Wyss Institute team unveils a low-cost, portable method to manufacture biomolecules for a wide range of vaccines, other therapies as well as diagnostics
Even amidst all the celebrated advances of modern medicine, basic life-saving interventions are still not reaching massive numbers of people who live in our planet’s most remote and non-industrialized locations. The World Health Organization states that one half of the global population lives in rural areas. And according to UNICEF, last year nearly 20 million infants globally did not receive what we would consider to be basic vaccinations required for a child’s health.
These daunting statistics are largely due to the logistical challenge of transporting vaccines and other biomolecules used in diagnostics and therapy, which conventionally require a “cold chain” of refrigeration from the time of synthesis to the time of administration. In remote areas lacking power or established transport routes, modern medicine often cannot reach those who may need it urgently.
A team of researchers at Harvard’s Wyss Institute for Biologically Inspired Engineering has been working toward a paradigm-shifting goal: a molecular manufacturing method that can produce a broad range of biomolecules, including vaccines, antimicrobial peptides and antibody conjugates, anywhere in the world, without power or refrigeration.
Now, in a new paper published September 22 in Cell journal, the team has unveiled what they set out to deliver, a “just add water” portable method that affordably, rapidly, and precisely generates compounds that could be administered as therapies or used in experiments and diagnostics.
“The ability to synthesize and administer biomolecular compounds, anywhere, could undoubtedly shift the reach of medicine and science across the world,” said Wyss Core Faculty member James Collins, Ph.D., senior author on the study, who is also Professor of Medical Engineering & Science and Professor of Biological Engineering at the Massachusetts Institute of Technology (MIT)’s Department of Biological Engineering. “Our goal is make biomolecular manufacturing accessible wherever it could improve lives.”
The approach, called “portable biomolecular manufacturing” by Collins’ team, which also included Neel Joshi, Ph.D., a Wyss Core Faculty member and Associate Professor of Chemical and Biological Engineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS), hinges on the idea that freeze-dried pellets containing “molecular machinery” can be mixed and matched to achieve a wide variety of end-products. By simply adding water, this molecular machinery can be set in motion.
To activate the biomolecular manufacturing process, freeze-dried components need simply be rehydrated (as seen in this mock demonstration). Credit: Wyss Institute at Harvard University
Compounds manufactured using the method could be administered in several ways to a patient, including injection, oral doses or topical applications. As described in the study, a vaccine against diphtheria was synthesized using the method and shown to successfully induce an antibody response against the pathogen in mice.
Subsequently, the team envisions that the method could be employed to create batches of tetanus or flu shots routinely manufactured in remote clinics. Vaccines against emerging infectious disease outbreaks could quickly be mobilized in the field to contain spiraling epidemics. Episodes of food poisoning could be dosed orally with the production of neutralizing antibodies produced on the spot. Flesh wounds susceptible to infection could be applied with topical antimicrobial peptides generated on demand. In these manners, the team’s approach could be leveraged to design a vast number of different lifesaving measures.
The approach is built upon work described in a seminal 2014 paper also published in Cell, when the team demonstrated that transcription and translation machinery could function in vitro, without being inside living cells, inside freeze-dried slips of ordinary paper embedded with synthetic gene networks.
The Wyss Institute team envisions that the compounds created using the portable manufacturing method could be administered to patients in a variety of ways, including injection (as seen in this mock demonstration), oral delivery, and topical application. Credit: Wyss Institute at Harvard University
Building off that work, the novel manufacturing method employs two types of freeze-dried pellets containing different kinds of components. The first kind of pellet contains the cell-free “machinery” that will synthesize the end product. The second kind contains DNA instructions that will tell the “machinery” what compound to manufacture. When the two types of pellets are combined and rehydrated with water, the biomolecular manufacturing process is triggered. The second type of pellet can be customized to produce a wide range of final products.
Since they are freeze-dried, the pellets are extremely stable and safe for long-term storage at room temperature for up to and potentially beyond one year.
“This approach could — with very little training — put therapeutics and diagnostic tools in the hands of clinicians working in remote areas without power,” said Keith Pardee, Ph.D., a co-first author on the study who was a Wyss Research Scientist and is now an Assistant Professor in the Leslie Dan Faculty of Pharmacy at the University of Toronto. “Currently, distribution of life-saving doses of protein-based preventative and interventional medicines are often restricted by access to an uninterrupted chain of cold refrigeration, which many areas of the world lack.”
The cost of the approach, at roughly three cents per microliter, could also give access to biomolecular manufacturing to researchers and educators who lack access to wet labs and other sophisticated equipment, impacting basic science beyond the immediately apparent promise in clinical applications.
“Synthetic biology has been harnessed to increase efficiency of manufacturing of biological products for medical and energy applications in the past, however, this new breakthrough utterly changes the application landscape,” said Wyss Core Faculty member Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s SEAS. “It’s really exciting because this new biomolecular manufacturing technology potentially offers a way to solve the cold chain problem that still restricts delivery of vaccines and other important medical treatments to patients in the most far-flung corners of the world who need them the most.”
TSRI Study Points Way to Better Vaccines and New Autoimmune Therapies
A new international collaboration involving scientists at The Scripps Research Institute (TSRI) opens a door to influencing the immune system, which would be useful to boost the effectiveness of vaccines or to counter autoimmune diseases such as lupus and rheumatoid arthritis.
The research, published August 1, 2016, in The Journal of Experimental Medicine, focused on a molecule called microRNA-155 (miR-155), a key player in the immune system’s production of disease-fighting antibodies.
“It’s very exciting to see exactly how this molecule works in the body,” said TSRI Associate Professor Changchun Xiao, who co-led the study with Professor Wen-Hsien Liu of Xiamen University in Fuijan province, China.
An Immune System Tango
Our cells rely on molecules called microRNAs (miRNAs) as a sort of “dimmer switches” to carefully regulate protein levels and combat disease.
“People know miRNAs are involved in immune response, but they don’t know which miRNAs and how exactly,” explained TSRI Research Associate Zhe Huang, study co-first author with Liu and Seung Goo Kang of TSRI and Kangwon National University.
In the new study, the researchers focused on the roles of miRNAs during the critical period when the immune system first detects “invaders” such as viruses or bacteria. At this time, cells called T follicular helpers proliferate and migrate to a different area of the lymph organs to interact with B cells.
“They do a sort of tango,” said Xiao.
This interaction prompts B cells to mature and produce effective antibodies, eventually offering long-term protection against infection.
“The next time you encounter that virus, for example, the body can respond quickly,” said Xiao.
Identifying a Dancer
Using a technique called deep sequencing, the team identified miR-155 as a potential part of this process. Studies in mouse models suggested that miR-155 works by repressing a protein called Peli1. This leaves a molecule called c-Rel free to jump in and promote normal T cell proliferation.
This finding could help scientists improve current vaccines. While vaccines are life-saving, some vaccines wear off after a decade or only cover around 80 percent of those vaccinated.
“If you could increase T cell proliferation using a molecule that mimics miR-155, maybe you could boost that to 90 to 95 percent,” said Xiao. He also sees potential for using miR-155 to help in creating longer-lasting vaccines.
The research may also apply to treating autoimmune diseases, which occur when antibodies mistakenly attack the body’s own tissues. Xiao and his colleagues think an mRNA inhibitor could dial back miR-155’s response when T cell proliferation and antibody production is in overdrive.
For the next stage of this research, Xiao plans to collaborate with scientists on the Florida campus of TSRI to test possible miRNA inhibitors against autoimmune disease.
A relatively unknown molecule that regulates metabolism could be the key to boosting an individual’s immunity to the flu – and potentially other viruses – according to research reported today in the journal Immunity.
The study, led by University of Vermont (UVM) College of Medicine doctoral student Devin Champagne and Mercedes Rincon, Ph.D., a professor of medicine and an immunobiologist, discovered that a protein called methylation controlled J – or MCJ – can be altered to boost the immune system’s response to the flu.
Metabolism is a crucial function that helps keep cells alive. It plays a role in a range of bodily processes – from the conversion of food into energy to the ability to fight off infection. MCJ is the part of the cell that produces energy and enables metabolism.
“It’s the engine of the cell,” says Rincon, who adds that previously, researchers assumed that the mitochondria were constantly active.
ACROSS 94 COUNTRIES, BENEFITS FAR EXCEED THE COSTS, RESEARCHERS FIND
Vaccinations, long recognized as an excellent investment that saves lives and prevents illness, could have significant economic value that far exceeds their original cost, a new study from researchers at the Johns Hopkins Bloomberg School of Public Health has found.
In what is believed to be among the first studies to examine the potential return on investment of vaccinations, the researchers assessed the economic benefits of vaccines in 94 low- and middle-income countries using projected vaccination rates from 2011 to 2020. When looking only at costs associated with illness, such as treatment costs and productivity losses, the return was $16 for every dollar spent on vaccines. In a separate analysis taking into account the broader economic impact of illness, vaccinations save $44 for every dollar spent.
The study appears in the February issue of Health Affairs.
“Vaccines are an excellent investment,” says lead author Sachiko Ozawa, PhD, MHS, an assistant scientist in the Department of International Health at the Bloomberg School. “But to reap the potential economic rewards, governments and donors must continue their investments in expanding access to vaccines.”
Without vaccination, millions of children would die from preventable illnesses and diseases across the decade. While billions of dollars will be spent to try and vaccinate more children, the goal of full coverage — that is, getting every child vaccinated — has not yet been met.
To measure the potential investment returns, researchers used two approaches. The first, known as the “cost-of-illness” approach, measures averted treatment costs, transportation costs, lost caretaker wages and productivity losses. The second, known as the “full-income approach,” estimates the broader economic and social benefits of vaccination and quantifies the value that people place on living longer and healthier lives. With both approaches, the costs of immunization programs were separately modeled to include supply chain, service delivery and vaccine costs.
Between 2011 and 2020, the estimated total cost of immunization programs in the 94 countries studied was $34 billion. Through these programs, an estimated $586 billion would be averted in cost of illness associated with vaccine-preventable diseases. Using the full-income approach, the benefit was estimated at $1.53 trillion dollars.
The study assessed 10 vaccine-preventable infections: Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitis serogroup A, rotavirus, rubella, Streptococcus pneumoniae and yellow fever.
“Our findings should encourage donors and governments to continue their financial investments in immunization programs. But we must keep in mind that these are estimates that assume immunization coverage continues to expand and improve,” Ozawa says.
Researchers at BYU have devised a system to speed up the process of making life-saving vaccines for new viruses.
“We could make the vaccine and be ready for distribution in a day.” The research, published in Biotechnology Journal, demonstrates the ability to store the drug and vaccine-making machinery for more than a year.
Bundy’s idea is a new angle on the emerging method of “Cell-free protein synthesis,” a process that combines DNA to make proteins needed for drugs.
The researchers believe their method can significantly reduce investment of time and money towards future drug production and, in turn, reduce treatment expenses for patients.
“The lifesaving cancer drugs we have now, the drugs for arthritis, the drugs with the greatest impact, are made out of proteins, not small chemical molecules. This method takes full advantage of that to provide a quicker, more personal response.”