Genomics has, in a remarkably short period of time, led to revelations across a wide range of scientific disciplines. It’s helped us better understand everything from cancer to dinosaurs to the intricacies of sexual selection.
In medicine, the study of genomics is already saving lives and driving trillions of dollars of economic activity. The ability to sequence and analyze an organism’s genome – the entire sequence of its DNA – is reshaping practices in the field. It’s also leading to important questions about the technological, ethical, legal, and economic realities of this new genomic era.
The ability to sequence and analyze an organism’s genome is revolutionizing medicine.
Today, everyday applications are relatively commonplace and becoming more so. Personalized medicine – medicine targeting people based on their DNA sequence – is transforming cancer research and treatment, risk assessment, drug development, and clinical practices (the tests and procedures patients experience at the doctor’s office).
“Genomic medicine, personalized medicine has already arrived,” said Gerardo Jimenez-Sanchez, founding director of the National Institute of Genomic Medicine in Mexico and director of the Genomic Medicine for Health Care Innovation program at Harvard T.H. Chan School of Public Health’s Center for Executive and Continuing Professional Education.
“It’s not something of the future,” he said. “The initial clinical applications have arrived, and we should be conscious of the fact it’s already here.”
And that’s just in medicine. Don’t forget genetic and genomic innovations in areas such as agriculture and energy.
The economic impact has been unmistakable. In his 2013 State of the Union Address, President Barack Obama said, “Every dollar we invested to map the human genome returned $140 to our economy – every dollar.”
The Battelle Memorial Institute, in 2013, calculated that genomic research, between 1988 and 2012, drove $965 billion in economic impact in the United States alone. In just the year 2012, human genome sequencing and related industry drove $65 billion in economic output, created $19 billion in personal income, and supported, directly and indirectly, 152,000 jobs – again, just in the United States.
“All of us in genetics think we’re going through a golden age,” said Raju Kucherlapati, from Harvard Medical School’s Department of Genetics, explaining the accumulation of knowledge is mounting at an “ever increasing pace.”
At the same time, genomic and genetic applications are not a magic wand that can cure every disease and solve every challenge in health care.
“There is a lot of hype. There is a lot of hope,” said David Hunter, a cancer researcher who serves as dean for academic affairs at Harvard Chan School. What’s important to consider, he said, is “what’s real.”
‘Within the last five years’
That’s how new – “within the last five years” – many mainstream clinical applications in genetics and genomics are, according to Kucherlapati.
He pointed to a famous example of DNA sequencing in clinical practice. It’s the story of Nicholas Volker, a then 4-year-old boy who had undergone more than 100 surgeries in his lifetime, including a colon removal, and basically lived in a hospital as doctors tried to identify the rare disorders he was dying from. It was 2009, and his doctors, having tried everything else, turned to something virtually untried, DNA sequencing, to see if they could identify gene mutations leading to his disorders.
“They found he had two changes in his DNA, and they figured he would respond well to a bone marrow transplant. Now he lives a normal life,” Kucherlapati said. Forbes Magazine called him “The First Child Saved by DNA Sequencing.”
Today, DNA sequencing has cut down on “diagnostic odysseys” in identifying rare disorders, which, when the approximately 7,000 known rare disorders are taken together, affect one in 10 Americans, Kucherlapati said. That’s a giant leap for mankind.
DNA sequencing moves into the doctor’s office
In fact, DNA sequencing, today, has become relatively commonplace, though it will become more common in years to come.
Until recently, pregnant women over 35 would receive an amniocentesis so doctors could test the fetus for genetic problems. This invasive trans-abdominal insertion – it involves sticking a needle into the mother’s abdomen – was the norm for 20 years. Today, said Kucherlapati, researchers have learned that some fetal DNA is present in the mother’s blood. Doctors can now take a small blood sample to test for the same genetic problems. “The whole [fetal testing] industry is changing,” he said.
Another example is with lung cancer, said Hunter. Tumors that exhibit an overexpression of the epidermal growth factor receptor (EGFR) often respond well to certain types of drugs, though only a small percentage of lung cancers fall into this category. Nonetheless, “In Boston, at teaching hospitals, everyone gets their lung cancer tested for EGFR overexpression. So this is essentially now mainstream,” he said.
“Every dollar we invested to map the human genome returned $140 to our economy.”
For more than a generation, newborn babies have been tested for phenylketonuria, or PKU, an inherited genetic disorder whose victims can develop intellectual disabilities if they eat foods high in protein (when detected early, it can be managed with diet). Newborns are now, often, screened for cystic fibrosis. As time goes on and DNA sequencing technology gets more cost-effective, newborns could be tested for more and more genetic problems.
Crucially, this technology will help medical practitioners assess individuals’ health risks, according to Jimenez-Sanchez and Kucherlapati. Those with a genetic risk of heart disease, for instance, could take preventative measures early on – say, by controlling their diet – to improve their overall health and quality of life. This would also help prevent their genetic risk from eventually becoming a serious and costly medical problem. When used wisely, DNA sequencing can inform preventative care strategies, improve people’s lives, and help keep health care costs down.
Assessing risk: the Angelina Jolie affair
A famous example of using genomic information to assess risk involves Academy Award-winning Hollywood actress Angelina Jolie. In 2013, she wrote about her decision to have a double mastectomy, which was based on family history and genetic testing that determined she had a mutated BRCA1 gene, which increases the risk of breast cancer. Two years later she had her ovaries and fallopian tubes removed due to the genetic risk of developing ovarian cancer. Having lost her own mother, grandmother, and aunt to cancer, she “decided to be proactive and minimize the risk as much as possible,” she wrote in 2013.
“That’s a very well-known case of how genomics can lead to personal decisions,” said Jimenez-Sanchez, “but I would say that’s an extreme example.”
“More and more we’re learning that genetic mutations can make someone at risk for cardiovascular disease or immune disorders such as asthma,” he said, describing less extreme examples, “and we can take care of those individuals, even if they don’t have any symptoms.”
If medical practitioners know there’s a risk – which, crucially, depends on their ability to properly assess the DNA evidence – they can begin “investing time and effort to try to catch that very disease at its very earliest stage,” he said.
Identifying and treating cancers
DNA sequencing has given clinical practitioners some of the best shots at identifying and treating cancers.
Genomic information has “opened our eyes” to the diverse characteristics of cancers and helped inform advances in drug development, Hunter said.
“Each tumor in each person is actually different,” he said, “so there may be characteristics in a specific cancer, in a particular person, that make it quite different than a cancer in another person.” It explains why one-size-fits all treatments, such as chemotherapy, aren’t effective with all people.
And it helps explain why big drug companies, such as Pfizer and Roche, are working on “targeted therapies for cancer,” said Kucherlapati.
Jimenez-Sanchez put it this way: “We used to classify tumors based on where they appear.” – lung cancer, prostate cancer, breast cancer, etc. – “More and more we’ve learned that tumors have certain mutations in common that make them more responsive or non-responsive to chemotherapy.”
He added, “By analyzing the DNA of those tumors, we can learn what therapy would be effective to that specific tumor, regardless of the tissue or the organ where that tumor arises.”
Advances in genomic and genetic screening can also help identify the presence of cancer, particularly cancer recurrences, earlier and with less invasive methods.
“This technology will help medical practitioners assess individuals’ health risks.”
“Often the only way of working out that [a] cancer has recurred is to see it, on an X-ray or an MRI, and in order to see it, it had to be a certain size, or you had to do an invasive procedure,” said Hunter. “So, with bladder cancer, you have to do a cystoscopy to have a look, and that’s not a pleasant procedure. Now, there are tools where, for instance, you look at the cancer cells in the urine, and if you see them recurring, you know the cancer has recurred.”
Health care systems, more and more, are setting up sequencing facilities, or turning to independently owned facilities, to conduct this type of work.
Meanwhile, pharmaceutical companies are investing billions of dollars into developing new, cancer-fighting drugs.
Pharmacogenomics: different people, different pills
Pharmacogenomics, explained Jimenez-Sanchez, involves assessing an individual’s genome and targeting specific drug treatments to fit that individual. Due to genetic variations, individuals can respond differently to common drugs, and specialized drugs can often be used with people – sometimes only a handful of them – who have rare disorders caused by genetic mutations.
The U.S. Food and Drug Administration maintains a list of drugs “where there is sufficient genomic evidence to make the consumer aware there is a pharmacogenomics test to explore how that individual would respond to that certain medication,” he said.
Or, as the old saying goes, “Liquor before beer, in the clear … and be cautious with Cevimeline if your CYP2D6 gene metabolizes the drug poorly.”
These advances have made “a huge amount of financial impact,” with drug companies showing a “huge amount of interest,” said Kucherlapati.
For cancer, there are “at least half a dozen [drugs] that are already in the market” – for diseases like colon cancer and lung cancer – “[that] will be effective if the tumor has that specific mutation for which the drug is designed,” said Jimenez-Sanchez.
It’s big business, and, arguably, high stakes business, with drug companies investing, “at a minimum, several hundred million dollars” to bring a drug to market, said Hunter.
‘There are a few catches’
Before you take out a second mortgage on your home to start a pharmaceutical company, you should be aware “there are a few catches,” said Hunter.
As of today, genomic innovation can’t outmaneuver market realities, and it can’t compete with the frightening complexity of cancer – at least not yet.
“One catch,” said Hunter, “is, like most drugs for cancer, given enough time, tumors will become resistant to the drug, and so sometimes, with some of these drugs, tumors melt away spectacularly but come back after a few months or a year or two … by and large, these drugs aren’t curative, they’re just keeping the cancer at bay.”
Hunter elaborated: “Cancer is complex. Even a single tumor may have a different genetic makeup at one side of the tumor versus the opposite side. So, a drug that is given due to a biopsy on one side might shrink the tumor, but it won’t treat the whole tumor. Cancers, being rapidly dividing ecosystems, are mutating fairly fast. The probability of resistance to any particular drug, over time, is very high.”
“So,” he added, “you’re unambiguously giving people several more months of life, which is hard to put a price on, so that’s a success. But, by and large we’re not getting cures, and many of these drugs add months to life, not years.”
Then there’s the cost of bringing a drug to market, which often dwarfs the potential demand for the drug, a.k.a. the number of people who need it. There’s laboratory testing, animal testing, multiple phases of human testing. If you compare a drug company’s research and development budget to the number of that company’s successfully approved drugs, those drugs cost hundreds of millions, even a billion dollars to make, Hunter said.
Advances in genomic medicine have made a huge amount of financial impact.
With those realities, “The drug companies have to then pick and choose targets they’re going to try to make a drug for,” Hunter explained.
“Particularly in the context of drugs that work only for a subset of people, that’s not an ideal market,” he said. “Particularly if [the drug] only works for months.”
It’s not uncommon for drugs that treat rare diseases to cost $10,000 or even $30,000 a month, Hunter said, especially if the drug treats only a few hundred people in the world. “Now we’re seeing that level of pricing … in [drugs for] breast cancer or prostate cancer or colon cancer or lung cancer,” he said.
Is the genetic makeup of your tumor common enough for a drug company to target? Is your drug cheap enough for an increasingly cost-conscious health care system to buy?
Developing an ethical and legal framework for genomics
As this work continues to jump from academic research labs into the mainstream, certain ethical, legal, and policy implications arise. If it’s known someone is genetically predisposed to a disease, it could lead to employment or health insurance discrimination, for instance. In the United States, the Genetic Information Nondiscrimination Act is intended to protect people against such discrimination, but in general, “we need to make sure we have appropriate ethical and legal foundations to conduct ourselves properly, to help and not harm people,” said Jimenez-Sanchez.
He continued: “There are challenges we have to be aware of in terms of what information we want to know about our genome and what kind of information is not ready for us to learn about – for instance, when there is nothing to do for someone who has a predisposition to a devastating disease.”
Also, policies should be established surrounding “who has the right to make decisions based on our human genome,” he said. “Would that be our parents if we are minors? Would that be our children if we are elderly people without really full capacity to make those decisions?”
Issues such as privacy, informed consent, and intellectual property all come into play as genomic research and technology moves forward.
Accessibility is another ethical issue. “There’s still a long way and a lot of work to do in bringing technologies to a lower cost, so they are accessible to everyone,” said Jimenez-Sanchez, adding, “when I say everyone I mean people from around the world, not only from the developed world.”
The road ahead
“Clearly, genomic medicine is here, and here to stay, and we will see important challenges in the next decade,” said Jimenez-Sanchez.
Some of those challenges involve technology and costs – the need to have “a quick, reliable technology to read DNA at a clinical quality level” that’s also “a cost benefit to the medical system,” he said.
“Another major challenge is, how do we train current medical practitioners in genomics?” he added. “Genomics is a discipline that has emerged very recently, in the last 10 years, and we need to make this translation into having doctors and other medical professionals analyze and interpret data and drive appropriate medical decisions based on their analysis of that data.”
What’s more, policy makers need to familiarize themselves with this rapidly evolving technology in order to make informed, ethically appropriate laws and policies surrounding genomics.
Said Hunter, “It is also important to realize that many of these changes are incremental. There are lots of incremental changes that add up to a substantial change. Some of the changes will be transformative, but they’ll be a spectrum of changes in practice that will be on a spectrum of efficacy. Some of them won’t work at all.”
He continued: “The big question is, how do we responsibly use the technologies that work while not driving medical cost inflation by using technologies that should work but don’t?”
Drs. Jimenez-Sanchez, Hunter, and Kucherlapati teach in Genomic Medicine for Health Care Innovation: Applications and Implications at Harvard T.H. Chan School of Public Health.