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Breaking the Mold in Learning Biology: A new experiment in undergraduate education in science

by Diane Tseng

A young woman briskly walks up to the second-floor of the Bio-X Clark Center building, swings open the door and takes off her sunglasses. She heads for the incubator, sorts through a stack of petri dishes and pulls one out containing a culture of yeast cells. Yet this undergraduate is not working in a professor’s research lab. Nor is she secretly planning to release a new strain of mutant yeast into Stanford’s sewer system. In fact, she is taking a lab course in the Biology department–one that is actually part of a larger experiment in undergraduate education.

The Mission

This experiment in life science education, officially entitled the “Pre-Grad Program,” is being conducted by Stanford Biology professor Tim Stearns. Prof. Stearns’s goal is ‘to identify a group of students who have a strong interest in research as well as an interest in going on to careers in research. [Central to] this program are excitement-generating classes that show students what doing research is like and where the leading-edge is in biology.” In addition to providing engaging classes, this program also provides faculty advising and graduate student mentoring for undergraduate students. The entire program package allows students to conduct independent cutting-edge research and to take relevant coursework in preparation for a career in biological and biomedical research.

The Pre-Grad Program

The main component of the pre-grad program is a two quarter joint seminar and lab course (Biology 54 and 55) entitled “Genes, Genomes and Proteins: Introduction to Advanced Independent Research Laboratory.” Taught collaboratively by Professor Stearns and Biology professor Martha Cyert, these two classes provide alternative lab courses to the core Biology laboratory course sequence (Biology 44X and 44Y) taken by pre-meds and biology majors. More specifically, Prof. StearnsÕs and CyertÕs courses examine the impact of genomic information on experimental biology through scientific literature and experimentation. Students first explore recent genomic techniques at a conceptual level and then discuss specific applications to the biology of a simple eukaryotic model, the yeast Saccharomyces cerevisiae. Finally, students design and execute experiments as part of their original research projects to examine how the genome functions in a eukaryotic cell. Prof. Cyert states, ÒTo me, one of the most important things about Bio54/55 is that the students get to decide not only how to do their experiments, but also to decide what experiments they want to do.Ó Both professors emphasize creativity and independent thinking in the lab. Prof. Cyert continues, ÒOne of the things that makes some scientists exceptional is their ability to come up with different questions than other people do.Ó

Although Biology 54 and 55 specifically focus on the nuts and bolts of yeast genetics, the science is not esoteric. First of all, genetics is not simply a narrow field of biology, but rather a tool for understanding the information that makes life possible. In addition, understanding genetics employs skills from other disciplines of science, including statistics, computer science, and biochemistry. Although the pre-grad program is offered through the Biology department and attracts many Biology majors, it also recruits students from other fields of science including chemistry, biomedical computation and math, reflecting the increasingly interdisciplinary nature of scientific research itself.

Breaking the Mold: Exploring the Unknown

In an academic curriculum that mirrors the very nature of scientific investigation, students are encouraged to probe unknown questions rather than try to regenerate expected results. As he was quoted in an article for the Howard Hughes Medical Institute, Òthe feeling of being on the edge of the unknown; that is what research is all about. In most undergraduate labs, particularly at large universities, students areÉ repeating experiments someone else already did many years ago.Ó

In fact, repeating experiments to witness and reinforce the concepts of Biology in the laboratory setting defines the way science is traditionally taught. The usual procedure is a process of learning through lectures followed by hands-on experimentation in the lab. The pre-grad program challenges the traditional framework of scientific education by taking the laboratory experience straight to the cutting-edge. Empowered by the tools to design, conduct and interpret these results, students have the opportunity to personally make new contributions to the field of Biology, a challenge both in itself and to tradition.

What do you do when the political leaders of the most influential nation in the world disagree with the majority of the scientific community about an impending global crisis? This is the question facing ecologists at research institutions throughout the United States and around the world. While there is a general consensus that the global climate has been changing and temperatures have increased on average by about one degree Celsius since the Industrial Revolution, there is still a raging debate about the implications of this finding between the majority of the scientific community and the majority of the American political leadership.

With a large and diverse ecosystem, Jasper Ridge near Stanford is an ideal place to study the effects of climate change in an isolated environment.

The majority of the scientific community agrees that global climate change is a very real and potentially dangerous issue but a few scientists argue the problem is overblown. Politicians, particularly those in the current administration, tend to focus on studies by this minority of researchers to argue that major policy changes to reduce the effects of global climate change are not of primary importance. Stanford University is trying to change that trend. Until now, essentially all the studies for both sides of the debate have focused only on one or two factors that could potentially lead to global climate change. As a result, such studies have been accused of flawed experimental design or inconclusive results by the other side. Here, at Stanford, a team of investigators have come together to put to rest some of the controversy by setting up “The Jasper Ridge Global Change Experiment.” This unprecedented study simultaneously examines four variables known to cause climate change, making it the most comprehensive study on global climate change ever conducted.

The most publicized element of global climate change is the changing global temperature. Studies that both sides of the debate support have concluded that global temperatures are on average about one degree warmer than they were a hundred and fifty years ago. On the one hand, one degree hardly seems like a noticeable amount given that the global climate is known to go through cycles of natural warming and cooling and that the current average temperature is still about ten degrees cooler than the warmest average global temperatures prior to the last Ice Age. Yet, on the other hand, one degree begins to sound significantly more dangerous given the realization that the majority of this change has happened within the last twenty years. And already, the effects of melting polar ice, rising sea levels, changing precipitation patters, falling crop yields, greater prevalence of infectious disease and dramatically changing ecosystems is resulting. The political and scientific struggle to deal with these issues have recently come to the forefront of public discourse as can be seen from four successive issues of the prestigious Science magazine published during the end of 2003, all of which discuss the human influence on “the global commons” that make up our world.

Studies have shown that atmospheric carbon dioxide has steadily increased over the past 40 years. But some argue that this is part of natural global climate change cycles.

At the forefront of the field, Stanford’s “Jasper Ridge Global Change Experiment” is addressing many of these ecological issues. Led by Christopher Field of the Carnegie Institution of Washington and Harold Mooney of Stanford University and conducted at Stanford’s Jasper Ridge Biological Reserve, the Global Change Experiment was designed to use California grasslands as a model system to investigate the effects of four major components of global change. These are known to be caused, at least partially, by the burning of fossil fuels: elevated carbon dioxide, elevated temperatures, increased precipitation and increased nitrogen deposition.

Grasslands were chosen as the model system because, as Dr. Field notes, “they respond quickly to manipulation of global change factors and they are fully functional ecosystems with a high diversity of plant functional types.” By choosing such a responsive system it is possible to see experimental effects within several years instead of waiting for several decades, as would be the case in an ecosystem such as a forest.

The four variables being studied were chosen based on an understanding of fossil fuel burning industries and the greenhouse effect. The variable of elevated carbon dioxide levels was chosen because industrial burning of fossil fuels involves the process of adding oxygen to hydrocarbons which produces carbon dioxide as a bi-product released into the air. The variable of elevated temperatures was chosen because the industries that burn fossil fuels often release other gases such as water vapor, methane, nitrous oxide or other man-made products like choloroflurocarbons (CFCs). These gases allow sunlight to enter the atmosphere unimpeded but tend to absorb the radiation that is reflected back towards space, trapping heat in the atmosphere. The variable of increased precipitation was chosen because, as Christopher Field notes, “warmer climate evaporates more water from the oceans. This needs to fall somewhere” and results in increased rain or snow. Field also explains that the variable of increased nitrogen deposition was chosen because “nitrogen deposition results from the fact that essentially all internal combustion engines oxidize a small amount of atmospheric nitrogen, while they are burning fuel.” This results in increased NO2 in the atmosphere which can either be oxidized to nitric acid which will fall as acid rain or be transferred directly to leaves and soil through a process known as dry deposition.

The effects of the four variables of carbon dioxide, temperature, precipitation and nitrogen deposition were studied by examining small grassland plots having every possible combination of either natural ambient levels or artificially elevated levels of each variable. Since there are four variables that are either ambient or elevated being studied, there are sixteen different combinations of possible treatments (all elevated, all ambient, various combinations of elevated and ambient). The end result is a set of 128 miniature ecosystems that can be studied in terms of plant growth, carbon deposition below-ground, water and nutrient availability and changes in species composition.

After three years, the Global Climate Change study’s results were sufficiently exciting to be published in the December 6, 2002 issue of the prestigious Science magazine. The results included the discovery that previous similar global change studies had been far oversimplified because they had only examined one variable at a time. Interestingly, the Jasper Ridge study showed that an ecosystem’s response to multiple global changes was not a simple combination of responses to individual global change factors. Given that the reality of global climate change is that multiple variables act at the same time this finding brings into question how applicable are the conclusions of most previous studies that examine only one thing at a time.

One specific example that illustrates the importance of examining the environment’s response to multiple variables at the same time can be seen in the conclusions regarding plant growth in response to climate change. The Jasper Ridge study found that when everything except carbon dioxide was at elevated levels, plant growth almost doubled. This result corresponded to the consensus among scientists who believe global climate change is overblown. These scientists argue that nature is able to adjust to changes in the environment; in this case increased nitrogen, water and temperatures are compensated for by changes in vegetation. The Jasper Ridge study, however, showed that this result was not the whole story. If all four variables being studied are elevated (ie-nitrogen, water, temperature and carbon dioxide) plant growth increases by less than half of what the skeptics of global climate change believe. This shows that in the real world, nature will not be able to adequately compensate for man-made environmental changes.

An extension of this point that contradicts many of the global climate change skeptics was the finding that at various increasing levels of carbon dioxide, plant growth does not compensate by increasing proportionally (or even significantly) in response. Given that we release 8 billion tons of carbon dioxide each year through deforestation and the burning of fossil fuels, politicians have been relying on data from other single-factor climate change studies which suggested that increased CO2 levels are not as significant as some have claimed because plants simply would take-up more of the gas and produce more biomass in the normal photosynthetic pathway. The Jasper Ridge study was able to show that in a more realistic system where precipitation, temperature and nitrogen deposition was also increased, there was no large change in carbon storage. Even worse, as CO2 increases, the nutritional quality of plants seems to decrease. In other words: the climate change problem is not going to solve itself and action needs to be taken.

Contrary to some studies, work at Jasper Ridge shows that climate change is definitely a valid concern.

While the Bush administration has acknowledged the existence of global climate change and has suggested the possible necessity of taking action to lessen the human impact, there has been little direct governmental action. Currently the administration’s policy stands as a “voluntary public-private partnership” to try and reduce emissions which contribute to global warming. While some companies have made strides to reduce their emissions as a part of this program, the vast majority are entirely free to ignore the administration’s gentle guidelines. Considering the US accounts for almost 20 percent of the world’s man-made greenhouse emissions and given the Jasper Ridge Global Climate Change Project’s results, in conjunction with the results by countless other ecologists, it seems somewhat short-sighted not to take more stringent action in reducing the emissions of industries which burn fossil fuels. No matter how much politicians would like to quote the small minority of single-factor scientific studies which have come out claiming that global climate change is not a major problem, the preponderance of evidence by the Stanford Jasper Ridge study and by the majority of the scientific community in general, provide evidence for the belief that a massive environmental transformation will result from global climate change. There is only one real solution: science and politics needs to come together in order to implement some real, significant policy modifications.

Dr. Stanley Cohen co-discovered recombinant DNA.

Just over 30 years ago, during a lull in a bacterial plasmid conference, Dr. Stanley Cohen and Dr. Herbert Boyer, researchers at Stanford and UCSF respectively, were chatting over sandwiches in a Waikiki Beach restaurant. As the conversation turned toward their areas of study (plasmid DNA for Cohen and restriction enzymes for Boyer), the scientists began to realize the complementary nature of their research. They wondered if by combining their methods for cleaving DNA and manipulating plasmids, they could insert foreign DNA into circular plasmid DNA and then insert that plasmid into a living organism. Returning to the Bay Area, they began to integrate their work and after only a year. In November of 1973, they published their discovery of a method to manipulate and re-insert DNA into microorganisms, the first such procedure.

Patenting the Cohen-Boyer Discovery

Although they initially did not apply for a patent because of their reluctance to commercialize the process, after speaking with Niels Reimers, a technology transfer professional at Stanford, they decided to apply for a patent one week before the filing deadline. Eight years after filing for the patent with the United States Patent and Trademark Office and after numerous ethical debates that included a National Academy of Sciences international convention held specifically to discuss the technology, the patent was granted in 1980.

Since the granting of the patent, the Cohen-Boyer discovery has been an incredibly successful and integral technology. Called recombinant DNA technology, this biochemical process is a major underlying foundation of the biotechnology industry. The primary reason for its widespread success lies in its extensive applicability, with uses ranging from agricultural modification of pest-resistant plants to pharmaceutical synthesis of human cellular products.

Stanford’s Office of Technology Licensing

Carrying the DNA technology through the tedious patent process and helping to balance ethical issues with profits was the responsibility of the Stanford Office of Technology Licensing, the office that organizes all University technology transfers. This office was established in 1969 after the signing of the Bayh-Dole Law, which gave universities the first right to any discovery developed using its resources. The Stanford Office of Technology Licensing promotes “the transfer of Stanford technology for society’s use and benefit while generating unrestricted income to support research and education.” Since its creation, the OTL has disclosed nearly five thousand new technologies, generating nearly 550 million dollars with about 475 million of that going directly back to the University and the inventors. Typically, the University reinvests this money back into the research occurring on campus. The Cohen-Boyer discovery alone accounts for nearly one-third of the total amount earned by Stanford patents. By transferring new technologies from the University inventors to the public, the OTL insures that society benefits from innovations at Stanford and that the University benefits monetarily from the research that takes place on campus.

Typically, the office receives about one invention disclosure every day from people working at Stanford, usually patenting about fifty percent of these submissions. According to Kathy Ku, the director of the Office of Technology Licensing, biotechnology accounts for “about half of these disclosures and usually ends up being significantly more profitable in part because it is much less likely to be phased-out.” After reviewing the application and meeting with the inventor, the licensing professional assesses whether or not the invention has the potential to create meaningful income for the University. If so, the office begins the patenting process and, after receiving a patent, begins marketing the invention to the public.

Molecular cloning involves inserting foreign DNA into a circular DNA plasmid.

Making the Technology Public

The final step in the transfer of the technology from lab bench to commercial interests is one of the most controversial steps in the development of biotechnology. The extreme costs and risks associated with the research and development of a biotech product, usually amounting to “between 200 and 350 million dollars (U.S.)” and “7 to 10 years of development” (Harvard v. Canada SCC 20), makes the patent and licensing system “the only protection available for the intellectual product of this research, and thus, the only hope of a fair return against the great financial risks that investment in biotechnology entails” (Harvard v. Canada SCC 24). Because of the extremely high research costs and risk of failure, developers must aggressively license the technology just to meet costs and satisfy shareholders. According to Kathy Ku, commercial entities are much more concerned with profit and end up seeking broad patents on everything that they discover, a necessary strategy in a field requiring such extensive initial investment.

Ethicists like Dr. David Magnus, co-director of the Stanford Center for Biomedical Ethics, feel that this profit-maximizing patenting and licensing of biotechnology, more specifically of genes, often stifles research and prevents public benefit from the technology. One example of this can be seen in Miami Children’s Hospital’s policy regarding Canavan’s disease research. In this case, the Ashkenazi Jewish people, who donated their tissue to further research into this neurodegenerative illness, were prevented from benefiting from the therapy that the hospital developed by the extra costs imposed by the licensing system. Another example, can be seen in the Bogart Triple Test, a blood test used to determine the probably of Down syndrome in the fetus of a pregnant woman. In this case, the discoverer of one aspect of the test, had used his patent privileges to set up a company to perform all of his tests, and if the patent holder for another aspect of the test had done the same, nobody would be able to perform the full test without some sort of compromise. In other words, if multiple patents addressing the same issue overlap, medical tests and procedures can be made ultimately impossible. A third theoretical example can be seen in a company that held an exclusive patent to perform a type of procedure that was a necessary component of further research. Without the permission of the company, any research involving this foundational procedure would be illegal, an outcome that could have a drastic impact on research reliant on existing technology.

Making the Technology Affordable

In the case of the Cohen-Boyer discovery, the Stanford OTL was able to use a liberal, research-oriented approach to license the technology, a strategy that paid off both monetarily and ethically in that the profits derived by Stanford but did not inhibit widespread use and benefit from the technology. According to Niels Reimers, the former director of the Stanford OTL, the “objectives [of the OTL] were to develop a licensing program consistent with the public service ideals of the university, to encourage the application of genetic engineering technology for public use and benefit, to minimize the potential for biohazardous development, and finally, to provide a source of income for educational and research purposes.” Thus, Stanford elected to license the recombinant DNA technology to an unlimited number of companies, making it “cheaper to take a license than to fight” for companies “big and small, rich and not-so-rich.” Through a combination of flat fees and a very modest 0.5% royalty, the OTL was able to devise a licensing strategy where “pretty much any company could afford” the technology. Because the Cohen-Boyer discovery “was really broad technology,” the OTL determined that giving the technology to one company would probably be neither smart business nor smart use of the technology.”

Gene Patenting and Commercial Interests

The Cohen-Boyer patent was an extraordinary discovery that allowed for ethical considerations to be taken into account and showed that such considerations can coexist with the need to finance research and make a profit. To ensure that these compromises are made, the practice of patenting and licensing biotechnology should change substantially. One particularly problematic issue is disease gene patenting. According to Dr. Magnus, disease gene patents are a form of biotech patenting akin to observing an object, such as a gene, and then patenting the process of “look[ing] at this object in any way using any process.” This “crazy” notion would be akin to using a microscope to look at a particular cell and then patenting any method of looking at that cell. The American Medical Association code of ethics “prohibits patenting of procedures” because such patents could inhibit doctors from practicing medicine.

The fundamental difference that Dr. Magnus sees between disease gene patenting and the patenting of other forms of biotechnology is that other forms require extensive research to bridge a fundamental gap between the original and end products. He argues that patents such as these other forms are necessary to promote research and that, although imperfect, no other system exists that can match the amount of money that the current patent system allows to be reinvested into research and development. Dr. Magnus feels that legislative action, while helpful, is highly improbable as a means of solving the ethical concerns of disease gene patenting. Rather, he feels that by applying a significant amount of pressure on companies through “public awareness, awareness within the medical community of the problem, and awareness by the disease suffers who are stakeholders in the research,” corporations may voluntarily adopt the AMA code of ethics, thereby alleviating the problem.

Additionally, the awareness of disease sufferers could give them “a better bargaining position” in the biotech industry, promising better access to technology. This fundamental change in the biotech industry will be difficult to accomplish, especially with the profit-driven nature of commercial enterprises. Even at research universities, where the goal is to promote public knowledge and well-being, more and more researchers are “try[ing] to raise revenue” and become “more aggressive” with patents than private companies. Despite the current complications and difficulties in balancing public access with profit, the Cohen-Boyer licensing strategy provides a positive, guiding example of the balance between ethics and profit motives.

Folding@Home, a leading research group at the James H. Clark Center, exemplifies the interdisciplinary vision and collaboration of the new Bio-X program through their integration of biomedical science and computer technology. This pioneering team in the field of biomedical computation is offering anyone who owns a computer the opportunity to contribute to their innovative work in the field of biomedical computation. People can take part in solving today’s medical mysteries - and developing tomorrow’s medical miracles - every time they turn on their computer.

Understanding Protein Folding

Computer simulations of protein folding are helping research to unlock the structure of molecules such as these. Their insights may ultimately lead to new drugs and treatments for a variety of human disease.

Folding@Home is an effort to better understand how many different classes of biological molecules “fold,” or assemble themselves into their final molecular form, before they assume their normal biochemical functions. The project, pioneered by Professor Vijay Pande and a team of 16 graduate students, employs novel computational algorithms to bring previously impossible problems into the realm of feasibility. Their broad interest is to understand the fundamentals of biochemical interactions, not just the dynamics of proteins but also of nucleic acids, amino acids, and other biological molecules.

Understanding Protein Misfolding

Pande’s group is seeking to understand biochemical questions which, although crucial to human life and health, are enormously complex and poorly understood. Protein misfolding is thought to be the cause of many serious diseases, such as Alzheimer’s, cystic fibrosis, and some forms of cancer. Misfolded proteins form insoluble chemical masses which impede biological processes and can even poison neighboring tissue. For example, Alzheimer’s disease results from tangles of neurofibrillary proteins blocking neural pathways in the brain. Unfortunately, these errors in protein folding are nearly impossible for other molecules to correct, just as it is extremely difficult to untangle a shoelace which has been knotted hundreds or thousands of times.

At the same time, however, the process of protein folding occurs so quickly that even today’s fastest supercomputers cannot model the molecular interactions. A typical desktop computer today can simulate a nanosecond - one billionth of a second - in about a day, assuming the fastest known algorithms are used. But proteins can take 10,000 nanoseconds or more to “fold,” meaning a single computer would need 10,000 days — 30 years — to complete the calculations necessary for one result!

The Solution: Distributed Computing

The Folding@Home team turned instead to “distributed computing,” a term signifying the allocation of work in a single, large computing project among many separate computers. They rely on the more than 500,000 users who have downloaded and installed the Folding@Home client program from their website (http://folding.stanford.edu), allowing their computers to take part in the university’s research efforts. The software only performs its calculations using a computer’s “idle cycles,” time when it is not completing any other processor-intensive tasks, and can be configured to display its progress in a graphical screensaver. Pande encourages as many people as possible to download the client, which is designed to provide a linear speed increase as each new computer joins the network. Folding@Home allows anybody from any community - local, national, or global - to take part in cutting-edge biomedical research. Many of the most active participants are technology enthusiasts who form teams by school, state, country, or even an alliance to a particular magazine or website.

The Folding Problem

The distributed approach to the “folding problem” necessitated the formulation of complicated new computer algorithms to effectively share the calculations among hundreds of thousands of computers. Although these computational techniques are difficult to describe, Pande offers an analogy to help envision their complexity. Suppose that a math professor, with a class of 60 students, chose not to give each student an hour-long exam, but instead to allow the entire class to work together on a one-minute exam. How would you design an algorithm which enabled the entire class to successfully complete the test? Or, in the most extreme case, how would you coordinate a class of 500,000 students in a group test lasting only one hundred thousandth of a second? As part of their solution, Pande’s group has drawn on collaboration with other researchers from the biology, chemistry, and computer science departments. The team’s offices, located in the Clark Center, serve as a hub for communication and facilitate associations with similarly interested groups.

Expanding the Project

Profesor Vijay Pande

Now in its third year as an active research endeavor, the Folding@Home group has published about one dozen papers. Their research results have been featured in prestigious scientific journals such as Nature and the team has enjoyed publicity through CNN, the New York Times, and Wired Magazine. Also, their client software has been integrated into the Google toolbar application (which integrates the Google search engineer into the web browser). Most importantly, Pande’s group has successfully simulated the folding of several simple proteins, and their results were validated experimentally in the laboratory. This has vindicated Folding@Home’s efforts by demonstrating that it is, in fact, possible to bridge the gap between simulation and experimentation. Pande’s unique approach of drawing from the vast computational power of hundreds of thousands of computers has enabled significant progress in the field of biochemistry.

While the Pande group continually refines and improves their computational algorithms and acquires a larger user base, they are also striking out in new directions in biomedical computation. Currently, the team is looking at medically important molecules and structures such as collagen, one of the most important proteins in the human body. Understanding the misfolding of collagen could result in earlier detection and drug treatment of various diseases, including osteogenesis imperfecta, scurvy, and Ehlers-Danlos syndrome.

As the Folding@Home team continues to explore the building blocks of human life, they depend on the enormous potential of distributed computing and the power of Internet users’ volunteerism. Anyone can support their research by downloading Folding@Home’s client program from http://folding.stanford.edu. Your computer could be the key to unlocking the next medical miracles.

Only the most ardent of space flight devotees tumbled out of bed to watch the flaring plume streak across the dawn sky that was the space shuttle Columbia reentering the Earth’s atmosphere on February 1, 2003.

A piece of the left wing.

For Stanford students, it was the looming first round of Winter Quarter midterms that commanded their attention. Not the end of NASA’s 113th space shuttle mission, a low-priority science flight to complete a mishmash of experiments, including studies designed by schoolchildren about the effects of microgravity on bugs. The apathetic inattention that greeted Columbia upon its return indicated that, 17 years and 89 shuttle flights after the shocking Challenger explosion, space shuttle flight had once again become old hat to the American public. But shuttle flight means people blasting off to an orbital velocity of 25 times the speed of sound in less than 10 minutes in a machine built out of more than 2.5 million parts, drifting at the mercy of celestial mechanics dodging hurtling space debris, and then returning to ground in a massive braking sequence from orbital velocity to 220 mph which superheats the air to a couple thousand degrees Fahrenheit. It remains today an inherently risky rather than routine business. At 9:00:18 (ET) on the first day of February in 2003, a thunderous reminder of this risk came in the sonic booms as Columbia disintegrated and hurled debris across a few thousand square miles of Texas and Louisiana. All seven astronauts aboard perished.

“Columbia, Houston, UHF comm check.” A couple minutes after the explosion, the Mission Control team continued working futilely to re-contact Columbia. “Columbia, Houston, UHF comm check.” In the ionizing atmosphere of Columbia’s funeral pyre, Mission Control had been cut off from the shuttle 46 seconds before its main breakup and was unaware of the disaster. Minutes passed in a bewildered stasis until a cell phone rang: someone who had seen live TV coverage of the breakup had called a Mission Control team member and broken the news. In shock, NASA personnel mechanically set a contingency plan in motion that was the legacy of the Challenger disaster response. Controllers locked the door to Mission Control and archived all the mission data. A debris recovery team began operation. NASA Administrator Sean O’Keefe activated an accident investigation board. The forensics work had begun.

The appointed chair of the board, retired four-star admiral Hal Gehman, deftly took the helm, dubbing his team the Columbia Accident Investigation Board (CAIB). In response to criticism from Congress that the investigation board had the makings of an inside job, Gehman appointed in early March several new “university types,” including Douglas Osheroff, the current Stanford Physics Department chair and Nobel Laureate in physics. Osheroff’s appointment drew comparisons to that of Nobel Prize-winning physicist Richard Feynman to the Rogers Commission that investigated the Challenger explosion. During the Challenger investigation, Feynman famously plunked a deformed O-ring into ice water to demonstrate how cold temperatures robbed the material of its resilience and thus its ability to seal a joint. His elegantly simple demonstration focused the nation on the failure of the O-ring of the left solid fuel rocket booster as the direct cause of the Challenger explosion.

Investigators pieced together the charred remains of Columbia to determine the physical cause of the Columbia disaster.

In an interview with The Stanford Report immediately after his appointment, though, Osheroff cautioned, “I am certainly no Richard Feynman. He was a brilliant physicist; I am a very good experimental physicist.” During Spring Quarter and the summer, Osheroff worked to uncover the physical cause of the accident, joining Gregory Kovacs, a Stanford professor in the Electrical Engineering department who was coordinating the CAIB debris and sensor analyses.

The physical cause for the disaster lay in the mangled innards that the failing Columbia had sprawled across seven states. The trail of debris recovered by a 250,000-person workforce after 1.5 million hours revealed that the left wing was the first part to be damaged and the most damaged. More clues came from the greatest find of the debris recovery: the miraculously intact flight recorder, which helped furnish a timeline for events leading to the shuttle breakup that pinpointed the site of a rupture in the left wing to heat-shielding Reinforced Carbon-Carbon (RCC) Panel 8. From the painstaking work of CAIB and NASA workers, all the lines of physical evidence inexorably converged to tell the same story: RCC Panel 8 on the leading edge of the left wing of the shuttle had been breached, allowing the superheated air upon re-entry to invade and incinerate Columbia from within. What caused the fateful breach of the shuttle’s thermal protection system was hardly a mystery. People inside and outside NASA had shaken accusatory fingers at foam from the infancy of the Columbia investigation. During liftoff, an external fuel tank that is half the height of Hoover Tower supplies supercooled liquid hydrogen and oxygen propellant to the main engines of the shuttle. A layer of foam is sprayed on the tank to keep the supercooled propellant from boiling and to prevent ice from forming on the tank surface that could break off and damage the orbiter. Just after Columbia’s launch, video cameras recorded a foam chunk falling off the external fuel tank and spraying debris in the vicinity of the left orbiter wing. Computational analysis estimated that a 1.67 pound chunk of foam from the left bipod ramp on the external tank had collided at 530 mph with RCC Panel 8, 81.9 seconds after launch.

Behind the crisp precision of decimal points lurked a muddled history of ignorance and denial in NASA’s dealings with foam. It exemplified the flawed NASA institutional culture–the default NASA modus operandi–that was the ultimate cause of the Columbia disaster. Eleven days after the shuttle disaster at a congressional hearing, O’Keefe downplayed the foam strike as a piffling dink: “The piece came off, dropped roughly 40 feet at a rate of something like 50 miles an hour, so it’s the functional equivalent, as one astronaut described to me, of a styrofoam cooler blowing off of a pickup truck ahead of you on a highway.”

On February 1, 2004, NASA lost the space shuttle Columbia and her crew, 17 years after the Challenger disaster.

Even as the CAIB investigation dragged on into the summer with investigators checking off piece after piece of evidence implicating the foam strike, NASA was not fully convinced. Such unfounded denial can be attacked in two complementary ways: fundamental physical understanding that counter gut instinct and careful experiments to provide concrete data. A back-of-the-envelope calculation using basic physics produces a foam strike velocity two orders of magnitude higher than what O’Keefe suggested (see sidebar). The rebutting experiments to determine whether foam traveling roughly 500 mph could have caused damage to an RCC panel came courtesy of Scott Hubbard, a CAIB board member and the director of NASA Ames Research Center. “NASA absolutely had not a clue, I should say; they had never done these sorts of tests,” Osheroff pointed out in an interview. On a hot July day in San Antonio, a compressed nitrogen cannon fired a foam chunk at an RCC Panel 8 in a painstakingly designed recreation of the foam strike on Columbia. The foam struck and bashed a sixteen by seventeen inch hole in the panel. The NASA spectators, some with tears in their eyes, could no longer deny that a little piece of foam had meant the demise of Columbia and her crew.

A simulated foam strike tore a hole in the RCC panel during CAIB tests, confirming suspicions that loose foam downed the Columbia.

NASA’s stubborn refusal to believe that foam strikes could seriously damage the shuttle turned out to be classic behavior. CAIB discovered that foam loss from the external tank had in fact occurred routinely without galvanizing a response since day one of space shuttle flight 25 years ago, on Columbia’s inaugural flight. Foam shedding has occurred in 65 of the 79 (82%) shuttle flights for which imagery is available. Once upon a time, foam strikes were considered a serious threat to the shuttle’s fragile thermal protection system. Engineers had stipulated that the delicate RCC panels were not to receive an impact greater than 0.006 ft-lbs, “which is probably a screwdriver being dropped from a distance of 6 inches” estimated Osheroff. As space shuttles kept going up, getting hit by foam, and coming down with no more than say, a hundred divots here and there, but oh, nothing irreparable, NASA came to accept foam strikes as an acceptable flight risk, as a maintenance rather than safety issue, without even understanding what the risk was. This disturbing pattern of institutional behavior was, like the foam strikes themselves, nothing new. In an interview on the Macneil/Lehrer Newshour in 1986 about his experiences investigating the Challenger disaster, Feynman described ridiculously similar behavior in NASA’s response to solid rocket booster defects:

I kind of imagined something like a child that runs in the road, and the parent is very upset and says, “It’s very dangerous!” The child comes back and says, “But nothing happened,” and he runs out in the road again, several times, and the parent keeps saying, “It’s dangerous!” Nothing happens. If the child’s view that nothing happened is a clue that nothing is going to happen, then there’s going to be an accident. You could hear brakes squealing a couple of times and that’s the leakage, then the gas going through the seals, and so forth. [. . . .] Sooner or later the child gets run over. Is it an accident? No, it’s not an accident.

Twenty years later, the brakes had squealed again in the form of especially large chunks of foam shedding from the left bipod ramp and in the egregious involvement of Columbia in five of the seven known foam shedding events from the left bipod ramp. NASA’s last sure chance to prevent the ensuing disaster had been two shuttle missions earlier in October 2002 during a launch of Atlantis. While NASA management had finally classified this foam strike as an action item, it had fatefully decided to wait just a couple more flights until resolving the foam problem.

NASA’s decisions regarding foam shedding rested on a shaky foundation. Osheroff discovered that NASA not only harbored an alarming lack of basic knowledge about the physical properties of foam it used but also had never properly analyzed the statistics of foam shedding.

Stanford professor Douglas Osheroff speaks at a Columbia Accident Investigation Board press conference.

“I mean, they didn’t know how often bipod ramp foam had fallen off; they’d done no aero calculations to suggest what it might hit,” Osheroff huffed. A venerable tenet of NASA foam shedding mythology was that liquid propellant condensed in voids in the foam; after launch, aeroheating caused it to evaporate, expand, and then explode the foam. Osheroff took a look at the data from the last Atlantis launch and realized that the foam had fallen off long before aeroheating could occur. As NASA should have done long ago, Osheroff did experiments to see if pressure in voids could explode foam. On the loading dock of the Varian physics building at Stanford, Osheroff and his graduate student Jim Baumgardner took a piece of foam and glued it on a brass plate which had a hole in the center of it. Into this hole, they injected a liquid dye under gradually increasing pressure from a bike pump. Osheroff waited for a violent explosion to no avail. Puzzled, he bisected the foam and, observing the dye pattern, found in fact that there was a planar crack that extended all the way through the surface of the foam. In further kitchen sink experiments, Osheroff found similar results. So much for NASA’s exploding foam model: the pressure always escaped harmlessly through a crack. While he was working on his own fast and cheap, yet informative foam experiments, Osheroff found technicians at Marshall Space Flight Center laboriously setting up a series of brute-force experiments “that must have cost several million dollars” to simulate foam shedding from the left bipod ramp. They could not do it, as they should have known by examining the statistics that only 7 in the 79 foam shedding events in the past had been from the left bipod ramp.

In his appendix to the Rogers Commission’s final report, Feynman complained that shuttle engines were “designed and put together all at once” to be tested without prior testing of individual components. Two decades later, NASA technicians relied on such “top down” rather than “bottom up” methods like Osheroff’s simple experiments to elucidate foam shedding, as NASA management again took uninvestigated risks at the expense of safety, it seems that Challenger’s didactic legacy had been slowly whittled down to nothing more than safer solid rocket boosters and an official plan of action in the event of another disaster. The newfound attention to risk analysis and safety in shuttle missions in the aftermath of the Challenger disaster died away over the years.

The infamous bipod foam ramp.

Additionally, NASA lost the probabilistic risk analysis reports on the shuttle thermal protection system that they commissioned in the early 1990s from Stanford Professor Elisabeth Pate-Cornell, now the head of the management science and engineering department. Together with then graduate student Paul Fischbeck, Pate-Cornell had clearly warned NASA that “they had to be careful with the insulation in the external tank and fix that soon.” But NASA only remembered the study after the Columbia disaster and “they did not remember where they had put it,” recounted Pate-Cornell. Similarly, the vaunted safety organization established after the Challenger disaster was, certainly by the time of the Columbia accident, regarded as largely a “silent safety organization.” Osheroff recalls:

“I got e-mail from [. . .] one of the NASA employees that oversaw the United Space Alliance [the safety organization] people as they were preparing shuttle stacks for launch. And he was told that his job was to prevent the USA people from writing up safety issues. So that’s exactly what he shouldn’t have been doing, of course. But the idea was that if USA wrote up something as unsafe, then in fact, it could delay the launch. So as a result of that, you’re compromising more or less on-time launch, and as a result, in fact, you are compromising the safety of the astronauts and the orbiter.”

The inescapable fact is that NASA has always been a political in addition to a scientific organization, beholden to the whims of the public and congressional funding. Delaying a launch has been the most consecrated taboo in NASA culture, and as long as schedule pressure drives NASA, more unnecessary deja vu disasters cannot be avoided. However what General Donald Kutyna, who held a role on the Challenger investigation board analogous to Gehman’s on CAIB, once said about launch schedules illustrates that schedule pressure will be difficult to eliminate:

“The shuttle schedules were very tight. It took a long time to process the flights, and there were only certain windows open in space-you could only launch at certain times, be it a certain time of the year or a certain time of day. If one shuttle launch was delayed for, say, mechanical reasons, it would delay all the shuttles in line following it. [. . . .] The other pressure on NASA to launch was the pressure from the press. The press had full coverage of the launches, and every time anyone dropped a screwdriver it would appear in the press: “Gee, we’ve goofed up, and we can’t fly.” Next, Congress gives you money according to how successful you are. They look at every mission you fly, and if the find something that is unsuccessful, that doesn’t test very well, then it affects your budget in the future.”

Osheroff happily reported that NASA is getting rid of the troublesome foam bipod ramp and adding a heater in its place to prevent ice buildup. Furthermore, NASA is finally starting to do ballistic experiments to properly determine how much impact an RCC panel can take. However, this is no indication that NASA will successfully fight off a regression to its default of staying on schedule at all costs. The support of the public, the attention of the press, and the financial backing of Congress will be crucial factors in NASA’s bid to reform. The current excitement about a manned mission to Mars may revive the swashbuckling glory of the Apollo days at best or allow a new set of impossible deadlines to ramp up the risk of another disaster if we do not heed the warnings of history.

A flash of lightning over a dark and eerie laboratory was a fitting backdrop for the creation of Frankenstein. The electrifying ’spark’ needed to breathe life into an organism has been popularly conceptualized. Only now are we beginning to realize just how critical this spark really is to life.

Stanford: A Breeding Ground for Bioengineering Research

As biology continues to permeate technology, Stanford’s new Bio-X facility has generated much hype as the ultimate marriage between the life sciences and engineering. While many of the researchers in Bio-X have been drawn to the integration of biology and their technological field simply by the availability of new facilities and funding in this area, the first seeds of this revolution were sown somewhat earlier. Many engineering research groups and medical researchers envisioned the power of technology to rapidly advance science and medicine.

Professor Krishna Shenoy

Stanford’s Neural Prosthetic group is one such collaboration that has earned much attention while still in the early stages of development. Joining forces between the department of Electrical Engineering and the School of Medicine’s department of Neurosciences, the Neural Prosthetics group is led by Prof. Krishna Shenoy, an electrical engineer who began studying biology during his postdoctoral work at the California Institute of Technology and who continues to integrate biology with engineering in cutting edge research at Stanford.

Shenoy’s Group: At the Juncture of Electrical Engineering and Biology

Shenoy’s group is working at the intersection of electrical engineering and neuroscience. The engineering side involves the study of signal processing, the quantitative analysis of time-varying quantities, and the ability to transmit information through systems relying on instantaneous delivery of information in a decision-making environment. The neuroscience side involves the study of neurons, the cells that enable information to be efficiently and effectively communicated between the brain and body. The power of joining these two disciplines is that quantitative models of signal processing can be used to systematically analyze neuronal information.

The focus of Shenoy’s group is to build engineering hardware that ‘reads’ neural activity, with the long term goal of developing functional artificial limbs for handicapped people. To be effective, the limbs need to read our brain signals indicating when and where to move. The group is thus fundamentally interested in determining how the brain collects information prior to decision-making, which parts of the brain demonstrate response, and the forms of this reponse. All of this knowledge is required in order to train artificial limbs to ‘read’ the brain and respond to decisions of movement.

Making the Dream a Reality

On a daily basis, people typically take motion for granted, not realizing the many bits and pieces that come together like discrete cogs in a wheel to keep us moving. There is little realization that our decision to touch this very page is preceded by a period in which the neurons decide that touch should be carried out, assess the distance of moving to the touch, and determine an appropriate speed and trajectory for physically executing the motion. These are all critical factors in the resulting effectiveness of the touch and must be taken into account by any prosthetic that is to have natural movement.

The Shenoy group is initially interested in interpreting the working of the brain as a system that despite its many intricacies can be broken down into fundamental processes mimicking the operation of a computer. The group then wishes to establish how the execution of each of the basic steps relates to the output ultimately conveyed to the limb.

The neurons of the brain contain the units of information that need to be analyzed to judge how best to extract this information from them.

It is important to select the correct part of the brain from which to study neurons, since different parts of the brain are responsible for different functions, and all are not equally relevant to the desired application. Shenoy’s group has chosen to focus on the parietal reach region, believed to be the first pathway of visual information used to assess the distance from the hand to an object to be gripped. Of critical importance is that this region seems to have the ability to prioritize the order of gripping. If there were many overlapping possibilities of how to go about the touching motion, it would be hard for the electro-mechanical limb to sift through the data to find what is most relevant. Shenoy’s group, however, is able to judge the order of movement that should be made from this region of the brain, and as a result provide the limb an ordered sequence of signals.

This order of events is being unravelled by studying the voltages surrounding the neurons, as this electric field is deemed to be the essence of the signal conveyed by the neuron. These voltages are read using high impedance electrodes implanted in the brain. Shenoy’s group has seen a clear distinction between the electrical activity of the neurons in the planning pre-motion period and in the peri-period that includes the conduction of motion.

An algorithm is needed to enable the prosthetic to read the electrical activity from the neurons at different intervals and to provide it with a procedure to interpret this data. Presently, the algorithm used is the Plan Movement Maximum Likelihood (PMML) which approximates each of the neurons as a point data source representing a Poisson distribution. Statistical analyses of large data sets have been done to attain quantitative results and give the prosthetic a reliable means of interpreting the data from these results.

Mimicking the Brain: Early Successes

The work done by Shenoy’s group has produced some encouraging results. The algorithm to read the neurons as a whole set has proven very effective, and the group has been able to predict with 90% certainty what the neurons are trying to say in terms of future movement simply by extracting information from 40 random neurons in the chosen region of the brain. The low number of neurons used for effective communication is critical since it minimizes the number of electrodes that have to be inserted into the brain, making the operation less invasive.

We have already seen many successful results of medical engineering in areas such as cochlear implants, tremor-control devices, and other neural prosthetic systems aimed at delivering signals to the nervous system. These successes are a source of encouragement to the researchers who are intensifying the efforts to take biological signal processing to a new level. What is most groundbreaking about Shenoy’s research is that this is the first example of a machine model that predicts cognitive states using neural activity. In previous models, neural decoding algorithms have typically used estimators that do not explicitly model internal dynamic states or the transitions between these states. However, the algorithm introduced by Shenoy’s group is versatile and can recognize the arrival of rapidly changing motions.

An important consideration is whether the electrical activity under study is effective during neuronal damage causing paralysis. However, since the parietal reach region of the brain relates to our system of vision and is not directly connected to our motor activities, it can continue to provide the necessary information even in the case of neuronal paralysis in other regions. This is of critical importance since it offers hope not only to people who have damaged limbs but also to those who are paralyzed.

What Next?

Shenoy’s group still has some work to do before it can claim to have a smoothly working prototype of such a limb. Development is in progress to create an adaptive filter that analyzes neural data with a computation time fast enough to operate in real time, even with hundreds of neurons added at intervals to the data set. This is expected to contribute to the ability of the arm to respond rapidly to the most recent data from the brain.

At present, Shenoy is also attempting to incorporate data from the peri-movement stage into the information system to optimize the trajectory of the arm movement. Extracting electrical information from the same neurons multiple times shows critical trends in the electrical potential planning period relating to the speed of movement and assessed distance, critical to judging the trajectory of the motion. If the trajectory can be optimized, it will minimize jerk, twisting, and torque effects in mechanical motions. This will reduce the response time, since the limb will be capable of picking the path of least time to its target.

With the rapid advances in technology and science, the integration of electrical engineering and neuroscience will one day direct the electrical spark to restore movement to those who are without it.