Findings FEBRUARY 2009

PAGE 2 African Adventures Tracing Our Past

PAGE 10 Evolution

Revolution SPECIAL ISSUE Finding Our Future Evolution February 2009 — The 200th Anniversary of Charles Darwin’s Birth

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of General Medical Sciences ••• Inside Science: Life in the Lab

1 Up Close With: Sarah Tishkoff 2 Genetic Footprints 6 The Big Family Tree

9 Up Close With: Joe Thornton 10 Past to Present 14 Joe the Scientist

••• Just Found: Quick Takes on Hot Science

5 Chimp Changes 8 Mystery Malaria 13 Bugs On Us 16 Lifestyle Effects

Edited by Alison Davis under contract HHSN263200800496P

Contributing Writers Emily Carlson Alison Davis Erin Fults

Production Manager Susan Athey

Online Editor Jilliene Mitchell

Produced by the Office of Communications and Public Liaison National Institute of General Medical Sciences National Institutes of Health U.S. Department of Health and Human Services

http://www.nigms.nih.gov/findings

On the Cover

1 Kidney Ischemia, Hamid Rabb, Johns Hopkins Medicine 2 G Protein, Protein Data Bank 6 7 8 3 Charles Darwin 4 Mouse Fibroblast Cells, Torsten Wittmann, Scripps Research Institute 1 2 9 10 5 Fruit Fly Embryo, Hyung Don Ryoo and Hermann Steller, Rockefeller University 6 Sarah Tishkoff, Tommy Leonardi 3 11 12 7 Samburu Girls, Jibril Hirbo 8 Bacteria Under Toenail, Darlyne Murawski, National Geographic Society 4 13 9 Africa Variation Map, Noah Rosenberg, Martin Soave 10 Berber Village, Luc Viatour, Wikimedia Commons 5 11 Joe Thornton, Jack Liu 12 Octopus, Joe Thornton 13 Ancestral Receptor, Joe Thornton Up Close With Sarah Tishkoff EVOLUTIONARY GENETICIST

“In some contexts, I’m a geneticist. In others I’m an anthropologist. And other times I’m an evolutionary biologist. I wear many hats.”

FAVORITE AFRICAN ANIMAL

Warthogs…or giraffes

INTERESTING FACT

Speaks Kiswahili

MUSICAL TALENT

Plays Beethoven on

the piano

MISSES MOST WHILE IN AFRICA

A hot shower TOMMY LEONARDI

Findings | FEBRUAR Y 2009 1 2 National Institute of General Medical Sciences Genetic Footprints

BY ERIN FULTS

Where did I come from? What makes me unique? What makes a human…a human?

These simple questions are not so easy to answer. We still do not know what makes you “you,” your mother “her” and your brother “him.” Nor do we know, precisely, why we do not look or act just like chimps.

Evolutionary geneticist Sarah Tishkoff doesn’t know the answers either. But these are the questions she asks every day as part of her job running a lab at the University of Pennsylvania in Philadelphia.

You might say Tishkoff has a long commute—traveling more than

8,000 miles to do her fieldwork in JIBRIL HIRBO Africa. There, she collects data to Sarah Tishkoff’s research gives her the opportunity to learn help her understand evolution and about African culture. its role in shaping human history and human health.

Working alongside African researchers, Tishkoff looks at DNA to trace the paths of human evolution. Her training in anthropology—the broad study of humanity itself—gives Tishkoff a unique perspective on genetic research, the study of heredity.

Tishkoff says that in many ways, genetics can begin to answer the questions of where we came from and what makes us unique—as individuals and as a species.

“What drove me to this work was being able to ask the questions philosophers ask,” says Tishkoff. Every new answer brings with it a new question. And that means a lot of changing and adapting. With each project she meets new people and finds new diseases. The work is not always easy, Tishkoff says.

TOMMY LEONARDI “Not easy” means setting up a lab in the middle of nowhere. It means using a car battery to power equipment, riding in a Land Rover® and colliding head-on with a bus, and sleeping in tents where zebras come to visit. It also means: She’d hardly give it up.

Findings | FEBRUARY 2009 3 What drove me to this work was being able to ask

whose families settled long ago in Korea. Medical researchers are interested in genetic variation because it helps them understand disease risk. For example, some people are naturally resistant to getting AIDS after becoming infected with HIV because they have a specific change, or variant, in their DNA. The variant is extremely rare, but examining the genetics of how it happens could lead to ways to prevent or treat this killer disease. Scientists like Tishkoff who study genetic variation are actually studying These two DNA sequence readouts show genetic variation, with either a G or A nucleotide at the same position in the DNA of two different people. evolution. Over time, changes occur in DNA, affecting the readout of the genetic message. If the changes are Little Letters, Big Dig person’s DNA. These spelling differ­ helpful to the organism, they have a A genome is all of the genetic infor­ ences, spread across many genes, greater chance of being passed on to mation in an organism, stored in the are what make you unique. future generations because they pro­ form of DNA. This DNA is Tishkoff’s vide a survival advantage. archaeological “dig site.” This genetic variation is enough to distinguish you from your next-door Of course, it takes many, many gener­ Often called the code of life, DNA neighbor, the president of the United ations for these changes to catch on. carries the genes you got from States and millions of other people your parents. all over the world. Into Africa Tishkoff first got hooked on tracking To an extent, genes are what give Genetic variation is inherited, so the evolution in the early 1990s while in you your mother’s eyes or your more closely related two people are, graduate school at Yale University in grandfather’s hair. Genes also affect the more similar their DNA is likely New Haven, Conn. She had the your health—if heart disease runs in to be. chance to scan one of the largest your family, you may be at risk for collections of DNA samples from getting it yourself. Individuals within a population have populations all over the globe. DNA that is more similar to each Of course, genes aren’t the whole One of Tishkoff’s first observations story. Where and how you live, what other’s than it is to that of people was that Africa was represented you eat and whether you exercise, in other populations, because they by genetic information from only drink alcohol or smoke are all hugely share an ancestry that is at least two ethnic groups. That’s hardly important in your health and your partly captured in DNA variation. So enough to cover this vast continent, appearance. people whose ancestors have lived she thought. for generations in Sweden will have DNA has four different nucleotide DNA more similar to other Swedish At the time, Tishkoff explains, “letters” that string together into people than to modern-day Koreans researchers hadn’t yet realized what gene “words.” Our bodies use genes as the templates to make RNA and proteins, which are the main workers in cells.

While the genome is mostly the same in all people, slight differences FIND MORE exist. This genetic variation makes up Hear a native Xhosa click-speaker at about one-tenth of a percent of each http://www.youtube.com/watch?v=gytCi5a7AJg&feature=related

4 National Institute of General Medical Sciences Just Found Just Found Just Found Just Found the questions philosophers ask.

they were missing. “People had no Tishkoff became interested in the idea how much genetic diversity phenomenon of click-speaking, there was in Africa. They thought, tonal languages in which the same ‘well, any African population will do,’” sequence of consonants and vow­ she recalls. els can have different meanings depending how you say them. One Tishkoff made her first trip to of the most distinctive features of South Africa in 1997. Working with a tonal language is its many click a researcher in Johannesburg, she consonants. For example, the !Xóõ analyzed DNA samples and was language, with roughly 4,000 speak­ amazed at what she saw. Tishkoff Chimp DNA may hold clues for improving ers in the South African nation of human health. discovered that the hundreds of Botswana, has 83 click sounds—the different African tribes who speak around 2,000 different languages largest number of consonants in any also had a tremendous amount of known language. Chimp Changes genetic variation. Because using clicks as a form of You may be surprised at how little One thing Tishkoff didn’t fully appre­ communication is very unusual, you human DNA differs from that of the ciate until she arrived in South Africa might assume that click speakers are great apes. Chimps, our closest liv­ was that she couldn’t take safety for closely related. But they’re not as ing relatives, share perfect identity with 96 percent of our genome. granted. At the time, the University of related as you might think. But chimps are unlike us in the Witwatersrand in Johannesburg Tishkoff looked for an explanation many ways besides being furry where she was working was in a dan­ in their DNA and uncovered only and really loving bananas: They gerous part of town, and Tishkoff had a very distant relation between do not get AIDS, many cancers to stay within the university’s walls. Tanzanian click-speaking tribes, but or deadly malaria. That meant a permanent curfew. a common ancestry between some Can evolution explain the dif­ ferences and help us combat “I could work day and night,” says click speakers and a non-click tribe called the Pygmies. killer diseases? Tishkoff. “It kind of forced me to.” Yes, says evolutionary biologist Since she couldn’t experience the Studying the click tribes and tracing Ajit Varki of the University of bustling city herself, Tishkoff learned tribal relationships is one example California, San Diego. He dis­ covered that chimps—but not about it from television. She watched of a new science called molecular people—produce the natural interviews with people from different anthropology (see “The Big Family glycan molecule “Gc.” Glycans Tree,” page 6). African tribes and started to pick up are essential body sugar mole­ on cultural differences. Molecular anthropology uses infor­ cules that can also attract mation from DNA and proteins to disease-causing microbes. determine evolutionary links between But Varki also found that many populations. In this way, scientists people have Gc in their bodies and anti-Gc antibodies in their like Tishkoff are molecular navigators blood. He thinks that people are who can investigate long-ago worlds. exposed to Gc by consuming red meat and milk, two rich sources Decoding Disease of the glycan. Tishkoff, like other medical research­ An evolutionary change that ers, is very interested in how what dropped a Gc-producing enzyme happened long ago shapes genes from human DNA may now put that affect our health. This evolu­ us at risk, Varki guesses. He is tionary information may translate investigating whether the human immune reaction against Gc may into ways to understand, treat and

JIBRIL HIRBO spur some cancers and infectious prevent human diseases. diseases. —Alison Davis In Africa, Tishkoff lived in areas with After work hours, a truck battery-powered high rates of malaria, an infectious television entertains Sarah Tishkoff and her research team in Africa. story continues on page 6

Findings | FEBRUARY 2009 5 I want to know

continued from page 5 disease spread by parasite-infested The Big Family Tree mosquitoes. Despite the fact that effective prevention methods exist—including bed nets and medi­ Where was your grandmother from? Your cines like chloroquine—malaria is great-grandmother? Now how about your great-great-great­ an enormous worldwide health men­ great-grandmother? ace. In Africa, where access to prevention and treatment is scarce No doubt your family tree gets fuzzy the further back you go. in many regions, the disease kills But as humans, we can all trace our roots back to a common a child every 30 seconds. ancestor. Evolution and the migration of ancient peoples made Yet some people inherit protection humans a large and diverse population today. against malaria. Variations in a gene called G6PD are common in people But how do we find our ancestors? How do we learn where we who live in areas of Africa with wide­ came from and how we got here? The answer is molecular spread malaria. But although this anthropology. variant of a particular gene guards against malaria, it also has a dark side, This field of science uses causing anemia and sometimes death. a blend of methods to deter- Another example of a double-edged mine evolutionary links genetic variation is sickle cell disease, between ancient and modern a lifelong problem in which the body people. It can also be used makes misshapen red blood cells that don’t move easily through blood to reveal our connections to vessels. They’re stiff, gummy and closely related species, like tend to form clumps that get stuck, chimps and gorillas. causing intense pain, serious infec­ tions and organ damage. To connect the dots using By any standard, sickle cell disease molecular anthropology, is not a good thing to have, except

NOAH ROSENBERG, MARTIN SOAVE scientists look at DNA. They for the fact that people who have a look for differences and simi­ sickle cell gene variant—along with larities in the sequences of one normal gene—have protection against malaria. As with the G6PD nucleotides—the “letters” genetic variant, evolution tolerates that make up the genetic the sickle cell gene variant and it material. gets passed on to future generations of people because it gives them a As different as people look, our DNA is actually amazingly alike. survival advantage. And, get ready for this: Your DNA is about 96 percent the same But the story gets even more com­ as a chimp and 85 percent the same as a mouse! plicated. Just as the human genome adapts, so too does that of the Molecular anthropology is important for understanding human parasite living inside the mosquito origins and human evolution. Knowing our DNA roots can also that transmits malaria. For this help us learn more about diseases and genetic changes that reason, Tishkoff laments, we will our ancestors developed and passed on to us. This knowledge probably never be fully protected from the disease. may be the key to finding new treatments and vaccines. —E.F. “We’re in an arms race with the parasite that causes malaria,” Tishkoff says.

6 National Institute of General Medical Sciences what makes everybody unique.

However, all is not lost. Tishkoff thinks that by finding the genetic variants that contribute to parasites’ resistance to our drugs, scientists may be able to develop more durable malaria treatments and vaccines.

Got Milk?® Tishkoff explains that the evolutionary race between the malaria parasite and human defense mechanisms is an example of co-evolution, where two species adapt and evolve in response to one another.

Other interactions occur, such as genetic adaptation to a cultural

change. Take the case of humans SARAH TISHKOFF who can drink milk and eat dairy African populations that domesticated cattle acquired a genetic variation enabling them to digest milk, products without getting sick. an advantage passed on to future generations.

Believe it or not, the inability to drink milk, called lactose intolerance, is their DNA. Her hunch was correct: change—the domestication of cat- very common in adults around the African populations with recent tle—occurred at the same time and world. Most have a burned-out ancestors who were pastoralists had created a selective advantage. People version of the enzyme lactase that a genetic change in the gene that with the genetic change could drink digests milk and dairy products. produces lactase, allowing them to milk, become stronger and have more children, thus passing on the That’s in contrast to baby mammals, digest milk. beneficial trait to more individuals who need milk to survive and can Tishkoff also found a link between and extending the benefit to future easily digest it because their lactase genetic and archaeological evidence. generations. enzyme is working fine. The genetic variant for lactose toler­ Most adults who trace their ancestry ance became common in East Africa But which came first? between 3,000 and 7,000 years ago. to Asia or Africa cannot digest milk. Did African farmers gradually gain Archaeological data suggest that However, some people from these the ability to digest milk after domes­ cattle were domesticated in parts African tribes are pastoralists, mean­ ticating cattle, or did they seek cattle of Eastern Africa at the same time. ing that they keep domesticated as a source of milk for protein? cows. These people can drink milk “To me, this was the ultimate find,” long into adulthood. Tishkoff is quick to point out that it’s says Tishkoff. “It was everything I had not so clear. Right now, no one been trying to do since college— Tishkoff wondered: Could there be a knows for sure. connection between raising cows and tying together history, anthropology being able to drink milk as an adult? and genetics.” Out of Africa She collected blood samples from So, a genetic change—the lactase Tishkoff has recently turned her different tribes in Africa and analyzed gene variation—and a cultural evolutionary focus toward height, weight, taste perception and metab­ olism. She has lots to do, since very basic traits like these are often the most complex at the genetic level. FIND MORE Height alone, she says, is thought to Watch an interview with Sarah Tishkoff at be controlled by around 100 genes. http://publications.nigms.nih.gov/multimedia/captions/tishkoff-captions.html story continues on page 8

Findings | FEBRUARY 2009 7 Every answer brings with it a new question.

continued from page 7 Studying genetic variation and more than 10 trips to Africa, metabolism may have important sometimes staying for months at a health benefits. In modern humans, time. Her international travels have JAMES GATHANY, CDC the ability to store fat and quickly inspired a taste for exotic and ethnic increase blood sugar can lead to foods and a rich appreciation for obesity and diabetes—widespread world culture. health conditions associated with It seems like forever since her first many other diseases. Parasite-infected mosquitoes can transmit trips abroad, Tishkoff says, adding malaria when they bite people. Tishkoff explains that in the not-too­ that she didn’t know what to expect distant past, these traits may have that first time in Africa. been adaptive. In times of food Mystery Malaria scarcity, the ability to store fat was “I didn’t know where I was going to an evolutionary plus. Now, with sleep. I didn’t know how I was going Malaria, caused by infection with to do my labwork. I had no idea if parasite-infected mosquitoes, is abundant food available in countries anything was going to work at all,” rampant in Africa. like the United States, obesity has she recalls. The disease also devastates pop­ become common. ulations in Latin America and Asia, Using molecular anthropology, “It was trial and error, and it was but the parasite culprit in these Tishkoff will try to figure out how miraculous that everything worked other regions, called P. vivax, differs so well.” from the African parasite in many metabolism-related genetic variants ways. evolved. In this way, she will effec­ Now, with two young children, Although P. vivax rarely kills, it tively retrace the paths of many of Tishkoff can’t just pack up and head does cause severe illness. And today’s “civilization” diseases like to Africa as frequently as she used to. because it can lie dormant in the obesity, high blood pressure and body for many years, those infected type 2 diabetes. “I miss it terribly,” she says. But it could get malaria again—months hasn’t stopped her research there, Aside from the obvious health impli­ or years later. and Tishkoff still works with African cations, Tishkoff is also driven by the Until now, researchers knew very researchers and looks forward to same curiosity we all have. little about P. vivax because they taking her children with her one day. could not get it to grow in the lab. “I want to know what makes every­ Now, parasitologist Jane Carlton But for now, her graduate students body unique,” she says. of the New York University Langone are the ones peeking through the Medical Center and an international Now 42, Tishkoff has visited more tent flaps, wondering just what that research team have broken new than 40 countries. She has made savanna sound was. ••• ground by cracking the parasite’s genetic code. Carlton and her team also com­ pared the P. vivax genome with that of other malaria parasites and learned that P. vivax is unusual in many ways. She hopes that its evolutionary secrets will point to effective ways to control malaria or to eradicate the parasite in affected regions.—A.D. SARAH TISHKOFF

Sarah Tishkoff wants to know how genetic variation contributes to differences in inherited traits like height and weight. 8 National Institute of General Medical Sciences Just Found Just Found Just Found Just Found Just Found Just Found Just Found Up Close With Joe Thornton EVOLUTIONARY BIOLOGIST

“To understand ourselves, we need to understand where we came from.”

JOB TITLES

Evolutionary biologist,

political activist, writer

PAST CAREER OPTIONS

Rock bassist, English

professor

HOW HE SPENDS HIS SPARE TIME

Hiking and skiing Oregon’s

mountains, playing music

with his family, shooting

ice-hockey pucks JACK LIU

Findings | FEBRUARY 2009 9 10 National Institute of General Medical Sciences Past to Present

BY EMILY CARLSON

Evolutionary biologist Joe Thornton rolls up his sleeve and reaches into a blue and white plastic cooler, just like the one you might take to a soccer game or the beach. But you won’t find cold sodas or turkey sandwiches in this one, and its contents might be among the grossest things you’ve ever seen. Inside, sand-colored, snakelike hagfish writhe like hoses bursting with water. They lunge against the side of the cooler and squirm under Thornton’s grip as he reaches in with his arm. When he pulls out his hand, it drips with wads of clear, snotty goo.

“A few of these hagfish can fill a 5-gallon bucket with slime in a few minutes,” Thornton says. “It’s amazing.” Hagfish are slimy, slithery creatures that offer a clue to our deep past. By studying the DNA of hagfish and other unusual animals, Thornton has been able to resurrect 450-million-year-old genes and use them to make equally ancient proteins. This archaic biology, he says, can help us better understand who we are today.

“Science isn’t just about shining a bright light on nature and seeing the truth,” says Thornton. “It’s a way to reflect on the human condition and to see our place in the world.”

Thornton’s research focuses on our endocrine system, a complex net­ work of glands and hormones found in most animals with well-developed nervous and circulatory systems. Glands like the thyroid, adrenal and ovary make hormones, which travel through the bloodstream as chemi­ cal signals that trigger our bodies to do all the things we need to survive.

Thornton studies a specific group of hormones called steroids. Examples include estrogen and testosterone. While known mostly for their role in reproduction, these hormones are also key players in bone and cardio­ vascular health, our stress response and diseases like cancer.

To do their jobs, all hormones must JOE THORNTON latch onto specific proteins called Steroid hormone receptors are ancient molecules

JACK LIU that are widespread throughout the animal kingdom, receptors on or inside cells. Think including this octopus. of them as part of a lock-and-key system. When you have a match,

Findings | FEBRUARY 2009 11 One of the most important aspects of doing science well is

the door opens—triggering a cas­ Thornton wrote dozens of reports “When it came time for me to move cade of biochemical changes within and articles describing the health on [from Greenpeace], I was so fasci­ the cell. hazards posed by chemical pollution nated with the science that I wanted and arguing for specific solutions. He to pursue it directly,” says Thornton. “Virtually everything a living cell explained these ideas to the press does is controlled by specific inter­ So he went back to school and took and testified before Congress. actions between molecules, like his first biology class at age 30. Now hormones and their receptors,” “I became a specialist in helping 43 and running his own lab at the explains Thornton. “But despite their communities understand the scien­ University of Oregon in Eugene, importance, we know very little tific literature to protect themselves Thornton is finding the answers to about how these kinds of specific and the environment,” says Thornton. the questions that drove him to sci­ interactions evolved.” ence and environmental activism. The experience sparked his interest in endocrine disruptors, synthetic Origin of a Scientist Molecular Time Machine chemicals that mimic our natural Like a historian studying the past Thornton wasn’t always interested hormones. They enter the air, water to make sense of current events or in studying steroid hormones. or food supply as byproducts of an anthropologist examining ancient Before graduating from college with many chemical, manufacturing and cultures to understand today’s cus­ a degree in English, Thornton says agricultural practices. toms, Thornton goes back in time to he wanted to “connect with reality” piece together the evolution of hor­ Because they are so widespread, and began working for Greenpeace, mones and their receptors. His main everyone is exposed to them. an international organization that objective: to unravel the history of Endocrine disruptors have been educates the public on global envi­ our endocrine system. The findings linked to reproductive problems, ronmental problems and solutions could help other researchers under­ impaired immune function and for a greener future. stand the origins of hundreds of various cancers. For about 10 years, Thornton traveled diseases related to the endocrine to communities with major sources Endocrine disruptors affect animals, system and identify new ways to treat or prevent them. of chemical pollution. Part of his job too. Scientists suspect they’re involved reading about scientific responsible for a decline in Florida’s Thornton starts by studying hor­ studies and translating the results alligator population, the feminization mone receptors in living animals. On for local residents. of male marine organisms, and dam­ any given day, Thornton’s lab might age to fish and bird populations. have a cooler full of undulating Alarmed by these potential threats octopi, jawless lampreys, predatory to our environment and our bodies, worms, sea slugs or the slimy hag­ Thornton started asking questions fish. These organisms, he says, of his own. occupy critical spots on the evolu­ tionary tree of animal life for Why do these chemicals have such understanding the evolution of the a big effect on biology? How did hor­ endocrine system. Each species mones and their receptors evolve? shares an ancient common ancestor Can we predict which chemicals are with humans and split off the evolu­ likely to cause endocrine disruption if tionary tree around the time that JOE THORNTON we have a better basic understanding certain receptors first evolved. Evolutionary biologists can learn a lot from jawless, slime-producing hagfish. of receptors? “My kids like coming in and seeing us dissect these fantastic creatures,” says Thornton, whose children are 8 and 11. FIND MORE Watch hagfish dance and make slime! http://www.uoregon.edu/~joet/hagfish.html

12 National Institute of General Medical Sciences Just Found Just Found Just Found Just Found being able to communicate your findings. DARLYNE MURAWSKI, NATIONAL GEOGRAPHIC SOCIETY

This microscopic image shows bacteria living underneath a human toenail.

Bugs On Us Believe it or not, bacteria are not so bad—they actually play key roles in our health. Bacteria help us digest food, provide vitamins we can’t make ourselves, and act as part of our immune defense. To understand more about the role of bacteria on human skin,

JOE THORNTON scientists need to know which ones are there and whether they differ much between people. Geneticist Elizabeth Grice of the Colored spheres show which pieces of an ancestral receptor evolved over time (back to front). NIH in Bethesda, Md., took an Joe Thornton resurrected an ancient version of the receptor in his lab. inventory of skin bacteria from several healthy people. “I think that exposure to what I’m For centuries, these “trees” were Grice collected bacteria by swabbing, scraping or cutting out doing gives them an appreciation for based mainly on visible traits, such as a tiny piece of inner elbow skin. how old and diverse life on Earth is,” bone structure, wings or the pres­ After analyzing the genetic material he adds. (And it makes their dad ence of fur. But as more tools for in all the samples, Grice found a seem forever young.) studying DNA have become available, common subset of elbow skin Thornton extracts genetic material evolutionary trees have expanded to microbes in all the people tested. But the bacteria were very different and hormone-containing serum from include genetic information. from those in the intestines and the hagfish and other organisms. Thornton then uses biochemistry other skin areas of the same people, Then, he examines the DNA to find techniques to actually synthesize the revealing an extraordinary diversity ancestral receptor genes. DNA for ancient genes and molecular of life in and on our bodies. He does this with the help of com­ biology methods to find out how The evolutionary question of how and why bacteria share our puters and other molecular biology they functioned. The search has bodies is likely to be important for tools. Thornton looks in huge data­ taken him back 450 million years to modern-day health. Altering the the time of the last common ances­ bases of DNA sequences to search balance of skin bacteria, for exam­ tor of you…and a hagfish. for similarities between the gene ple, may promote health and fight sequences from his living creatures Back then, the only vertebrates disease.—A.D. and those of hundreds of other re­ around were fish without jaws. The ceptors cataloged in the database. climate, which had been quite warm, Software programs can turn this cooled. Water temperatures dropped information into phylogenies— to about what they are today, making family trees that show varying degrees of relatedness. story continues on page 14

Findings | FEBRUARY 2009 13 By doing science

continued from page 13 the sea a more hospitable environ­ Joe the Scientist ment. That was a good thing, because the ocean offered just about the only real estate. I became a scientist for two reasons. I wanted to use knowledge to help protect the environment and human health. It might seem nearly impossible to imagine we’d share anything in com­ And I wanted to contribute to culture—our shared understanding mon with the ocean dwellers that of ourselves and our world—the same way writers and artists do. lived hundreds of millions of years ago. But Thornton has a fridge of tiny Think of an interesting or controversial issue, and science probably test tubes and incubators with petri has something important to offer on it. For some issues, like global dishes to prove that we do. warming or high breast cancer rates, science’s role is obvious. But Each tube contains millions of science has a lot to say about less technical questions, too, includ- copies of resurrected receptor ing some that go right to the core of our self-understanding. genes. Cells living on the plastic plates in the incubator produce the Consider the biggest one of all: What does it mean to be human? receptor proteins encoded by these Writers and philosophers have been wrestling with this one for ancient genes. Thornton and others centuries. But scientific discoveries have radically reshaped the can use these proteins to see how answers we can give today. they respond to different hormones. By changing the ancient DNA, they We have learned that we share can retrace the process by which many behaviors—and even more evolution tweaked the receptors’ sensitivity to various hormones. aspects of the nervous and endocrine systems that produce With the help of a technique called structural biology, they can also see them—with chimpanzees, how the receptor proteins’ shapes zebrafish and even sea slugs. In changed over time. Under certain my lab, we are discovering pre­ conditions, proteins form crystals that cisely when and how some of can be bombarded with high-energy X-rays to determine their shape. By these features first evolved. using these methods, Thornton has Big cultural issues will never be determined the precise atomic struc­ ture of several ancient receptors answered by science alone, and has shown how that structure because they also involve values, changed as the receptors evolved to JACK LIU ethics and spirituality. But our bind new hormones in a lock-and-key biology is a significant part of fashion (see image, page 13). who we are, and science is the best way to generate knowledge Evolution Explained about nature. Often called the father of evolution, biologist Charles Darwin thought When a scientific discovery changes the lens through which we see of evolution as a tree where all ourselves and the world, we can appreciate it the same way we do species branched from a common a van Gogh painting or a Shakespeare play. ancestor. As nature selected for certain advantageous traits, he My job is to go to the lab each day and try to continue that tradition. reasoned, organisms with helpful genetic changes survived to pass How cool is that?—Joe Thornton those genes to offspring.

14 National Institute of General Medical Sciences we’re contributing to culture.

Repeated over long periods of resurrection, Thornton says evolu­ time, populations would adapt to tionary biologists can now study their environments. Isolated popu­ evolutionary changes and the lations that evolve independently processes driving them in a much would diverge, eventually forming more detailed and decisive way than new species. has ever been possible. Can this explanation of such gradual Citizen Scientist adaptation apply to the evolution of But understanding evolution can systems in which the function of the also help us to understand the pres­ whole requires all the parts to be ent and future, Thornton says. The present? If a hormone needs a recep­ concept of molecular exploitation,

tor and a receptor needs a hormone, NIGMS then how do you explain the evolu­ for example, helps him explore endocrine disruption and try to make tion of one without the other? Over time, genetic changes create new species on the evolutionary “tree of life.” sense of it. Or, for that matter, how do you explain the evolution of any complex The discovery that hormone recep­ system with many parts? shaped hormones that emerged tors are only as specific as they need later in evolution. Today, this recep­ to be at any one time in evolution, he The explanation is beautifully simple, tor interacts with aldosterone, the says, explains why they are suscepti­ Thornton says. hormone that regulates salt and ble to disruption by pollutants. “These systems were assembled by water balance in humans and four- “The chemical industry has produced evolution in a piece-by-piece fashion legged animals. tens of thousands of chemicals in from molecules that once did other As for the other duplicated copy, the last 60 years, but our receptors jobs.” And his research tells the Thornton has tracked the changes in evolved hundreds of millions of years whole story, from beginning to end. its DNA over time. He showed that ago and have not had a chance to Here’s what Thornton has learned. two mutations altered the receptor’s evolve resistance against them,” he says. In distant times, there was a single shape in a way that changed its lock- ancient hormone receptor that and-key fit. As a result, the receptor Could our bodies evolve to shut out worked in partnership with a single lost its ability to interact with the endocrine disruptors? That process ancient hormone. That receptor was ancestral hormone but gained an could take thousands of generations, only as specific as it needed to be ability to partner with cortisol, a “and I’m not willing to wait for evolu­ at that time. Other hormones with hormone that today controls our tion to solve the problem for us,” slightly different shapes could have response to long-term stress. Thornton says. activated it, but only one of these was actually available. Thornton explains that the specific So Thornton does what he can for hormone-receptor pairs we have in the environment. After his time with Then, about 450 million years ago, our bodies today came about by Greenpeace, Thornton wrote a the gene for the ancient receptor subtle modifications of hormones 600-page book, Pandora’s Poison, got duplicated. Over millions of and receptors that already existed outlining the health dangers of years, the two copies gradually for different purposes. He calls this chemical pollution. It was printed amassed different sets of genetic idea “molecular exploitation.” on chlorine-free paper. changes, leading to two different receptors present in most verte­ “It’s taking old parts and reusing On a more personal level, Thornton brates living today. them for new purposes by bringing and his family try to leave a small them into newly built systems,” environmental footprint. When he One of these duplicate receptors he says. and his wife built their house, they retained the ancestral shape and avoided using materials containing continued to partner with the Because of modern scientific tools ancient hormone and other similarly and technologies like ancestral gene story continues on page 16

Findings | FEBRUARY 2009 15 How did hormones and their receptors evolve?

continued from page 15 polyvinyl chloride (PVC, a type of vinyl). The Thorntons buy organic food and leave the car at home as often as they can.

“We try to be as low-impact as possible,” Thornton says, but

LUC VIATOUR, WIKIMEDIA COMMONS admits, “We’re not perfect. Very Some African tribes live in mountainous few families are.” regions, while others are nomadic or live in cities. He assists environmental groups, and he uses his knowledge about the evolution of hormones to teach Lifestyle Effects a course that inspires students to explore the intersections of science In many ways, our DNA is like a fossil record, accumulating genetic and policy. changes due to lifestyle, climate “I take every opportunity I can to and other shifts. discuss how research can affect our Geneticist Greg Gibson of understanding of the effects of

North Carolina State University JOE THORNTON chemicals on health and what we in Raleigh wanted to know more Joe Thornton’s concern about chemical about how the environment we can do about it,” says Thornton. pollution led him to write the book Pandora’s Poison. live in shapes our DNA. He considers sharing his work and He sampled blood from sub­ its implications with the public and groups of Moroccan Amazighs in the broader research community to These activities also prepared him Northwest Africa and then meas­ be among the most crucial—and ured the activity of several hundred well for thinking about science and genes. The Amazighs, while geneti­ rewarding—jobs of a scientist. doing experiments, he says. cally similar as an ethnic group, live “One of the most important aspects Thornton believes that scientists very different lives as subgroups. of doing science well is being able to leave an important mark on society. Some wander as nomads, while communicate your findings, to tell others have settled in the moun­ their story,” he says. “A great experi­ “By doing science, we’re contributing tains or in coastal cities. to culture in the same way novelists Gibson discovered that the ment won’t contribute anything if you and philosophers and historians and activity of about one-third of the can’t make other people understand Amazigh white blood cell genes it and appreciate why it’s important.” artists are,” Thornton says. varied among the three subgroups, Thornton says this perspective didn’t “Science allows us to reflect on suggesting that environmental come from working in the lab. It our condition and our place in the triggers cause genes to be read differently according to region. came from reading literature, writing world, and what it means to be Tracking the interplay between a book and simply talking to people. who we are.” ••• genes and the environment will be key to understanding how modern-day diseases gain a foot­ hold, Gibson thinks. And intercepting these interactions may help researchers find new ways to steer clear of disease. —A.D. FIND MORE Listen to Joe Thornton talk about his research at http://publications.nigms.nih.gov/multimedia/thornton.html

16 National Institute of General Medical Sciences Just Found Just Found Just Found Just Found Just Found Just Found Just Found Discrimination Prohibited Under provisions of applicable public EXPLORE IT PUZZLE IT FIND IT laws enacted by Congress since 1964, no person in the United States shall, on the grounds of race, color, national ? origin, handicap, or age, be excluded from participation in, be denied the What is the process by which benefits of, or be subjected to discrimination under any program or advantageous traits are passed to offspring? activity (or, on the basis of sex, with respect to any education program or activity) receiving Federal financial assistance. In addition, Executive Order What are the building blocks 11141 prohibits discrimination on of DNA? the basis of age by contractors and subcontractors in the performance of Federal contracts, and Executive Order 11246 states that no federally How many genes are thought to control height? funded contractor may discriminate against any employee or applicant for employment because of race, color, What do hormones religion, sex, or national origin. Therefore, the programs of the National latch onto Institute of General Medical Sciences must be operated in compliance with to do their jobs? these laws and Executive Orders.

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