Precision Medicine concept
Is the value of "personalized medicine" over-promised? Why is the quality of health care declining for many people despite the pace of innovation? Do patients and doctors have conflicting priorities? What is the best path forward?
"How do we generate evidence for value, which is what everyone is asking for?"
Some of the country's leading medical experts recently debated these questions at the prestigious annual Personalized Medicine Conference, held at Harvard Medical School in Boston, and LeapsMag was there to bring you the inside scoop.
Personalized Medicine: Is It Living Up to the Hype?
The buzzworthy phrase "personalized medicine" has been touted for years as the way of the future—customizing care to patients based on their predicted responses to treatments given their individual genetic profiles or other analyses. Since the initial sequencing of the human genome around fifteen years ago, the field of genomics has exploded as the costs have dramatically come down – from $2.7 billion to $1000 or less today. Given cheap access to such crucial information, the medical field has been eager to embrace an ultramodern world in which preventing illnesses is status quo, and treatments can be tailored for maximum effectiveness. But whether that world has finally arrived remains debatable.
"I've been portrayed as an advocate for genomics, because I'm excited about it," said Robert C. Green, Director of the Genomes2People Research Program at Harvard Medical School, the Broad Institute, and Brigham and Women's Hospital. He qualified his advocacy by saying that he tries to remain 'equipoised' or balanced in his opinions about the future of personalized medicine, and expressed skepticism about some aspects of its rapid commercialization.
"I have strong feelings about some of the [precision medicine] products that are rushing out to market in both the physician-mediated space and the consumer space," Green said, and challenged the value and sustainability of these products, such as their clinical utility and ability to help produce favorable health outcomes. He asked what most patients and providers want to know, which is, "What are the medical, behavioral, and economic outcomes? How do we generate evidence for value, which is what everyone is asking for?" He later questioned whether the use of 'sexy' and expensive diagnostic technologies is necessarily better than doing things the old-fashioned way. For instance, it is much easier and cheaper to ask a patient directly about their family history of disease, instead of spending thousands of dollars to obtain the same information with pricey diagnostic tests.
"Our mantra is to try to do data-driven health...to catch disease when it occurs early."
Michael Snyder, Professor & Chair of the Department of Genetics and Director of the Center for Genomics and Personalized Medicine at Stanford University, called himself more of an 'enthusiast' about precision medicine products like wearable devices that can digitally track vital signs, including heart rate and blood oxygen levels. "I'm certainly not equipoised," he said, adding, "Our mantra is to try to do data-driven health. We are using this to try to understand health and catch disease when it occurs early."
Snyder then shared his personal account about how his own wearable device alerted him to seek treatment while he was traveling in Norway. "My blood oxygen was low and my heart rate was high, so that told me something was up," he shared. After seeing a doctor, he discovered he was suffering from Lyme disease. He then shared other similar success stories about some of the patients in his department. Using wearable health sensors, he said, could significantly reduce health care costs: "$245 billion is spent every year on diabetes, and if we reduce that by ten percent we just saved $24 billion."
From left, Robert Green, Michael Snyder, Sandro Galea, and Thomas Miller.
(Courtesy Rachele Hendricks-Sturrup)
A Core Reality: Unresolved Societal Issues
Sandro Galea, Dean and Professor at Boston University's School of Public Health, coined himself as a 'skeptic' but also an 'enormous fan' of new technologies. He said, "I want to make sure that you all [the audience] have the best possible treatment for me when I get sick," but added, "In our rush and enthusiasm to embrace personalized and precision medicine approaches, we have done that at the peril of forgetting a lot of core realities."
"There's no one to pay for health care but all of us."
Galea stressed the need to first address certain difficult societal issues because failing to do so will deter precision medicine cures in the future. "Unless we pay attention to domestic violence, housing, racism, poor access to care, and poverty… we are all going to lose," he said. Then he quoted recent statistics about the country's growing gap in both health and wealth, which could potentially erode patient and provider interest in personalized medicine.
Thomas Miller, the founder and partner of a venture capital firm dedicated to advancing precision medicine, agreed with Galea and said that "there's no one to pay for health care but all of us." He recalled witnessing 'abuse' of diagnostic technologies that he had previously invested in. "They were often used as mechanisms to provide unnecessary care rather than appropriate care," he said. "The trend over my 30-year professional career has been that of sensitivity over specificity."
In other words: doctors rely too heavily on diagnostic tools that are sensitive enough to detect signs of a disease, but not accurate enough to confirm the presence of a specific disease. "You will always find that you're sick from something," Miller said. He lamented the counter-productivity and waste brought on by such 'abuse' and added, "That's money that could be used to address some of the problems that you [Galea] just talked about."
Do Patients and Providers Have Conflicting Priorities?
Distrust in the modern health care system is not new in the United States. That fact that medical errors were the third leading cause of death in 2016 may have fueled this mistrust even more. And the level of mistrust appears correlated with race; a recent survey of 118 adults between 18 to 75 years old showed that black respondents were less likely to trust their doctors than the non-Hispanic white respondents. The black respondents were also more concerned about personal privacy and potentially harmful hospital experimentation.
"The vast majority of physicians in this country are incentivized to keep you sick."
As if this context weren't troubling enough, some of the panelists suggested that health care providers and patients have misaligned goals, which may be financially driven.
For instance, Galea stated that health care is currently 'curative' even though that money is better spent on prevention versus cures. "The vast majority of physicians in this country are incentivized to keep you sick," he declared. "They are paid by sick patient visits. Hospital CEOs are paid by the number of sick people they have in their beds." He highlighted this issue as a national priority and mentioned some case studies showing that the behaviors of hospital CEOs quickly change when payment is based on the number of patients in beds versus the number of patients being kept out of the beds. Green lauded Galea's comment as "good sense."
Green also cautioned the audience about potential financial conflicts of interest held by proponents of precision medicine technologies. "Many of the people who are promoting genomics and personalized medicine are people who have financial interests in that arena," he warned. He emphasized that those who are perhaps curbing the over-enthusiasm do not have financial interests at stake.
What is the Best Path Forward for Personalized Medicine?
As useful as personalized medicine may be for selecting the best course of treatment, there is also the flip side: It can allow doctors to predict who will not respond well—and this painful reality must be acknowledged.
Miller argued, "We have a duty to call out therapies that won't work, that will not heal, that need to be avoided, and that will ultimately lead to you saying to a patient, 'There is nothing for you that will work.'"
Although that may sound harsh, it captures the essence of this emerging paradigm, which is to maximize health by using tailored methods that are based on comparative effectiveness, evidence of outcomes, and patient preferences. After all, as Miller pointed out, it wouldn't do much good to prescribe someone a regimen with little reason to think it might help.
For the hype around personalized medicine to be fully realized, Green concluded, "We have to prove to people that [the value of it] is true."
Phages, which are harmless viruses that destroy specific bacteria, are becoming useful tools to protect our food supply.
Food producers and packagers fight bacteria by potent chemicals, with chlorine being the go-to disinfectant. Cattle carcasses, for example, are typically washed by chlorine solutions as the animals' intestines are removed. Leafy greens are bathed in water with added chlorine solutions. However, because the same "bath" can be used for multiple veggie batches and chlorine evaporates over time, the later rounds may not kill all of the bacteria, sparing some. The natural and organic producers avoid chlorine, substituting it with lactic acid, a more holistic sanitizer, but even with all these efforts, some pathogens survive, sickening consumers and causing food recalls. As we farm more animals and grow more produce, while also striving to use fewer chemicals and more organic growing methods, it will be harder to control bacteria's spread.
"It took us a long time to convince the FDA phages were safe and efficient alternatives. But we had worked with them to gather all the data they needed, and the FDA was very supportive in the end."
Luckily, bacteria have their own killers. Called bacteriophages, or phages for short, they are viruses that prey on bacteria only. Under the electron microscope, they look like fantasy spaceships, with oblong bodies, spider-like legs and long tails. Much smaller than a bacterium, phages pierce the microbes' cells with their tails, sneak in and begin multiplying inside, eventually bursting the microbes open—and then proceed to infect more of them.
The best part is that these phages are harmless to humans. Moreover, recent research finds that millions of phages dwell on us and in us—in our nose, throat, skin and gut, protecting us from bacterial infections as part of our healthy microbiome. A recent study suggested that we absorb about 30 billion phages into our bodies on a daily basis. Now, ingeniously, they are starting to be deployed as anti-microbial agents in the food industry.
A Maryland-based phage research company called Intralytix is doing just that. Founded by Alexander Sulakvelidze, a microbiologist and epidemiologist who came to the United States from Tbilisi, the capital of Georgia, Intralytix makes and sells five different FDA-approved phage cocktails that work against some of the most notorious food pathogens: ListShield for Listeria, SalmoFresh for Salmonella, ShigaShield for Shigella, another foodborne bug, and EcoShield for E.coli, including the infamous strain that caused the Jack in the Box outbreak in 1993 that killed four children and sickened 732 people across four states. Last year, the FDA granted its approval to yet another Intralytix phage for managing Campylobacter contamination, named CampyShield. "We call it safety by nature," Sulakvelidze says.
Intralytix grows phages inside massive 1500-liter fermenters, feeding them bacterial "fodder."
Photo credit: Living Radiant Photography
Phage preparations are relatively straightforward to make. In nature, phages thrive in any body of water where bacteria live too, including rivers, lakes and bays. "I can dip a bucket into the Chesapeake Bay, and it will be full of all kinds of phages," Sulakvelidze says. "Sewage is another great place to look for specific phages of interest, because it's teeming with all sorts of bacteria—and therefore the viruses that prey on them."
In lab settings, Intralytix grows phages inside massive 1500-liter fermenters, feeding them bacterial "fodder." Once phages multiply enough, they are harvested, dispensed into containers and shipped to food producers who have adopted this disinfecting practice into their preparation process. Typically, it's done by computer-controlled sprayer systems that disperse mist-like phage preparations onto the food.
Unlike chemicals like chlorine or antibiotics, which kill a wide spectrum of bacteria, phages are more specialized, each feeding on specific microbial species. A phage that targets salmonella will not prey on listeria and vice versa. So food producers may sometimes use a combo of different phage preparations. Intralytix is continuously researching and testing new phages. With a contract from the National Institutes of Health, Intralytix is expanding its automated high-throughput robot that tests which phages work best against which bacteria, speeding up the development of the new phage cocktails.
Phages have other "talents." In her recent study, Jaroni found that phages have the ability to destroy bacterial biofilms—colonies of microorganisms that tend to grow on surfaces of the food processing equipment, surrounding themselves with protective coating that even very harsh chemicals can't crack.
"Phages are very clever," Jaroni says. "They produce enzymes that target the biofilms, and once they break through, they can reach the bacteria."
Convincing the FDA that phages were safe to use on food products was no easy feat, Sulakvelidze says. In his home country of Georgia, phages have been used as antimicrobial remedies for over a century, but the FDA was leery of using viruses as food safety agents. "It took us a long time to convince the FDA phages were safe and efficient alternatives," Sulakvelidze says. "But we had worked with them to gather all the data they needed, and the FDA was very supportive in the end."
The agency had granted Intralytix its first approval in 2006, and over the past 10 years, the company's sales increased by over 15-fold. "We currently sell to about 40 companies and are in discussions with several other large food producers," Sulakvelidze says. One indicator that the industry now understands and appreciates the science of phages was that his company was ranked as Top Food Safety Provider in 2021 by Food and Beverage Technology Review, he adds. Notably, phage sprays are kosher, halal and organic-certified.
Intralytix's phage cocktails to safeguard food from bacteria are approved for consumers in addition to food producers, but currently the company sells to food producers only. Selling retail requires different packaging like easy-to-use spray bottles and different marketing that would inform people about phages' antimicrobial qualities. But ultimately, giving people the ability to remove pathogens from their food with probiotic phage sprays is the goal, Sulakvelidze says.
It's not the company's only goal. Now Intralytix is going a step further, investigating phages' probiotic and therapeutic abilities. Because phages are highly specialized in the bacteria they target, they can be used to treat infections caused by specific pathogens while leaving the beneficial species of our microbiome intact. In an ongoing clinical trial with Mount Sinai, Intralytix is now investigating a potential phage treatment against a certain type of E. coli for patients with Crohn's disease, and is about to start another clinical trial for treating bacterial dysentery.
"Now that we have proved that phages are safe and effective against foodborne bacteria," Sulakvelidze says, "we are going to demonstrate their potential in therapeutic applications."
This article was first published by Leaps.org on October 27, 2021.