Turning to Sharks to Protect Humans
In terms of defense, sharks present humans with a teachable moment. It’s not about bared teeth aggression, but about this fish’s seemingly simple immune system, which could prove superior in some key ways to a human’s complex, layered approach to fighting countless invisible microbes.
A shark can so effectively fight viruses that clinicians might be able to readily borrow and replicate parts of their system — which is really a network of secreted chemicals — to improve human antiviral resistance.
Or so says Michael Zasloff, MD, PhD, professor of surgery and pediatrics and scientific director of the Georgetown Transplant Institute in the September 19 issue of the Proceedings of the National Academy of Sciences (PNAS).
Zasloff is the guru of the wonders of shark immunity. In 1993 when he was a professor of pediatrics and genetics at the University of Pennsylvania searching for novel antibacterial agents, he discovered a steroid-like compound in the dogfish shark that was unlike, in its chemical structure, any substance previously described in animals. It was as potent against bacteria as the most powerful antibiotics known, Zasloff says, adding “I was interested in sharks because of their seemingly primitive but effective immune system. No one could explain why the shark was so hardy.”
He “played” around with the compound, which he called squalamine, synthesizing it in 1995 so no fresh shark tissue was needed for experimentation. He found that this new substance had a lot of interesting properties. It inhibited the growth of rapidly growing blood vessels, such as those found in tumor growth and certain retinal diseases such as macular degeneration and diabetic retinopathy.
Zasloff began to test squalamine to treat these conditions in a biotech company he founded, prior to his coming to Georgetown University Medical Center in 2002 as Dean of Research and Translational Science, and some of those clinical trials are ongoing by other pharmaceutical companies.
Since his discovery of squalamine, Zasloff continued researching the compound, trying to solve the longstanding puzzle of how sharks can so effectively fight the viruses that plague all living creatures. He knows, for example, that there is no evidence in the DNA of sharks that viruses have ever effectively attacked these vertebrates — unlike humans, whose genome contains lots of embedded bacterial and viral DNA.
Such mysteries fascinate Zasloff. He has discovered antimicrobial compounds in the skin of frogs, one of which he developed as a treatment for infected diabetic foot ulcers, and he is keen to discover why a dolphin recovers so quickly from the gaping wounds and deep flesh tears that are often delivered by predatory sharks. They appear not to suffer from significant pain, and the wounds heal quickly without infection.
He has also been impressed by examples of what he calls “wondrous” immunity in humans, such as why the tongue heals so well after it is bitten. He found out, and published the explanation in the journal Science in 1995.
Zasloff says he first became interested in the human innate immune system when he was a resident in pediatrics at Boston’s Children’s Hospital in 1975. “I had seen many children with cystic fibrosis [CF] but could not understand why they developed the chronic bronchial infections that characterize the disease,” he says. He thought the explanation had to do with emerging science that suggested many creatures use antimicrobial peptides, which are small proteins, to protect against bacteria. “I thought humans likely retained the same system, and that it could be involved in protection of the lungs,” he says. “CF patients might be missing it.”
If it existed in humans, this peptide system would be an adjunct to the innate and adaptive immune system, he says. So, to learn more about these peptides, Zasloff went looking for them in animals he knows have fantastic microbial resilience —frogs and sharks.
Now, almost 20 years after he discovered squalamine in sharks, Zasloff has figured out how it works as an antiviral, which he details in the PNAS study.
He knew that the compound, a natural cholesterol-like molecule, has a net positive electrical charge. He later discovered that when it enters cells — squalamine can access only certain cells, like those in blood vessels, capillaries, and in the liver — it “kicks off” positively-charged proteins that are bound to the negatively-charged surface of the cell’s inner membrane. Some of these proteins are used by viruses to replicate, and Zasloff discovered that once these proteins are displaced, and can’t be used by viruses, the virus’s life cycle is disrupted, the microbe is rendered inert, and the cell that contains it is destroyed.
What most intrigued Zasloff is that squalamine seems so well designed to fight certain viral infections. “To me, the key to squalamine is that once in the body it times its action to match the life cycle of most viruses. Most viruses take hours to complete their life cycle, the same time period that squalamine renders tissues and organs viral resistant after administration. In addition, it acts fast to stop viral replication, clearing the body of these predators within hours,” he says.
To help prove the potency of squalamine, he sent the compound to researchers around the country, and they successfully tested it against a wide variety of viruses that infect the liver and blood tissues — dengue virus, hepatitis B and D, yellow fever, Eastern equine encephalitis virus, and murine cytomegalovirus.
These studies suggest that squalamine, which has long been in clinical study and has a known safety profile in humans, can readily be tested as a unique broad-spectrum antiviral agent, Zasloff says.
“To realize that squalamine potentially has broad antiviral properties is immensely exciting, especially since we already know so much from ongoing studies about its behavior in people,” he says.
He adds that squalamine is just one member of a family of several compounds related in structure to squalamine in sharks, and that others could potentially be harnessed to protect humans.
“That would be revolutionary. While many antibacterial agents exist, doctors have few antiviral drugs to help their patients, and few of those are broadly active.”
“As a scientist, I have had a few deep insights, but none has been as exciting as the understanding of how squalamine prevents viral infection, which is completely novel,” Zasloff says. “Its existence speaks to a new and unprecedented system of immunity that could potentially revolutionize the treatment of viral diseases.”
Zasloff is the inventor on a patent application that has been filed related to the technology described in the PNAS study.
By Renee Twombly, GUMC Communications