A new method could help the smallest of medicines hit their targets
Jacob Brenner and his partners at the University of Pennsylvania's Perelman School of Medicine are finding new ways to get nanomedicines to arrive at their targets.
Its strength is in its lack of size.
Using materials on the minuscule scale of nanometers (billionths of a meter), nanomedicines have the ability to provide treatment more precise than any other form of medicine. Under optimal circumstances, they can target specific cells and perform feats like altering the expression of proteins in tumors so that the tumors shrink.
Another appealing concept about nanomedicine is that treatment on a nano-scale, which is smaller yet than individual cells, can greatly decrease exposure to parts of the body outside the target area, thereby mitigating side effects.
But this young field's huge potential has met with an ongoing obstacle: the recipient's immune system tends to regard incoming nanomedicines as a threat and launches a complement protein attack. These complement proteins, which act together through a wave of reactions to get rid of troubling microorganisms, have had more than 500 million years to refine their craft, so they are highly effective.
Seeking to overcome a half-billion-year disadvantage, nanomaterials engineers have tried such strategies as creating so-called stealth nanoparticles.
“All new technologies face technical barriers, and it is the job of innovators to engineer solutions to them,” Brenner says.
Despite these clever attempts, nanomedicines largely keep failing to arrive at their intended destinations. According to the most comprehensive meta-analysis of nanomedicines in oncology, fewer than 1 percent of nanoparticles manage to reach their targets. The remaining 99-plus percent are expelled to the liver, spleen, or lungs – thereby squandering their therapeutic potential. Though these numbers seem discouraging, systems biologist Jacob Brenner remains undaunted. “All new technologies face technical barriers, and it is the job of innovators to engineer solutions to them,” he says.
Brenner and his fellow researchers at the Perelman School of Medicine at the University of Pennsylvania have recently devised a method that, in a study published in late 2021 involving sepsis-afflicted mice, saw a longer half-life of nanoparticles in the bloodstream. This effect is crucial because “the longer our nanoparticles circulate, the more time they have to reach their target organs,” says Brenner, the study's co-principal investigator. He works as a critical care physician at the Hospital of the University of Pennsylvania, where he also serves as an assistant professor of medicine.
The method used by Brenner's lab involves coating nanoparticles with natural suppressors that safeguard against a complement attack from the recipient's immune system. For this idea, he credits bacteria. “They are so much smarter than us,” he says.
Brenner points out that many species of bacteria have learned to coat themselves in a natural complement suppressor known as Factor H in order to protect against a complement attack.
Humans also have Factor H, along with an additional suppressor called Factor I, both of which flow through our blood. These natural suppressors “are recruited to the surface of our own cells to prevent complement [proteins] from attacking our own cells,” says Brenner.
Coating nanoparticles with a natural suppressor is a “very creative approach that can help tone and improve the activity of nanotechnology medicines inside the body,” says Avi Schroeder, an associate professor at Technion - Israel Institute of Technology, where he also serves as Head of the Targeted Drug Delivery and Personalized Medicine Group.
Schroeder explains that “being able to tone [down] the immune response to nanoparticles enhances their circulation time and improves their targeting capacity to diseased organs inside the body.” He adds how the approach taken by the Penn Med researchers “shows that tailoring the surface of the nanoparticles can help control the interactions the nanoparticles undergo in the body, allowing wider and more accurate therapeutic activity.”
Brenner says he and his research team are “working on the engineering details” to streamline the process. Such improvements could further subdue the complement protein attacks which for decades have proven the bane of nanomedical engineers.
Though these attacks have limited nanomedicine's effectiveness, the field has managed some noteworthy successes, such as the chemotherapy drugs Abraxane and Doxil, the first FDA-approved nanomedicine.
And amid the COVID-19 pandemic, nanomedicines became almost universally relevant with the vast circulation of the Moderna and Pfizer-BioNTech vaccines, both of which consist of lipid nanoparticles. “Without the nanoparticle, the mRNA would not enter the cells effectively and would not carry out the therapeutic goal,” Schroeder explains.
These vaccines, though, are “just the start of the potential transformation that nanomedicine will bring to the world,” says Brenner. He relates how nanomedicine is “joining forces with a number of other technological innovations,” such as cell therapies in which nanoparticles aim to reprogram T-cells to attack cancer.
With a similar degree of optimism, Schroeder says, “We will see further growing impact of nanotechnologies in the clinic, mainly by enabling gene therapy for treating and even curing diseases that were incurable in the past.”
Brenner says that in the next 10 to 15 years, “nanomedicine is likely to impact patients” contending with a “huge diversity” of conditions. “I can't wait to see how it plays out.”
Catching colds may help protect kids from Covid
A new study shows that the immune system's response to colds can help prepare it to defend against COVID-19 - but only in the very young.
A common cold virus causes the immune system to produce T cells that also provide protection against SARS-CoV-2, according to new research. The study, published last month in PNAS, shows that this effect is most pronounced in young children. The finding may help explain why most young people who have been exposed to the cold-causing coronavirus have not developed serious cases of COVID-19.
One curiosity stood out in the early days of the COVID-19 pandemic – why were so few kids getting sick. Generally young children and the elderly are the most vulnerable to disease outbreaks, particularly viral infections, either because their immune systems are not fully developed or they are starting to fail.
But solid information on the new infection was so scarce that many public health officials acted on the precautionary principle, assumed a worst-case scenario, and applied the broadest, most restrictive policies to all people to try to contain the coronavirus SARS-CoV-2.
One early thought was that lockdowns worked and kids (ages 6 months to 17 years) simply were not being exposed to the virus. So it was a shock when data started to come in showing that well over half of them carried antibodies to the virus, indicating exposure without getting sick. That trend grew over time and the latest tracking data from the CDC shows that 96.3 percent of kids in the U.S. now carry those antibodies.
Antibodies are relatively quick and easy to measure, but some scientists are exploring whether the reactions of T cells could serve as a more useful measure of immune protection.
But that couldn't be the whole story because antibody protection fades, sometimes as early as a month after exposure and usually within a year. Additionally, SARS-CoV-2 has been spewing out waves of different variants that were more resistant to antibodies generated by their predecessors. The resistance was so significant that over time the FDA withdrew its emergency use authorization for a handful of monoclonal antibodies with earlier approval to treat the infection because they no longer worked.
Antibodies got most of the attention early on because they are part of the first line response of the immune system. Antibodies can bind to viruses and neutralize them, preventing infection. They are relatively quick and easy to measure and even manufacture, but as SARS-CoV-2 showed us, often viruses can quickly evolve to become more resistant to them. Some scientists are exploring whether the reactions of T cells could serve as a more useful measure of immune protection.
Kids, colds and T cells
T cells are part of the immune system that deals with cells once they have become infected. But working with T cells is much more difficult, takes longer, and is more expensive than working with antibodies. So studies often lags behind on this part of the immune system.
A group of researchers led by Annika Karlsson at the Karolinska Institute in Sweden focuses on T cells targeting virus-infected cells and, unsurprisingly, saw that they can play a role in SARS-CoV-2 infection. Other labs have shown that vaccination and natural exposure to the virus generates different patterns of T cell responses.
The Swedes also looked at another member of the coronavirus family, OC43, which circulates widely and is one of several causes of the common cold. The molecular structure of OC43 is similar to its more deadly cousin SARS-CoV-2. Sometimes a T cell response to one virus can produce a cross-reactive response to a similar protein structure in another virus, meaning that T cells will identify and respond to the two viruses in much the same way. Karlsson looked to see if T cells for OC43 from a wide age range of patients were cross-reactive to SARS-CoV-2.
And that is what they found, as reported in the PNAS study last month; there was cross-reactive activity, but it depended on a person’s age. A subset of a certain type of T cells, called mCD4+,, that recognized various protein parts of the cold-causing virus, OC43, expressed on the surface of an infected cell – also recognized those same protein parts from SARS-CoV-2. The T cell response was lower than that generated by natural exposure to SARS-CoV-2, but it was functional and thus could help limit the severity of COVID-19.
“One of the most politicized aspects of our pandemic response was not accepting that children are so much less at risk for severe disease with COVID-19,” because usually young children are among the most vulnerable to pathogens, says Monica Gandhi, professor of medicine at the University of California San Francisco.
“The cross-reactivity peaked at age six when more than half the people tested have a cross-reactive immune response,” says Karlsson, though their sample is too small to say if this finding applies more broadly across the population. The vast majority of children as young as two years had OC43-specific mCD4+ T cell responses. In adulthood, the functionality of both the OC43-specific and the cross-reactive T cells wane significantly, especially with advanced age.
“Considering that the mortality rate in children is the lowest from ages five to nine, and higher in younger children, our results imply that cross-reactive mCD4+ T cells may have a role in the control of SARS-CoV-2 infection in children,” the authors wrote in their paper.
“One of the most politicized aspects of our pandemic response was not accepting that children are so much less at risk for severe disease with COVID-19,” because usually young children are among the most vulnerable to pathogens, says Monica Gandhi, professor of medicine at the University of California San Francisco and author of the book, Endemic: A Post-Pandemic Playbook, to be released by the Mayo Clinic Press this summer. The immune response of kids to SARS-CoV-2 stood our expectations on their head. “We just haven't seen this before, so knowing the mechanism of protection is really important.”
Why the T cell immune response can fade with age is largely unknown. With some viruses such as measles, a single vaccination or infection generates life-long protection. But respiratory tract infections, like SARS-CoV-2, cause a localized infection - specific to certain organs - and that response tends to be shorter lived than systemic infections that affect the entire body. Karlsson suspects the elderly might be exposed to these localized types of viruses less often. Also, frequent continued exposure to a virus that results in reactivation of the memory T cell pool might eventually result in “a kind of immunosenescence or immune exhaustion that is associated with aging,” Karlsson says. https://leaps.org/scientists-just-started-testing-a-new-class-of-drugs-to-slow-and-even-reverse-aging/particle-3 This fading protection is why older people need to be repeatedly vaccinated against SARS-CoV-2.
Policy implications
Following the numbers on COVID-19 infections and severity over the last three years have shown us that healthy young people without risk factors are not likely to develop serious disease. This latest study points to a mechanism that helps explain why. But the inertia of existing policies remains. How should we adjust policy recommendations based on what we know today?
The World Health Organization (WHO) updated their COVID-19 vaccination guidance on March 28. It calls for a focus on vaccinating and boosting those at risk for developing serious disease. The guidance basically shrugged its shoulders when it came to healthy children and young adults receiving vaccinations and boosters against COVID-19. It said the priority should be to administer the “traditional essential vaccines for children,” such as those that protect against measles, rubella, and mumps.
“As an immunologist and a mother, I think that catching a cold or two when you are a kid and otherwise healthy is not that bad for you. Children have a much lower risk of becoming severely ill with SARS-CoV-2,” says Karlsson. She has followed public health guidance in Sweden, which means that her young children have not been vaccinated, but being older, she has received the vaccine and boosters. Gandhi and her children have been vaccinated, but they do not plan on additional boosters.
The WHO got it right in “concentrating on what matters,” which is getting traditional childhood immunizations back on track after their dramatic decline over the last three years, says Gandhi. Nor is there a need for masking in schools, according to a study from the Catalonia region of Spain. It found “no difference in masking and spread in schools,” particularly since tracking data indicate that nearly all young people have been exposed to SARS-CoV-2.
Both researchers lament that public discussion has overemphasized the quickly fading antibody part of the immune response to SARS-CoV-2 compared with the more durable T cell component. They say developing an efficient measure of T cell response for doctors to use in the clinic would help to monitor immunity in people at risk for severe cases of COVID-19 compared with the current method of toting up potential risk factors.
In this week's Friday Five: The eyes are the windows to the soul - and biological aging?
Plus, what bean genes mean for health and the planet, a breathing practice that could lower levels of tau proteins in the brain, AI beats humans at assessing heart health, and the benefits of "nature prescriptions"
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on new scientific theories and progress to give you a therapeutic dose of inspiration headed into the weekend.
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Here are the stories covered this week:
- The eyes are the windows to the soul - and biological aging?
- What bean genes mean for health and the planet
- This breathing practice could lower levels of tau proteins
- AI beats humans at assessing heart health
- Should you get a nature prescription?