Tiny, Injectable Robots Could Be the Future of Brain Treatments
In the 1966 movie "Fantastic Voyage," actress Raquel Welch and her submarine were shrunk to the size of a cell in order to eliminate a blood clot in a scientist's brain. Now, 55 years later, the scenario is becoming closer to reality.
California-based startup Bionaut Labs has developed a nanobot about the size of a grain of rice that's designed to transport medication to the exact location in the body where it's needed. If you think about it, the conventional way to deliver medicine makes little sense: A painkiller affects the entire body instead of just the arm that's hurting, and chemotherapy is flushed through all the veins instead of precisely targeting the tumor.
"Chemotherapy is delivered systemically," Bionaut-founder and CEO Michael Shpigelmacher says. "Often only a small percentage arrives at the location where it is actually needed."
But what if it was possible to send a tiny robot through the body to attack a tumor or deliver a drug at exactly the right location?
Several startups and academic institutes worldwide are working to develop such a solution but Bionaut Labs seems the furthest along in advancing its invention. "You can think of the Bionaut as a tiny screw that moves through the veins as if steered by an invisible screwdriver until it arrives at the tumor," Shpigelmacher explains. Via Zoom, he shares the screen of an X-ray machine in his Culver City lab to demonstrate how the half-transparent, yellowish device winds its way along the spine in the body. The nanobot contains a tiny but powerful magnet. The "invisible screwdriver" is an external magnetic field that rotates that magnet inside the device and gets it to move and change directions.
The current model has a diameter of less than a millimeter. Shpigelmacher's engineers could build the miniature vehicle even smaller but the current size has the advantage of being big enough to see with bare eyes. It can also deliver more medicine than a tinier version. In the Zoom demonstration, the micorobot is injected into the spine, not unlike an epidural, and pulled along the spine through an outside magnet until the Bionaut reaches the brainstem. Depending which organ it needs to reach, it could be inserted elsewhere, for instance through a catheter.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu.
Imagine moving a screw through a steak with a magnet — that's essentially how the device works. But of course, the Bionaut is considerably different from an ordinary screw: "At the right location, we give a magnetic signal, and it unloads its medicine package," Shpigelmacher says.
To start, Bionaut Labs wants to use its device to treat Parkinson's disease and brain stem gliomas, a type of cancer that largely affects children and teenagers. About 300 to 400 young people a year are diagnosed with this type of tumor. Radiation and brain surgery risk damaging sensitive brain tissue, and chemotherapy often doesn't work. Most children with these tumors live less than 18 months. A nanobot delivering targeted chemotherapy could be a gamechanger. "These patients really don't have any other hope," Shpigelmacher says.
Of course, the main challenge of the developing such a device is guaranteeing that it's safe. Because tissue is so sensitive, any mistake could risk disastrous results. In recent years, Bionaut has tested its technology in dozens of healthy sheep and pigs with no major adverse effects. Sheep make a good stand-in for humans because their brains and spines are similar to ours.
The Bionaut device is about the size of a grain of rice.
Bionaut Labs
"As the Bionaut moves through brain tissue, it creates a transient track that heals within a few weeks," Shpigelmacher says. The company is hoping to be the first to test a nanobot in humans. In December 2022, it announced that a recent round of funding drew $43.2 million, for a total of 63.2 million, enabling more research and, if all goes smoothly, human clinical trials by early next year.
Once the technique has been perfected, further applications could include addressing other kinds of brain disorders that are considered incurable now, such as Alzheimer's or Huntington's disease. "Microrobots could serve as a bridgehead, opening the gateway to the brain and facilitating precise access of deep brain structure – either to deliver medication, take cell samples or stimulate specific brain regions," Shpigelmacher says.
Robot-assisted hybrid surgery with artificial intelligence is already used in state-of-the-art surgery centers, and many medical experts believe that nanorobotics will be the instrument of the future. In 2016, three scientists were awarded the Nobel Prize in Chemistry for their development of "the world's smallest machines," nano "elevators" and minuscule motors. Since then, the scientific experiments have progressed to the point where applicable devices are moving closer to actually being implemented.
Bionaut's technology was initially developed by a research team lead by Peer Fischer, head of the independent Micro Nano and Molecular Systems Lab at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany. Fischer is considered a pioneer in the research of nano systems, which he began at Harvard University more than a decade ago. He and his team are advising Bionaut Labs and have licensed their technology to the company.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu, who leads the cooperation with Bionaut Labs. He agrees with Shpigelmacher that the Bionaut's size is perfect for transporting medication loads and is researching potential applications for even smaller nanorobots, especially in the eye, where the tissue is extremely sensitive. "Nanorobots can sneak through very fine tissue without causing damage."
In "Fantastic Voyage," Raquel Welch's adventures inside the body of a dissident scientist let her swim through his veins into his brain, but her shrunken miniature submarine is attacked by antibodies; she has to flee through the nerves into the scientist's eye where she escapes into freedom on a tear drop. In reality, the exit in the lab is much more mundane. The Bionaut simply leaves the body through the same port where it entered. But apart from the dramatization, the "Fantastic Voyage" was almost prophetic, or, as Shpigelmacher says, "Science fiction becomes science reality."
This article was first published by Leaps.org on April 12, 2021.
What makes people turn against science? After two years of a global pandemic, the world has never felt more divided on questions of science. But this is not a new phenomenon. People have resisted scientific and technological advances throughout history.
This video by Leaps.org, with support from the Gordon and Betty Moore Foundation, captures noteworthy examples from history when people rejected science. What do these cases have in common? Scientific breakthroughs can be revolutionary, but revolutions can be disorienting and anxiety-producing. They transform our livelihoods, culture and even our understanding of what it means to be human. But there's reason for optimism. Many of history’s controversies were overcome. Science has a way of enduring, because it changes things for the better.
Scientists search for a universal coronavirus vaccine
The Covid-19 pandemic had barely begun when VBI Vaccines, a biopharmaceutical company based in Cambridge, Massachusetts, initiated their search for a universal coronavirus vaccine.
It was March 2020, and while most pharmaceutical companies were scrambling to initiate vaccine programs which specifically targeted the SARS-CoV-2 virus, VBI’s executives were already keen to look at the broader picture.
Having observed the SARS and MERS coronavirus outbreaks over the last two decades, Jeff Baxter, CEO of VBI Vaccines, was aware that SARS-CoV-2 is unlikely to be the last coronavirus to move from an animal host into humans. “It's absolutely apparent that the future is to create a vaccine which gives more broad protection against not only pre-existing coronaviruses, but those that will potentially make the leap into humans in future,” says Baxter.
It was a prescient decision. Over the last two years, more biotechs and pharma companies have joined the search to find a vaccine which might be able to protect against all coronaviruses, along with dozens of academic research groups. Last September, the US National Institutes of Health dedicated $36 million specifically to pan-coronavirus vaccine research, while the global Coalition for Epidemic Preparedness Innovations (CEPI) has earmarked $200 million towards the effort.
Until October 2021, the very concept of whether it might be
theoretically possible to vaccinate against multiple coronaviruses remained an open question. But then a groundbreaking study renewed optimism.
The emergence of new variants of Covid-19 over the past year, particularly the highly mutated Omicron variant, has added greater impetus to find broader spectrum vaccines. But until October 2021, the very concept of whether it might be theoretically possible to vaccinate against multiple coronaviruses remained an open question. After all, scientists have spent decades trying to develop a similar vaccine for influenza with little success.
But then a groundbreaking study from renowned virologist Linfa Wang, who runs the emerging infectious diseases program at Duke-National University of Singapore Medical School, provided renewed optimism.
Wang found that eight SARS survivors who had been injected with the Pfizer/BioNTech Covid-19 vaccine had neutralising antibodies in their blood against SARS, the Alpha, Beta and Delta variants of SARS-CoV-2, and five other coronaviruses which reside in bats and pangolins. He concluded that the combination of past coronavirus infection, and immunization with a messenger RNA vaccine, had resulted in a wider spectrum of protection than might have been expected.
“This is a significant study because it showed that pre-existing immunity to one coronavirus could help with the elicitation of cross-reactive antibodies when immunizing with a second coronavirus,” says Kevin Saunders, Director of Research at the Duke Human Vaccine Institute in North Carolina, which is developing a universal coronavirus vaccine. “It provides a strategy to perhaps broaden the immune response against coronaviruses.”
In the next few months, some of the first data is set to emerge looking at whether this kind of antibody response could be elicited by a single universal coronavirus vaccine. In April 2021, scientists at the Walter Reed Army Institute of Research in Silver Spring, Maryland, launched a Phase I clinical trial of their vaccine, with a spokesman saying that it was successful, and the full results will be announced soon.
The Walter Reed researchers have already released preclinical data, testing the vaccine in non-human primates where it was found to have immunising capabilities against a range of Covid-19 variants as well as the original SARS virus. If the Phase I trial displays similar efficacy, a larger Phase II trial will begin later this year.
Two different approaches
Broadly speaking, scientists are taking two contrasting approaches to the task of finding a universal coronavirus vaccine. The Walter Reed Army Institute of Research, VBI Vaccines – who plan to launch their own clinical trial in the summer – and the Duke Human Vaccine Institute – who are launching a Phase I trial in early 2023 – are using a soccer-ball shaped ferritin nanoparticle studded with different coronavirus protein fragments.
VBI Vaccines is looking to elicit broader immune responses by combining SARS, SARS-CoV-2 and MERS spike proteins on the same nanoparticle. Dave Anderson, chief scientific officer at VBI Vaccines, explains that the idea is that by showing the immune system these three spike proteins at the same time, it can help train it to identify and respond to subtle differences between coronavirus strains.
The Duke Human Vaccine Institute is utilising the same method, but rather than including the entire spike proteins from different coronaviruses, they are only including the receptor binding domain (RBD) fragment from each spike protein. “We designed our vaccine to focus the immune system on a site of vulnerability for the virus, which is the receptor binding domain,” says Saunders. “Since the RBD is small, arraying multiple RBDs on a nanoparticle is a straight-forward approach. The goal is to generate immunity to many different subgenuses of viruses so that there will be cross-reactivity with new or unknown coronaviruses.”
But the other strategy is to create a vaccine which contains regions of the viral protein structure which are conserved between all coronavirus strains. This is something which scientists have tried to do for a universal influenza vaccine, but it is thought to be more feasible for coronaviruses because they mutate at a slower rate and are more constrained in the ways that they can evolve.
DIOSynVax, a biotech based in Cambridge, United Kingdom, announced in a press release earlier this month that they are partnering with CEPI to use their computational predictive modelling techniques to identify common structures between all of the SARS coronaviruses which do not mutate, and thus present good vaccine targets.
Stephen Zeichner, an infectious disease specialist at the University of Virginia Medical Center, has created an early stage vaccine using the fusion peptide region – another part of the coronavirus spike protein that aids the virus’s entry into host cells – which so far appears to be highly conserved between all coronaviruses.
So far Zeichner has trialled this version of the vaccine in pigs, where it provided protection against a different coronavirus called porcine epidemic diarrhea virus, which he described as very promising as this virus is from a different family called alphacoronaviruses, while SARS-CoV-2 is a betacoronavirus.
“If a betacoronavirus fusion peptide vaccine designed from SARS-CoV-2 can protect pigs against clinical disease from an alphacoronavirus, then that suggests that an analogous vaccine would enable broad protection against many, many different coronaviruses,” he says.
The road ahead
But while some of the early stage results are promising, researchers are fully aware of the scale of the challenge ahead of them. Although CEPI have declared an aim of having a licensed universal coronavirus vaccine available by 2024-2025, Zeichner says that such timelines are ambitious in the extreme.
“I was incredibly impressed at the speed at which the mRNA coronavirus vaccines were developed for SARS-CoV-2,” he says. “That was faster than just about anybody anticipated. On the other hand, I think a universal coronavirus vaccine is more equivalent to the challenge of developing an HIV vaccine and we're 35 years into that effort without success. We know a lot more now than before, and maybe it will be easier than we think. But I think the route to a universal vaccine is harder than an individual vaccine, so I wouldn’t want to put money on a timeline prediction.”
The major challenge for scientists is essentially designing a vaccine for a future threat which is not even here yet. As such, there are no guidelines on what safety data would be required to license such a vaccine, and how researchers can demonstrate that it truly provides efficacy against all coronaviruses, even those which have not yet jumped to humans.
The teams working on this problem have already devised some ingenious ways of approaching the challenge. VBI Vaccines have taken the genetic sequences of different coronaviruses found in bats and pangolins, from publicly available databases, and inserted them into what virologists call a pseudotype virus – one which has been engineered so it does not have enough genetic material to replicate.
This has allowed them to test the neutralising antibodies that their vaccine produces against these coronaviruses in test tubes, under safe lab conditions. “We have literally just been ordering the sequences, and making synthetic viruses that we can use to test the antibody responses,” says Anderson.
However, some scientists feel that going straight to a universal coronavirus vaccine is likely to be too complex. Instead they say that we should aim for vaccines which are a little more specific. Pamela Bjorkman, a structural biologist at the California Institute of Technology, suggests that pan-coronavirus vaccines which protect against SARS-like betacoronaviruses such as SARS or SARS-CoV-2, or MERS-like betacoronaviruses, may be more realistic.
“I think a vaccine to protect against all coronaviruses is likely impossible since there are so many varieties,” she says. “Perhaps trying to narrow down the scope is advisable.”
But if the mission to develop a universal coronavirus vaccine does succeed, it will be one of the most remarkable feats in the annals of medical science. In January, US chief medical advisor Anthony Fauci urged for greater efforts to be devoted towards this goal, one which scientists feel would be the biological equivalent of the race to develop the first atomic bomb
“The development of an effective universal coronavirus vaccine would be equally groundbreaking, as it would have global applicability and utility,” says Saunders. “Coronaviruses have caused multiple deadly outbreaks, and it is likely that another outbreak will occur. Having a vaccine that prevents death from a future outbreak would be a tremendous achievement in global health.”
He agrees that it will require creativity on a remarkable scale: “The universal coronavirus vaccine will also require ingenuity and perseverance comparable to that needed for the Manhattan project.”