An attacking rogue hippo, giant jumping spiders, even a coup in Timbuktu couldn't knock out Tom Patterson, but now he was losing the fight against a microscopic bacteria.
Death seemed inevitable, perhaps hours away, despite heroic efforts to keep him alive.
It was the deadly drug-resistant superbug Acinetobacter baumannii. The infection struck during a holiday trip with his wife to the pyramids in Egypt and had sent his body into toxic shock. His health was deteriorating so rapidly that his insurance company paid to medevac him first to Germany, then home to San Diego.
Weeks passed as he lay in a coma, shedding more than a hundred pounds. Several major organs were on the precipice of collapse, and death seemed inevitable, perhaps hours away despite heroic efforts by a major research university hospital to keep Tom alive.
Tom Patterson in a deep coma on March 14, 2016, the day before phage therapy was initiated.
(Courtesy Steffanie Strathdee)
Then doctors tried something boldly experimental -- injecting him with a cocktail of bacteriophages, tiny viruses that might infect and kill the bacteria ravaging his body.
It worked. Days later Tom's eyes fluttered open for a few brief seconds, signaling that the corner had been turned. Recovery would take more weeks in the hospital and about a year of rehabilitation before life began to resemble anything near normal.
In her new book The Perfect Predator, Tom's wife, Steffanie Strathdee, recounts the personal and scientific ordeal from twin perspectives as not only his spouse but also as a research epidemiologist who has traveled the world to track down diseases.
Part of the reason why Steff wrote the book is that both she and Tom suffered severe PTSD after his illness. She says they also felt it was "part of our mission, to ensure that phage therapy wasn't going to be forgotten for another hundred years."
Tom Patterson and Steffanie Strathdee taking a first breath of fresh air during recovery outside the UCSD hospital.
(Courtesy Steffanie Strathdee)
From Prehistoric Arms Race to Medical Marvel
Bacteriophages, or phages for short, evolved as part of the natural ecosystem. They are viruses that infect bacteria, hijacking their host's cellular mechanisms to reproduce themselves, and in the process destroying the bacteria. The entire cycle plays out in about 20-60 minutes, explains Ben Chan, a phage research scientist at Yale University.
They were first used to treat bacterial infections a century ago. But the development of antibiotics soon eclipsed their use as medicine and a combination of scientific, economic, and political factors relegated them to a dusty corner of science. The emergence of multidrug-resistant bacteria has highlighted the limitations of antibiotics and prompted a search for new approaches, including a revived interest in phages.
Most phages are very picky, seeking out not just a specific type of bacteria, but often a specific strain within a family of bacteria. They also prefer to infect healthy replicating bacteria, not those that are at rest. That's what makes them so intriguing to tap as potential therapy.
Tom's case was one of the first times that phages were successfully infused into the bloodstream of a human.
Phages and bacteria evolved measures and countermeasures to each other in an "arms race" that began near the dawn of life on the planet. It is not that one consciously tries to thwart the other, says Chan, it's that countless variations of each exists in the world and when a phage gains the upper hand and kills off susceptible bacteria, it opens up a space in the ecosystem for similar bacteria that are not vulnerable to the phage to increase in numbers. Then a new phage variant comes along and the cycle repeats.
Robert "Chip" Schooley is head of infectious diseases at the University of California San Diego (UCSD) School of Medicine and a leading expert on treating HIV. He had no background with phages but when Steff, a friend and colleague, approached him in desperation about using them with Tom, he sprang into action to learn all he could, and to create a network of experts who might provide phages capable of killing Acinetobacter.
"There is very little evidence that phage[s] are dangerous," Chip concluded after first reviewing the literature and now after a few years of experience using them. He compares broad-spectrum antibiotics to using a bazooka, where every time you use them, less and less of the "good" bacteria in the body are left. "With a phage cocktail what you're really doing is more of a laser."
Collaborating labs were able to identify two sets of phage cocktails that were sensitive to Tom's particular bacterial infection. And the FDA acted with lightning speed to authorize the experimental treatment.
A bag of a four-phage "cocktail" before being infused into Tom Patterson.
(Courtesy Steffanie Strathdee)
Tom's case was scientifically important because it was one of the first times that phages were successfully infused into the bloodstream of a human. Most prior use of phages involved swallowing them or placing them directly on the area of infection.
The success has since sparked a renewed interest in phages and a reexamination of their possible role in medicine.
Over the two years since Tom awoke from his coma, several other people around the world have been successfully treated with phages as part of their regimen, after antibiotics have failed.
The Future of Phage Therapy
The experience treating Tom prompted UCSD to create the Center for Innovative Phage Applications and Therapeutics (IPATH), with Chip and Steff as co-directors. Previous labs have engaged in basic research on phages, but this is the first clinical center in North America to focus on translating that knowledge into treating patients.
In January, IPATH announced the first phase 2 clinical trial approved by the FDA that will use phages intravenously. The viruses are being developed by AmpliPhi Biosciences, a San Diego-based company that supplied one of the phages used to treat Tom. The new study takes on drug resistant Staph aureus bacteria. Experimental phage therapy treatment using the company's product candidates was recently completed in 21 patients at seven hospitals who had been suffering from serious infections that did not respond to antibiotics. The reported success rate was 84 percent.
The new era of phage research is applying cutting-edge biologic and informatics tools to better understand and reshape the viruses to better attack bacteria, evade resistance, and perhaps broaden their reach a bit within a bacterial family.
Genetic engineering tools are being used to enhance the phages' ability to infect targeted bacteria.
"As we learn more and more about which biological activities are critical and in which clinical settings, there are going to be ways to optimize these activities," says Chip. Sometimes phages may be used alone, other times in combination with antibiotics.
Genetic engineering using tools are being used to enhance the phages' ability to infect targeted bacteria and better counter evolving forms of bacterial resistance in the ongoing "arms race" between the two. It isn't just theory. A patient recently was successfully treated with a genetically modified phage as part of the regimen, and the paper is in press.
In reality, given the trillions of phages in the world and the endless encounters they have had with bacteria over the millennia, it is likely that the exact phages needed to kill off certain bacteria already exist in nature. Using CRISPR to modify a phage is simply a quick way to identify the right phage useful for a given patient and produce it in the necessary quantities, rather than go search for the proverbial phage needle in a sewage haystack, says Chan.
One non-medical reason why using modified phages could be significant is that it creates an intellectual property stake, something that is patentable with a period of exclusive use. Major pharmaceutical companies and venture capitalists have been hesitant to invest in organisms found in nature; but a patentable modification may be enough to draw their interest to phage development and provide the funding for large-scale clinical trials necessary for FDA approval and broader use.
"There are 10 million trillion trillion phages on the planet, 10 to the power of 31. And the fact is that this ongoing evolutionary arms race between bacteria and phage, they've been at it for a millennia," says Steff. "We just need to exploit it."
In December 1958, on a vacation with his wife in Kenya, a 28-year-old British tea broker named Robin Cavendish became suddenly ill. Neither he nor his wife Diana knew it at the time, but Robin's illness would change the course of medical history forever.
Robin was rushed to a nearby hospital in Kenya where the medical staff delivered the crushing news: Robin had contracted polio, and the paralysis creeping up his body was almost certainly permanent. The doctors placed Robin on a ventilator through a tracheotomy in his neck, as the paralysis from his polio infection had rendered him unable to breathe on his own – and going off the average life expectancy at the time, they gave him only three months to live. Robin and Diana (who was pregnant at the time with their first child, Jonathan) flew back to England so he could be admitted to a hospital. They mentally prepared to wait out Robin's final days.
But Robin did something unexpected when he returned to the UK – just one of many things that would astonish doctors over the next several years: He survived. Diana gave birth to Jonathan in February 1959 and continued to visit Robin regularly in the hospital with the baby. Despite doctors warning that he would soon succumb to his illness, Robin kept living.
After a year in the hospital, Diana suggested something radical: She wanted Robin to leave the hospital and live at home in South Oxfordshire for as long as he possibly could, with her as his nurse. At the time, this suggestion was unheard of. People like Robin who depended on machinery to keep them breathing had only ever lived inside hospital walls, as the prevailing belief was that the machinery needed to keep them alive was too complicated for laypeople to operate. But Diana and Robin were up for the challenges – and the risks. Because his ventilator ran on electricity, if the house were to unexpectedly lose power, Diana would either need to restore power quickly or hand-pump air into his lungs to keep him alive.
Robin's wheelchair was not only the first of its kind; it became the model for the respiratory wheelchairs that people still use today.
In an interview as an adult, Jonathan Cavendish reflected on his parents' decision to live outside the hospital on a ventilator: "My father's mantra was quality of life," he explained. "He could have stayed in the hospital, but he didn't think that was as good of a life as he could manage. He would rather be two minutes away from death and living a full life."
After a few years of living at home, however, Robin became tired of being confined to his bed. He longed to sit outside, to visit friends, to travel – but had no way of doing so without his ventilator. So together with his friend Teddy Hall, a professor and engineer at Oxford University, the two collaborated in 1962 to create an entirely new invention: a battery-operated wheelchair prototype with a ventilator built in. With this, Robin could now venture outside the house – and soon the Cavendish family became famous for taking vacations. It was something that, by all accounts, had never been done before by someone who was ventilator-dependent. Robin and Hall also designed a van so that the wheelchair could be plugged in and powered during travel. Jonathan Cavendish later recalled a particular family vacation that nearly ended in disaster when the van broke down outside of Barcelona, Spain:
"My poor old uncle [plugged] my father's chair into the wrong socket," Cavendish later recalled, causing the electricity to short. "There was fire and smoke, and both the van and the chair ground to a halt." Johnathan, who was eight or nine at the time, his mother, and his uncle took turns hand-pumping Robin's ventilator by the roadside for the next thirty-six hours, waiting for Professor Hall to arrive in town and repair the van. Rather than being panicked, the Cavendishes managed to turn the vigil into a party. Townspeople came to greet them, bringing food and music, and a local priest even stopped by to give his blessing.
Robin had become a pioneer, showing the world that a person with severe disabilities could still have mobility, access, and a fuller quality of life than anyone had imagined. His mission, along with Hall's, then became gifting this independence to others like himself. Robin and Hall raised money – first from the Ernest Kleinwort Charitable Trust, and then from the British Department of Health – to fund more ventilator chairs, which were then manufactured by Hall's company, Littlemore Scientific Engineering, and given to fellow patients who wanted to live full lives at home. Robin and Hall used themselves as guinea pigs, testing out different models of the chairs and collaborating with scientists to create other devices for those with disabilities. One invention, called the Possum, allowed paraplegics to control things like the telephone and television set with just a nod of the head. Robin's wheelchair was not only the first of its kind; it became the model for the respiratory wheelchairs that people still use today.
Robin went on to enjoy a long and happy life with his family at their house in South Oxfordshire, surrounded by friends who would later attest to his "down-to-earth" personality, his sense of humor, and his "irresistible" charm. When he died peacefully at his home in 1994 at age 64, he was considered the world's oldest-living person who used a ventilator outside the hospital – breaking yet another barrier for what medical science thought was possible.
Sarah Watts is a health and science writer based in Chicago. Follow her on Twitter at @swattswrites.
In June 2012, Kirstie Ennis was six months into her second deployment to Afghanistan and recently promoted to sergeant. The helicopter gunner and seven others were three hours into a routine mission of combat resupplies and troop transport when their CH-53D helicopter went down hard.
Miraculously, all eight people onboard survived, but Ennis' injuries were many and severe. She had a torn rotator cuff, torn labrum, crushed cervical discs, facial fractures, deep lacerations and traumatic brain injury. Despite a severely fractured ankle, doctors managed to save her foot, for a while at least.
In November 2015, after three years of constant pain and too many surgeries to count, Ennis relented. She elected to undergo a lower leg amputation but only after she completed the 1,000-mile, 72-day Walking with the Wounded journey across the UK.
On Veteran's Day of that year, on the other side of the country, orthopedic surgeon Cato Laurencin announced a moonshot challenge he was setting out to achieve on behalf of wounded warriors like Ennis: the Hartford Engineering A Limb (HEAL) Project.
Laurencin, who is a University of Connecticut professor of chemical, materials and biomedical engineering, teamed up with experts in tissue bioengineering and regenerative medicine from Harvard, Columbia, UC Irvine and SASTRA University in India. Laurencin and his colleagues at the Connecticut Convergence Institute for Translation in Regenerative Engineering made a bold commitment to regenerate an entire limb within 15 years – by the year 2030.
Dr. Cato Laurencin pictured in his office at UConn.
Photo Credit: UConn
Regenerative Engineering -- A Whole New Field
Limb regeneration in humans has been a medical and scientific fascination for decades, with little to show for the effort. However, Laurencin believes that if we are to reach the next level of 21st century medical advances, this puzzle must be solved.
An estimated 185,000 people undergo upper or lower limb amputation every year. Despite the significant advances in electromechanical prosthetics, these individuals still lack the ability to perform complex functions such as sensation for tactile input, normal gait and movement feedback. As far as Laurencin is concerned, the only clinical answer that makes sense is to regenerate a whole functional limb.
Laurencin feels other regeneration efforts were hampered by their siloed research methods with chemists, surgeons, engineers all working separately. Success, he argues, requires a paradigm shift to a trans-disciplinary approach that brings together cutting-edge technologies from disparate fields such as biology, material sciences, physical, chemical and engineering sciences.
As the only surgeon ever inducted into the academies of Science, Medicine and Innovation, Laurencin is uniquely suited for the challenge. He is regarded as the founder of Regenerative Engineering, defined as the convergence of advanced materials sciences, stem cell sciences, physics, developmental biology and clinical translation for the regeneration of complex tissues and organ systems.
But none of this is achievable without early clinician participation across scientific fields to develop new technologies and a deeper understanding of how to harness the body's innate regenerative capabilities. "When I perform a surgical procedure or something is torn or needs to be repaired, I count on the body being involved in regenerating tissue," he says. "So, understanding how the body works to regenerate itself and harnessing that ability is an important factor for the regeneration process."
The Birth of the Vision
Laurencin's passion for regeneration began when he was a sports medicine fellow at Cornell University Medical Center in the early 1990s. There he saw a significant number of injuries to the anterior cruciate ligament (ACL), the major ligament that stabilizes the knee. He believed he could develop a better way to address those injuries using biomaterials to regenerate the ligament. He sketched out a preliminary drawing on a napkin one night over dinner. He has spent the next 30 years regenerating tissues, including the patented L-C ligament.
As chair of Orthopaedic Surgery at the University of Virginia during the peak of the wars in Iraq and Afghanistan, Laurencin treated military personnel who survived because of improved helmets, body armor and battlefield medicine but were left with more devastating injuries, including traumatic brain injuries and limb loss.
"I was so honored to care for them and I so admired their steadfast courage that I became determined to do something big for them," says Laurencin.
When he tells people about his plans to regrow a limb, he gets a lot of eye rolls, which he finds amusing but not discouraging. Growing bone cells was relatively new when he was first focused on regenerating bone in 1987 at MIT; in 2007 he was well on his way to regenerating ligaments at UVA when many still doubted that ligaments could even be reconstructed. He and his team have already regenerated torn rotator cuff tendons and ACL ligaments using a nano-textured fabric seeded with stem cells.
Even as a finalist for the $4 million NIH Pioneer Award for high-risk/high-reward research, he faced a skeptical scientific audience in 2014. "They said, 'Well what do you plan to do?' I said 'I plan to regenerate a whole limb in people.' There was a lot of incredulousness. They stared at me and asked a lot of questions. About three days later, I received probably the best score I've ever gotten on an NIH grant."
In the Thick of the Science
Humans are born with regenerative abilities--two-year-olds have regrown fingertips--but lose that ability with age. Salamanders are the only vertebrates that can regenerate lost body parts as adults; axolotl, the rare Mexican salamander, can grow extra limbs.
The axolotl is important as a model organism because it is a four-footed vertebrate with a similar body plan to humans. Mapping the axolotl genome in 2018 enhanced scientists' genetic understanding of their evolution, development, and regeneration. Being easy to breed in captivity allowed the HEAL team to closely study these amphibians and discover a new cell type they believe may shed light on how to mimic the process in humans.
"Whenever limb regeneration takes place in the salamander, there is a huge amount of something called heparan sulfate around that area," explains Laurencin. "We thought, 'What if this heparan sulfate is the key ingredient to allowing regeneration to take place?' We found these groups of cells that were interspersed in tissues during the time of regeneration that seemed to have connections to each other that expressed this heparan sulfate."
Called GRID (Groups that are Regenerative, Interspersed and Dendritic), these cells were also recently discovered in mice. While GRID cells don't regenerate as well in mice as in salamanders, finding them in mammals was significant.
"If they're found in mice. we might be able to find these in humans in some form," Laurencin says. "We think maybe it will help us figure out regeneration or we can create cells that mimic what grid cells do and create an artificial grid cell."
What Comes Next?
Laurencin and his team have individually engineered and made every single tissue in the lower limb, including bone, cartilage, ligament, skin, nerve, blood vessels. Regenerating joints and joint tissue is the next big mile marker, which Laurencin sees as essential to regenerating a limb that functions and performs in the way he envisions.
"Using stem cells and amnion tissue, we can regenerate joints that are damaged, and have severe arthritis," he says. "We're making progress on all fronts, and making discoveries we believe are going to be helping people along the way."
That focus and advancement is vital to Ennis. After laboring over the decision to have her leg amputated below the knee, she contracted MRSA two weeks post-surgery. In less than a month, she went from a below-the-knee-amputee to a through-the-knee amputee to an above-the-knee amputee.
"A below-the-knee amputation is night-and-day from above-the-knee," she said. "You have to relearn everything. You're basically a toddler."
Kirstie Ennis pictured in July 2020.
Photo Credit: Ennis' Instagram
The clock is ticking on the timeline Laurencin set for himself. Nine years might seem like forever if you're doing time but it might appear fleeting when you're trying to create something that's never been done before. But Laurencin isn't worried. He's convinced time is on his side.
"Every week, I receive an email or a call from someone, maybe a mother whose child has lost a finger or I'm in communication with a disabled American veteran who wants to know how the progress is going. That energizes me to continue to work hard to try to create these sorts of solutions because we're talking about people and their lives."
He devotes about 60 hours a week to the project and the roughly 100 students, faculty and staff who make up the HEAL team at the Convergence Institute seem acutely aware of what's at stake and appear equally dedicated.
"We're in the thick of the science in terms of making this happen," says Laurencin. "We've moved from making the impossible possible to making the possible a reality. That's what science is all about."