Evolving dogma: proteins come next

Transcription

1 Evolving dogma: proteins come next Energy harvesting Locomotion RNA Protein Sensation Cell division Building block synthesis The last stage was the appearance of DNA, the most chemically and structurally boring of all life s macromolecules. Once the invention of protein synthesis had released RNA from its role as the source of the cell s catalytic activities, selection could turn to looking for a chemically more stable molecule to use for storing information. As David pointed out, eliminating the 2 hydroxyl on ribose converts chemically unstable RNA into DNA, producing a much more chemically stable information carrier. In addition, making the DNA double helical served two purposes, providing a completely general mechanism for the replication of the genetic material and partially hiding the vulnerable bases from the action of a variety of chemicals. 25

2 Evolving dogma: DNA comes last Energy harvesting Locomotion DNA RNA Reverse transcriptase (first DNA polymerase) Protein Sensation Cell division Building block synthesis The last stage was the appearance of DNA, the most chemically and structurally boring of all life s macromolecules. Once the invention of protein synthesis had released RNA from its role as the source of the cell s catalytic activities, selection could turn to looking for a chemically more stable molecule to use for storing information. As David pointed out, eliminating the 2 hydroxyl on ribose converts chemically unstable RNA into DNA, producing a much more chemically stable information carrier. In addition, making the DNA double helical served two purposes, providing a completely general mechanism for the replication of the genetic material and partially hiding the vulnerable bases from the action of a variety of chemicals. 26

3 Structure and function: Two views of DNA Structure (Chemist): sugar 2 OH gives RNA extra catalytic and binding capacity Function (Biologist): RNA was selected for diverse catalytic functions DNA was selected for structural and chemical stability Evidence: Catalytically active DNAs can be created by artificial selection They are harder to find than catalytically active RNAs This last step prompts me to revisit the question of why different nucleic acids molecules have different shapes as a way of indicating how differently chemists and biologists think about the same questions. When David told you about the structures of RNA and DNA he pointed out that DNA has a single boring shape, whereas RNA molecules come in a glorious range of shapes and sizes. He argued that the primary source of this difference was the extra hydroxyl group of the ribose ring in RNA which gave more conformational flexibility and more hydrogen bonding opportunities in RNA than DNA. My perspective is evolutionary. I argue that the difference in the shapes of DNA and RNA molecules reflects what they were selected to do, rather than their intrinsic, chemical potential for forming different structures. RNA dates back to the RNA world where it had to act both as catalyst and information carrier, and many of the most structurally interesting RNA molecules, including ribosomal and transfer RNA, retain something of this dual role. Thus in the beginning RNA was selected to be chemically active, and the selection for different chemical activities led to different structures. In contrast, DNA was selected to be safe, stable, and boring. It s double helical structure is not a reflection of its chemical limits but its limited biological role, where the strands are kept paired to ensure the safe storage and maintenance of information, and only separated briefly to allow for the synthesis of new strands of RNA during transcription, and new strands of DNA during replication. 27

4 Structure and function: Two views of DNA Structure (Chemist): sugar 2 OH gives RNA extra catalytic and binding capacity Function (Biologist): RNA was selected for diverse catalytic functions DNA was selected for structural and chemical stability Evidence: Catalytically active DNAs can be created by artificial selection They are harder to find than catalytically active RNAs So who s right? The diplomatic answer is that both arguments have to be partly true. There is chemical evidence that it s harder, but not impossible, for DNA rather than RNA to form discrete structures that bind specific molecules. But because it s not impossible to make DNA molecules that form interesting structures and perform chemical reactions, it s hard not to believe that the difference in the structure of DNA and RNA reflects selection for their very different function at least as much as it does their inherent potential to form different structures. 28

5 Deducing evolution from sequence information: Linus Pauling saw molecules as evolutionary messages The description of the evolution of the central dogma differs in a fundamental way from our description what has happened in evolution since the central dogma appeared in its current form. The actual origin of life is shrouded in mystery, and although many biologists find the idea that life originated with self-replicating RNA molecules compelling, there are others who prefer alternative hypotheses. But both camps are agreed on what happened afterwards because we have very strong evidence for what has happened since and the purpose of this section is to present that evidence in its briefest and most skeletal form. I believe that this is important since repeated surveys over the last fifty years have failed to find a time when more than half of Americans believed in evolution. The evidence for evolution is that we can trace an unbroken line of descent that connects every creature living today back to a single common ancestor that existed roughly 3 billion years ago. Even when inferences about evolution, like Darwin s, were based on the appearance and function of current day organisms and the appearance and deduced functions of fossils from the past, this was a powerful argument. It became enormously stronger in 1965 when Emile Zuckerkandl and Linus Pauling (of chemical bond, vitamin C, and antinuclear war fame) suggested that the sequences of the same protein derived from different organisms held clues about the evolutionary history and relationships of the organisms. To paraphrase them, they asked the question What is the richest source of information about the past history of living organisms and how can this information be extracted? and answered it The sequences of proteins and nucleic acids. 29

6 Pauling s evolutionary Q & A Question: What is the richest source of information about the past history of living organisms and how can this information be extracted Answer: The sequences of proteins and nucleic acids The basic idea is simple. If we assume that mutations arise and are incorporated into a the DNA sequence of any given gene at a roughly constant rate over evolutionary time, we can compare the DNA sequence of that gene and the protein sequence the gene encodes amongst many living organisms and deduce which organisms are most closely related to each other. We can even use statistical methods to make useful inferences about the sequence of the ancestral form of the protein in ancestors that are no longer living. It is exactly this logic that Rob referred to in his discussion of the evolutionary tree of life, and such comparisons offer a straightforward way of assessing evolutionary relationships between living organisms.. 30

7 Reconstructing Evolution: a monastic analogy 31

8 DNA sequences imply an evolutionary tree ATTCTGGAGC ATTCTGGAGC ATTCTGGAGT AT?CT?GA?C ATGCT?GACC ATGCTGGACC ATGCTTGACC time The idea is shown in cartoon form on this slide, for a small section of a gene that has been sequenced from four different organisms. We start by collecting the two pairs of sequences that are most similar to each other and arguing that the two organisms within a pair must have shared a common ancestor more recently than either has with a creature that is part of the other pair. The argument is simply that if mutations rain down and are accepted at a roughly constant rate, two DNA (or protein) sequences that are more similar shared a common ancestor more recently than two DNA sequences that have more differences between them. This process of grouping sets of sequences by similarity can be continued to create higher and higher levels of organization leading to the demonstration that the ribosomal RNA of every organism be it E. coli or an elephant is far more similar to that of other organisms than we would have any right to expect if the organisms had been created independently, rather than evolving from a single common ancestor. What I have just said is that evolutionary arguments can make detailed inferences about the past, using a single simple principle. To me, this is an extremely strong argument that the theory that Darwin and Wallace invented is the correct explanation of the origin and subsequent diversification of life. There is a second argument for evolution that is at least as compelling as the first. We can see evolution in action on time scales where important changes happen within a human lifetime. Examples include the evolution of antibiotic resistance in bacteria and DDT resistance in mosquitoes both of which have occurred in a single human lifetime, but to me, the most compelling examples are those that occur within the course of a disease in a single individual. 32

9 AIDS and cancer: evolution in action AIDS: virus mutates to drug resistance and to alter cell preference Cancer: patient s own cells mutate to escape social rules of cell behavior The two most medically important examples are AIDS and cancer. As HIV replicates mutations appear at random at every different position in the genome. Most of these mutations interfere with viral replication or infection and are selected against. But, as we have seen, some of them allow the mutant viruses to escape from antibodies the immune system has made to the original infecting virus, invade new types of cells, or replicate in the presence of antiviral drugs. These mutations that help the virus aren t called into existence by the various selections and they represent a very tiny fraction of all the different types of mutation that are occurring in the virus, but they are the ones that take over the population, because the viruses that contain them outcompete their predecessors who do not. AIDS and cancer also give the lie to the notion that evolution is an process for improving life. Mutations that benefit HIV by making it resistant to protease inhibitors are clearly deleterious for the patient in which they occur. As we will see, cancer reveals the blindness of evolution even more clearly. Mutations in cancer cells allow them to grow and divide at their host s expense, but this is the ultimate in disastrous victory, since the unchecked growth and division of the cancer cells ultimately kills the patient and the cancer cells die with their victim. 33

10 AIDS and cancer: evolution in action AIDS: virus mutates to drug resistance and to alter cell preference Cancer: patient s own cells mutate to escape social rules of cell behavior Because viruses are inert outside cells they provide a dramatic demonstration of what is needed for life. They can replicate because cells provide them with the building blocks to make the macromolecules that will make new viruses, the energy and enzymes needed to couple those building blocks together, and a sheltered and tightly controlled environment for assembling the macromolecules into new viruses. For HIV, only two of the enzymes in the viral life cycle, reverse transcriptase and the viral protease, are encoded by the virus and provide targets for modern medicine to attack. The reason that viruses can so easily exploit cells, is that all the same things are needed to convert one cell into two. In this sense, viruses are the ultimate gatecrashers, uninvited guests who can have a good time at the host s expense precisely because the host needs to provide food, drink, and entertainment for all the guests who were actually invited. 34

11 AIDS and cancer: evolution in action AIDS: virus mutates to drug resistance and to alter cell preference Cancer: patient s own cells mutate to escape social rules of cell behavior If viruses are enemies without who descend to exploit cells, must we also deal with enemies within. Sadly, the answer is yes. Just as an invited guest who drinks too much can ruin your sophisticated and urbane party as easily as a gatecrasher, we are as vulnerable to misbehavior of rogue cells within our own bodies as we are to viral and microbial enemies from without. As you have probably guessed, the rogue cells are cancer cells, and like viruses they exploit the normal machinery used to produce the cell growth and division that converts a fertilized egg into us. Like AIDS cancer, offers us a way of appreciating the normal behaviors of cells, understanding how, under special circumstances, the basic principle of evolution can work against us, and seeing how planning and serendipity can come together in medicine. 35

12 3A. Cancer: the enemy within 1. An introduction to cancer Alberts, The germ line and soma Alberts, a. Multicellularity and the division of labor b. Germ line mutations affect the next generation c. Somatic mutations affect this generation 3. Cell Proliferation and Cancer a. Balancing cell birth and death b. Multiple changes in cell behavior cause cancer 4. The epidemiology of cancer Alberts, a. Cancer results from multiple mutations b. Environmental contributions to cancer c. Genetic contributions to cancer The material you covered in the first half of the course dealt with two large areas, introducing you to enough chemistry so that you could understand the chemical basis of life, and showing you the remarkable sophistication of the chemistry living cells do, from the passage and expression of genetic information by replication, transcription, and translation to the extraordinary speed and subtlety of the reactions carried out by enzymes, nature s catalysts. The second half of the course will make use of these concepts and refer back to them, but it will also introduce the second amazing capacity of living cells and organisms, their ability to monitor their environments and interiors and use this information to precisely regulate the vast number of chemical reactions they contain in a way that helps them fulfill their evolutionary destiny of leaving as many viable offspring as possible. This regulation has to be flexible enough to allow a given species to survive and prosper in a wide range of environments and for multicellular creatures like us, it has to make sure that the behavior of a vast number of individual cells and the chemical reactions inside them are regulated in the interest of the enormous cellular cooperative that constitutes a human being. 1

13 3A. Cancer: the enemy within 1. An introduction to cancer Alberts, The germ line and soma Alberts, a. Multicellularity and the division of labor b. Germ line mutations affect the next generation c. Somatic mutations affect this generation 3. Cell Proliferation and Cancer a. Balancing cell birth and death b. Multiple changes in cell behavior cause cancer 4. The epidemiology of cancer Alberts, a. Cancer results from multiple mutations b. Environmental contributions to cancer c. Genetic contributions to cancer Just as we did in the first half of the course, we use a disease to illustrate these concepts. Cancer is our second major story because it shows what happens when biological regulation fails and members of the cellular cooperative no longer obey its rules. This section will introduce the basic biology of cancer by describing the fundamental features of the disease and the factors that determine who suffers from it. The following two lectures will describe how normal cells grow and divide, and will deal with the challenges they must solve so that they can produce daughters that are free of mutations and do so only where and when the production of new cells will help rather than harm us. Finally, the last three lectures of the course discuss how cells choose which genes to express, and the chemical details of a class of enzymes called protein kinases, which regulate the activity of an enormous range of biological reactions. We will close by discussing a particular form of cancer called chronic myelogenous leukemia or CML and a remarkable drug called Gleevec which comes close to curing patients who suffer from it. Both in our general introduction, and in our treatment of CML, we will see that like AIDS, cancer is an evolutionary disease, in which the pathogenic agent, in this case our own cells, changes during the course of the disease thus, outwitting our bodies and the medical profession s defenses. 2

14 3A. Cancer: the enemy within 1. An introduction to cancer Alberts, The germ line and soma Alberts, a. Multicellularity and the division of labor b. Germ line mutations affect the next generation c. Somatic mutations affect this generation 3. Cell Proliferation and Cancer a. Balancing cell birth and death b. Multiple changes in cell behavior cause cancer 4. The epidemiology of cancer Alberts, a. Cancer results from multiple mutations b. Environmental contributions to cancer c. Genetic contributions to cancer This section of the course begins our discussion of cancer as the enemy within. It starts with an introduction to cancer and then moves on to consider the separation between two cell lineages in our bodies, the germ line and the soma, and the different implications of mutations in these two types of cells. Next, we discuss the need to carefully regulate cell birth and cell death during development and adult life to ensure that our bodies function as well behaved cell cooperatives where there are neither too few or too many of the 100 or so different types of cell that make up our bodies, and discuss how a series of mutations can convert these well behaved cells into cancer cells, which grow, proliferate, and spread throughout the body precisely because they ignore these strict social rules. Finally we discuss the epidemiology of cancer and how it has revealed that there are mixture of environmental and genetic contributions to cancer. 3

15 Cancer definitions Cell growth: increase in cell mass Cell proliferation: increase in cell number Tumor: a group of cells that has grown and proliferated inappropriately Benign tumor: confined to one part of the body, no migration Malignant tumor: cells can escape, migrate, and settle at new locations, and establish secondary tumors (metastasis) Cancer: malignant tumor Before we can go further, we need to introduce some of the terms used to describe cancer and the behavior of the cells that cause it. We begin by defining what we mean by cell growth and proliferation. Many biologists use growth loosely to refer both to the increase in the size of individual cells and the increase in the number of cells in a population that is due to cell division. We will use growth exclusively to refer to the increase in the mass of a cell and proliferation to refer to the increase in cell number, although, as we will see later, most cells cannot proliferate for long without growing. Tumors are masses of cells that have grown and divided where they shouldn t have. Benign tumors are confined to one part of the body and because of this, most can be removed by surgery, giving a complete cure. Tumors become malignant when some of their cells escape from the original site, enabling them to migrate to other sites in the body and establish secondary tumors, known as metastases. Once a tumor has metastasized, surgery cannot remove it, and many malignant tumors are resistant to chemotherapy and radiation therapy. Strictly speaking, the term cancer is reserved for malignant tumors. The last century has seen spectacular progress in our ability to prevent and control infectious diseases, but we have made much less progress in defeating cancer and it is still a disease that will kill one American in five. This year, 40,000 US women will die of breast cancer. 4

16 Committing to a man on the moon: May 25th,1961 Apollo 11 landing: July 20th 1969 Apollo program cost: $135 billion One way of appreciating how hard a disease cancer has been to tackle is to compare the pronouncements of two former Presidents. On May 25 th, 1961 John Kennedy declared that the United States should place a man on the moon, and $135 billion (in 2005 dollars) and 8 years, 1 month, and 29 days later Neil Armstrong stepped out of the Lunar Excursion Module. Since Richard Nixon declared war on cancer on January 22nd 1971, the US has spent roughly $200 billion on cancer research from federal funds, charitable donations, and research and development by pharmaceutical and biotech companies. 5

17 Declaring war on cancer: Jan 22nd, 1971 Cost so far: > $200 billion 6

18 Little progress on deadliest cancers Lymphoma: solid white blood cell tumor Leukemia: cancer with circulating white blood cells 34 years later, our success in this war mirrors that of our country s adventure in Iraq. Although victory has been declared, people are still dying. This slide shows what has happened since Nixon s pronouncement by showing what how deaths from two different cancers have changed in Britain over the last 25 years. The blue line shows the number of men who die from Hodgkin s lymphoma. Lymphomas and leukemias are both cancer that affect cells of the immune system; in a leukemia, the cancerous immune cells circulate in the blood, whereas in a lymphoma, they are mostly found as solid masses in one of the organs of the immune system. The good news is that there has been dramatic progress in the therapies for Hodgkin s lymphoma which has reduced the number of deaths from these cancers by 75% and completely cured many patients. The bad news is that this cancer is relatively rare and that we have made far less progress on more common cancers. The red line on the graph describes deaths from colon cancer, which have fallen by less than 20%. Roughly 20 times more people are diagnosed with colon cancer than with Hodgkin s leading us to conclude that we are defeating some of the rarer cancers but losing to the commoner ones. The picture this slide paints is a general one. Although there has been dramatic progress in cancer therapy it has mainly affected rarer cancers and for the big killers, lung, colon, breast, and prostate cancers, there has been little progress. 7

19 Little progress on deadliest cancers Lymphoma: solid white blood cell tumor Leukemia: cancer with circulating white blood cells Why can we send men to the moon and not cure cancer? At one level, the answer is simple. Sending a spacecraft to the moon and bringing it back is purely an engineering challenge, since the equations that govern the motion of the spacecraft are those of Newtonian physics. For cancer we need to understand what distinguishes cancer cells from normal ones and how one cancer differs from another before we can reliably kill all the cancer cells and spare the normal ones. As we will see, we have are only beginning to appreciate the full dimensions of our task, let alone devise strategies to accomplish it. One of the most important realizations has been that cancer is not a single disease, but a whole host of related disease, and that even cancers that look identical to a pathologist can have different molecular defects. 8

20 Little progress on deadliest cancers Lymphoma: solid white blood cell tumor Leukemia: cancer with circulating white blood cells In the last few lectures, we will end up focusing on a particular form of cancer, chronic myelogenous leukemia, and a remarkable drug, Gleevec, that can spectacularly improve the health of patients suffering from CML. Unfortunately, like the single therapies for AIDS, Gleevec dramatically eliminates the effects of the disease but doesn t cure it. When patients stop taking the drug, their symptoms rapidly reappear, and even when they do keep taking it, mutant cancer cells appear that are resistant to the drug. To tell this story, we will begin by worrying how cells can accurately replicate genomes as large as ours, talk about how our bodies cells cooperate with each other to send our genes into the future, discuss simple observations that give important clues about the nature of cancer, talk about the control of cell growth and proliferation (processes that are profoundly affected by cancer), discuss how cells receive and process the signals from their environment that control growth and proliferation, and finish with a discussion of how Gleevec was discovered, how it works, and how the evolution of the cancer cells eventually makes it fail. 9

21 Germ Line & Soma Multicellularity and the division of labor Germ line mutations affect the next generation Somatic mutations affect this generation We begin our journey by pointing out that cancer arises because some cells accumulate mutations that alter their behavior in a way that eventually allows them to proliferate uncontrollably. Thus our bodies first defense against cancer is to make as few mutations as possible, which means replicating their DNA as faithfully as possible. What are the consequences of mutations that occur in our cells? To frame this question, we need to digress so that we can understand a fundamental distinction between two sorts of cells in our bodies, those that can give rise to our children and those that are destined to die with us. However proud we may be of our own or our societies accomplishments, we exist for a brutally simple evolutionary purpose, to project our genes as efficiently and as far into the future as possible. The projectiles in our bodies are our eggs and sperm, which can fuse with each other to give rise to new humans who will produce new eggs and sperm, and so on into what we hope will be the distant future. Collectively the eggs and sperm and the complete lineage of cells that connect them back to the fertilized egg they developed from are called the germ line, because they contain the germ of the next generation of human beings. All the cells outside the germ line, form the soma (Greek for body) and are called somatic cells. They have a simple role and a finite future. They exist as a support system for the germ line that helps the germ cells push their genes into the future, and none of the somatic cells outlive us. 10

22 Germ-line and Soma This slide shows the distinction between germ line and soma in a well known family. Queen Elizabeth s egg and Prince Philip s sperm came together to produce the fertilized egg that would become the Prince of Wales. When this embryo had reached a size of roughly 1000 cells, the few cells that were to give rise to the germ line could have been identified and it is the descendants of these cells that produced the sperm that fused with Princess Diana s egg to give rise to Prince William. The rest of the cells in the embryo became the soma of Prince Charles accounting for every part of him except the germ cells that give rise to his sperm and thus the line of succession in the British monarchy. 11

23 Germ-line and Soma If, like Prince Charles, our bodies are mortal machines aiming to immortalize our genes, why have our somatic cells accepted a supporting role in the movie that will ultimately star your eggs or sperm? The answer is simple. The genes in your somatic and germ line cells are exactly identical. By helping your eggs and sperm escape into the next generation, your somatic cells are propagating their own genes. Although there are a small minority of cells where this statement is not strictly true, the ability to produce animals like Dolly, where the nucleus of an egg was replaced with that from a somatic cell, demonstrates that a sheep s somatic cells have all the genes needed to produce a normal animal. This experiment very strongly suggests that your somatic cells have all the genes needed to produce a normal human and gives rise to the ethical dilemmas about reproductive cloning. Thus although your somatic cells die when you do, their genes do not have to, because each time you make an egg or sperm, half of your genes enter a germ cell that can give rise to a child. I should make it as clear as possible that I am not describing a moral, philosophical, religious, or political position, simply explaining why the blind forces of evolution can accept the separation between germ line and soma. Having explained the distinction between germ line and soma, we can return to the discussion of mutations. Mutations in the germ line affect our descendants. If they are deleterious, they harm or kill them, if they are advantageous they allow them to reproduce better. For mutations that cause cancer, they cause cancer in our children if they occur in our germ lines and cancer in us if they occur in the soma; 12

24 Germ-line and somatic mutations and cancer Germ-line mutations can cause cancer in our children Somatic mutations can cause cancer in us Because mutations can either help or hurt, the mutation rate matters. If it is too high, enough embryos will die that the population falls in each succeeding generation, eventually extinguishing the species. If it is zero, no advantageous mutations occur, and evolution grinds to a halt. 13

25 All cells except eggs and sperm are diploid 3 x 10 9 bp 6 x 10 9 bp (46 chromosomes) 6 x 10 9 bp 3 x 10 9 bp (23 chromosomes) 3 x 10 9 bp 25 cell divisions What is the mutation rate in humans and what are its consequences? To make things easy, we will assume that human cells are haploid, containing 23 chromosomes and 3 x 10 9 base pairs of DNA. This is an accurate description of an egg or sperm, but when they fuse with each other they make a single diploid cell with 23 pairs of chromosomes and 6 x 10 9 base pairs of DNA, from which all of the cells that form your bodies have descended. But when you make your contribution to the next generation you pass on only half of your 46 chromosomes, half of your genes, and 3 billion base pairs of DNA. Thus for these simple calculations, we will worry only about the 3 billion base pairs of DNA that you might pass on to a child. We also need to take account of how many cell divisions separate the egg that gave rise to our mothers from the one that produced the egg that we developed from. In the female germ line, roughly 25 divisions separate the first division of a fertilized egg that will go on to produce a woman from the division that produces the egg that that will give rise to her children. 14

26 Mutation rates in HIV and woman Haploid Genome size Mutations per bp per generation Mutations per genome per generation HIV x Human cell 3 x * Human being 3 x x * * Only 5% of these are in useful DNA The best estimates suggest that when a human cell replicates its DNA, it makes a mistake about once for every billion base pairs of DNA it copies. Since each cell must replicate about 3 billion base pairs of DNA, this suggests that about three new mutations occur in each cell division. Thus roughly 25 * 3 = 75 new mutations will appear in the cell lineage that connects the egg your mother arose from to the one that she produced to create you. Careful estimates suggests that only 5% of the human genome is subject to natural selection, with the remainder being effectively junk, and leading us to conclude that each new egg contains 0.05* 75 4 mutations that could be deleterious. The situation with sperm is slightly worse, since more cell divisions separate next generation s sperm from the fertilized egg that began this generation. 15

27 Mutation rates in HIV and woman Haploid Genome size Mutations per bp per generation Mutations per genome per generation HIV x Human cell 3 x * Human being 3 x x * * Only 5% of these are in useful DNA We have now calculated how many new mutations we have inherited from our parents with roughly 4 from our mothers and 6 from our fathers for a total of 10 new mutations, of which we might expect something like half to be deleterious. These mutations are unlikely to affect our health for the simple reason that most deleterious mutations are recessive to the wild type version of the same gene. This is a concept that many of you will have already encountered, but for those who have not, a simple example comes from considering human eye color. One of the genes that controls eye color exists in two forms, which we will call blue and brown. The blue version (or allele to give it its technical name) is recessive to the brown version, or stated another way the brown version is dominant to the blue one. This means that if you get a blue copy from one parent and a brown copy from the other, your eyes will be as brown as if you got two brown copies, one from each parent, and that the only way you can end up with blue eyes is to get two blue copies, one from each parent. 16

28 Dominant and recessive forms of a gene blue/blue blue/brown BROWN /BROWN blue is recessive, BROWN is DOMINANT Because most deleterious mutations are recessive, they will only cause problems if you get a mutant copy of the gene from each of your parents. As long as we are not European royalty or some other strongly inbred group, we have children with people who are not closely related to us, and the chance of both sperm and egg harboring mutations in the same gene is small. For most genes, we can do perfectly well with one wild type and one mutant copy of the gene, allowing the human race to prosper despite what initially seems like a frighteningly high mutation rate. 17

29 Different cells, different life styles Neutrophil Red blood cells Life: 3 days Life: 120 days Number: 2 x 1010 Number: 2 x ,000 born/sec 2,000,000 born/sec Neuron (Purkinje cell) Life: 100 years Number: 2 x Within the soma, mutations cannot be transmitted to our descendants, since our somatic cells die with us. Thus you might hope that these mutations aren t important. For the vast majority of these mutations, this is true but we have already mentioned that there is one important and tragic exception: cancer results from mutations that remove the normal restraints over when and where cells proliferate. Like mutation, cell proliferation is a double-edged sword; too little cell division means that new cells are born more slowly than old ones die, and we waste away; too much and a particular cell type tries to take over our bodies. 18

30 Different cells, different life styles Neutrophil Red blood cells Life: 3 days Life: 120 days Number: 2 x 1010 Number: 2 x ,000 born/sec 2,000,000 born/sec Neuron (Purkinje cell) Life: 100 years Number: 2 x We are made up of more than 100 different types of cells that perform different functions and must be present in precise but flexible proportions to each other. Before talking about how these proportions are maintained it is worth making the different cell types concrete, and this slide shows three. Neutrophils are one of the types of white blood cells that track down and consume bacteria that enter our bodies. We contain about 20 billion of these cells and they have an average lifespan of only three days, implying that your body is making 7 billion new neutrophils a day and 80,000 new neutrophils a second. Your red blood cells, which carry oxygen from your lungs to your tissues live about 120 days, and you contain a staggering 25 trillion of these cells, meaning that as you listen to this lecture about 12 billion red blood cells will die and 12 billion new ones will be made to replace them, an astonishing number when we remember the world s current population is 6 billion. Finally, there are the nerve cells found in the part of your brain called the cerebellum that are called Purkinje neurons. Each one of the 20 million Purkinje cells was born before you were, contacts hundreds of other nerve cells, and lives as long as you do. 19

31 Cancer: cell proliferation & behavior Balancing cell birth and death Multiple changes in cell behavior cause cancer 20

32 Balancing death and proliferation Cell birth rate = 1.01 x Cell death rate Start 1 month ( = 1.36 x) 1 year ( = 38 x) This introduction reveals that different cells in our bodies need to proliferate at very different rates. Some, such as those that line our intestines, must be replaced as often as once a day, whereas others like the neurons in our brains rarely die or divide. To get from egg to embryo to infant to child to adult requires precisely controlling where and when cells grow, divide, and die. The same is true for maintaining our adult form; for our bodies to keep working without changing in size or shape, cells must grow and divide to produce new cells at exactly the same rate as cells die. This applies not just to the somatic cells taken as a whole, but to each particular type of somatic cell. For example if your red blood cells die faster than new ones are born, the concentration of these cells in your blood will fall and you will become anemic. If you are a healthy person who takes erythropoietin, a protein that induces the proliferation of the precursors to red blood cells, the opposite is true and the concentration of red cells will increase, improving your performance at sports that require endurance, but putting you at risk of being banned from competing in them. 21

33 Balancing death and proliferation Cell birth rate = 1.01 x Cell death rate Start 1 month ( = 1.36 x) 1 year ( = 38 x) It is worth trying to appreciate how precise this coordination must be. Some of you will have heard during your high school biology classes that if you flattened out the lining of your small intestine it would occupy the same area as a standard tennis court. The cells that cover this area are replaced roughly once day. If 1% more cells were born each day than the number of cells that died, the number of cells lining your intestine would go up by 1% a day. Over a month, the number of cells in lining your intestine would increase by corresponding to 1.36 fold. This seems mildly troubling but is nothing compared to what happens over a year, since equals a 38 fold increase in the number of intestinal cells, which would imply that either the surface of the intestine or the thickness of its lining must have increased dramatically. This calculation shows that it would be almost impossible to achieve the precise balance between the birth of new cells and the loss of old ones, if the rates of the two processes are controlled independently. Instead supply must be matched to demand, implying that the body has ways of detecting that it has too few or too many of a particular cell type and then increasing or decreasing the rate at which it produces new cells. Although we understand some of the features of this market economy, for no cell type do we understand the precise details of how our bodies match cell birth and death rates to our needs. In totality, your somatic cells are the perfect socialist state, with each contributing according to their ability and growing and proliferating in response to your bodies needs. 22