Chapter One
Medicine on the Brink
When, nearly a decade ago, scientists painstakingly documented the entire genetic instruction book for a human being, the human genome, it was a seedling for a new era in medicine. This new era is one where doctors will treat and prevent diseases based on the subtle differences in our DNA.
That feat and subsequent efforts at refinement have unleashed a torrent of information that is just beginning to trickle into physicians’ offices as they diagnose and treat more diseases at earlier and earlier stages.
As that trickle becomes a stream, I grow increasingly convinced that the physicians of today, those who graduated at the same time as my son in 2011, will have new tools to treat diseases never before treatable. They will predict and prevent many others. The whole emphasis of medical care will change from treating illness to creating and preserving wellness.
Medicine, western medicine in particular, suffers from an imperfect, but understandable focus. Physicians usually don’t intervene until a problem exists. Ever since the first human suffered an ache or pain, our species has sought to alleviate suffering whether through the ministrations of a witch doctor, or a simple brew of the aspirin-like willow bark tea, or in recent times, the newest modern blockbuster drug. For the past five thousand years, medicine has focused on diagnosing and treating already sick and symptomatic people.
Physicians aren’t entirely to blame. Patients generally only show up when symptoms appear. Too often that means treating a disease at a very late stage when much damage has already been done. Surgeons have become quite adept at replacing clogged arteries that feed oxygen to the heart, but physicians have been less successful at identifying people at risk for that coronary artery-clogging disease in the first place.
It’s not that doctors wouldn’t prefer to help their patients stay healthy and well. Intervening in a disease process at its earliest stages is always preferred. Treating a disease before today’s laboratory tests or images would show the telltale damage, or being able to prevent it altogether, offers an unprecedented opportunity to deliver optimum health and life expectancy. Doctors just haven’t had tests capable of detecting potential problems or the tools needed to avert them.
That is all changing.
Medicine is moving rapidly from a “diagnose and treat” model to a “predict and prevent” model and that will have huge implications for both patients and society.
Imagine going to the doctor who looks at your individual genetic makeup and uses that information to advise you on the most appropriate lifestyle adjustment to prevent a condition years or even decades before it starts causing symptoms. Better still, your doctor may prescribe a precisely targeted medicine for you that will work at the level of a faulty genetic message. So you should never have to worry about falling prey to the condition at all.
This fundamental change in medicine is already taking place.
Driving that change is the torrent of genetic information emerging from efforts to sequence the entire human genome.
In 2003, Nobel Prize winner James Watson was the first to undergo full sequencing of his genome. This effort cost about three billion dollars and took thirteen years.
Now, science and medicine are beginning to harness the information contained within the genome to aid drug development.
At the time of writing this book, there are roughly thirty thousand drugs used in the world. They target about two percent of the proteins found in human cells. This has led to the concept of the “druggable genome”. This is the subset of the human genome that contains codes for proteins that small molecule drugs can interact with and affect.
Small molecule drugs are those with a low molecular weight, less than one thousand Daltons, compared to biological molecules that have a much greater weight, and oligomers whose weight is typically between six and seven thousand Daltons. A Dalton, named after the English chemist and physicist, John Dalton (1766 – 1844), is a measurement first coined in 1803 and is set as one-twelfth of the weight of an unbound carbon atom. It is equivalent to 1.66 x 10-27 kg. To make that more meaningful, a small grain of sand weighs about 0.67 mg, or 6.7 x 10-4 kg, meaning that it would take roughly 2 x 1022 atoms of carbon, each weighing 1 Dalton, to weigh as much as a single grain of sand.
Small molecules are chemically synthesized and are manufactured to high levels of purity. In addition, they rarely cause an immune response in humans and generally have the same positive and negative effects in animals. That allows them to be tested in animals first before testing in humans. Biological products, especially the newer monoclonal antibodies, are capable of triggering a marked immune response but often only with a specific species.
Scientists, led by Andrew Hopkins and Colin Groom of the drug company Pfizer, looked into the druggable genome in 2002 and found that a mere 399 proteins had successfully been targeted. Later Hopkins lowered this figure to 207.
About half of the targets fell into one of five protein families: G-protein coupled receptors (GPCRs), kinases, proteases, nuclear hormone receptors, and phosphodiesterases.
But not all of the protein targets may actually modify disease. Some examples within each class may be too difficult to target. With fewer and fewer new small molecule drugs reaching approval, there is great anxiety within the medical and pharmaceutical communities that we may be getting close to having identified all the potential targets that small molecules can reach, and that we are reaching the limit of drug discovery, at least for small molecule drugs.
Since Watson’s genome was sequenced, scientists have discovered multiple genes that can predict the risk of one day developing a multitude of diseases. They have discovered genes that can predict how you will burn fat and whether you will develop diabetes. At present, we know of six different genes that affect your chances of developing dementia as a result of Alzheimer’s disease. Those genes, however, only play a role in about sixty percent of all Alzheimer’s cases. Dr. William Thies, the Chief Medical and Scientific Officer for the Alzheimer’s Association, speculates that up to one hundred genes could ultimately play a role.
One approach to Alzheimer’s disease is already being explored in a rather unique situation. In the area around Medellin in Colombia, approximately five thousand people are participating in an experiment. They are all descended from 28 original families who carried a single mutation, E280A of the presenilin 1 gene, a gene that causes Alzheimer’s disease. These people are at risk of developing the disease not as senior citizens, but in their forties and fifties. In this area of Antioquia, subjects with the mutation are being identified and tested with potentially preventative drugs in their thirties, in the hope that early onset, familial Alzheimer’s disease can be prevented.
Here are some other DNA-related health discoveries that are important: Several genes residing on chromosome five turn out to be related to developing asthma, another common disease. A genetic component has yet to be identified for many cases of schizophrenia, as well as obesity and diabetes. Genes are likely to play a part in whether you develop heart disease and chronic obstructive pulmonary disease (COPD), although a much greater risk is run if you smoke. But if you do smoke, maybe it is because you have inherited the desire, or have the gene that predisposes you to become addicted to nicotine.
The list goes on.
Some diseases are described as “complex” because they result from the interplay of a number of different genes and biological systems, such as your environment.
Cancer is the poster child for complex diseases among those where scientists have discovered that genes confer risk. Because cancer can affect any organ or tissue in the body, it is actually a set of diseases rather than a single ailment. There are faulty genes, named BRCA1 and BRCA2 that increase the risk of developing breast and ovarian cancer in women and breast cancer in men. Similarly, defects in the genes APC and MLH1 raise the risk for developing different types of colon cancer. The ever-growing list of cancer-causing genes is broadly divided into those that cause or promote cancer and those that usually suppress cancer (tumor-suppressor genes). One that was discovered at the Memorial Sloan-Kettering Cancer Center in New York City in 2005, originally called the Pokemon gene and now renamed as Zbtb7, plays a key role in promoting cancer proliferation in surrounding tissues when triggered by another cancer causing gene.
While sequencing Watson’s genome proved time consuming and expensive, genome sequencing today can be completed in days and the cost is plummeting towards the one thousand dollar mark. Genetic Testing Laboratory Inc., 23andMe and deCODE genetics are companies that offer a limited service for considerably less than a thousand dollars, directly to consumers or via a healthcare professional.
Many people are already getting their genomes (i.e. all of their ~25,000 genes) sequenced. All it requires are a few cells from inside your cheek that can be provided in a spit sample. Several biotech companies responsible for sequencing the genome have actually held “spit parties” to advertise how easy it is now to provide a suitable sample to permit a full genome sequence. In fact, a party hosted by 23andMe even made the “Fashion & Style” section of The New York Times. A photo of a young couple spitting into collection tubes was captioned, “When in doubt, spit it out.”
Patients who enjoy being in the vanguard are taking these analyses into their physician’s office to serve as a basis for decisions about their health.
It’s at the physician’s office where the excitement about tomorrow’s personalized medicine can come up against today’s cold hard reality. The field of genomics has moved so quickly that many physicians haven’t learned how to interpret the results of genome sequencing, which are often quite complex.
Personalized medicine is a developing field and there is a learning curve associated with implementing it. Physicians will be grappling with that learning curve for the next five years, but by the end of this decade, reading the results of genome sequencing will be commonplace for them.
So far the revolution has focused most on detecting risk for disease and many books are being written on the subject. But that is a far cry from being able to effectively treat it.
A doctor who learns that you are harboring genes that increase your risk for diabetes will still advise you to lose weight, especially if other obesity-related genetic variations are part of the mix. However, with a genetic map your doctor may have some extra tools in his arsenal. He may be able to use the genetic information to advise you about the type, frequency and duration of exercise and even the best foods to consume, either before or after exercise, to improve your chances of losing weight. In addition your physician will start more frequent screening for elevated blood sugar levels.
Your physician would be able to advise another patient with a genetically greater risk of developing colon cancer to start routine colonoscopy screening at a younger age and to have those screenings more frequently.
Admittedly, these are today’s routine recommendations that you hear from your doctor based on your family history.
But a personalized medicine approach can more precisely define and even quantify the risks that you have inherited from your parents. That may serve as potent motivation for you to make lifestyle changes.
Certain savvy physicians are already employing personal genomic information when prescribing particular drugs.
This will be especially true when it comes to the possible side effects of a drug. Look at any advertisement for a commonly used pharmaceutical. First, you see information about the uses of the drug, then comes a long list of potential side effects and problems you could encounter. Such “adverse events” are common to all pharmaceuticals, and the FDA requires the public to be warned about them. The fact is, we are all subtly different on a genetic level. For some of us, the drug is ineffective. For others, the drug is perhaps harmful. For most, we hope to get a Goldilocks effect where the drug works just right. With modern genomic sequencing, we will be able to tell you whether the drug will provide the required beneficial effects and if those effects will come with harmful side effects.
Take the blood-thinning drug Coumadin, one of the trade names for a drug called warfarin. It’s one of the most widely prescribed pharmaceuticals in the United States. Doctors use it to prevent potentially fatal blood clots from forming or growing in blood vessels. People with irregular heartbeats, those who have suffered a heart attack, or those who have had blood clots in their lungs or legs often take the drug.
Warfarin is a lifesaver for many. However, it can have devastating side effects. It is one of the top three drugs associated with emergency room visits in the United States. It has been estimated to cause 85,000 serious bleeds and 17,000 hemorrhagic strokes as well as other adverse drug reactions every year in the U.S. at a cost of one billion dollars.
What makes it so helpful and yet so dangerous at the same time? The genetic makeup of the patients who are taking it is the answer.
You may have genes that break the drug down very slowly, letting too much warfarin into your bloodstream, so that your blood does not clot at all. In that case, you could suffer from life-threatening bleeding. For you, the drug works “too well.”
On the other hand, you could break down the drug so quickly that very little ends up in your bloodstream, so it won’t actually prevent clots from forming. Warfarin won’t work for you.
Doctors can test for the genes responsible for these different responses before prescribing warfarin. They can also now test for genes that affect how well certain antidepressants, painkillers, cancer drugs, blood pressure medications, and other pharmaceuticals work. The tests aren’t yet routine and are often only conducted once you have had some problem with a particular drug. But, with the costs of sequencing declining and expected to decline further in the next decade or two, we will all carry electronic versions of our genomes like a credit card in our wallets, on a key fob, or in some as yet unimagined form so that medicines prescribed to us can be more assuredly predicted to be both safe and effective.
When you weed the garden, you must get hold of the weed’s root to be successful. That holds for efforts to treat illness too. I doubt there will ever be weed-free gardens. Nor will we ever eliminate all diseases even once the power to predict and prevent has been fully developed. But any disease is best tackled as close to the source as possible, which, in most cases, is our genes.
This isn’t a new idea. Scientists have been trying for decades to develop gene therapy approaches that would simply replace faulty DNA and avoid disease entirely. However, getting new genes reliably into cells has so far eluded our best efforts. Perhaps the next best option is to camouflage the faulty messages coming from mutant genes from the rest of the cell. If the faulty part of the message isn’t “seen” by the cell’s protein making machinery, the defective genetic information can’t cause problems. If the protein making machinery, the ribosome, sees something else, something better, the gene’s message will have been camouflaged, and the cell will build a protein according to what it sees.
When that happens, the previously inevitable disease will be avoided.
This remarkably simple concept is inspiring an entirely new field of work in the pharmaceutical industry.
Tricking the body into ignoring faulty genetic instructions doesn’t require complex efforts to insert new genetic material or delete faulty DNA. It can be accomplished by using drugs made from building blocks remarkably similar to naturally occurring genetic material, the DNA itself. These drugs can camouflage or patch parts of the message that come from our genes. This will stop the cell producing a disease-causing protein, or allow a healthy version of the message to be delivered, rather than a faulty one. If a healthy message is delivered to the cellular machinery carrying vital blueprints, a missing protein may at last be generated.
This is a fundamental change in treatment strategy that promises to render some of the most vexing of today’s diseases treatable. Many patients with rare diseases today, like Deepak, if he is still alive, simply don’t make an essential protein. That failure to create a single, critical molecule out of the approximately 150,000 protein molecules produced every day by the human body plays out with devastating effect. What’s worse is that with a very few exceptions, modern pharmaceuticals today offer nothing more to these patients than they did when I started studying medicine in 1975.
Scientists are making tremendous advances in blocking or camouflaging faulty messages with very precisely targeted new drugs. The work, which has been conducted in animals first, is rapidly maturing. We are now in a position to harness the formidable global resources of science and medicine to find effective and safe treatments for more diseases today than at any previous point in human history.
For families like the Singhs, sadly, it may be too late, but for the next generation of Duchenne boys, we will be close to providing them with highly specific and personal treatment, perhaps at birth, that will allow them to lead full and active lives.
And this revolution won’t be limited just to those suffering rare diseases. The shift from an illness to a wellness model, employing information about your genetic makeup to predict subsequent disease and prescribing very precisely targeted medicines, will benefit everyone. Those suffering from common and rare ailments alike.
The genomic information revolution already permits some of today’s downstream therapeutics to be used safely with more confidence. That predictive capacity will only grow. The favored approach for developing new drugs even for common diseases will soon be to tackle the faulty messages from mutant genes.
These new technologies will necessitate significant changes in medical education, regulatory review and approval, marketing and reimbursement. These changes are already starting. The U.S. Food and Drug Administration recognizes the need to change. In their October 2011 publication “Driving Biomedical Innovation: Initiatives to Improve Products for Patients,” they acknowledge the challenges facing new drugs inherent in the current regulatory pathway, and the need for change to ensure continuing American leadership of global drug development.
As medicine evolves, so too will the physician’s work. The next generation of doctors will routinely interpret genomic data and guide you to make lifestyle decisions earlier, including encouraging you to use these highly targeted medications before you develop symptoms. It’s an entirely different skills set from those needed now to battle already established disease, which is what doctors are trained for today. Physicians will still need to monitor for early disease, but the effort will become much less invasive, more community-based, and focused especially on you if you are predicted to be at higher risk.
It’s even possible that huge hospital facilities will go out of style because the extensive testing and intervention we use them for nowadays will no longer be necessary.
Drug development and regulation will adapt in exciting ways. Currently, the multiple steps of testing necessary for a drug to be proven safe and effective too often rely on a good dose of luck. With science able to more precisely predict how new drugs will work, in whom, when and at what dose, luck will no longer be a principal ingredient of that process. Such precisely targeted medicines might be tested on fewer patients and still be proven safe.
These fundamental changes will lead to alterations in how personalized medicines are manufactured, labeled, distributed, stored, marketed, sold, and reimbursed.
And that will trigger a change in the way society views the role of medicine and doctors.
Currently, you may turn to your physician with a disease already established and their skill at diagnosis and prescribing treatment or performing surgery clearly bears on the outcome. In the future, their most valuable skill will be helping you make wiser lifestyle, behavioral, and medical decisions. The doctor-patient relationship will be different, less paternalistic perhaps, but no less powerful.
And with the benefit of knowledge about your personal genetic makeup, the relationship you have with your physician will become much more personal. After all, your physician will have access to the blueprint that makes you “you.”
With this book, I dare to dream about a world where healthcare and lifestyle decisions will one day be taught alongside reading, writing and arithmetic at the heart of education available for all. It will still be up to you whether to follow the advice from your doctor, but in the future the confidence with which that advice is given will be much greater than today. This is truly the greatest leap that medicine has ever made, and with it, medicine will keep us well enough to enjoy a long, happy, and healthy life. For those unlucky enough to have disease-causing genetic mutations, the new era will allow you to truly defy your DNA.