by Greg Gibson
There were actually two genomes sequenced—one by an international consortium that was financed by public money, and the other by a commercial enterprise known as Celera Genomics. It is legitimate to ask why hundreds of millions of taxpayers’ dollars were spent on a project that turned out to be doable by private initiative. There are many answers to this question. One is that Celera might never have started without the incentive provided by the public effort (and similarly, the public effort would not have finished so quickly without being pushed by Celera). Another is that there were legitimate reasons to believe that the strategy adopted by Celera would not work, whereas the public approach was guaranteed both to work and to provide useful information as it progressed.
The two projects took what we might refer to as MapQuest and Google Earth strategies toward sequencing the human genome. Suppose that you are asked to come up with a brand new atlas of the United States, complete with street names and house numbers. Most of us would probably start by employing someone in each state and charging them with the task of mapping out the major cities and highways. Lake Tahoe and Fresno would be placed on the atlas as the cartographers radiated out from Los Angeles and San Francisco, eventually linking up with Reno and Las Vegas. The approach would be painstaking and slow, but for most intents and purposes, guaranteed to be accurate, and the drafts could be used even before the final version was available. This is what the public effort did: Each chromosome was assigned to a major sequencing center, and the consortium put the pieces together over a period of five years.
By contrast, the maverick visionary behind Celera, J. Craig Venter, decided to do the equivalent of renting a satellite to take hundreds of millions of photographs. Every piece of land would be present on at least ten of the photographs, and a massive supercomputer was programmed to find the bits of similarity at the edges, assembling the complete atlas simultaneously based on overlaps between adjacent photographs. The process was fast and relatively cheap, but you might imagine that all those Main Streets and repetitive cornfields in the Midwest would confuse the alignment of photographs, making for some odd distance estimates, and that bits of New York might turn up in the middle of Philadelphia by accident. However, the Celera people were clever enough to devise ways around these problems, and their atlas of the human genome turned out to be just fine. It also turned out to be Craig Venter’s own genome!
Bear in mind that an atlas is just a set of guides: It doesn’t tell you where steel is manufactured, where cotton is grown, or who lives at 286 Magnolia Lane. For that we need classical genetics, bioinformatics, and molecular biology. The biggest emphasis right now, though, is on comprehending the variation at each of the positions in the atlas. This is the quest to find the tens of millions of places in the genome where we all differ, and to work out which few thousand of these differences are associated with disease and behavioral, physiological, and physical variation.
We don’t need to get into the gory details of how the genetic code can possibly hold the secret to life; suffice it to say that it consists of four letters, A, T, G, and C, strung together in long molecules of DNA. Each human gene is made of something like 10,000 of these letters, and there are around 1,000 genes per chromosome. The sequence of these letters specifies the nature and function of each gene; sequences can vary among individuals in three basic ways. Single nucleotide polymorphisms (SNPs) are positions in the genome where two or more different letters might be found if you compare two people. Indels are insertions and deletions, usually of just one or a few letters. Thus, comparing the sequence AATGCGCA with AGTGCGCCA, it appears that there is an A/G SNP at the second position, and an insertion of an extra C two bases from the end of the second sequence. The third class is copy number variation (CNV), which is much larger insertions and deletions of thousands of bases at a time.
Ultimately, change in the sequence of letters translates into susceptibility to disease or blue eyes or a cheery disposition. Remarkable as it may seem, a person who has an A instead of a G at position 102,221,163 on chromosome 11, may be born with a mild heart defect. This insight leads to the idea that if we could sequence a person’s genome, we could maybe work out what diseases that person may be likely to get. Venter has written a book that does just this for himself, but it must be stated that our ability to interpret sequence differences is primitive, and like a Shakespearian play or a T. S. Eliot poem, the genetic words will always be subject to interpretation.
So what has the sequencing of the human genome achieved, and when should we expect to see some impact on medical care? The achievement is that we now have the solid foundation upon which twenty-first century biomedicine will be erected. To see this, think about the analogy of the genome sequence as a road atlas once more. Prior to its completion, molecular biologists were simply working with the obvious features in the genomic landscape, or laboring painstakingly to find where they were headed. Now they know exactly where the residential areas are, where to find businesses or manufacturing sectors, and what type of agriculture is carried out where. They have the street names and addresses for most families and can readily find the government regulators.
To identify what is going wrong when a genetic disease occurs, though, they need to be able to peer inside the houses and offices. Sometimes the cause of a problem is obvious, as if the roof were missing. More generally, though, subtle problems get in the way. The most interesting cases don’t involve a single mutation, but rather the accumulated effects of many regular, everyday variants in the genome. These variants are behind diabetes, asthma, and depression, and they take advanced statistical and computational procedures to find.
Genomewide Association
Until the middle of 2006, the search for new genes that influence disease was pretty much restricted to studies of extended families. Typically, geneticists would identify pedigrees in which a particular type of cancer or heart disease was unusually common and look for parts of the genome that affected individuals have in common. This approach, called linkage mapping, has been the main method for finding single gene disorders, but has had limited success for more complex diseases.
Your parents have between them four copies of every gene. You have two of these, and your children each have a 50-50 chance of receiving each one. Suppose now that you, your father, and two of your three kids have a heart murmur, and both of these kids received the same allele from you, which is also the one you got from your Dad, while their sibling received the other allele. So, four out of seven members of the family have the murmur, each of whom has the same allele of the gene. Something fishy is going on, and you would likely conclude that the level of correspondence between having the allele and having the disease is unlikely to be due just to coincidence. You would suspect that the allele actually causes the murmur.
However, since there are thousands of genes and millions of families with murmurs, that level of coincidence is bound to occur occasionally. But if geneticists find a similar correspondence in dozens of even bigger pedigrees, their confidence that the particular allele of the gene actually causes or at least contributes to the murmur increases. With enough data, the correlation between the gene and the disease does not have to be 100 percent. As a result, it is also possible to detect linkage between regions of the genome and complex diseases where each gene only has a small influence on the disease. On this basis we know, for example, that a dozen or so places in the genome influence type 2 diabetes. For reasons we needn’t concern ourselves with here, those places typically stretch over perhaps a tenth of a chromosome, or hundreds of genes. So they do not pinpoint the problem.
To get around this, the field has now turned to a revolutionary approach called genomewide association mapping, or GWA. Instead of looking in families, geneticists now look at unrelated individuals drawn from an entire population. Two companies, Affymetrix and Illumina, have manufactured little gene chips with up to a million common genetic differences printed on them. These markers stand as proxies for the tens of million
s of places in the genome that are different among people. For less than $1,000 a pop, geneticists can now effectively measure what a person’s genetic constitution is, almost as if they were determining the sequence of the person’s entire genome.
For a few million dollars geneticists can go out and compare the genomes of 10,000 people who have a disease, with the genomes of 10,000 people who do not have it. If the frequency of the A at position 102,221,163 on chromosome 11 is 29 percent in people with a heart defect, but only 19 percent in people without the defect, then after appropriate crunching of the numbers we can infer that this site is contributing to the problem. This is a gross oversimplification; all sorts of possible alternative explanations can be made for such a difference. But if another group replicates the result in an independent sample (often from another country), then confidence that the gene is involved in the disease shoots up still higher.
It turns out that this approach is a sufficiently fine genetic scalpel that it actually leads us to one or a few genes involved in the disease. Genomewide association scans for disease will be to human genetics what the microscope was to nineteenth century biology, and what they are telling us is rightly the subject of the remainder of this book.
2. Breast cancer’s broken genes
cancer of the breast Breast cancer is the most frightening source of mortality for women but is rarely genetic, and early detection of the disease offers the best protection.
broken genes, broken lives The genetic component of cancer is because genes break during your own lifetime, more than because you inherit already broken genes.
epidemiology and relative risk The incidence of breast cancer varies across the globe in ways that implicate modern lifestyle as a major culprit.
brakes, accelerators, and mechanics Three types of things go wrong in cancer that affect the control of cell growth and division.
familial breast cancer BRCA1 and BRCA2 are the best known genes involved in breast cancer, having a major effect in some families, but they account for a only small fraction of susceptibility in the general population.
growth factors and the risk to populations New genetic methods are finding common genetic variants that increase your risk of breast cancer ever so slightly.
pharmacogenetics and breast cancer How you respond to drugs such as tamoxifen is also influenced by your genetic makeup.
why do genes give us cancer? Until recently, cancer was not a major cause of human ill health and mortality, so there has been little pressure to rid the genome of hundreds of variants that predispose to cancer.
Cancer of the Breast
The list of famous women who have had breast cancer contains some extraordinary pairings that on the face of it suggest something other than coincidence: both of Charlie’s brunette Angels, Kate Jackson and Jaclyn Smith; the American singer-songwriters Carly Simon and Sheryl Crow; similarly the Australian pop divas a generation apart, Olivia Newton-John and Kylie Minogue; the classical actresses Bette Davis and Greta Garbo; and the diametrically opposite feminist personalities Suzanne Somers and Gloria Steinem. But at a lifetime incidence of one in nine contemporary women having breast cancer, such a list is not unusual, shocking as it is.
Less well known is the fact that lung cancer is even more common in women and, given the incidence of cigarette smoking in teenage girls and twenty-something women, is likely to increase. Heart attacks are a still greater source of mortality, but breast cancer is undoubtedly the lightening rod for women’s health issues.
Chances are, everyone knows someone who has had breast cancer. If they are friend or family, we will have shared some of the ordeal, experienced secondhand some of the pain and anxiety. In all likelihood and without realizing it we all also know women who have survived. A generation ago, breast cancer carried such a stigma and was so closely associated with a death sentence that it was kept as private as possible, almost a taboo topic of discussion. Some people may have felt the disease was contagious; others may have attached shame to the symptoms, as if contracting cancer is a woman’s fault—as if conquering the physical illness were not enough to deal with.
The reality today is that the vast majority of patients will survive. Catch a small tumor early enough, and the improvements in surgical procedures, drugs, and more focused radiation therapies almost guarantee recovery. Five- and ten-year survivorship rates are on the up, and we have started to hear that refractory cases (those stubborn or resistant to control) may not be curable but are certainly manageable.
Read any of the self-help books on the topic, and you actually get the impression that surviving breast cancer can be an extraordinarily life-affirming experience. One of the best is Barbara Delinsky’s Uplift, a compendium of short testimonials on how to use a positive outlook to cope and overcome. Many are the families that have been brought closer together by sharing the ordeal. Many are the women who find an inner strength they never knew they had, or who reevaluate what really matters in their lives. Many are the new friendships that are made through membership of the sisterhood.
The book is full of vignettes ranging from the prosaic to the profound. There’s advice for padding bras and purchasing wigs, for organizing drainage tubes after a mastectomy, and for being creative with the little tattoos that oncologists use to guide their X-ray machines. There are funny stories of flat-chested daughters welcoming formerly buxom mothers to their world, and of sadly drooping older women finding new confidence in the simply fabulous shape of an implant. There is the man with a lump in his breast who presents to a clinic where he is asked to fill out pages of forms documenting the recent regularity of his menstrual cycling or early signs of menopause. And most shocking to me was the sense that so many women are afraid to tell their husband for fear that he will think less of them if they have a breast removed, as if men are that superficial!
Early detection of breast cancer generally begins with a mammogram. Next time you are in a crowd, perhaps at a baseball game or a concert, contemplate the fate of the middle-aged and older women around you. One in nine will be diagnosed with breast cancer over the next 30 years. If 1,000 of these women were to attend a clinic that day, it is almost certain that several new cases of the disease would be detected. For the most part, the diagnosis would be early enough for physicians to intervene, and the prognosis would be excellent.
Perhaps in a few cases the woman may have been able to detect a lump by self-examination; or may have experienced unusual tenderness or discharges from a nipple, that she put down—understandably—to stress or growing older. Some will have delayed making a doctor’s appointment, out of work commitments or denial. One thing we do know, though, is that the more advanced the tumor, the larger it is, and the more time it has had to spread out of the breast, the worse are the prospects.
Of the 1,000 women, statistics indicate that about 70 would be called back for follow-up consultation. A mammogram is a low-intensity X-ray of the front and side of the breast, designed to reveal abnormal densities of cells. For the most part, these turn out on closer examination to be just a normal aspect of the breast tissue. In fact, particularly in women under the age of 40, there is typically so much density that it can obscure tumors that are present: It is thought that about ten percent of early breast tumors are missed on mammograms. More accurate procedures such as ultrasound and magnetic resonance imaging will quickly tell the doctors that 60 of the possible cases actually had a benign explanation.
Of the ten out of each thousand women whose situation looks dire enough that they are next referred for biopsy, only three or four will in fact have a cancer. Two-thirds of these will be early enough that they will almost certainly be cured. So the screening of 1,000 women will likely save the life of a couple of them, at the expense of several months of distress for as many as 100 others, while it may have missed a case as well. There is also the issue of whether the energy of the X-rays themselves can induce cancer. While this risk is miniscule for a single scan, it is incremental, so annual mammog
rams starting in the thirties are no longer recommended. One every few years starting at menopause seems a reasonable compromise.
Broken Genes, Broken Lives
Cancer touches every one of our lives in one way or another, seeming to show little care or concern for whom it attacks. There does not seem to be much we can do about preventing it, aside from eating more carefully and avoiding smoking. Perhaps because of the visceral nature of the disease that so clearly arises inside our bodies, unlike an infection transmitted by sex or perhaps an insect bite, cancer is commonly regarded as a genetic problem.
We’re told it is often hereditary, and this is a source of particular worry when common experience reveals that a couple of relatives in the extended family have had cancer. But since it is so common and so diverse, in most cases coincidence is a more likely explanation than inheritance. In fact, relative to the other major maladies of our time, cardiovascular disease, diabetes, asthma, and depression, cancer is the least attributable to a common set of genetic factors. Yet it certainly involves defective DNA. It is natural to ask, then, why would evolution tolerate our genes causing so much suffering?
The short answer is that it really doesn’t. There just aren’t a lot of differences mulling around in the gene pool that cause cancer. Rather, cancer is a collection of diseases that all have some fundamental things in common—most basically, cells grow out of control. Control of the growth and division of cells is so complex, that inevitably it goes wrong in most individuals at some point in their life.
Similarly, for most of us, regulating our personal finances is so complex that inevitably some combination of debt, kids, and taxes puts us under financial stress that threatens to get out of control, and sometimes does. Certainly there are intrinsic reasons why some people are more susceptible (either to cancer or bankruptcy) than others, but for the most part it is things breaking in our own lives that cause the loss of control. In the case of cancer, the breaking of genes is the primary problem, more so than inheriting broken genes from our parents.
