Chapter 3: On the Job: Cellular Specialties: Inside the …

Chapter 3: On the Job: Cellular Specialties

By Alison Davis

Liver cells look almost nothing like nerve cells. Muscle cells bear little physical resemblance to white blood cells. Yet every cell (with just a few exceptions) is encased in a membrane, contains a nucleus full of genes, and has ribosomes, mitochondria, ER, and Golgi. How can cells be so similar, yet so different?

Despite decades of hard work, cell biologists still don’t fully understand how developing cells turn into all the different types in your body. But they do know that this process, called differentiation, is governed by genes. Your body “tunes” the genes of each cell type differently. Depending on where in the body it is located, a given gene can be turned off, weakly on, or strongly on. For example, the gene for globin, which composes hemoglobin, is strongly on in cells that will mature into red blood cells and off in every other cell type.

Cells control the tuning, or expression, of genes by keeping a tight rein on RNA polymerase. For genes that are strongly on, cells use special molecular tags to lure in RNA polymerase and to ensure that the machine works overtime transcribing those genes. For genes that are off, cells use different tags to repel RNA polymerase.

The tuning of a cell’s genes determines which products it can make. Liver cells make loads of enzymes to break down drugs and toxins. Certain immune cells produce antibodies to help fight infections. Cells in a variety of organsincluding the pancreas, brain, ovary, and testeswhip up hormones that are secreted into the bloodstream. Many of these substances are produced throughout life in response to the body’s need for them. Others are made only at specific times, like the milk proteins produced in a woman’s breasts after she gives birth.

The pattern of gene expression also determines a cell’s shape, allowing it to perform its job. For example, cells lining your small intestine have hundreds of miniature extensions (microvilli) used to absorb nutrients. Each sperm cell turns on genes needed to develop its wagging flagellum. Rod and cone cells in your eye express genes needed to form their characteristic shapes (cyclindrical and cone-shaped respectively).

The body even alters the balance of organelles in different tissues. Take your heart, for example. This incredibly durable machine is designed to produce the extraordinary amount of ATP energy required for nonstop pumpingit pumps 100,000 times a day, every day, for your whole life. To do this, it is made up of specialized muscle cells jam-packed with mitochondria. A human heart cell contains several thousand mitochondriaaround 25 percent of the cell’s volume. Cells that don’t need much energy, like skin cells, contain only a few hundred mitochondria.

Your cells function within organs and tissues, such as the lungs, heart, intestines, and kidney. Scientists seek to create artificial tissues to use for research and, in the future, for transplantation.

Within cells, much of the action takes place in organelles. Similarly, but on a larger scale, most bodily functions occur in compartmentsour organs and tissues. Each compartment contains a number of different cell types that work together to accomplish a unique function.

Despite years of effort, scientists have had a frustrating time making tissues and organs in the lab from scratch. Researchers desperately want to succeed in this endeavor to develop more natural replacements for body parts that are destroyed or damaged by disease or injury. Lab-made tissues also might be useful as research tools and in developing and testing new medicines.

So, how do scientists make a tissue? Many researchers are going about it by thinking like engineers. Just as a civil engineer designs and builds a bridge, bioengineers figure out how to combine biological molecules into three-dimensional structures. After all, that’s what a tissue is: a sophisticated “apartment building” of cells joined together, nourished by fluid byways, and wired with nerves.

As you already know, the cytoskeleton serves as internal scaffolding to give cells their shape and to provide railways for molecules and organelles. Cells also have building materials on their outsides, coatings of special proteins that make up what’s called the extracellular matrix. The molecular arrangement of the extracellular matrix is extremely complex, and scientists are still struggling to understand exactly how it is put together and how it works. They do know, however, that the matrix not only helps cells stick together, but also contributes to the overall texture and physical properties of tissues. It is firm in bones to give rigidity and elastic in ligaments so you can move your joints.

Mechanical engineer Andrs Garca of the Georgia Institute of Technology in Atlanta, is working toward building new tissues by measuring the forces that cells use to stick to the extracellular matrix. Garca does this by growing living cells in arrays of tiny wells coated with extracellular matrix components. He then spins the arrays at a high speed to see how many cells fly off. This shows him how much force is required to dislodge cells from the extracellular matrixin other words, how tightly the cells are stuck to the matrix. Garca also studies how cells change when they are grown on different surfaces. Based on his findings, he is tailoring artificial surfaces to be ideal materials on which to grow tissues.

The work of Garca and other researchers studying the extracellular matrix may have important and unforeseen applications, as the extracellular matrix influences almost every aspect of a cell’s life, including its development, function, shape, and survival.

There is only one type of cell that is completely genericits gene expression is tuned so broadly that it has unlimited career potential to become any kind of cell in the body. These undifferentiated cells cease to exist a few days after conception. They are embryonic stem cells.

Each of us was once a hollow ball of 100 or so identical embryonic stem cells. Then, as dozens of hormones, sugars, growth-promoting substances, and other unknown chemical cues washed over us, we began to change. Certain cells grew long and thin, forming nerve cells. Others flattened into skin cells. Still others balled up into blood cells or bunched together to create internal organs.

Now, long after our embryonic stem cells have differentiated, we all still harbor other types of multitalented cells, called adult stem cells. These cells are found throughout the body, including in bone marrow, brain, muscle, skin, and liver. They are a source of new cells that replace tissue damaged by disease, injury, or age. Researchers believe that adult stem cells lie dormant and largely undifferentiated until the body sends signals that they are needed. Then selected cells morph into just the type of cells required. Pretty cool, huh?

Like embryonic stem cells, adult stem cells have the capacity to make identical copies of themselves, a property known as self-renewal. But they differ from embryonic stem cells in a few important ways. For one, adult stem cells are quite rare. For example, only 1 in 10,000 to 15,000 cells in bone marrow is capable of becoming a new blood cell. In addition, adult stem cells appear to be slightly more “educated” than their embryonic predecessors, and as such, they do not appear to be quite as flexible in their fate. However, adult stem cells already play a key role in therapies for certain cancers of the blood, such as lymphoma and leukemia. Doctors can isolate from a patient’s blood the stem cells that will mature into immune cells and can grow these to maturity in a laboratory. After the patient undergoes high-dose chemotherapy, doctors can transplant the new infection-fighting white blood cells back into the patient, helping to replace those wiped out by the treatment.

Although researchers have been studying stem cells from mouse embryos for more than 20 years, only recently have they been able to isolate stem cells from human embryos and grow them in a laboratory. In 1998, James A. Thomson of the University of Wisconsin, Madison, became the first scientist to do this. He is now at the forefront of stem cell research, searching for answers to the most basic questions about what makes these remarkable cells so versatile. Although scientists envision many possible future uses of stem cells for treating Parkinson’s disease, heart disease, and many other disorders affected by damaged or dying cells, Thomson predicts that the earliest fruits of stem cell research will be the development of powerful model systems for finding and testing new medicines, as well as for unlocking the deepest secrets of what keeps us healthy and makes us sick.

If scientists could figure out how salamanders regrow their legs and tails, they might be a step closer to helping people who have lost limbs. ALISA Z. MACHALEK

If a salamander or newt loses a limb, the creature can simply grow a new one. The process is complicatedcells must multiply, morph into all the different cell types present in a mature limb (such as skin, muscle, bone, blood vessel, and nerve), and migrate to the right location. Scientists know that special growth factors and hormones are involved, but no one knows exactly how regeneration happens. Some believe that understanding how amphibians regenerate their tissues might one day enable doctors to restore human limbs that have been amputated or seriously injured.

It may seem a distant goal, but researchers like Alejandro Snchez Alvarado are fascinated with this challenge. Several years ago, Snchez Alvarado, a biologist at the University of Utah School of Medicine in Salt Lake City, set out to find a way to help solve the regeneration mystery. After reading scientific texts about this centuries-old biological riddle, Snchez Alvarado chose to study the problem using a type of flatworm called a planarian. This animal, the size of toenail-clippings, is truly amazing. You can slice off a piece only 1/300th the size of the original animal, and it will grow into a whole new worm.

To understand the molecular signals that can make this feat possible, Snchez Alvarado is reading the worm’s genetic code. So far, he and his coworkers have used DNA sequencing machines and computers to read the spellings of over 4,000 of the worm’s genes.

To focus in on the genes that enable planarians to regenerate, Snchez Alvarado and his coworkers are using RNA interference (RNAi). As we discussed in the previous chapter (RNA’s Many Talents), RNAi is a natural process that organisms use to silence certain genes. Snchez Alvarado’s group harnesses RNAi to intentionally interfere with the function of selected genes.

The researchers hope that by shutting down genes in a systematic way, they’ll be able to identify which genes are responsible for regeneration. The researchers are hoping that their work in planarians will provide genetic clues to help explain how amphibians regenerate limbs after an injury. Finding the crucial genes and understanding how they allow regeneration in planarians and amphibians could take us closer to potentially promoting regeneration in humans.

A scanning electron microscope picture of a nerve ending. It has been broken open to reveal vesicles (orange and blue) containing chemicals used to pass messages in the nervous system. TINA CARVALHO

What happens when you walk barefoot from the swimming pool onto a section of sun-baked pavement? Ouch! The soles of your feet burn, and you might start to hop up and down and then quickly scamper away to a cooler, shaded spot of ground. What happened?

Thank specialized cells again. Networks of connected cells called neurons make up your body’s electrical, or nervous, system. This system works to communicate messages, such as, “Quick, move off the hot pavement!” Cells of the nervous system (specifically neurons) possess special features and a unique shape, both of which suit them for their job in communication. Or, as scientists like to put it, structure determines function.

Neurons have long, spindly extensions called axons that carry electrical and chemical messages. These messages convey information to your brain”The ground is burning hot!”and responses back from the brain”Pick up your foot!”

To transmit these messages, charged particles (primarily sodium ions), jet across a nerve cell membrane, creating an electrical impulse that speeds down the axon. When the electrical impulse reaches the end of the axon, it triggers the neuron to release a chemical messenger (called a neurotransmitter) that passes the signal to a neighboring nerve cell. This continues until the message reaches its destination, usually in the brain, spinal cord, or muscle.

Most neurons can convey messages very fast because they are electrically insulated with a fatty covering called myelin. Myelin is formed by Schwann cellsone of the many types of glial cells that supply support and nutrition to nerve cells.

Nerves coated with myelin transmit messages at a speed of about 250 miles per hour, plenty of time for the message to get to your brain to warn you to lift your foot before it burns.

One reason young children are at a higher risk for burning themselves is because the neurons in children’s bodies do not become fully coated with myelin until they are about 10 years old. That means it takes dangerously long for a message like, “The stove is hot!” to reach a young children’s brains to tell them to pull their hands away.

Myelin formation (and consequently the conduction of nervous system messages) can be disrupted by certain diseases, such as multiple sclerosis. Symptoms such as numbness, double vision, and muscle paralysis all result from faulty nerve conduction that ultimately impairs muscle cell function.

Squid nerve cells often are used in research because they are large and easy to work with. About the size of small, straightened-out paperclips, squid nerve cells are a thousand times fatter than human nerve cells. JOE DiGIORGIS

Although many of our nerve cells are designed to convey electrical messages to and from our brains, they also can be co-opted for more nefarious purposes. For example, the herpes virus enters through the mucous lining of the lip, eye, or nose, then hitches a ride in a nerve cell to the brain. There, the virus copies itself and takes up long-term residence, often undetected for years.

Researchers had thought that herpes made its way toward the brain by successively infecting other nerve cells along the way. However, Elaine Bearer of Brown University in Providence, Rhode Island, recently learned something different. Bearer recreated the virus transport process in nerve axons from squid found off the coast of Massachusetts. While human nerve cells are difficult to grow in the lab and their axons are too small to inject with test transport proteins, squid axons are long and fat.

Bearer and her coworkers at the Marine Biological Laboratory in Woods Hole, Massachusetts, injected the huge squid axons with a modified form of the human herpes virus. The researchers were amazed to measure its travel speed at 2.2 micrometers per second. This speed can only be achieved, Bearer concluded, by a virus particle powered by a protein motor whipping down a cytoskeletal track. Apparently, the virus exploits the cytoskeleton and molecular motors in our nerve cells for its own use.

Studies of fruit fly oocytes, which are each served by 15 nurse cells, are shedding light on how human eggs mature. IMAGE COURTESY OF LYNN COOLEY

As we saw from examining the dependent relationship between nerve and glial cells, bodily tissues often contain different cell types in close association. Another example of such pairing is between oocytes (immature eggs) and nurse cells.

A distinguishing feature of being female is the ability to form eggs. Halfway through pregnancy, a baby girl growing inside her mother’s uterus already contains an astonishing 6 to7 million oocytes. By birth, however, 80 percent of these oocytes have died off naturally. By the time the girl reaches puberty, only a few hundred thousand are left, and over her lifetime, fewer than 1 percent of these oocytes will travel through her Fallopian tubes in a hormone-triggered process called ovulation. If an oocyte is then fertilized by a sperm cell, it becomes a zygote, the first cell of a new baby.

For the most part, scientists are baffled by how the body determines which oocytes make it to maturity and which don’t. Researchers do know that one key to surviving and becoming a mature oocyte is getting the right molecular signal from your cellular neighbors. Lynn Cooley of Yale University is studying how the cytoskeleton in certain ovarian cells orchestrates this. To do so, she is using fruit flies, since, believe it or not, fly oocytes develop in much the same way as human oocytes.

A growing oocyte is surrounded and protected by several nurse cells, which deliver RNA, organelles, and other substances to their oocyte. To deliver these important materials, the nurse cells actually donate their own cytoplasm to oocytes. The cytoskeleton enables the giving of this gift. As Cooley’s studies show, molecular signals prod the cytoskeleton to form specialized structures called ring canals that serve as nozzles to connect oocytes directly to their nurse cells. In a final act of self-sacrifice, the nurse cells contract their cytoskeletons to squeeze their cytoplasm into the oocyte, then die. Cooley’s research in this area should help scientists better understand some of the mysteries of how oocytes matureknowledge that may unravel fertility problems and the root causes of some birth defects.

What about your ears, your nose, and your tongue? Each of these sensory organs has cells equipped for detecting signals from the environment, such as sound waves, odors, and tastes. You can hear the phone ring because sound waves vibrate hairlike projections (called stereocilia) that extend from cells in your inner ear. This sends a message to your brain that says, “The phone is ringing.” Researchers have discovered that what’s sending that signal is a channel protein jutting through a cell membrane, through which charged particles (primarily potassium ions) pass, triggering the release of neurotransmitters. The message is then communicated through the nervous system.

Similarly, for you to see and smell the world around you and taste its variety of flavors, your body must convey molecular signals from the environment into your sensory cells. Highly specialized molecules called G proteins are key players in this transmission process.

Imagine yourself walking down a sidewalk and catching the whiff of something delicious. When odor molecules hit the inside of your nose, they are received by receptor molecules on the surfaces of nerve cells. The odor message fits into a specially shaped site on the receptors, nudging the receptors to interact with G proteins on the inner surface of the nerve cell membrane. The G proteins then change their own shape and split in two, which sets off a cascade of chemical reactions inside the cell. This results in an electrical message that travels from your nose to your brain, and evokes your response”Yummm…fresh baked bread,” in this case.

Figuring out the molecular details of this process led to the 2004 Nobel Prize in physiology or medicine for two researchers, Richard Axel of Columbia University in New York, and Linda B. Buck of the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle.

2002 WILLIAM LEONARD

The human body operates by many of the same molecular mechanisms as a mouse, a frog, or a worm. For example, human and mouse genes are about 86 percent identical. That may be humbling to us, but researchers are thrilled about the similarities because it means they can use these simpler creatures as experimental, “model” organisms to help them understand human health. Often, scientists choose model organisms that will make their experiments easier or more revealing. Some of the most popular model organisms in biology include bacteria, yeast cells, roundworms, fruit flies, frogs, rats, and mice.

Barry Gumbiner of the University of Virginia in Charlottesville, performs experiments with frogs to help clarify how body tissues form during development. Gumbiner studies proteins called cadherins that help cells stick together (adhere) and a protein (beta-catenin) that works alongside cadherins.

Scientists know that beta-catenin is critical for establishing the physical structure of a tadpole as it matures from a spherical fertilized egg. Specifically, beta-catenin helps cadherin proteins act as molecular tethers to grip onto cell partners. This function is critical because cell movement and adhesion must be carefully choreographed and controlled for the organism to achieve a proper three-dimensional form.

While cell adhesion is a fundamental aspect of development, the process also can be a double-edged sword. Cell attraction is critical for forming tissues in developing humans and frogs, but improper contacts can lead to disaster.

Although many types of cells move in some way, the most well-traveled ones are blood cells. Every drop of blood contains millions of cellsred blood cells, which carry oxygen to your tissues; platelets, which are cell fragments that control clotting; and a variety of different types of white blood cells. Red blood cells, which get their deep color from rich stores of ironcontaining hemoglobin protein, are carried along passively byand normally retained withinthe bloodstream. In contrast, other blood cells can move quickly out of the bloodstream when they’re needed to help heal an injury or fight an infection.

White blood cells protect us from viruses, bacteria, and other invaders. IMAGE COURTESY OF JIM EHRMAN, DIGITAL MICROSCOPY FACILITY, MOUNT ALLISON UNIVERSITY

White blood cells serve many functions, but their primary job is protecting the body from infection. Therefore, they need to move quickly to an injury or infection site. These soldiers of the immune system fight infection in many ways: producing antibodies, engulfing bacteria, or waging chemical warfare on invaders. In fact, feeling sick is often the result of chemicals spilt by white blood cells as they are defending you. Likewise, the pain of inflammation, like that caused by sunburn or a sprained ankle, is a consequence of white cells moving into injured tissue.

How do white blood cells rush to heal a wound? Remarkably, they use the same basic process that primitive organisms, such as ameobae, use to move around.

Dictyostelia can completely transform themselves from individual cells into a multicellular organism. Studies of these unique creatures are teaching scientists important lessons about development, cell movement, and cell division. REX L. CHISHOLM

In a remarkable example of cell movement, single-celled organisms called amoebae inch toward a food source in a process called chemotaxis. Because they live, eat, and die so fast, amoebae are excellent model systems for studying cell movement. They are eukaryotic cells like the ones in your body, and they use many of the same message systems your own cells use.

Peter Devreotes of Johns Hopkins University School of Medicine in Baltimore, Maryland, studies the molecular triggers for chemotaxis using bacteria-eating amoebae named Dictyostelia that undergo dramatic changes over the course of their short lifespans.

Individual Dictyostelia gorge themselves on bacteria, and then, when the food is all eaten up, an amazing thing happens. Tens of thousands of them come together to build a tower called a fruiting body, which looks sort of like a bean sprout stuck in a small mound of clay.

Devreotes and other biologists have learned that Dictyostelia move by first stretching out a piece of themselves, sort of like a little foot. This “pseudopod” then senses its environment for the highest concentration of a local chemical attractantfor the amoebae this is often food, and for the white blood cell, it is the scent of an invader. The pseudopod, followed by the entire cell, moves toward the attractant by alternately sticking and unsticking to the surface along which it moves. The whole process, Devreotes has discovered, relies on the accumulation of very specific lipid molecules in the membrane at the leading edge of a roving cell. Devreotes is hopeful that by clarifying the basics of chemotaxis, he will uncover new ways to design treatments for many diseases in which cell movement is abnormal. Some of these health problems include asthma, arthritis, cancer, and artery-clogging atherosclerosis.

The coverings for all your body parts (your skin, the linings of your organs, and your mouth) are made up primarily of epithelial cells. You might think that of all the cell types, these would be the ones staying put. Actually, researchers are learning that epithelial cells are also good at snapping into action when the situation calls for them to get moving.

Say you get a nasty gash on your foot. Blood seeps out, and your flesh is exposed to air, dirt, and bacteria that could cause an infection. Platelets stick together, helping to form a clot that stops the bleeding. At the same time, your skin cells rapidly grow a new layer of healed skin over the wound.

Researchers have learned that epithelial cells have the wondrous ability to move around in clumps. These clumped cells help clean up an injured area quickly by squeezing together and pushing away debris from dead cells.

All organisms get wounds, so some researchers are studying the wound-healing process using model systems. For example, William Bement of the University of Wisconsin, Madison, examines wounded membranes of frog oocytes. He chose these cells because they are large, easy to see into, and readily available. Looking through a specialized microscope, Bement watches what happens when wounds of different shapes and sizes start to heal.

Bement learned that just as with human epithelial cells, the wounds in frog oocytes gradually heal by forming structures called contractile rings, which surround the wound hole, coaxing it into a specific shape before gradually shrinking it. He is now identifying which molecules regulate this process. His research may help find better ways to treat injuries in people and animals.

As you can see, all of your 200-plus cell types work in harmony, each playing its own role to keep you alive and healthy. Next, we’ll cover how cells replenish themselves, and how certain cells enable us to pass on somebut not allof our genes through sexual reproduction.

Gene chips let scientists visualize the activity of thousands of molecules. BRIAN OLIVER

“-Omics.” You probably won’t see this suffix in the dictionary just yet, but chances are you’ve heard it in words like genomics and proteomics. A new scientific catchphrase of the 21st century, -omics tagged on to the end of a word means a systematic survey of an entire class of molecules. For example, genomics is the study of all of the genes of a particular organism (rather than one gene or just a few). Scientists interested in metabolomics study how metabolism (the body’s breakdown of certain molecules and the synthesis of others) is governed by thousands of enzymes and signaling networks in an organism.

Name just about any branch of life science, and chances are researchers are working on its -omics, in an attempt to figure out how the zillions of separate pieces of biological information can explain the whole of biology. You can probably figure out what lipidomics is. You’re right! It relates to lipids, the oily molecules in cell membranes. Researchers in this field try to identify, determine the function of, and analyze how all the lipids in a cell respond to cellular stimuli (like hormones). Do they shift around? Break apart? Change the texture of the membrane?

Because this sort of blanket approach means evaluating millions of molecules, it requires and generates a landslide of data. Only extremely sophisticated computer programs can process the amount of data typical of -omics experiments. Consequently, information management is becoming a big challenge in biology. Many years from now, scientists hope to be able to construct computer models of how organisms as simple as bacteria and as complex as people do all the incredible things they do. Such models will have great practical use in testing medicines and in understanding and predicting many aspects of health and disease.

Many scientists doing -omics experiments collect their data using microarrays. These high-tech grids contain tiny samples of hundreds or even thousands of types of molecules. Using microarrays, scientists can observe and compare molecules under carefully controlled conditions.

For example, a kind of microarray known as a gene chip lets genome scientists track the activity of many genes simultaneously. This allows researchers to compare the activities of genes in healthy and diseased cells and, in that way, pinpoint the genes and cell processes that are involved in the development of a disease.

How do cells specialize (differentiate), and why is this important?

Give three examples of different specialized cells and explain how they are customized to accomplish their cellular duties.

How are adult stem cells different from embryonic stem cells?

Name four model organisms scientists use to study basic biological processes.

Give two examples of why a cell’s shape is important.

Give two examples of why the ability to move is important to cells.

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