor molecules embedded in the cell’s membrane is fundamental to virtually every vital physiological function. Better knowledge of these mechanisms may lead to development of new disease treatments, using detailed structures of receptors complexed with their ligands as templates for engineering novel drugs.

K. Christopher Garcia is studying the structure and function of cell surface receptor recognition and activation in biological systems directly implicated in human health and disease. The receptor systems he studies are at the interface between immunity, neurobiology, and microbial pathogenesis. He focuses on “shared” receptors, which can recognize and bind to several different molecules, or ligands, often eliciting unique responses. Although this is a common phenomenon in biological signaling, until recently, researchers puzzled over how a single molecule could recognize so many different binding partners.

While others puzzled, Garcia pursued the question with extraordinary tenacity, bringing to bear his broad knowledge of many areas of science. Uniting structural studies of these receptors with biochemical and biophysical experiments, Garcia has identified new paradigms for recognition and activation of a variety of receptors that play critical roles in autoimmunity (T cell receptor and peptide-MHC), cancer (gp130 and cytokine receptors), neural growth and repair (p75 neurotrophin and Nogo receptors), and blood pressure regulation (ANP receptor).

Each of these receptors acts in a unique way. For example, the T cell receptor interacts with antigenic peptide and MHC in a manner representing the convergence of 400 million years of coevolution by our cellular immune system. Garcia and his colleagues determined the structure of the first complete TCR and its complex with peptide-MHC. Subsequent biophysical studies have shown that activation of the TCR is achieved through a complex combination of conformational change and kinetic discrimination. However, the precise molecular basis of TCR recognition and activation, as well as other lineages of immune receptors, remains a long-term challenge for the Garcia lab.

Another receptor binding paradigm elucidated by the Garcia lab is that of gp130—a growth factor receptor that is frequently aberrantly activated in disorders of the blood, such as leukemia. Its components cluster together in a precise temporal and geometric sequence, like pieces of a jigsaw puzzle, to assemble a receptor signaling complex. In contrast to the positive cooperativity exhibited by gp130 during signaling, the p75 neurotrophin receptor appears to induce a conformational change in its ligand, nerve growth factor, in order to prevent assembly of a higher order signaling complex. And the ANP receptor, which is crucial to the body’s response to high blood pressure, is activated by a large conformational change that does not require the assembly of multiple components.

Garcia’s long-term goal is to probe these systems more deeply, working to examine entire receptor molecules before and after activation, loaded with their full complements of extracellular ligands and intracellular adapter molecules. Understanding the many ways in which the relatively simple act of ligand binding prompts conformational change and ultimately activates receptors should help researchers design drugs targeting receptors whose functions affect human disease.

Dr. Garcia is also Associate Professor of Microbiology and Immunology and of Structural Biology at Stanford University School of Medicine.


K. Christopher Garcia studies the structure and function of cell surface receptor recognition and activation, in the immune and nervous systems.

Howard Hughes Medical Institute, November 18, 2007
K. Christopher Garcia, PhD

Despite extensive vaccination efforts, measles remains a dangerous, highly contagious disease worldwide, infecting some 20 million people a year. Structural information about the protein the virus uses to attach itself to its target cells could provide a new strategy to fight infection. A new structure from Howard Hughes Medical Institute (HHMI) researchers reveals important features of the propeller-like molecule, known as measles virus hemagglutinin (MVH), that drug designers will need to consider as they attempt to thwart infection by interfering with the virus’s grip on its host cell.

Researchers Leremy Colf and Sean Juo determined the structure in the laboratory of Howard Hughes Medical Institute investigator Christopher Garcia. The researchers published their findings November 18, 2007, as an advance online publication of the journal Nature Structural and Molecular Biology. They are at the Stanford University School of Medicine.

“Neuraminidases act as a kind of general molecular Velcro, sticking the virus to the surface of cells.”
K. Christopher Garcia

Colf and Juo employed X-ray crystallography to solve the structure of MVH. In this widely used technique, X-rays are directed through crystals of a protein, allowing the protein’s structure to be deduced from the diffraction pattern of the X-ray beam.

The resulting structure revealed that MVH is shaped like a propeller, with its blades spread such that they can attach to the host cell in the infection process. This propeller shape is commonly found on the surfaces of viruses as a protein called a neuraminidase. Viruses such as influenza use a cleft at the center of the propeller to bind carbohydrates on the cells they infect. “Neuraminidases act as a kind of general molecular Velcro, sticking the virus to the surface of cells,” said Garcia.

One feature that makes the measles virus unique is that it doesn’t use carbohydrates to bind to host cells. “While MVH exhibits the neuraminidase fold, it is a `dead’ neuraminidase, having lost all function,” he said. “Rather, the measles virus hemagglutinin has evolved the ability to bind to two non-overlapping host cell receptors, called SLAM and CD46. This is a completely novel mechanism for this class of viruses. So, if a drug is to block measles virus binding, it has to interfere with both of these receptors.”

Garcia said that the structure of MVH provides “a starting point to identifying cavities and clefts on the protein surface that one could target with small molecules.” The next step, he said, is to solve the structure of MVH complexed with the host cell receptors, to elucidate the details of the host-virus attachment. So far, his group has begun to analyze the structure of MVH complexed with the SLAM receptor.

“Once we have high-resolution pictures of the determinants of this attachment interface, it will be possible to begin to think about therapeutic intervention in that attachment,” he said.


The image shows a eukaryotic voltage-dependent potassium channel viewed along the four-fold axis from the extracellular surface. The protein, depicted as helical ribbons (blue) consists of a central pore surrounded by four voltage sensors. The green sphere depicts potassium ions in the selectivity filter. The yellow objects represent lipid molecules, which are observed in the crystal structure.

Howard Hughes Medical Institute researchers are unveiling the most detailed views yet of the structure of a voltage-dependent potassium ion channel. The new images, which show the channel in a more natural environment than previous studies, reveal that the channel’s function is likely to be profoundly influenced by lipid molecules within the cell membrane in which the channel is embedded.

The research team, led by HHMI investigator Roderick MacKinnon, hopes that a technique they used to prepare the ion channel for analysis — called lipid-detergent-mediated crystallization – will make it possible to capture membrane proteins in a more native, membrane-like environment.

“This new approach gave us dramatic new insight, because we could actually see the lipid molecules gathered around the protein, and see them form the characteristic leaflets of the bilayer biological membrane.”
Roderick MacKinnon

MacKinnon and his colleagues at The Rockefeller University published their findings on the structure of the ion channel in the November 15, 2007, issue of the journal Nature.

Voltage-dependent potassium ion channels are central to the function of nerves and muscles. Without them the brain would immediately suffer neural gridlock, and the heart would seize up. The channels are precise molecular machines that propagate electrical impulses in the brain, heart and other cell types. The potassium channels are large proteins with a central pore that pierces the cell membrane and allows only potassium ions to pass through.

When an electrical impulse travels along a nerve, it changes the charge separation across the cell membrane—with the inside becoming more positive. This electrical polarity change triggers voltage-dependent potassium ion channels to open, allowing positively-charged potassium ions to flow out of the cell. This outflow of potassium allows the membrane to return to its resting state and prepares it for the next electrical impulse.

In earlier studies, MacKinnon and his colleagues deduced the structure of the voltage sensor, which is the component of the voltage-dependent potassium ion channels that senses changes in voltage. The voltage sensor reacts to a change in the membrane electrical polarity to open or close the pore. MacKinnon and his colleagues used x-ray crystallography to determine the structure of the voltage sensor. In x-ray crystallography, protein crystals are bombarded with x-ray beams. As the x-rays pass through and bounce off of atoms in the crystal, they produce a diffraction pattern, which can then be analyzed to determine the three-dimensional shape of the protein.

The pictures that emerged from those structural studies showed that the voltage sensors contained a helix-turn-helix structure, which MacKinnon’s group has called the voltage sensor paddle. The voltage sensor paddle contains positively charged amino acids that enable the voltage sensor to respond to the membrane’s electrical polarity.

MacKinnon and his colleagues theorized that the positively charged paddle moves within the membrane at the protein-lipid interface. When the membrane becomes positively charged on the inside, the paddles is attracted to move toward the outside and open the channel, allowing potassium to flow out and restoring the membrane charge to its resting state. When the inside of the membrane becomes negatively charged, the paddles move inward snapping the channel shut.

Those earlier studies, however, left some questions about ion channel function unanswered because significant details of the structure remained unresolved. “We could not see many of the individual side chains of this protein that are important to its function,” MacKinnon noted. Answering remaining questions meant developing new experimental approaches. “These are very difficult structures to determine, and our progress has been like taking one step at a time up a very big mountain,” he explained.

The researchers’ latest steps entailed engineering a new form of the channel that they could then use to obtain improved protein crystals. The higher quality crystals would enable more detailed structural and functional insights from the x-ray crystallography studies.

The researchers produced a “paddle-chimera” channel by swapping the normal paddles of a channel with those from a different channel. “This gave us a new crystal packing that helped us get better definition of the atoms in the protein that we couldn’t see in the original structure,” said MacKinnon.

The scientists also attempted to mimic the oily cell membrane in which the channel exists naturally. By immersing the channel protein in a mixture of detergent and lipid -instead of the more traditional method of using detergent alone —MacKinnon’s team was able to see the channel in a more natural environment.

“This new approach gave us dramatic new insight, because we could actually see the lipid molecules gathered around the protein, and see them form the characteristic leaflets of the bilayer biological membrane,” said MacKinnon. “With an earlier structure that we published in 2005 we could only speculate why the use of lipids was important, but now we can see it very clearly,” he said.

Specialized proteins called ion channels move electrical signals across a cell surface, turning a thought into an action.
Each type of channel has its own particular configuration. The type shown above is specific to a potassium ion.
Ion channels work according to the power of diffusion. But they must be selective and diffuse only those ions that move the signal.
Because of the selectivity filter within the channel, only potassium ions readily move through, while smaller sodium ions do not.

Adapted from a diagram by The Rockefeller University/Office of Communications and Public Affairs

MacKinnon said that knowing the atomic structures have changed his perspective on the role of the membrane in ion channel function. “I used to think that the voltage sensor didn’t have much to do with the lipid membrane,” he said. “But these structures have informed us that the voltage sensor has a great deal to do with the lipid membrane.

“When you examine the structure of usual alpha-helical membrane proteins, they look like a big disk of protein that snakes back and forth through the membrane. But when you look at the voltage-dependent potassium channel, you see the pore embedded in the membrane, but you also see the voltage sensors that stick out like Mickey Mouse’s ears. They are mostly surrounded by lipid membrane, and what that means is that the voltage sensor can’t help but be influenced by the lipid. This influence is so profound, that you can’t simply say what the properties of a given voltage-dependent channel are without specifying the composition of the surrounding lipid. And what makes this influence of lipid biologically significant is that we know that different cells in the body do not have the same lipid composition,” MacKinnon explained.

As a result of these studies, MacKinnon’s group hypothesizes that the function of voltage-dependent channels in different kinds of lipid membrane may be very different. “To me, this has been the most interesting aspect of our structural studies—that the lipid membrane would influence the channel’s function.”

MacKinnon said that his group is now exploring the influence of membrane structure on ion channel properties, in order to understand the biological context in which the ion channels function.

Image: Courtesy of Roderick MacKinnon/HHMI at Rockefeller University

image0023.jpgAntigenic shift in influenza can lead to a super dangerous strain like avian flu

Influenza viruses are extremely changeable. Their RNA often mutates and acquires subtle changes that alter the characteristics of the virus enough so that it can evade host antibodies.

Influenza can also undergo major, rapid changes that cause it to change so dramatically that host defenses are practically useless.

These major changes or “antigenic shifts” can occur when two separate strains of influenza infect the same cell simultaneously. When this happens, a new strain, combining characteristics of the two previous strains can emerge.

Here you see viral particles of two separate influenza strains: H3N2, which commonly infects humans and H5N1, which commonly infects birds. H5N1 has recently been known to also infect humans with a fatality rate of 40%. Fortunately, so far, the H5N1 virus does not transmit easily between humans like an H3N2 virus does.
To infect a cell, the virus particles must cross the cell membrane. The hemagglutinin (H) proteins help the virus to attach to the membrane. It may be that the H5N1 virus is so virulent (deadly) to humans because the H5 hemagglutinin is particularly efficient at attaching to human host cells.
Once inside the cell, the virus can go to work. Here, you can see that particles of both the H5N1 virus and the H3N2 virus have infected this cell.
First, the viral particles are uncovered. The lipid envelope and protein capsid are removed.
The RNA strands are transcribed.
The host cell’s machinery contructs the new viral proteins coded for by the viral DNA.
New influenza particles are assembled from the new viral proteins. The lipid envelope is formed from host cell materials.
The newly assembled viral particles bud off from the host cell. The protein neuraminidase (N) seems to be important in the budding process and may be involved in determining transmissability of the virus.

How the Flu Virus Can Change – “Drift” and “Shift”

Influenza viruses can change in two different ways.

One is called “antigenic drift.” These are small changes in the virus that happen continually over time. Antigenic drift produces new virus strains that may not be recognized by the body’s immune system. This process works as follows: a person infected with a particular flu virus strain develops antibody against that virus. As newer virus strains appear, the antibodies against the older strains no longer recognize the “newer” virus, and reinfection can occur. This is one of the main reasons why people can get the flu more than one time. In most years, one or two of the three virus strains in the influenza vaccine are updated to keep up with the changes in the circulating flu viruses. So, people who want to be protected from flu need to get a flu shot every year.

The other type of change is called “antigenic shift.” Antigenic shift is an abrupt, major change in the influenza A viruses, resulting in new hemagglutinin and/or new hemagglutinin and neuraminidase proteins in influenza viruses that infect humans. Shift results in a new influenza A subtype. When shift happens, most people have little or no protection against the new virus. While influenza viruses are changing by antigenic drift all the time, antigenic shift happens only occasionally. Type A viruses undergo both kinds of changes; influenza type B viruses change only by the more gradual process of antigenic drift.

The recovering politician is teaming with a legendary venture capitalist and bigtime moneyman to make over the $6 trillion global energy business. A Fortune exclusive

By Marc Gunther and Adam Lashinsky, Fortune

November 12 2007:

David Blood, Al Gore, and John Doerr, photographed at Gore’s Nashville home on Oct. 16, 2007.

(Fortune Magazine) — It’s lunchtime on Sand Hill Road, and Al Gore wants answers. “How does the efficiency decline with latitude?” he asks. “What size community could be served by one plant? If a manufacturer like GE wanted to make smaller turbines, would the technology support a smaller scale?”

We’re sitting in the giant conference room at Kleiner Perkins Caufield & Byers, where the partners hold their weekly meetings. After loading his plate with Chinese food from a buffet, Gore is firing detailed questions at the management team of Ausra, a Kleiner-backed company in Palo Alto whose technology uses mirrors the width of a flatbed truck that focus the sun’s energy to generate electricity.


Blood, Gore, and Doerr all had long resumes before diving into green investing. Here’s a snapshot.

David Blood (co-founder and managing partner, Generation)
Blood spent 18 years at Goldman, where he ran asset management and was a popular “culture keeper,” before hooking up with Gore in 2003.

Al Gore (Chairman, Generation; partner, Kleiner Perkins)
You may have heard of him: The former Veep is an author, activist, cable TV exec, Google advisor, Apple director, Nobelist, and newly minted VC.

John Doerr (Partner, Kleiner Perkins; advisory board member, Generation
A deejay and debater at Rice University, then an Intel salesman, Doerr has been proselytizing on behalf of Kleiner startups since 1980.

Once Gore is satisfied — sunlight lags north of South Dakota, an Ausra plant can serve 120,000 homes, and yes, smaller turbines will work fine — he shifts from inquisitor to fixer. He was chatting with California Senator Barbara Boxer “on the way over,” he reports, and he isn’t optimistic that Congress will extend the tax credits Ausra has been relying on. On the upside, he offers on the spot to organize a summit highlighting the company’s solar thermal technology to educate lawmakers and other policymakers on its potential. He also thinks a powwow at General Electric (Charts, Fortune 500) would be beneficial, even though Ausra is a tiny customer.

“I know Immelt well,” he says, referring to GE’s CEO. “We ought to set up a meeting.”

Gore appears utterly comfortable with this drill, but in fact he’s engaging in some on-the-job training. The recovering politician, environmental activist, and Nobel laureate is adding another title to his résumé: venture capitalist. After “a conversation that’s gone on for a year and a half,” according to Gore, he has decided to join his old pal John Doerr as an active, hands-on partner at Kleiner Perkins, Silicon Valley’s preeminent venture firm.

The move is more than another Colin Powell moment (the former Secretary of State signed on as a Kleiner “strategic limited partner” two years ago and has hardly been heard from since). Gore is joining the firm as Kleiner makes a risky move beyond information technology and health-care investing into the fast-growing and increasingly competitive arena of “clean technology.”
According to Doerr, by 2009 more than a third of Kleiner’s latest fund, which was raised in 2006 and totals $600 million, will be invested in technologies that aim to reduce emissions of carbon dioxide. Already Kleiner has invested more than $270 million from various funds in 26 companies that make everything from microbes that scrub old oil wells to electric cars to noncorn ethanol. Twelve of Kleiner’s 22 partners now spend some or all of their time on green investments.

In turn, Doerr, the master networker whose greatest hits include initial investments in Netscape, Amazon (Charts, Fortune 500), and Google (Charts, Fortune 500), will join the exclusive advisory board of Generation Investment Management. That’s the $1 billion investment company Gore started three years ago in London with David Blood, the former head of Goldman Sachs Asset Management, to analyze and invest in publicly traded “sustainable” companies. Over the past five weeks Gore, Doerr, and Blood agreed to give Fortune an exclusive look at their new alliance.

Already they’ve begun to pool information. Generation came across a small company engaged in carbon trading that Kleiner is analyzing, and Kleiner has shared intelligence about which startups could threaten the established companies in Generation’s portfolio. In the long term, though, they want to help drive something much larger, “bigger than the Industrial Revolution and significantly faster,” as Gore puts it.

They argue that to halt global warming, nothing less will be required than a makeover of the $6 trillion global energy business. Coal plants, gas stations, the internal-combustion engine, petrochemicals, plastic bags, even bottled water will have to give way to clean, green, sustainable technologies. “What we are going to have to put in place is a combination of the Manhattan Project, the Apollo project, and the Marshall Plan, and scale it globally,” Gore continues. “It’d be promising too much to say we can do it on our own, but we intend to do our part.”

Does that sound grandiose? Sure. Will they be accused of being partisan? Probably. Is there something incongruous about globetrotting rich guys jetting between multiple homes and lecturing the rest of us about climate change? Of course.

But there are good reasons to take Gore and Doerr seriously. Gore, who never seemed fully at ease as a presidential candidate, has demonstrated a real knack for using mass communications to influence public opinion. (He estimates that he’s shown his homespun slide show on global warming more than 1,000 times, while the documentary version, An Inconvenient Truth, won him an Oscar.) Doerr, meanwhile, has displayed a real talent for deploying venture capital to create or disrupt whole industries.

In short, the foremost eco-activist and the dean of Sand Hill Road could, together, draw a huge amount of attention and cash to companies that are aiming to reduce our reliance on fossil fuels.

There is, however, one thing standing in their way. Five years after Kleiner Perkins made its first green investment, the firm hasn’t had one “exit” — VC-speak for an IPO or a sale of a company that validates the investment thesis. Doerr equates this moment to Internet investing (which he famously called “the greatest legal creation of wealth in the history of the planet”) before Kleiner took a certain search engine public in 1995. Now, he wonders, “what’s the company that will lead the boom? What’s the Netscape of green innovation?”

A look at Kleiner’s energy portfolio

A bleary-eyed Al Gore needs another cup of coffee, and no wonder. It’s a Tuesday morning, and four days earlier he and his wife, Tipper, were up into the wee hours in San Francisco waiting to learn if he’d won the Nobel. (He was cited “for informing the world of the dangers posed by climate change.”) They then flew home to Nashville after a stopover in Phoenix, where Gore spoke to an advertising industry convention about Current TV, the youth-oriented cable television network he co-founded in 2002. Over the weekend, Tipper threw him a party with 150 or so of their closest friends. Country singers Kathy Mattea and Kim Richey preformed at the bash, at Nashville’s Park Café.

“It was a good weekend,” Gore says with a grin.

Now Gore, Doerr, and Blood are gathered on the back patio of Gore’s $2.3 million, 10,000-square-foot home in the Belle Meade section of Nashville. That’s the mansion — to Gore’s critics it’s always a mansion — that tagged the former Vice President as an energy hog. He’s quick to point out that the house generates electricity from more than 30 solar photovoltaic panels on the roof as well as seven 300-foot geothermal wells in the ground, and that it has been certified as an energy-efficient home by the U.S. Green Building Council.

After offering everyone coffee or bottled water (hey, no one’s perfect), Gore explains why he’s combining his advocacy work with a profit motive. “We want to give a big shout-out, though that’s not the corporate term, to every inventor and entrepreneur and idea generator at the micro, macro, systems-integration, and global-thinker level to create with this alliance a clearinghouse for the identification and selection of the most promising ideas on the planet for quickly solving this climate crisis,” he says, without pausing to take a breath. Then, clearly catching himself in a moment of speechifying, Gore boils it down: “We all believe that markets must play a central role.”

Professionally Gore, Doerr, and Blood have little in common. Once the boy wonder of American politics, Gore turns 60 in March. In addition to his roles at Kleiner, Generation, and Current, he’s an advisor to Google and a director at Apple (Charts, Fortune 500). He also founded an advocacy organization in Palo Alto called the Alliance for Climate Protection.

At times his schedule seems downright presidential: the week after our interview in Nashville, Gore visited the leaders of France, Germany, and Austria to talk about the environment. Says Gary Hirschberg, a climate-change activist and the CEO of Stonyfield Farm, who has known Gore for years: “I had an easier time seeing him when he was in the White House.”

Technically, of course, Gore was never “in” the White House. But he’s been dealing with continual speculation about whether he still has designs on the place. Is there a chance he’ll jump into the race? “It’s a luxury to be able to focus on what you are most passionate about all the time,” he says. When asked to elaborate he adds, “Casting about for words to describe this with precision is less productive than just saying that what I’m doing feels like the right thing to do.” So the answer is probably not, though like any good politician, he’s left the door open.

For now Gore truly seems to enjoy kicking around Nashville, where he’ll continue to be based. Since he won’t be on Sand Hill Road daily, he explains, he’s installed a high-definition videoconferencing system to dial into Kleiner’s weekly partner meetings.

If Gore is the elder statesman of the group, Doerr is the salesman. Famous both for his boundless energy and his high-end hucksterism, at 56 he is wiry and birdlike in his tendency to flit from topic to topic. He specializes in making everyone around him believe as passionately about his current cause — -first the PC, then the Internet, now the environment — as he does.

By Ryan Paul | Published: November 10, 2007 – 10:10AM CT

Electronic Arts announced yesterday plans to donate the original version of the SimCity computer game to the One Laptop Per Child (OLPC) project so that it can be distributed to schoolchildren in developing countries on OLPC’s XO laptop.

The original SimCity game, which won numerous awards and paved the way for an immensely successful franchise, transforms the player into the mayor of a virtual city. The simulation encourages cultivation of problem-solving skills and requires users to plan elaborate city infrastructure and respond to the needs of virtual citizens. The idea of including SimCity on the OLPC XO laptop was conceived by Electronic Frontier Foundation cofounder and OLPC advisor John Gilmore.

The game is currently being ported to the OLPC by Don Hopkins, the man responsible for the original multiplayer Unix port of the game. Hopkins created the Unix port of SimCity—which uses TCL and Tk—for DUX software in 1991. When the ten-year distribution contract between Maxis and DUX expired, Hopkins contacted Maxis parent company EA and attempted to negotiate for licensing rights so that he could adapt the program for educational uses and continue distributing. He didn’t succeed at the time, but now that EA is gifting the program to the OLPC project, Hopkins finally has a new chance to reinvent SimCity for academic uses.

Hopkins has already managed to port the game and make it run on the XO laptop and is now working on making it integrate well with the OLPC’s Python-based Sugar environment. Hopkins says that the final version of SimCity for the XO will be fully scriptable in Python and he hopes to make much of the underlying components reusable in order to provide generic building blocks for building XO games.

“The goal is to enable the open-source community to renovate SimCity and take it in new educational directions, by applying Seymour Papert’s ideas about constructionist education, Alan Kay’s ideas about interactive user interfaces and object-oriented programming, Ben Shneiderman’s ideas about direct manipulation and info visualization, and many exciting ideas about multiplayer games, blogging, storytelling, game mods, player created content, and lessons learned from World of WarCraft, The Sims, Spore, etc,” Hopkins wrote in a comment at Slashdot earlier this year.

Those of us who have fond memories of the original SimCity know that EA’s contribution will provide many students with a valuable and entertaining learning experience. The continued involvement of Don Hopkins in the porting effort is a promising sign that the game will remain true to its roots while it continues to evolve.


Target Health Inc. has spoken with Will Wright at one of the PopTech conferences 2 years ago. He is one of the most interesting visionaries we’ve met and happens to be the creator of Sim City. His latest creation is his dream of a universe game — one in which the player could evolve life from the simple cellular level all the way up through galactic scale civilizations. This game is called Spore. Wright wanted to create a game that would enable players to experience the wonder and creative potential of the universe at all levels of scale. If it sounds amazing, try it; it is!

Engineers at New York’s Rensselaer Polytechnic Institute have transformed a 1) ___ found in common brown seaweed into a device that can support the growth and release of stem cells at the site of a bodily injury or at the source of a disease. The findings mark an important step in efforts to develop new medical therapies using stem cells. A 2) ___ has been developed for stem cell culture that can degrade in the body at a controlled rate. With this level of control, the growth of stem cells can be controlled in the scaffold as to how, when, and where to release them into the body. This device is created from a material known as alginate. Alginate is a complex 3) ___ found naturally in brown seaweed. When mixed with calcium, alginate gels into a rigid, three-dimensional 4) ___. The device has a wide-ranging potential for use in regenerative medicine. For example, the scaffolds could one day be used in the human body to release stem cells directly into injured tissue. The scaffold could eventually be used for medical therapies such as releasing healthy bone stem cells right at the site of a broken bone, or releasing neural stem cells in the brain where cells have been killed by diseases such as 5) ___. The research team encapsulated healthy neural stem cells in the alginate mesh, producing a three-dimensional scaffold that degrades at a controlled rate. Once the scaffold was implanted, an enzyme called alginate lyase was used, which eats away at alginate, to release the stem cells. Alginate lyase is naturally produced in some marine animals and bacterial strains, but not in humans. In order to control the degradation of the alginate scaffold, varying amounts of alginate lyase were encapsulated into microscale beads, called 6) ___. The microspheres containing the alginate lyase were then encapsulated into the larger alginate scaffolds along with the stem cells. As the microspheres degraded, the alginate lyase enzyme was released into the larger alginate scaffold and slowly began to eat away at its surface, releasing the healthy 7) ___ cells in a controlled fashion. The microspheres also can be filled with more than just alginate lyase. Drug or proteins can be added to the microspheres along with the alginate lyase that, when released into the larger alginate scaffold, could influence the fate of the encapsulated stem cells. By adding these materials to the larger scaffold, the stem cells can be directed to become the type of mature, differentiated cell that is desired, such as a neuron. This will prove very valuable for applications of stem cells in 8) ___ medicine. The findings are detailed in the December 2007 edition of Biomaterials.

ANSWERS: 1) polymer; 2) scaffold 3) carbohydrate; 4) mesh; 5) Alzheimer’s; 6) microspheres; 7) stem; 8) regenerative

This year Target Health has been directly involved with 4 major FDA submissions including 2 NDAs, 1 BLA and 1 PMA. For one NDA and the PMA, we performed turnkey clinical research management/monitoring, biostatistics, medical writing, and regulatory affairs services including preparation of the NDA and PMA. For the BLA, we performed data management and for the NDA just submitted this month, we performed questionnaire validation and regulatory affairs services. Three of the submissions used Target e*CRF® for the pivotal trials, and one NDA used Target e*CRF® for questionnaire validation. There are now 13 marketed products that used Target e*CRF® for pivotal trials. A more detailed list of accomplishments will be provided shortly through ON TARGET.

For more information, please contact Dr. Jules T. Mitchel or Joyce Hays. For new business opportunities, contact Adrian Pencak, Vice President, Business Development).

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