Brave New Cures

Genetic testing’s expansion of medical horizons

Your father feels unwell and you take him to the hospital. They do various tests and take blood samples. The doctors tell you that all he needs is medication. But they also tell you that he must never, ever take the commonly prescribed medication for this illness. They prescribe a slightly different alternative. Within a few weeks he looks and feels great.

Your sister gives birth. Before she goes home from the hospital, the staff takes a blood sample from her healthy newborn. A week later, you accompany her to her first postpartum appointment with her doctor, who proceeds to lay a stack of documents on her desk. The child has an increased chance of developing heart disease at age 48, will likely get dementia at age 74, and should try to stay away from sweets as there is an elevated risk of diabetes.

Your other sister develops ovarian cancer. Doctors are able to remove the tumour but due to its aggressive nature, it has spread. Her doctor searches a database and finds a treatment that will specifically target and destroy the cancer cells like a homing missile, with little impact on the rest of her body. She is successfully treated and the cancer repelled.

In all three of these cases, doctors are doing something they would not have done even a decade ago. They have used the sequencing of someone’s DNA to gain tremendous insight into a current health crisis and to anticipate future health challenges. This is personalized medicine. It is exactly what the name implies. Health treatment tailored to you, based on the uniqueness of your DNA.

Armed with this sort of information, parents can make choices about how to raise a child. People can develop the best habits to reduce health risks. Diseases can be rapidly identified and cured. According to Pieter Cullis in The Personalized Medicine Revolution: How Diagnosis and Treating Disease Are About to Change Forever, this is the future of medicine. And it is a future coming at revolutionary speed, thanks in large part to recent scientific advances and technological innovations.

Cullis has written a book for non-experts, but his own expertise is rather impressive. He heads the Life Sciences Institute at the University of British Columbia and has extensive experience in drug design. He and his colleagues are positioned at the leading edge of the charge to bring personalized medicine into practice.

To appreciate this exploding area, one must first understand the basics of our molecular selves. Inside every one of your cells is a blueprint for your body, in some respects for your life. The genome refers to all of the DNA that makes up the chromosomes we inherited from our parents. Our DNA is composed of building blocks called bases, referred to by the abbreviations A, T, G or C. Scattered among our three billion bases are genes, the units of genetic information. Humans possess roughly 21,000 unique genes that each spell out a code to make a protein, which in turn has a particular job in the body. Each person has a unique genome, with lots of slight variations. These differences determine our unique physical appearances, which is obvious at first sight. But these variations in DNA also determine a lot we do not see. And this is what can be critical for both preventive and healing medicine.

It has been appreciated for decades that mutations in our DNA can also have direct health consequences. Sickle cell anemia is caused by a single base change from an A to a T in the gene encoding hemoglobin, a protein needed for red blood cell function. This tiny change alters the properties of hemoglobin and causes a crippling disease. Red blood cells that are normally disc shaped become bent and curved like sickles and painfully block blood flow in those carrying two defective copies of this gene. A single base mutation in genes of the so-called Ras family can cause the production of a mutant Ras protein. Such mutations are found in roughly 25 percent of tumours and because of their abnormal function are thought to contribute to the development of many cancers.

Determining our individual DNA sequence can unlock many mysteries and reveal insight into our health. Cullis states “the sequence of your genome contains detailed and accurate info on your risk for diseases ranging from heart disease to diabetes, to depression and dementia, as well as which drugs might work best for you and which might produce harmful side effects.” When scientists in 1987 first proposed to determine the sequence of the human genome, the task was technically and financially daunting. Following its completion by an international consortium and a private biotech firm in 2003, it was hailed as the biggest advance in genetics since the determination of the DNA structure. According to U.S. president Bill Clinton “With this profound new knowledge, humankind is on the verge of gaining immense, new power.” Craig Venter, one of the leaders in the race to sequence the genome, took a more philosophical view: “The complexities and wonder of how the inanimate chemicals that are our genetic code give rise to the imponderables of the human spirit should keep poets and philosophers inspired for millennia.”

Sequencing a genome 25 years ago might have cost $100 million. Today companies tout the $1,000 genome, about the cost of one MRI scan or two ultrasounds. For Cullis this is a big deal and provides the technological breakthrough that will propel his revolution in personalized medicine.

The human genome sequencing project revealed that humans possess tremendous variation in their DNA sequence. Scientists devote careers to determining what these changes mean, and how we can use this knowledge to improve medical care. It is becoming increasingly understood that even small variants in the billions of letters can tip the balance in an individual from a healthy outcome to illness. As Cullis states “the concept that differences in protein structure, which arise as a result of mutations in your DNA, can cause disease is essential to understanding the importance of a personalized approach to medicine.” Today, personalized medicine is still in its infancy, limited to academic health centres, well-informed patients and technology-keen physicians. But, according to Cullis, that will change rapidly, and he outlines some of the leading applications that he predicts will see widespread implementation in the coming five to ten years.

In fact, Cullis contends that the rapid advances in DNA sequencing will combine with our exploding communications technologies to produce a brave new era of personalized medicine. Medical information websites, chat rooms, even Wikipedia are already empowering patients. Studies show that some patients afflicted with similar diseases have created virtual communities in which they share treatment successes and failures, and personal details. These rapidly expanding web-based communities will, according to Cullis, not only embrace the added element of DNA knowledge, but actually become data sources themselves. Indeed, one goal of personalized medicine is to obtain as much patient data as possible and correlate that to the individual DNA variations. Ideally, certain DNA changes would occur more often in certain patients, and the outcomes of these would then be predictive as new patients are identified. And all this information could easily be carried in apps on our smart phones.

Indeed, after the latest upgrade of my iPhone I discovered a new app (placed there unbeknownst to me by Apple) called Health. It allows me to track my health data, including body measurements, fitness, nutrition, lab test results and vital signs. It even monitors my daily activity without prompting. This app just needs one more tab for DNA data and it will be telling me what to eat, how much to sleep and when to go see my doctor.

Personal genetic empowerment is already enabling some individuals to get their genome sequenced and make life decisions based on the results. Perhaps the best-known example concerns the U.S.-based direct-to-consumer genomic sequencing company 23andMe (referring to the 23 chromosomes humans possess). For $199 and some spit, you can learn about your risk factors for more than 100 health conditions, physical traits and even your ancestry.

One specific and powerful application of personalized medicine applies to adverse drug reactions, possibly the fourth leading cause of death in hospital patients in the United States. When a doctor prescribes a certain drug, the recommended dose is based on clinical trials and thus presumed beneficial. But this assessment is based on averages. Certain people can have severe adverse reactions, even fatal, while others derive no benefit at all.

Genome sequencing has allowed scientists to identify a small number of gene variants that have profound effects on how well a drug is absorbed and metabolized by our bodies. If we rapidly metabolize a drug due to a slight variation in a gene sequence, then the drug cannot deliver its full effect. In contrast, slow metabolizers cannot break down the drug and it remains in their system too long, in effect creating an overdose. Neither situation is desirable. Rapid identification of such patients could avoid many unnecessary deaths per year. Thus, the field of pharmacogenics seeks to understand the genetic basis for this phenomenon and use sequence information to guide patient treatment. In the future, doctors would check your genome data before prescribing any drug. Because the few variants that have already been identified have such profound effects, this arm of personalized medicine is likely to be one of the first that is more widely implemented.

Each cancer harbours mutations in various genes that collectively contribute to the severity and outcome. Tumour samples are routinely biopsied and pathologists make predictions about tumour variety and grade. Genome sequencing of such tumours can provide a far more precise molecular entry point and thus allow a targeted treatment based on the unique properties of the cancer cells. The development of Herceptin to target certain forms of breast cancer and Gleevec to treat chronic myelogenous leukemia are just the beginning of success stories based on such molecular clues.

The area of personalized medicine that is least developed, yet promises to have great impact, is preventive care. Cullis predicts that we will be able to monitor all aspects of our bodily function as shown in analyses of our proteome (the subset of proteins being expressed at a certain time), microbiome (what species of microbes are present in our bodies) and metabolome (how well we are breaking down our nutrients and what our bodies are lacking). Indeed, he predicts that we will wear wristbands, implants or high-tech Band-Aids that will give us minute-by-minute updates on our health status, which, coupled with our complete genome sequence, will prescribe our path to a long healthy life. Armed with this information, we will eat well, exercise and avoid certain behaviour if we possess genetic variants that put us at higher risk.

But this is where I must inject a couple of notes of caution. Will people really start doing the things Cullis suggests? And if so, how many? And how quickly? In some respects, humans can have a curious and irrational way of dealing with risk and probability. So it will be interesting to see what most people actually do with this information about their genetic risk. Virtually everyone knows that smoking greatly increases the chance of lung cancer, yet some continue to smoke. Most people know that a well-balanced diet and exercise are essential to avoid heart disease and diabetes, yet more people are obese and sedentary than ever before. We know that too much sun exposure can cause skin cancer, yet we flock to the beaches. Knowledge does not always translate into changes in behaviour.

Moreover, it is unclear how people will deal with potential access to their personal genetic information. Some may choose the “ignorance is bliss” route, and leave it to medical professionals to sort out. Others may inadvertently learn things they did not really want to know, whether it is a bleak health outlook or different paternity. But others may indeed make constructive changes in their lives to take full advantage of the genetic hand they were dealt. In some cases the information may enable a pre-emptive strike. Angelina Jolie learned through DNA testing that she inherited the BRCA1 mutation that caused her mother to die of breast cancer at age 56. As a result Jolie had a double mastectomy and very publicly shared her story while encouraging others to become empowered through DNA testing.

But Jolie’s story raises another possible concern with the brave new world Cullis describes. Might it exacerbate inequality in our healthcare system? Will these innovations increase the ability of wealthier people to bypass long waiting times for diagnostic and surgical procedures? Will these self-diagnostic techniques and helpful knowledge about risks only be accessed by the well educated? Perhaps. But Cullis hints that the net effect can go the other way with the right healthcare policies. These innovations are lowering the cost of personal health-relevant knowledge. And the ability to access that knowledge is getting cheaper and easier thanks to the growing sophistication and capacity of basic communication devices that all but the very poorest are acquiring. If our public health system uses these innovations effectively in its provision of universally provided services, the ultimate effect could well be to increase healthcare equality.

Overall, Cullis presents a compelling and informative look into the molecular revolution in personalized medicine. Whether it will happen as soon as Cullis predicts is still unclear, but it is the future of medicine for certain. He provides many examples and scenarios to demonstrate his claims and raises ethical and social issues that need to be considered. In this personalized medicine explosion we will be deluged with information and Cullis’s book is an excellent starting point to get our bearings.