第一章 绪论（专题1）——细胞、基因组与生命的多样性

Despite their apparent diversity, living things are fundamentally similar inside. The whole of biology is thus a counterpoint between two themes: astonishing variety in individual particulars and astonishing constancy in fundamental mechanisms. In this chapter, we begin by outlining the universal features common to all life on our planet, along with some of the fundamental properties of their cells.

Most living organisms are single cells. Others, such as us, are like vast multicellular cities in which groups of cells perform specialized functions that are linked by intricate systems of intercellular communication. But even for the aggregate of more than 1013 cells that makes up a human body, the whole organism has been generated by cell divisions from a single cell. The single cell therefore contains all of the hereditary information that defines a species (Figure 1–1). The cell must also contain all of the machinery needed to gather raw materials from the environment and to construct from them a new cell in its own image, complete with a new copy of the hereditary information of its parent. Every cell on Earth is truly amazing.

The individual cell is the minimal self-reproducing unit of life. A cell consists of a self-replicating collection of catalysts, enclosed in a plasma membrane. All cells operate as biochemical factories, driven by the free energy released in a complicated network of chemical reactions. Central to a cell's ability to reproduce is the transmission of its genetic information to its progeny cells when it divides.

All cells on Earth today store their hereditary information in the form of double-strand molecules of DNA—long, unbranched, paired polymer chains, which are always composed of the same four types of monomers. These monomers, chemical compounds known as nucleotides, have nicknames drawn from a four-letter alphabet—A, T, C, G—and they are strung together in a long linear sequence that encodes the hereditary information, just as the sequence of 1's and 0's encodes the information in a computer file. We can take a piece of DNA from a human cell and insert it into a bacterium or a piece of bacterial DNA and insert it into a human cell, and, with only a few minor modifications, the information will be successfully read, interpreted, and copied.

One might not expect that they would all store their information in the same form or that the hereditary information carried by one type of cell should be readable by the information-handling machinery of another. And yet it is so. This fact provides compelling evidence that all living things on Earth have inherited the form of their genetic instructions, as well as how to use them, from a universal common ancestral cell. This ancestor is thought to have existed roughly 3.5–3.8 billion years ago.

The translation of genetic information from the 4-letter alphabet of polynucleotides into the 20-letter alphabet of proteins is a complex process. The rules of this translation seem in some respects neat and rational but in other respects strangely arbitrary, given that they are (with minor exceptions) identical in all living things. These arbitrary features, it is thought, reflect frozen accidents in the early history of life. They stem from the chance properties of the earliest organisms that were passed on by heredity and have become so deeply embedded in the constitution of all living cells that they cannot be changed without disastrous consequences.

It turns out that the information in the sequence of a messenger RNA (mRNA) molecule is read out in groups of three nucleotides at a time: each triplet of nucleotides, or codon, specifies (codes for, or encodes) a single amino acid in a corresponding protein. Because the number of distinct triplets that can be formed from four nucleotides is 43, there are 64 possible codons, all of which occur in nature. However, there are only 20 naturally occurring amino acids, which means there are necessarily many cases in which several codons correspond to the same amino acid. This genetic code is read out by a special class of small RNA molecules, called transfer RNAs (tRNAs).

To make a living cell requires matter, as well as free energy. DNA, RNA, and protein are composed of just six elements: hydrogen, carbon, nitrogen, oxygen, sulfur, and phosphorus. These are all plentiful in the nonliving environment, in Earth's rocks, water, and atmosphere. But they are not present in chemical forms that allow easy incorporation into biological molecules.

Because all cells make DNA, RNA, and protein, they all have to contain and manipulate a similar collection of small organic (carbon-containing) molecules, including simple sugars, nucleotides, and amino acids, as well as other substances that are universally required. All cells, for example, require the phosphorylated nucleotide ATP (adenosine triphosphate), not only as a building block for the synthesis of DNA and RNA but also as a carrier of the free energy that is needed to drive a huge number of chemical reactions in the cell. Although all cells function as biochemical factories of a broadly similar type, many of the details of their small-molecule transactions differ.

Each living cell is enclosed by a membrane—the plasma membrane. This membrane acts as a selective barrier that enables the cell to concentrate nutrients gathered from its environment and retain the products it synthesizes for its own use, while excreting its waste products. Without a plasma membrane, the cell could not maintain its integrity as a coordinated chemical system. The molecules that form cell membranes have the simple physicochemical property of being amphiphilic; that is, they consist of one part that is hydrophilic (water-soluble) and another part that is hydrophobic (water-insoluble). Such molecules placed in water aggregate spontaneously, arranging their hydrophobic portions to be as much in contact with one another as possible to hide them from the water, while keeping their hydrophilic portions exposed.

The cell boundary cannot be totally impermeable. If a cell is to grow and reproduce, it must be able to import raw materials and export waste across its plasma membrane. All cells therefore have specialized proteins embedded in their plasma membrane that transport specific molecules from one side to the other. Some of these membrane transport proteins, like some of the proteins that catalyze the fundamental small-molecule reactions inside the cell, have been so well conserved over the course of evolution that we can recognize the family resemblances between them when even the most distantly related organisms are compared.

But how complex are real living cells? In particular, what are the minimum requirements of a living cell? One measure of complexity is based on the total number of genes in an organism's genome. A species that has one of the smallest known genomes is the bacterium Mycoplasma genitalium, which causes a common, sexually transmitted, human disease (Figure 1–8). This organism lives as a parasite in mammals, where the environment provides it with many of the small molecules it needs ready-made. Nevertheless, it still has to make all the large molecules—DNA, RNAs, and proteins. It has 525 genes, most of which are essential. Its genome of 580,070 nucleotide pairs represents 145,018 bytes of information—about as much as it takes to record the text of one chapter of this book. Cell biology may be complicated, but it is not unimaginably so.

In addition, and as previously mentioned, random thermal motions of molecules (including water) are prominent at the scale of cells—whose dimensions can be as small as a micrometer (10–6 meters) in diameter. This type of spontaneous movement, called thermal or Brownian motion, was first observed by Robert Brown in 1827, while looking through a microscope at pollen grains immersed in water. Caused by random molecular collisions, the constant fluctuating movement has important repercussions. Brownian motion drives a process called diffusion, and it determines the rates of biochemical reactions as molecules collide with one another within the interior of a cell.

Natural selection has evidently favored mitochondria with small genomes. By contrast, the nuclear genomes of most eukaryotes seem to have been free to enlarge. Perhaps the eukaryotic way of life has made large size an advantage: predatory cells, for example, typically need to be bigger than their prey, and cell size generally increases in proportion to genome size.

For constructing a comprehensive tree of life, it is necessary to begin with a segment of DNA that is easily recognized in the genomes of all organisms. We discussed earlier how all cells use the same fundamental mechanism to translate a nucleotide sequence into a protein sequence, and we saw that the ribosome is the "decoding machine" that carries this out. Ribosomes are fundamentally similar in all organisms, and an especially well-conserved component of them is the RNA molecules that make up their core. Although the exact sequence of these ribosomal RNAs (rRNAs) differs across organisms, they are similar enough to use them as a ruler to judge how closely two species are related: the more similar the ribosomal RNA sequences, the more recently the two species diverged from a common ancestor and the more related they must be.

This approach has revealed that the living world consists of three major divisions, or domains: eukaryotes, bacteria, and archaea, as illustrated in Figure 1–9; in the following paragraphs, we briefly introduce each in turn.

The great variety of living creatures that we see around us are eukaryotes. The name is from the Greek, meaning "truly nucleated" (from the words eu, "well" or "truly," and karyon, "kernel" or "nucleus"), reflecting the fact that the cells of these organisms have their DNA enclosed in a membrane-bound organelle called the nucleus. Visible by simple light microscopy, this feature was used in the early twentieth century to classify living organisms as either eukaryotes (those with a nucleus) or prokaryotes (those without a nucleus). We now know that prokaryotes comprise two of the three major domains of life, the bacteria and archaea.

Like bacteria, the archaea we know most about are small and lack the internal, membrane-bound organelles that distinguish the eukaryotes. But they differ from bacteria in many ways, including the chemistry of their cell walls, the kinds of lipids that make up their membrane, and the range of biochemical reactions that they can carry out. Another surprising conclusion came from genome comparisons: although archaea resemble bacteria in their outward appearances, their genomes are much more closely related to eukaryotes than to bacteria (see Figure 1–9). It has even been proposed that the tree of life should be considered to have only two principal domains, with the archaea and eukaryotes making up one domain and bacteria constituting the other.

At first it was thought that archaea occupied only extreme environments such as volcanoes, salt lakes, acid hot springs, and the stomachs of cattle, but they are now recognized to be present also in more congenial surroundings such as soils, seawater, and our skin. Commensurate with the wide variety of ecological niches in which they have been found, different species of archaea have highly diverse chemistries. They are believed to be the predominant life-form in soil and seawater, and they play major roles in recycling nitrogen and carbon, two of the most important elements for all cells.

Bacteria are usually very small (and invisible to the unaided eye), and they generally live as independent individuals or in loosely organized communities, rather than as multicellular organisms. They are typically spherical or rod-shaped and measure a few micrometers (μm) in linear dimension (Figure 1–10). They often have a tough protective coat, called a cell wall, beneath which a plasma membrane encloses a single cytoplasmic compartment—the cytoplasm—containing DNA, RNA, proteins, and the many small molecules needed for life (Figure 1–11). Although difficult to discern in the light microscope, the interior of a bacterium is nevertheless highly organized, a topic we discuss in Chapter 16.

There exist species that can utilize virtually any type of organic molecule as food, ranging from sugars and amino acids to hydrocarbons, including the simplest hydrocarbon, methane gas (CH4). Other species (Figure 1–12) harvest light energy in a variety of ways; some, like plants, carry out photosynthesis and generate oxygen as a by-product. Still others can feed on a plain diet of inorganic nutrients, getting their carbon from CO2, and relying on a host of other chemicals that occur in the environment to fuel their energy needs—including H2, Fe2+, H2S, and elemental sulfur (Figure 1–13).

The standard laboratory strain E. coli K-12 has a genome of approximately 4.6 million nucleotide pairs contained in a single circular molecule of DNA that codes for about 4300 different kinds of proteins (Figure 1–38). In molecular terms, we probably have a more complete understanding of E. coli than of any other living organism. Most of our understanding of the fundamental mechanisms of life—for example, how cells replicate their DNA or how they decode the instructions represented in the DNA to direct the synthesis of specific RNAs and proteins—initially came from studies of E. coli and its viruses.

By definition, eukaryotic cells keep almost all their DNA in a membrane-enclosed internal compartment—the nucleus, which is usually the most conspicuous organelle (Figure 1–21). The long DNA polymers in the nucleus are packaged with proteins to form chromosomes, which only become visible in a light microscope when they condense in preparation for cell division. The nuclear envelope, a double layer of membrane, surrounds the nucleus and separates the nuclear DNA from the cytoplasm, which, in a eukaryotic cell, includes everything between the plasma membrane and the nucleus. As shown in the figure, the nuclear envelope is perforated by nuclear pores, which are channels formed by protein complexes that mediate the two-way traffic of large molecules between the nucleus and the cytoplasm.

Eukaryotic cells have many other features that set them apart from bacterial and archaeal cells. They are typically 10–30 times bigger in linear dimension and 1000–10,000 times larger in volume than a typical prokaryotic cell. They have an elaborate cytoskeleton in the cytoplasm, consisting of several types of protein filaments (see Figure 1–21) that, together with the many proteins that attach to them, form a network of girders, ropes, and motors that gives the cell mechanical strength and performs various other functions: when the cell divides, for example, the cytoskeleton reorganizes and pulls the replicated chromosomes apart and distributes them equally to the two daughter cells.

There are many other membrane-enclosed organelles in eukaryotic cells. Unlike the nucleus, most of them are enclosed by single membranes. The most extensive organelle is the endoplasmic reticulum (ER), which is where most cell membrane components are made, along with materials destined for secretion to the outside of the cell. The Golgi apparatus receives these molecules from the ER and modifies and packages them for secretion or transport to another cell compartment. Lysosomes are small irregularly shaped organelles in which intracellular digestion occurs. Peroxisomes are small vesicles where hydrogen peroxide is used to inactivate toxic molecules.

To connect the eukaryotic cell with its surroundings, a similar vesicle-mediated exchange goes on continually at the cell surface. Here, portions of the plasma membrane pinch in to form intracellular vesicles that carry material captured from the external medium into the cell—a process called endocytosis; and in the reverse process, called exocytosis, vesicles from inside the cell fuse with the plasma membrane and release their contents to the exterior (Figure 1–23). Besides the nucleus, there are two other eukaryotic cell organelles that are enclosed in double membranes—mitochondria and, in plant cells and algae, chloroplasts. Mitochondria take up oxygen and harness energy from the oxidation of food molecules, such as sugars and fats, to produce most of the ATP (adenosine triphosphate) that powers the cell’s activities. Chloroplasts perform photosynthesis in plant cells and algae, using the energy of sunlight to synthesize carbohydrates from atmospheric CO2 and water, delivering these energy-rich products to the host cell as food.

Instead, they wrap themselves in a tough, protective cell wall. If some eukaryotic cells can be viewed as hunters, then one might view plant cells as having given up hunting for farming. Fungi represent yet another eukaryotic way of life. Fungal cells, like animal cells, possess mitochondria but not chloroplasts; they have a tough outer wall that limits their ability to move rapidly or to take up other cells. Fungi, it seems, have turned from hunters into scavengers. Other cells secrete nutrient molecules or release them after death, and fungi feed on these leavings—often performing whatever digestion is necessary extracellularly, by secreting digestive enzymes to the exterior.

A fundamental question in both evolution and cell biology is how did the first eukaryotic cell arise? The evidence suggests that it happened when an archaeal and a bacterial cell merged about 2 billion years ago, in a world that had contained only prokaryotes for more than 1.5 billion years. All eukaryotic cells contain (or at one time did contain) mitochondria (Figure 1–25). Mitochondria are similar in size to small bacteria, and both reproduce by dividing. The mitochondria contain their own DNA, with genes that resemble bacterial genes; they also contain their own ribosomes and translation factors that resemble those in bacteria.

There are also good reasons to believe that the ancestral capturing cell was an archaeon. As we have seen, the genomes of present-day archaea encode many proteins that are characteristic of present-day eukaryotic cells. Those archaea with the most eukaryotic-like genes belong to the Asgard lineage, first identified by sequencing DNA fragments obtained from the seabed.

Chloroplasts (Figure 1–28) perform photosynthesis in plant cells and algae, using the energy of sunlight to synthesize their own "food" (in the form of carbohydrates) from atmospheric CO2 and water. Like mitochondria, they are enclosed in double membranes, have their own "circular" genomes, and reproduce by dividing. They almost certainly evolved from a symbiotic photosynthetic bacterium that was captured by an ancient eukaryotic cell that already possessed mitochondria.

When the mitochondrial DNA and the chloroplast DNA are separated from the nuclear DNA and individually sequenced, both the mitochondrial and chloroplast genomes are found to be cut-down versions of the corresponding bacterial genomes: in a human cell, for example, the mitochondrial genome consists of only 16,569 nucleotide pairs, and it codes for only 13 proteins plus a set of 24 RNAs involved in protein synthesis. Many of the genes that are missing from the mitochondria and chloroplasts have not been lost; instead, they have moved from the endosymbiont genomes into the DNA of the host-cell nucleus. Thus the nuclear DNA of animals contains many genes coding for proteins that serve essential functions inside the mitochondria; in plants and algae, the nuclear DNA contains many genes specifying proteins required in chloroplasts. In both cases, the DNA sequences of these nuclear genes still show clear evidence of their bacterial origins.

Whatever the reason, the genomes of most eukaryotes have become hundreds of times larger than those of bacteria and archaea (Figure 1–30). The freedom to be extravagant with DNA has had profound implications. Eukaryotes not only have more genes than prokaryotes; they also have vastly more DNA that does not code for protein or RNA. The human genome contains about 700 times as many nucleotide pairs as the genome of a typical bacterium such as E. coli, but it contains only about 4.5 times as many protein-coding genes because a much greater proportion of the human genome does not code for protein (∼98.5% compared to 11% in E. coli).

As in all eukaryotic organisms, at least some of the noncoding DNA certainly has important functions. In particular, it regulates the expression of genes. With this regulatory DNA, eukaryotes have evolved distinctive, highly sophisticated ways of controlling when and where a gene is brought into play. Elaborate mechanisms for gene regulation are especially crucial for the formation and function of complex multicellular organisms, which have many different cell types, each with different functions, as we now discuss.

The cells in an individual animal or plant are extraordinarily varied. Blood cells, skin cells, bone cells, nerve cells—they seem as dissimilar as any cells could be (Figure 1–31). Yet all these cell types are the descendants of a single fertilized egg cell, and all (with very minor exceptions) contain identical copies of the genome of the species. The differences result from the way in which the cells make selective use of their genetic instructions according to their developmental history and the cues they receive from their surroundings in a developing embryo.

Because all cells appear to have descended from a common ancestor, whose fundamental properties have been conserved through evolution, the knowledge gained from the study of one organism contributes to our understanding of all others, including ourselves. It turns out that certain organisms are much more accessible than others for study in the laboratory.

The popular choice for this role of minimal model eukaryote has been the yeast Saccharomyces cerevisiae (Figure 1–39)—the same species that is used by brewers of beer and bakers of bread. S. cerevisiae is a small, single-cell member of the kingdom of fungi and, in terms of its genome sequence, much more closely related to animals than to plants (see Figure 1–35). It is robust and easy to grow in a simple nutrient medium. Like other fungi, it has a tough cell wall, is relatively immobile, and possesses mitochondria but not chloroplasts.

Powerful new technologies, including rapid and cheap genome sequencing, are enabling rapid advances in our knowledge of human biology, with implications for understanding and treating human disease. But living systems are incredibly complex, and simpler model organisms have played a critical part in revealing universal genetic and molecular cell biological mechanisms. Thus, for example, early research on the bacterium E. coli and its viruses provided the foundations needed to decipher the fundamental genetic mechanisms in all cells. And research on the unicellular yeast Saccharomyces cerevisiae, which continues to serve as a simple model organism for eukaryotic cell biology, has revealed the molecular basis for many critical processes that have been strikingly conserved during more than a billion years of eukaryotic evolution. Biologists have also chosen a small number of multicellular organisms for intensive study: a worm, a fly, a fish, the mouse, and humans serve as model organisms for animals, and a small member of the cabbage family serves as a model for plant biology.

Viruses are small packets of genetic material that have evolved as parasites that depend on the reproductive and biosynthetic machinery of the host cells they infect. Viruses are not strictly alive, because they depend on the machinery of their host cells for their reproduction. Although we now know that viruses are the most abundant—in terms of sheer numbers—of all the biological entities on this planet, they are too small to be seen in the light microscope. For this reason, they were completely missed until the end of the nineteenth century, when a few viruses were identified as infectious agents that pass through filters that trap bacteria, but are retained by the even-finer filters that allow large molecules to pass. Only with the invention of the electron microscope could viruses finally be visualized as tiny particles with defined shapes and sizes.

At a minimum, a virus requires a genome that encodes two core functions: first, a nucleic acid replication process that produces multiple copies of its genome once inside its host cell, and second, a genome-packaging process that surrounds these new genomes with a protective protein coat, while allowing the viruses to exit the host cell and subsequently enter others.

As described in Chapter 6, cells are believed to have first evolved in an "RNA world," before there were proteins or DNA molecules. Scientists suspect that even at that time, parasitic genetic elements were present, in the form of small RNA molecules that took advantage of more advanced replicating entities to proliferate. These are believed to have been the ancestors of today's smallest viruses, which contain single-strand RNA genomes composed of as few as 3000 nucleotides. Thus, virus-like entities have probably been a ubiquitous feature of life on Earth for more than 3 billion years.

Although not themselves living cells, viruses often serve as vectors for gene transfer between cells. A virus will replicate in one cell, emerge from it with a protective wrapping, and then enter and infect another cell, which may be of the same or different species. Often, the infected host cell is killed by the massive proliferation of virus particles inside it, but sometimes the viral DNA, instead of directly generating new virus particles, may persist in its host for many cell generations as a relatively innocuous passenger—either as a separate intracellular fragment of DNA, known as a plasmid, or as a DNA sequence inserted into the cell's own genome.

Coronavirus genomes are large, single-strand RNA molecules, about 30,000 nucleotides long. This RNA is packaged in a protein coat that is covered with a lipid bilayer envelope, from which protein spikes protrude (Figure 1–49A and B). Many coronavirus strains circulate in animal species, including pigs, birds, and bats. Some strains also circulate among humans; these so-called "endemic" strains cause only mild symptoms and are responsible for about one in four common colds.