E5A12003-9833-4068-91C6-B6B9040FD79A.jpg

Cross section of the mouse spinal cord, showing that the FoxP1 protein (red) marks the nuclei of motor neurons that innervate limb muscles. These neurons also express a retinoid synthetic enzyme RALDH2 (green) which is controlled by FoxP1 and directs later aspects of motor neuron development. Expression of FoxP1 in these neurons is essential for the activity of Hox proteins that control motor neuron diversity. Image: Tom Jessell

“It is a complicated but satisfying genetic logic, one that appears to have evolved to ensure the generation of the diverse array of motor neuron subtypes needed for fine motor control of the limbs.” Research published in the July 25, 2008, issue of Cell
Thomas M. Jessell

July 25, 2008, Howard Hughes Medical Institute – Simple, everyday movements require the coordination of dozens of muscles, guided by the activity of hundreds of motor neurons. Now, researchers have revealed an important step in the process that guides the early development of neurons themselves, as they establish the precise connections between the spinal cord and muscles. This knowledge will help scientists search for drugs to treat diseases that destroy motor neurons, such as amyotrophic lateral sclerosis, or Lou Gehrig’s disease.

As a vertebrate organism develops, the long, outstretched processes of motor neurons wend their way from the spinal column to wire up every muscle in the body. In mammals, many hundreds of different types of motor neurons are needed to control the variety of muscle types used to coordinate movement. The highly specialized motor neurons that innervate muscles in the arms, legs, hands, and feet are the most recent of these to evolve. As an animal develops, these neurons become increasingly specialized – first establishing themselves as motor neurons, then taking on the characteristics needed to control a limb, then preparing to target a specific muscle. Proper function depends on each of these neurons finding its way from the spinal cord to the group of muscle cells that it is equipped to control.

Now, Howard Hughes Medical Institute investigator Thomas M. Jessell, working together with Jeremy Dasen of New York University and Philip Tucker of The University of Texas at Austin, has discovered the genetic recipe for making these specialized motor neurons. The key ingredient is a gene called Foxp1, which regulates the activity of a series of crucial patterning genes of the Hox family, and thereby coordinates the identity and connectivity of motor neurons. Without FoxP1, the axons of motor neurons that extend into an animal’s limb wander aimlessly and connect to muscles at random, Jessell and Dasen have found. The paper describing these findings is published in the July 25, 2008, issue of the journal Cell.

The Hox genes are among the most highly conserved of the developmental genes and are best known for their role in controlling the overall pattern of body development. Like many developmental regulators, the proteins produced by Hox genes control the activity of a diverse assortment of target genes. In previous work, Jessell, who is at Columbia University Medical Center, and Dasen discovered that 21 of the 39 mammalian Hox genes orchestrate the program of motor neuron development and connectivity. Their new work shows that FoxP1 is an essential co-factor for the entire set of Hox proteins that generate the motor neurons that control limb movement. Intriguingly, the level of FoxP1 expressed by developing motor neurons determines the precise subtype that they will form.

“This paper makes the surprising discovery that one accessory co-factor, FoxP1, is needed for the output of each of the 21 Hox proteins that make motor neurons different,” says Jessell. “Depending on which Hox gene is turned on, FoxP1 is induced to different levels. And this difference in level programs which motor neuron subtype is generated. It is a complicated but satisfying genetic logic, one that appears to have evolved to ensure the generation of the diverse array of motor neuron subtypes needed for fine motor control of the limbs.”

To emphasize the importance of this highly-evolved class of motor neurons, Jessell points to a relatively primitive vertebrate, the eel-like jawless fish known as a lamprey. “Lampreys don’t play the violin and they don’t run – their motor programs are designed for simple swimming behaviors,” Jessell says. “The lamprey represents the most extreme example of vertebrate organisms whose lifestyle permits them to survive with a highly reduced array of motor neuron subtypes.

“At some point in evolution, vertebrates acquired the ability to generate hundreds of motor neuron subtypes, presumably to accommodate the appearance of limbs new muscle classes,” says Jessell. He and his colleagues suspect this diversity may have arisen when FoxP1 began to be expressed in the spinal cord But exactly when FoxP1 expression first appeared in the spinal cord and how its expression is linked to Hox activities remain unsolved puzzles that Jessell and Dasen are now pursuing. Together with Sten Grillner of the Karolinska Institute and Manuel Pombal of the University of Vigo in Spain, they are beginning these studies by analyzing the expression and function of the FoxP1 gene in lampreys.

Jessell, Dasen, and Tucker demonstrated the significance of FoxP1 in mice by inactivating the gene and showing that the spinal cord lacked the full repertoire of motor neurons without it. “This mutation, in effect, reverts the spinal cord to a primitive ancestral state, generating a lamprey-like spinal cord encased in a mammalian body,” Jessell says. Mice without FoxP1 die before birth because the gene is also critical for heart development, so the scientists are now analyzing genetically-modified mice in which FoxP1 is deleted selectively from motor neurons. “We anticipate that these animals will have a severe impairment in motor behavior, and studying later phases of FoxP1 function should reveal insights into the assembly of motor circuits in the spinal cord as well as the periphery” he says.

Jessell’s Columbia colleagues Hynek Wichterle and Mirza Peljto, in work supported by ProjectALS, are already using the Fox-Hox recipe in their attempts to create better ways of screening for drugs to treat Lou Gehrig’s disease and other types of motor neuron degeneration. Fine-tuning the expression of the these proteins has recently permitted Wichterle and Peltjo to convert embryonic stem cells into the highly-specialized motor neurons that innervate limb muscles.

“This is a promising screening strategy for identifying drugs that prevent or slow the degeneration of motor neurons,” says Jessell. “Hopefully, many researchers will build upon these advances in basic motor neuron biology to design better and more predictive therapeutic screens.”

…………………………………………o……………………………………………..

HHMI INVESTIGATOR

Thomas M. Jessell, Ph.D.

5F9ECCF7-977D-4DF1-AEB7-6CBED11EAC47.jpgFor the past two decades, Thomas Jessell has worked to understand how nerve cells in the developing spinal cord assemble into functional circuits that control sensory perception and motor actions. Ultimately, his research may provide a more thorough understanding of how the central nervous system is constructed and suggest new ways to repair diseased or damaged neurons in the human brain and spinal cord.

“There is increasingly persuasive evidence to suggest that many neurodevelopmental and psychiatric disorders—from motor neuron diseases to autism and schizophrenia—result from defects in the initial assembly of connections in the developing brain,” said Jessell. “By understanding the cellular and molecular processes that control the normal wiring pattern of these connections, we may eventually be able to design more rational and effective strategies for repairing the defects that underlie brain disorders.”

Jessell’s work has revealed the details of a molecular pathway that converts naïve progenitor cells in the early neural tube into the many different classes of motor neurons and interneurons that assemble together to form functional locomotor circuits. This molecular pathway involves critical environmental signaling molecules such as Sonic hedgehog, and a delicate interplay of nuclear transcription factors that interpret Sonic hedgehog signals to generate diverse neuronal classes. The principles that have emerged from Jessell’s studies in the spinal cord have now been found to apply to many other regions of the central nervous system, thus establishing a basic ground plan for brain development. His work has also defined many of the key steps that permit newly generated neurons to form selective connections with their target cells.

One potential strategy for brain repair involves the use of stem cells, and Jessell and his colleague Hynek Wichterle recently demonstrated that mouse embryonic stem cells can be converted into functional motor neurons in a simple procedure that recapitulates the normal molecular program of motor neuron differentiation. Remarkably, these stem cell-derived motor neurons can integrate into the spinal cord in vivo and contribute to functional motor circuits. This work may uncover additional aspects of the basic program of motor neuron development, as well as pointing the way to new cell and drug-based therapies for motor neuron disease and spinal cord injury.

“I enjoy the search for answers to intriguing problems in biology,” explained Jessell. “On those rare occasions when a definitive answer emerges, there is great pleasure in having deciphered a small fragment of a much larger and still elusive puzzle. And when frustration comes, it is usually from a sense of impatience—the desire to know answers more rapidly than they emerge.”

Dr. Jessell is also Professor of Biochemistry and Molecular Biophysics and a Member of the Center for Neurobiology and Behavior at Columbia University Medical Center in New York City.

RESEARCH ABSTRACT SUMMARY:

Thomas Jessell’s research explores the mechanisms that direct the assembly of neural circuits and how the organization of these circuits controls vertebrate behavior. He is examining these general problems through an analysis of circuits in the spinal cord that coordinate locomotor behavior.

30DA67B6-39C0-4EE3-AAE3-1C075EE9A233.jpg
Shizuo Kambayashi/Associated Press
Victor A. McKusick with his Japan Prize this year.

By Lawrence K. Altman, July 24, 2008, The New York Times – Dr. Victor A. McKusick, a cardiologist who went on to become a founder of medical genetics and helped make the discipline a central part of medicine, died on Tuesday at his home in Baltimore. He was 86.

The cause was complications of cancer, said officials of the Johns Hopkins University School of Medicine, where Dr. McKusick had worked for more than 60 years, including a period as physician in chief.

Dr. McKusick was also an early proponent of completely mapping the human genome, 34 years before the feat was achieved in 2003. He influenced the training of the vast majority of medical geneticists through his textbooks, which cataloged thousands of genetic disorders.

Victor Almon McKusick was born on a dairy farm in Parkman, Me., on Oct. 21, 1921. His parents were teachers. He attended grammar school in a one-room schoolhouse, and he had the same teacher for seven of the eight years.

As a child, he had planned to become a minister. Then, at 15, he developed a spreading streptococcal infection of his arm and had to spend 10 weeks in a hospital while receiving a sulfa drug, one of the first antibiotics. That experience led him to medicine.

After attending Tufts University from 1940 to 1943, he entered the Johns Hopkins medical school without receiving his bachelor’s degree.

He had intended to return to Maine to go into general practice. But he won a prestigious fellowship, and while training as a cardiologist he became fascinated by patients with unusual inherited disorders.

In 1957, Dr. McKusick established a medical genetics clinic, the same year that Dr. Arno G. Motulsky started a similar clinic at the University of Washington. They are believed to be the first medical genetics clinics in this country. It was only four years after the discovery of the structure of the DNA molecule by James Watson and Francis Crick, and one year after scientists had established that the correct number of human chromosomes was 46, a finding that helped genetics begin to flourish.

Dr. McKusick, a spry man known for his jolly sense of humor, said in an interview that in 1957 some of his colleagues “thought I was committing professional suicide in leaving cardiology to focus on rare and unimportant genetic disorders.”

Today, there are more than 100 accredited clinical genetics units in North America, with thousands of trainees.

In studying genetic disorders, Dr. McKusick kept meticulous records of the inheritance patterns and clinical features of many syndromes.

As a cardiologist in the early 1950s, Dr. McKusick became fascinated with Marfan’s syndrome, an inherited disorder in which affected patients show an array of signs, including long arms and legs and dislocated eye lenses. They often died of a rupture of the aorta, the body’s main artery.

Dr. McKusick theorized, correctly, that all of these seemingly unrelated findings were because of the action of a single abnormal gene that disturbs the formation of connective tissue.

He also studied the medical histories of members of the Old Order Amish of Pennsylvania to identify genes responsible for their inherited disorders.

Dwarfism, which was unusually common in the Amish population, was the first one that he studied in detail. He then went on to discover previously unrecognized inherited disorders.

As an avid historian of a field he helped define, Dr. McKusick told students that if they wanted to get on top of a topic, they needed to learn its course of development.

Also in the 1950s, Dr. McKusick was intrigued by genetic maps of the fruit fly and began to think seriously about a genetic map for humans. In studying links between inheritance and disease, Dr. McKusick began mapping genes on human chromosomes. And in a lecture on a landmark study in genetics at a meeting at the Hague in 1969, he made a bold proposal: he said that the time was ripe to map all the human genes as a way of understanding the basic derangements in birth defects.

“In part, the proposal reflected the exuberant mind-set that followed the first moon landing,” Dr. McKusick wrote in an autobiographical paper.

But the audience’s reaction was flat, Dr. Joseph Goldstein said in presenting him with an Albert Lasker Award in 1997 for special achievement in medicine. Dr. McKusick was the founding president of HUGO, the Human Genome Organization, a coordinating group for international genome mapping and sequencing programs, and a member of the National Academy of Sciences. He received the Gairdner award in Canada in 1977; the National Medal of Science, the United States’ highest scientific honor, in 2001; and the Japan Prize in Medical Genetics and Genomics this year.

He is survived by his wife, Anne, a rheumatologist at Johns Hopkins; two sons, Kenneth A. of Ruxton, Md., and the Rev. Victor W. of Herkimer, N.Y.; a daughter, Carol Anne of Urbana, Ill.; and his identical twin, Vincent, a retired chief justice of the Supreme Court of Maine.

July 24, 2008, The New York Times – The head of a prominent cancer research institute has warned his faculty and staff to limit cellphone use because of a possible cancer risk, The Associated Press reports.

Dr. Ronald B. Herberman, the director of the University of Pittsburgh Cancer Institute, notes that while the evidence about a cellphone-cancer link remains unclear, people should take precautions, particularly for children.

“Really at the heart of my concern is that we shouldn’t wait for a definitive study to come out, but err on the side of being safe rather than sorry later,” Dr. Herberman told The Associated Press.

Earlier this year, three prominent brain surgeons raised similar concerns while speaking on “The Larry King Show.” Their concerns were largely based on observational studies that showed only an association between cellphone use and cancer, not a causal relationship. The most important of these studies is called Interphone, a vast research effort in 13 countries, including Canada, Israel and several in Europe.

Some of the research suggests a link between cellphone use and three types of tumors: glioma; cancer of the parotid, a salivary gland near the ear; and acoustic neuroma, a tumor that essentially occurs where the ear meets the brain. All these tumors are rare, so even if cellphone use does increase risk, the risk is still very low.

On Wednesday, Dr. Herberman sent a memo to about 3,000 faculty and staff saying that children should use cellphones only for emergencies because their brains are still developing. He advised adults to keep cellphones away from the head and use the speakerphone or a wireless headset, he said.

“Although the evidence is still controversial, I am convinced that there are sufficient data to warrant issuing an advisory to share some precautionary advice on cellphone use,” he wrote in his memo.

4A2D8EDF-6791-4694-A990-D6A4DE3321BD.jpg
Check Out the Future of the Environment

http://www.popsci.com/futurecity/

Doug Selsam’s Sky Serpent uses an array of small rotors to catch more wind for less money

5FD283FE-B87C-4B96-BD2A-EEF8DB9D739F.jpg
WIND WIZARD: Doug Selsam sits beneath a prototype 25-rotor turbine that can produce three kilowatts of power. The other end is held aloft by a balloon. Photo by John B. Carnett

Sky Serpent
Cost to Develop: $250,000
Time: 9 years
Prototype | | | | | Product

By Kalee Thompson, Popular Science – Today’s largest wind farms are the size of small towns, made up of turbines 30 stories tall with blades the size of 747 wings. Those behemoths produce a great deal of power, but manufacturing, transporting, and installing them is both expensive and difficult, and back orders are common as the industry grows by more than 40 percent a year. The solution, says inventor Doug Selsam, is to think smaller: Capture more power with less material by putting 2, 10, someday dozens of smaller rotors on the same shaft linked to the same generator.

“The wind-turbine design out there right now is a thousand years old,” Selsam points out, as he lets one of his carved wooden blades speed to a blur in the makeshift wind tunnel he’s made of the alley behind his Fullerton, California, apartment. He brainstormed his multi-rotor approach in the early ’80s, in a fluid-dynamics class at the University of California at Irvine. “The textbook said, this single-rotor turbine design is the most power you can get. I knew then it wasn’t right. More rotors equals more power.”

57B9FC44-CFF4-47E2-B054-629E388BC703.jpg
How the Sky Serpent Works: Aligned at the optimal angle, each rotor receives its own wind, increasing efficiency.

Of course, more rotors also means more-complicated physics. The key to increasing efficiency is to make sure each rotor catches its own fresh flow of wind and not just the wake from the one next to it, as previous multi-rotor turbines have done. That requires figuring out the optimal angle for the shaft in relation to the wind and the ideal spacing between the rotors. The payoff is machines that use one tenth the blade material of today’s megaturbines yet produce the same wattage.

Selsam never did graduate from Irvine, but over the next couple decades he kept investigating novel wind designs, and by 1999, after an extended hiatus as a heavy-metal guitarist (he claims that the band Metallica stole its name from his group, Metallix), he turned to wind development full-time. In 2003, he landed a $75,000 grant from the California Energy Commission to develop a 3,000-watt turbine—his seven-rotor design met the challenge—and he has now sold more than 20 of his 2,000-watt dual-rotor turbines to homeowners. He’s built them all in his suburban garage.

“We’ve tested all kinds of wacko things that people think should make a lot of wind energy,” says Brent Scheibel, a former turbine tester for General Electric who now runs a wind-testing facility in Tehachapi, California. “The laws of physics take most of them out of the equation very early. Doug’s idea is one of the very, very few that I’ve seen that actually has a strong chance of making strides into the commercial world.”

Selsam says two rotors is just a start. Someday he sees his multi-rotor turbines stretching for miles across the sky. “We can go big,” he says, “and make turbines using this technique that are way more powerful than anything in GE’s wildest imagination.”

EC45C29F-044C-448C-9052-996CB8484FE2.jpg
Bacillus subtilis going into lockdown mode. This spore-forming bacteria is a close cousin of anthrax.
[Credit: Patrick Eichenberger]

Both deadly and benign spore-forming bacteria’s genes allow them to eke it out in extreme conditions.

By Adam T. Hadhazy, SciencelineNYU – The bacteria in the test tube are harmless, but boy are they stinky—a general swampiness with hints of manure, leavened with a moldy food funk. Lab workers retrieve vials of these foul-smelling, soil-dwelling microbes and then set about starving them.

But this cruelty on a microscopic scale has a purpose, and besides, Bacillus subtilis is a tough customer. The bacteria have a special method of survival—when under duress, they encapsulate themselves in protective shells called spores. By studying the genetic underpinnings of B. subtilis’ fortress-making abilities, scientists hope to be better armed against its dangerous bacterial cousin anthrax. In addition, analyzing the dynamics of spore formation may reveal more about the cellular mechanics of microorganisms in general.

Back in the lab, B. subtilis is out of food and begins to show off its bunker mentality by entering a process called sporulation. This undertaking produces a durable, spherical spore that allows B. subtilis to withstand severe dehydration, boiling, freezing and even high levels of radiation. The microbe can remain in this stasis indefinitely, waiting it out until conditions improve. Bacterial spores are so rugged there is concern they could survive on spacecraft and end up on places like Mars.

“They are the most resistant of all [known] living cells,” says Patrick Eichenberger, a professor of biology at New York University whose laboratory is dedicated to the study of B. subtilis.

This invulnerability makes spore-forming bacteria like B. subtilis and its relative Bacillus anthracis, better known as anthrax, notoriously difficult to wipe out. Take the case of the 2001 attacks on the Hart Senate Office Building: After the arrival of a couple of envelopes containing anthrax spores, it took months to thoroughly decontaminate the premises at a cost of about $27 million, according to the Government Accountability Office. Five people died and 17 were injured as a result of this still-unsolved biological assault. Cleansing of a nearby mail facility cost an additional $130 million and took over two years.

Any insight into how stubborn microbes remain safe behind their defensive shields would be useful in rooting out a future anthrax infestation. In fact, a 2002 grant from the Department of Defense initially funded the lab that Eichenberger now runs. “If we know more about what makes subtilis resistant, then we know more about what makes anthracis resistant,” he explains.

Finding Answers in the Genes

Eichenberger intends to uncover the network of genes involved in B. subtilis’ spore-making ability. Besides aiding efforts to thwart bioterrorism, this research may help curtail more common infections from other spore-formers, such as Clostridium difficile. The scourge of hospitals, this bacterium afflicts one in five in-patients with diarrhea and can even cause death in elderly victims.

Though B. subtilis is among the most studied organisms on the planet, researchers understand relatively little about how the single-celled bacterium accomplishes the feat of sporulation. Once researchers have obtained a complete “assembly map” for spore-forming, drugs and chemicals could be manufactured to either halt the transformation or go after chinks in the bacteria’s armor, according to Eichenberger.

While scientists have unveiled the genome, or entire DNA sequence, of hundreds of species (including our own), this is not the same thing as knowing how that sequence is actually translated into action. DNA is segmented into a number of genes, which are the instructions that cells use to make proteins. In turn, these proteins perform specific tasks in the cell or around a creature’s body.

But even with the genome of the single-celled B. subtilis organism in hand, microbiologists still do not know when certain genes are turned on and off, and what they all do once activated. Overall, gene regulation is a byzantine process of organic molecules having far-flung, miniscule effects amid a myriad of redundancies.

“It’s comparable to the economy of, say, Thailand,” offers Rich Bonneau, a professor of biology and computer science at New York University who is collaborating with Eichenberger. “We can make general predictions and observations, and we can tell to some extent what disrupting one trucking line will do, or if a port is shut down, for example.” But he and his colleagues cannot really extrapolate how each “truck,” or protein, influences the entire organism’s overall economy.

And until scientists know how each part contributes to the whole, they cannot bridge the gap between a genetic blueprint and a living bacterium, whether it is innocuous B. subtilis or deadly B. anthracis. “You haven’t solved a system unless you can predict results,” says Eichenberger.

Even the smallest genomes are awfully large chunks of information for researchers to organize into a sensible system. The size of B. subtilis’ genome, at least when compared to the human genome’s 3 billion base pairs, is a slightly more manageable 4 million base pairs. These are segregated into a little over 4,000 genes. It is quite difficult to fathom how a fully functioning, odoriferous creature springs forth from these sparse genetic instructions. But by isolating the 400 to 500 genes responsible for sporulation, or roughly 10 percent of the bacterium’s genome, researchers hope to start small and then work their way up.

“We have only reduced the complexity of our problem by a factor of 10,” says Eichenberger, but he says this is still a big step in finding out what each gene and the proteins it codes for are doing.

Tracking the Proteins Wherever They Go

Meanwhile, the experiment in Eichenberger’s laboratory continues—the famished B. subtilis bugs have given up all hope of sustenance and are hunkering down for the interim. This transition from vulnerable wet specks to ultra-hardy spores will take about eight hours. Eichenberger wants to find out how the proteins in this process assemble into regular patterns and form the outermost perimeter of the spore, called the spore coat. He has already identified 24 novel proteins involved in setting up these fortifications.

“We have certain tricks we can use,” he says. The students in his lab have tagged individual proteins in the fasting B. subtilis with green or red fluorescent markers so they can catalog when the protein is created and where it ends up in the spore-making process.

Another technique is to “knock out” individual genes that alter the bacterium’s formation of the spore coat. If the coat develops improperly, the researchers can infer which genes are needed to yield the spore coat and what role each particular gene plays. But this is a time-consuming process, and many times there will be no discernible damage to the formed spore coat, if it develops at all. Instead there may just be a bunch of dead microbes, which doesn’t reveal a whole lot.

“It’s like taking pliers to your DVD player and randomly popping something out. Then you try turning it back on to figure out how the whole thing works,” says Bonneau.

To further complicate things, sporulation itself is not a straightforward, sequential process. While the genes do turn on in a step-wise, biblical “X begets Y begets Z” manner, the effect that the genes have is not that simple. A study (pdf) published in the Journal of Bacteriology last year showed how a series of consecutively activated genes modify the forming spore coat in opposing ways. It is similar to putting more than enough icing on the first layer in a cake, only to then wipe some of the icing off to achieve the ideal, intended coating before moving on to the next layer.

“We were surprised by this level of fine-tuning in the sporulation process,” says Lee Kroos, an author of the paper and a professor of biochemistry and molecular biology at Michigan State University in East Lansing. But despite this observed specificity, the paper also showed that B. subtilis can tolerate suboptimal situations—even if some of the genes in the sequence are “skipped” or de-emphasized, the spore coat can still turn out just fine. “It’s a remarkably robust system,” adds Kroos.

Enlightening Evidence

The lab work at NYU carries on: After centrifuging the spores in a beaker to obtain a nice, sample-ready clump of B. subtilis, Eichenberger or a team member prepares a slide and then heads to the microscopy room. By applying special illuminators, researchers can make the fluorescent dyes in the microbe’s proteins light up like glow sticks at a jam-band concert. A mini-camera then snaps some shots of the glowing germs, and with that, the two-day experiment is over.

Often, particular strains are preserved for future lab inquiry in a bureau-like freezer that has drawers full of mutated B. subtilis. Nearby, a growing chamber agitates more microbes in a nutrient solution for the next round of tests. Life is good right now for the feasting little guys, and in accordance, they emit a powerful reek.

“The smell gets pretty nasty sometimes,” Eichenberger admits, still not quite accustomed after years of manipulating the microorganisms.

This mild annoyance, however, isn’t all that bad when compared to the life-threatening traits of anthrax, B. subtilis’ close relative. As Eichenberger continues to decipher sporulation, and eventually the entire life cycle of B. subtilis gene-by-gene, perhaps he will unveil the origin of this milder form of nastiness as well.

Neil Shubin’s new book explores the intersection of developmental biology, paleontology and genetics

9F0ACC3D-E829-4B38-8FBE-577C7287FE31.jpg
Neil Shubin holds part of a fossil from Tiktaalik roseae, a species that fills the gap between fish and land animals. [Credit: Dan Dry]

Your Inner Fish: A Journey into the 3.5-Billion-Year History of the Human Body

By Stuart Fox, SciencelineNYU – Working at the American Museum of Natural History as a teenager, I often heard paleontology derided by scientists in other disciplines. They would call it glorified stamp collecting that lacked experimental rigor. They would question what it contributed to other scientific fields. And most vociferously, they would complain that dinosaurs always made the news while other more useful, if less photogenic, experiments languished without similar fanfare.

For a long time, some of those claims had an air of truth to them. Paleontologists, especially vertebrate paleontologists, didn’t conduct repeatable experiments in the same way physicists or chemists did. And the advances made in vertebrate paleontology didn’t carry over into other fields in the same way chemistry, physics and medicine feed into each other. As for the claim that dinosaurs received undue attention, well, all I can say is people find T-Rexes more interesting than genes. And geneticists better get used to that.

However, in the 1990’s, the chiding became more and more unwarranted. The discovery that a single group of genes regulated body plan and limb development in all animals introduced a genetic angle to the well understood link between development and evolution. That discovery directly connected the evolution studied in paleontology and the human body studied in medicine. After all, many pathologies result from developmental problems in the womb. There, at the intersection of evolution, genetics and development, a new field began to emerge.

Called evolutionary development, or “Evo-Devo” for short, this new field linked human health to evolution by way of the genes that control our progress from worm-like fetus to cute child to jaded, book-reviewing journalist. In short, our eyes, hands, hair, every part of our body is nothing more than the piled-on artifacts of our evolutionary ancestors. Thus, by studying our ancestors, we can gain insight into the way we function. For the first time, paleontology, the field responsible for finding and studying those ancestors, became linked with human health.

Neil Shubin stood at the center of that change. He could be seen as a paleontologist who does genetic experiments or a molecular biologist who also conducts Arctic expeditions in search of fossils. Either way, Shubin embodies the interdisciplinary nature of Evo-Devo.

Shubin discovered a fossil later named Tiktaalik rosae during one of those Arctic expeditions. With a front like an amphibian and a rear like a fish, Tiktaalik became to devotees of Evo-Devo what Archaeopteryx (the part-bird, part-dinosaur fossil) was to the first generation of evolutionary biologists. It was proof of concept, pulled from the rocks at the top of the world.

I met Shubin as a student at the University of Chicago. It was in his class that I first learned about the link between paleontology, genetics and medicine. He was teaching just as much paleontology to the students in his medical school anatomy class as to his paleontology students. Skeptical that paleontology could teach them about medicine, Shubin’s med students needed to be convinced that they couldn’t understand the human body without understanding the evolution of its parts.

That lesson forms the subject of Shubin’s new book, Your Inner Fish. With Tiktaalik as that fish inside us all, and the Evo-Devo paradigm, Shubin explains how our bodies are living zoos, harboring the evolutionary remnants of our many animal ancestors. Throughout the book he details the evolution of different parts of our bodies: how we inherited ears from an ancient fish, our eyes from a jellyfish, and our arms from Tiktaalik. Essentially, we are all missing links, chimeras formed from the lengthy and inexact process of evolution.

The book makes the argument with great élan. Shubin does an excellent job taking the reader on a tour of the natural history of the body by filling the book with colorful facts. For instance, who knew that the evolution of teeth also provided our bodies with the chemical blueprint for making breasts or that the formation of the jaw is linked to the functioning of the inner ear?

But if I was one of Shubin’s medical students, I’m not sure I would be convinced that knowing sharks don’t get hernias would help me practice sports medicine. While the book does an excellent job of reviewing the history behind the human form, the final chapter, where Shubin attempts to link the discoveries of Evo-Devo to familiar ailments, falls a bit flat. He brings up numerous pathologies that result from artifacts left over from our haphazard evolution, such as knee problems and even choking. But he doesn’t say how, if at all, knowing the evolutionary background of the disorders enhances our ability to cure them.

And in a way, that failure is not so much Neil Shubin’s problem as it is the last great problem of Evo-Devo. To fulfill the link Shubin makes between evolution, development and pathology, Evo-Devo needs to point a clear path from fossil to gene to cure. Despite the book’s deft take on a complex subject, I imagine that many people won’t care about their inner fish unless that fish can cure cancer. Of course, those are probably the same people who complain about dinosaurs making more news than proteins. So you probably shouldn’t be listening to them anyways.

Using parasites, viruses and bacteria as tools to confirm the migration of early man and to mark the trail of human evolution

F977EBF5-10A0-407F-AD35-CDDDEE8C7C88.jpg
Microscopic view of T. solium– a pork tapeworm. [CREDIT: STANFORD.EDU]

By Kristin Elise Phillips, SciencelineNYU – Ask most people to describe the bugs that infect our hair, gut and cells, and you’ll get responses like: disgusting, vile, yucky. But ask some scientists to describe them and you’ll get a different response: a window into human evolutionary history.

Lice, tapeworms, viruses, fungi, and bacteria have hitched a ride on the migration, colonization, and social contact that defines the evolutionary history of our species. Tracing changes in parasitic organisms complements what physical anthropologists already know about human evolutionary history from the fossil record and from studying the human genome.

“A goal of science is independent corroboration, and you can’t get more independent than another organism’s genome,” said molecular anthropologist Todd Disotell of New York University.

The organisms that evolved along with humans are quite varied:

Tapeworms were once thought to have first colonized human intestines during the domestication of grazing animals about ten thousand years ago. But a new, careful analysis of the tapeworm family tree using DNA from different species of the parasite has rewritten this story in detail. The association between the host and parasite began two million years ago when tapeworms surreptitiously infested in our small-brained hominin ancestors while they scavenged on carnivore carcasses on the African savannah. We then gave tapeworms to our livestock, not the other way around.

Many theories of human evolutionary history are rooted in the migration of modern peoples from Africa about 60,000 years ago. This migration began from a population of one to ten thousand humans –who are the ancestors of all living people –and led to both the extinction of Neanderthals in Europe and the disappearance of other human species like Homo erectus from other parts of the Old World.

Insight into the African exodus of modern humans comes from comparing the DNA of the only bacteria known to live in the harsh, acidic conditions of the human stomach: Helicobacter pylori. Research by Martin Blaser of New York University’s Medical School and colleagues suggests that Helicobacter pylori first infected our ancestors’ bellies more than 58,000 years ago when humans left Africa, making it an excellent tool for tracing human migration patterns. The global distribution of different strains of stomach bacteria follows the same splits that separated humans into four geographically distinct populations. In fact, stomach bacteria confirm that groups crossing the Bering Straight peopled the Americas since the East Asian strains infect indigenous Amazonians while the European strain is found in South American decedents of colonists.

Several viruses also followed the modern human migration from Africa. In 1993, pathogen research on the human papillomavirus at the National University of Singapore yielded a glimpse into our ancient past. Virologists discovered that this virus, a virus known to cause cervical cancer, splits into three distinct geographical lineages – Caucasian, African and East Asian.

These distinct populations were confirmed in another virus, the ubiquitous human polyomavirus that is associated with harmless kidney infections. This virus similarly splits into Asian/Native American, Caucasian, African and U.S. groupings according to research by Chei Sugimoto, a virologist at the University of Tokyo.

The human polyomavirus has since been used to tease apart genetic relationships among populations of humans from the same geographical region. For example, a group led by Hansjurgen Agostini of the University of Freiburg in Germany confirmed the distinct lineage of the Basque people of the Pyrenees when compared to other Europeans. Agostini and colleagues also found a possible link between the Basques – long thought to be a unique population because of their unusual language – and Spanish gypsies. Other virologists have used polyomavirus to figure out the genetic distinctness of different human populations, the migration pattern among the Pacific Islands, and the number of migrations humans made into the Americas from Asia.

Viruses and bacteria confirm the migration of East Asians into the Americas, but a soil fungus that causes the virulent Valley Fever tells the story of human movement within the Americas. Plant biologist Matthew Fisher of U.C. Berkeley and colleagues found that all Coccidioides immitis infections in South America are of the same strain. The South American strain shares a history with only one of the many North American varieties, suggesting that a subset of people from the north moved south about 10,000 years ago.

Head lice provide insight into an unusual part of the human saga — the time when multiple species of humans simultaneously inhabited parts of the world. David Reed of the University of Florida at Gainesville and colleagues found that head lice have two major lineages. One coincides with the modern human emigration from Africa. The second, however, is more than a million years older. In fact, analysis of louse distribution around the globe proves there was physical contact between modern humans and Homo erectus who had already populated much of the Old World. Homo erectus later went extinct.

The evolution of human pathogens is exciting to physical anthropologists like Disotell. Parasites and viruses not only confirm the human fossil and genomic evidence of our evolutionary history but could potentially answer so much of the unknown. “We may be able to do ancient DNA [tests] on parasites.” Disotell’s eyes pop ever so slightly at the possible avenues of research. “We think syphilis came from New World into the Old World, and we can now test our assumptions. And the plague – did it travel from Asia to the Black Sea to Europe?” Scientists may use ancient parasites to figure out these questions.

4C8CD2A4-ECCF-4787-A134-BE91E5F36169.jpg
Side-blotched lizards duke it out in a genetic battle of the sexes. [Credit: Erin and Lance Willett]

A lizard family tree offers clues to the balance between reproduction and survival.

By Rachel Mahan, SciencelineNYU – A battle of the sexes is raging in side-blotched lizards, but this is no spectator sport. Until recently, even the scientists who studied them did not have an accurate play-by-play. The conflict happens at the microscopic level of the gene where it is difficult to tell how much it costs to reproduce because some lizards take their genetic secrets to the grave.

“There’s always been this missing piece of the puzzle,” says Andrew McAdam, an evolutionary ecologist at the University of Guelph in Ontario. The lizards that die early and the males, which don’t produce eggs but still carry egg-laying genes from their mothers, have not always been included in estimates of reproductive cost.

McAdam and his colleague Barry Sinervo used a family tree to determine how well lizards survive if they produce different numbers of eggs. When the researchers examined 20 generations of 7000 side-blotched lizards—including males and females that died young—they exposed a lizard tug-of-war. Their results were published recently in the Proceedings of the Royal Society B.

Although the lizards do not actually fight, the battle is over survival. The scientists found that females survive better with the genes for more eggs, while the same genes make males less likely to survive. In other words, “the genes that make you a good female make you a bad male,” says David Reznick, a professor of biology at the University of California, Riverside, who was not associated with the research.

By counting how many eggs female relatives laid, the researchers could approximate how many eggs the males would have laid had they been females. McAdam and Sinervo, the lead author of the study and a professor of ecology and evolutionary biology at the University of California, Santa Cruz, also used the same technique for lizards that died before laying eggs.

Because the researchers knew the parentage of each of the 7000 lizards, “it’s a pretty remarkable study,” says Loeske Kruuk, co-editor of the journal issue, who studies evolutionary biology at the University of Edinburgh in the U.K.

The tiny lizards, which are found in the southwestern U.S. and northern Mexico, are not endangered but offer insight into how evolution works. Common sense would tell scientists that if females produce lots of eggs, they will not be able to waddle fast enough to escape predators. However, the researchers found that more fertile females have a better chance of survival.

“The answer is in the males,” says Sinervo, who is also McAdam’s former mentor. Males fare better if they carry the genes for fewer eggs. The researchers think that hormones associated with increased egg production may hurt males’ survival but help females.

In the grand scheme of things, this battle creates a balance between the sexes and is part of what preserves diversity. If evolution selected the genes for lots of eggs in males and females, scientists might only see lots of eggs.

For other traits, the lizards use a strategy to help ameliorate the tug of war between the sexes. Lizard moms will mate with more than one male and then “sort” the sperm to ensure that all of their babies have the best genes. For example, they give sperm from big males to their sons and sperm from small males to their daughters. Sinervo thinks something like this also could be happening with the genes that determine the number of eggs, although he has yet to investigate.

The study ultimately gives a more complete picture of what is happening in the evolutionary struggles of the side-blotched lizards. Selection, which drives evolution, is “pushing one sex one way, pushing one sex the other way, and the evolutionary equilibrium is in the middle,” says Sinervo.

Even wasps may have the genetic blueprint for motherly love

76227A4B-BAAA-4FDC-B407-1345D053A56F.jpg
Wasps’ behavior is strongly influenced by the maternal care they receive, according to a new study. [Credit: Eric Wheeler]

By Greg Soltis, SciencelineNYU – Tell your mom that she has the maternal instinct of a wasp. It’s a compliment. Really, it is. New research shows that some of these insects have motherly love in their genes.

Previous behavioral observations of wasps led scientists to consider that maternal behavior can serve as a stepping stone along the transition from solitary to social behavior. In the first experiment to confirm these observations, scientists at the University of Illinois at Urbana-Champaign used a new sequencing method to show a genetic link between the maternal behavior of Polistes metricus paper wasps and the nurturing and provisioning behavior of the worker wasps.

“Based on gene expression results, brains of altruistic individuals look like maternal individuals,” says Amy Toth, a postdoctoral researcher and lead author of the study, which appeared in the journal Science.

Although the queen is the genetic mother of the workers, researchers showed that the gene expression of the givers and recipients of maternal care was more similar than those of the mother and offspring. The behavior-related genes provided the molecular basis of this altruistic behavior in wasps. Researchers also found different behavioral gene expressions in the brain of the wasp during the maternal and reproductive stages.

Wasps’ behavior changes over the course of their lives, unlike the behavior of ants and honey bees. Foundresses, who often lead a solitary life before becoming caretakers, assume a maternal role. They establish new colonies and, like a nanny, care for their adopted larvae on their own. When these larvae mature into workers, they mimic this behavior and go on to forage for food and care for their siblings. Successful foundresses become queens after rearing this generation of workers and no longer provide for the younger wasps. But other foundresses ultimately sacrifice their opportunity to reproduce.

The maternal phase seems to provide a connection between less and more evolutionarily advanced stages in the life of a wasp. “This is why it is interesting to study the maternal transitional state between solitary and honey bee-like behavior,” Toth notes.

Nature provides other examples of individuals like foundresses who care for newborns outside their genetic family, such as younger wolves who eat their prey and later regurgitate for hungry pups. These roles often permit higher growth rates and larger families in the animal community, says Sarah Hardy, an anthropologist at the University of California, Davis.

Genes that help a species survive and reproduce, like those that foster maternal behavior, are more likely to be inherited by the next generation. “The evolution of altruism across species is linked to the preservation of offspring, and the most hard-core manifestation of this is the occurrence of maternal altruism,” says Stephen Post, president of the Institute for Research on Unlimited Love at Case Western Reserve University in Cleveland. Human parents strongly invest in their offspring since they have a limited number of eggs at their disposal, according to Post, who is also a professor of biology, philosophy and theology. He says this underlies the importance of parental tenderness and cherishing.

Like Post, Toth recognizes the uniqueness of humans. But she points out that a lot of criteria for human behavior are found in animal studies. “Animals and insects are more complex than you think,” Toth says.

Because of the sequencing method used in collaboration with the company 454 Life Sciences, which pioneered this technique, these researchers were not restricted to model species such as rats or flies. The new application allowed them to test an evolutionary hypothesis on a species without a genome sequence, which saved researchers both time and money. Instead of analyzing the entire genome, they focused on genes that could be detected in wasp brains and sequenced using this new approach.

Since little data was previously available for paper wasps, bioinformaticians from the Illinois crop sciences department compared the sequenced wasp DNA fragments to parts of the fully sequenced honey bee genome. They found 32 wasp genes, also known to be related to honey bee behavior, and used these genes as the basis for the study.

Wasps and honey bees had a common ancestor between 100 million and 150 million years ago. While their DNA sequences have changed significantly, proteins encoded by these genes that relate to behavior have not. This allowed researchers to confidently identify relevant genes and compare the two species.

Current attempts are under way to broaden the scope of this study, according to Toth. She recognizes that 32 genes are “a lot better than one but certainly not the whole picture.”

Because genes do not act in isolation, these researchers have developed the technology to study 5,000 genes at once. Toth hopes to apply these new methods and technologies to learn more about which genes affect aggressive behavior.

But the significance of this study cannot be overlooked. Rather than using rats, flies or other model species, Toth acknowledges that she and her co-workers successfully studied a species without a genome sequence and “used a sequencing method to get a ton of information about wasp species and test an interesting hypothesis about evolution.”

← Previous PageNext Page →