Today, we have tools to cut out faulty genes and replace them with healthy ones. We can 3D-print human tissue. Does this mean we will soon be able to direct cells to build almost any human organ or part to then integrate into our bodies? What’s holding us back from a Frankensteinian future?

We may face two different outcomes:

• The downside is that we are on a path to creating chimeras or Frankenstein monsters.
• The upside is a path to medical breakthroughs that correct congenital defects, reverse Down’s Syndrome, regrow traumatized and severed body parts, reverse the course of degenerative diseases and more.

Imagine the Possibilities

It is no longer just imagination. The neuroscience researchers at the University of Wisconsin-Madison are 3D printing functional human brain tissue describing their work as opening a new window into tackling neurological and psychiatric disorders and creating re-engineering treatments for Alzheimer’s and Parkinson’s. What’s not to like?

Sy-Chun Zhang is a professor of neuroscience at Wisconsin’s Waisman Center. He describes what 3D-printing human brain tissue could lead to: “This could be a hugely powerful model to help us understand how brain cells and parts of the brain communicate in humans. It could change the way we look at stem cell biology, neuroscience and the pathogenesis of many neurological and psychiatric disorders.”

Zhang and his associates have used a bio-ink containing human pluripotent stem cells to print stacking layers of brain tissue allowing “the neurons to grow into each other and start talking.” The printed brain tissue includes the cerebral cortex and the striatum. The cells from different brain parts when printed start communicating with each other.

Regrowing Tissues Using Bioelectricity

Work being done on tissue regeneration at Tufts University is leading us to the potential to regrow severed or damaged limbs. Michael Levin is a biologist and professor at the university studying cell tissue regeneration and bioelectricity. He runs the Levin Lab with research that goes well beyond uncovering the cellular and genetic mechanisms responsible for tissue growth.

Levin is integrating biological electrical signalling into experiments when working with stem cells to regenerate complex tissues. He sees bioelectricity as the next big step in human tissue regeneration. It’s not quite Frankenstein, but it sounds a lot like it.

Levin theorizes that genome editing technology has limitations. He states by understanding the bioelectricity that binds cellular networks we will start untangling the software code of life.

When the Wisconsin researchers printed the brain cell tissue, the neurons and other cells started communicating using electrical signals. They didn’t understand how this happened, nor did they understand the shared messages being sent by the brain cells.

Levin wants to do a deep dive into the nature of bioelectric messaging in living things. He is co-editor of the journal Bioelectricity, where leading-edge research in this field is being published. He believes that we limit our scientific understanding of how biology works by studying only the genome and DNA. By manipulating bioelectric signals, he believes, it will give our bodies the equivalent of what we do when we adjust the thermostat in our homes to change a room temperature. Today in biology to make that type of adjustment we do the equivalent of rewiring the entire house.

Levin along with serial entrepreneur, Jess Mah, have founded Astonishing Labs, a company that plans to do more research in this area to understand bioelectric messages and the role they play in the body. Can they help to regrow worn and broken parts and extend our body’s healthy lifespan?

For medicine, agriculture, biofuels, pharmacology and even space science and exploration, CReATiNG is a monumental change maker. In a USC Dornsife news release that describes this new process of synthetically assembling DNA from natural components in yeast, Ian Ehrenreich, lead researcher and professor of biological sciences, states, “With CReATiNG, we can genetically reprogram organisms in complex ways previously deemed impossible, even with new tools like CRISPR. This opens up a world of possibilities in synthetic biology, enhancing our fundamental understanding of life and paving the way for groundbreaking applications.”

Synthetic genomics is a new field of study. It involves working with whole chromosomes and even entire genomes of organisms. It doesn’t chemically synthesize pieces of DNA, but instead, uses natural pieces from yeast as parts in an assembly to create whole chromosomes. The method is described by its creators as being cost-effective, lowering the barrier to developing new uses for the advancement of biotechnology and medicine. CReATiNG can lead to new cell therapies for treating cancer. It can through specifically-engineered bacteria improve the remediation of toxins and pollutants left over from the production of synthetic fuels, different industrial processes and mining.

CReATiNG may help us to slow down ageing extending the human life span. It may allow us to change our genome to make us more adaptable to living in space, or on the Moon or Mars. It can be used to engineer microorganisms and plants suitable for growing on space stations and for long-duration missions in space. It can help us synthesize the plants that will support human colonies on the Moon and Mars.

In experiments conducted at USC Dornsife, CReATiNG has been used to synthetically recombine chromosomes between different strains in species, and even different species, to modify chromosome structure, and to delete many linked, non-adjacent regions amounting to 39% of the entire body. It illustrates that CReATiNG can help to recover from flaws in chromosome design between synthetic and native versions.

It appears that this new tool could have a dramatic impact on biological sciences. The research results have been published today, December 20, 2023, in Nature Communications in an article entitled, Building synthetic chromosomes from natural DNA.

Why engineer blood vessels? Blocked blood vessels, particularly coronary arteries, are responsible for cardiovascular and cerebrovascular diseases that lead to heart attacks and strokes. One-third of those under the age of 70 suffering from cardiovascular or cerebrovascular disease die prematurely.

When I first came across this research I was reminded of my own recent experience after a cardiac catheter punctured the wall of my femoral artery during an ablation procedure. I needed a vascular repair to stop the shunting of blood from the artery to the femoral vein which caused swelling in my lower extremities. If the condition had persisted I could have experienced clotting or other complications. Fortunately, the surgical repair worked.

The Highways of Our Bodies Are Blood Vessels

Blood vessels form the transportation network within our bodies. They are streets where red and white blood cells drive. They are the delivery system to oxygenate our brain and other vital organs and muscles. There are other highways in our bodies such as our nervous and lymphatic systems, but blood vessels are the ones that are central to healthy heart function and keeping our brain supplied with oxygen. When blood vessels are compromised we can suffer a stroke, heart attack, aneurysm or die.

When usual causes of heart attacks are blocked coronary arteries. The coronary arteries supply blood and oxygen to the heart. When partially blocked people experience symptoms like angina. When blocked they can suffer a myocardial infarction, the fancy name for a heart attack.

Today, harvested blood vessel grafts from human donors or the patient are used for bypassing coronary blood vessel blockages. But researchers at the University of Melbourne believe that fabricated blood vessel tissue that can be shaped to any need would be an effective substitute for existing grafts. The team in its search for a graft alternative has combined a variety of materials and living tissue with a fabrication technique to create complex blood vessels that can serve multiple purposes.

States Daniel Heath: “Current methods are slow, require specialized and expensive equipment like bioreactors, and are low throughput – meaning it’s difficult to provide the needed supply of engineered vessels…By combining multiple materials and fabrication technologies, our method brings us closer to a future where engineered blood vessels will become a transformative solution for cardiovascular disease, especially for those patients who lack suitable donor vessels.”

The fabrication technique produces tissue-engineered vascular grafts (TEVGs) as opposed to harvested grafts from human donors. The inventors claim that their TEVGs are low-cost and use electrospun polycaprolactone (PCL) that can be conformed to any required shape to fit surgical requirements. The technology fabricates a custom graft in hours. They are not synthetic and will not cause blood clotting or obstructions. They are made from human cells and tissues, and although not yet ready for prime time, the advancements being made here in tissue engineering should allow for the rapid and cheap manufacture of living tissue with appropriate properties soon, to become a life-saving alternative for replacing severely damaged arteries and veins.

Researchers, however, are exploring a future where bioprinting will go below the sub-cellular level in constructing living tissue and biopolymers at a nanoscale. States Professor Seung Soo Oh, of Pohang University in South Korea, “The significance of this research lies in proving for the first time the possibility of printing 100% functionally and structurally active biopolymers in ultrafine 3D structures.”

What are biopolymers? They constitute the building blocks of cells. And now, research being done by Professor Oh and others, published recently in Advanced Science, indicates the development of technology to 3D print biopolymers molecule by molecule.

Pohang isn’t the only place where researchers are pushing the technological limits of 3D bioprinting. Back in 2018 scientists at the Lawrence Berkeley National Laboratory and UC Berkeley invented a way to synthesize DNA making DNA printing a future possibility. With the work at Pohang combined with Berkeley, we are a step closer to bioprinting DNA.

For researchers and bioengineers, the ability to 3D-print DNA opens new opportunities that can potentially revolutionize medicine. Imagine a printer that not only can produce living organs and tissues, but also DNA-specific constructs at the sub-cellular level including RNA, proteins, genes, and individual strings of nucleotides.

If unfamiliar with the term nucleotides, these are the fundamental chemical components of nucleic acids. We have named them adenine (A), thymine (T), guanine (G), and cytosine (C). They pair to form chemical bonds with A and G and C combining to form DNA strands. In other words, they are the building blocks of life as we know it here on Earth.

When you start bioprinting nucleotides, personalized medical therapies take on a whole new meaning. It means you can print healthy genes and replace defective ones that cause congenital diseases.

Where CRISPR/Cas9, also developed at UC Berkeley, gives researchers and medical practitioners the ability to cut out individual gene sequences and replace them with healthy ones, now with DNA bioprinting it becomes possible to print an entire chromosome. Imagine what this could mean in cancer treatment and for many other intractable diseases.

The bioprinting dream, however, goes even further. Using the technology will revolutionize agriculture, pharmaceuticals, manufacturing, and even the fuels we make to create energy. Reinforcing this extended capability, Professor Oh states that 3D bioprinting isn’t restricted to just the “bio.” He sees its use with “various materials with diverse optical and electrical properties, including complex materials such as quantum dots and carbon nanotubes.”

Combining the South Korean advancements in nanoscale 3D printing of biopolymers with the work at Berkeley and biomedical engineers may soon see a future where we will print genes, chromosomes, replacement organs and tissue.

This is not Frankenstein’s monster pieced together and made animate, but rather a technological advancement that will allow us to reconstruct our damaged selves from the DNA level and up and even integrate nanomachines and non-biological components.

When Ray Kurzweil first envisioned what he called the Singularity, it involved the merging of human and artificial intelligence, in other words, what Star Trek would call a “mind meld.” I don’t think Kurzweil envisioned integration at the level of DNA.

His prediction of 2045 as the date when humans would become one with our technology is still 22 years in the future. But the evolution of 3D printing of biology with technology capable of adding integrated nanosized circuits puts a new spin on what the Singularity will be and when it might occur.

The robotic arm was developed at UNSW’s Medical Robotics Lab under the supervision of Dr. Thanh Nho Do, a Scientia Senior Lecturer in the Graduate School of Biomedical Engineering, Mai Thank Thai, one of his Ph.D. students, and other UNSW staff. They recently published their research in the journal of Advanced Science.

Bioprinters up until now have tended to be large desktop printers. Creating living constructs, therefore, has been done outside the body. That means transporting the finished print job to the operatory and then inserting it into a host. This method can lead to many things going wrong. The finished print may not fit where it is intended to go. The threat of contamination is real. And during transport, the bioprinted material could be damaged.

The UNSW team decided that a better approach would be to do bioprinting inside a living body. So they created a proof-of-concept 3D bioprinter called the F3DB. It features a flexible robotic arm, a soft printing head, and software based on a kinematic inversion model and machine-learning-based controllers.

This bioprinter is intended to be a model for the future development of endoscopic surgical robots to allow for minimally-invasive procedures to be used to repair tissue damage from disease, trauma, and injury. How soon will this go from concept to common usage?

The team sees with further improvements to the F3DB, such as an integrated camera and real-time scanning to create 3D tomography, its successors within the next five years will be used by medical teams to do minimally invasive procedures to go to places hard to reach to make necessary repairs.

The team has demonstrated the F3DB using a variety of shaped biomaterials in an artificial colon as well as on a pig kidney. Their experiments did no damage to living cells which continued to grow after usage.

In a UNSW press release,  Dr. Do states, “This system offers the potential for the precise reconstruction of three-dimensional wounds inside the body, such as gastric wall injuries or damage and disease inside the colon.”

He continues, describing the F3DB as “able to 3D print multilayered biomaterials of different sizes and shape…thanks to its flexible body.”

How big is the F3DB proof-of-concept? It is similar in size to commercial therapeutic endoscopes used today for gastroscopies and endoscopies. But the team believes it can be made even smaller for future applications.

The F3DB features:

• a three-axis printing head mounted on the tip of a soft robotic arm that can be configured to print pre-determined shapes, or can be operated manually for custom print jobs.
• a head that consists of soft artificial muscles allowing it to move in three directions.
• an ability to bend and twist using built-in hydraulics.
• a nozzle in the head that can direct water that can clean blood and excess tissue from the site where the biomaterial is implanted. The nozzle can also act like an electric scalpel to cut away cancerous lesions and other damaged tissue to create a clean field for applying the living bioprinted material.
• the use of a variety of materials to construct it to variable lengths and stiffness depending upon the application.

Losing your sense of smell is a big deal. As we age it happens to many of us. Diseases can cause temporary or permanent loss of our olfactory abilities. Traumatic brain injuries can lead to similar outcomes. Without your sense of smell, a condition called anosmia, there are dangers that can occur if you are home, for example, and cannot detect the smell of a gas leak. Without your sense of smell, you also lose your sense of taste. The tongue has limited taste receptors (sweet, sour, hot and cold) but without the nose working, odours draw a blank. A year ago, we hired painters to redo our apartment. One of them told us he got COVID-19 and lost his sense of smell. He had yet to get it back. To him, food tasted like metal or garbage.

How A Neuroprosthetic Works

In the presence of an odour, one of hundreds of sensors in the neuroprosthetic recognizes a distinct smell and transmits the signal to an implant linked directly to the olfactory bulb of our brain which is responsible for identifying odours. The prosthetic works similarly to cochlear and retinal implants, devices used to restore hearing and sight.

The neuroprosthetic has to be a pretty complex device to come close to matching our noses. The 400 or so receptors we naturally have in our noses distinguish one trillion different smells. When a smell converted to an electrical signal reaches our olfactory bulb its sets off other brain interactions triggering mood, memory, and cognition. Smells bring back childhood memories. Smells can even be used therapeutically to overcome post-traumatic stress.

The Current State of Odour Detectors

Commercial and industrial odour sensors are specific. For example, we have in our apartment smoke and carbon monoxide detectors. Homes may have detectors for natural gas leaks, or radon gas leaking into basements. A detector, however, that can discriminate among these limited number of odours doesn’t exist at present. That’s why we have three or four. Creating a form factor that contains multiple sensors is both an engineering and size problem. So imagine trying to build a neuroprosthetic that detects not four by forty or four hundred different smells.

Where the VCU Team Is At

In experiments using rats as subjects so far, the VCU researchers have demonstrated they can create odour maps when areas of the olfactory bulb are stimulated. Working with human subjects is on the agenda with plans for a first-generation device to detect and differentiate dozens of smells. The device would incorporate several hundred microsensors. The VCU team is even talking about creating specialty neuroprosthetics to detect particular smells, for example, an e-nose for bakers or one for hikers to differentiate the smells of the forest.

Recently an article appeared in IEEE Spectrum describing the work being done at VCU and in other universities tackling the loss of sense of smell, largely being driven by the growing number of Long COVID sufferers. States Costanzo, “It’s a long process to make a device and get it to the point where you can safely implant it in patients…But the scientific part of it has moved very nicely. We laid the groundwork with injury and repair research, and after studying it for 40 years, have finally come up with something that might actually work.” When? He predicts within ten to fifteen years.

Restoring damaged nerves from an injury is difficult. You cannot easily suture broken nerve ends and make them reconnect. I’ll give you an example from personal experience. I broke my legs in a tobogganing accident when I was in university. After multiple surgeries to rebuild the broken weight-bearing bones of my left limb, my nerves from the mid-point below my knee to the ankle no longer worked. This didn’t impede me from walking but I constantly had to pay attention to bumping into things, or accidentally burning or cutting myself on that leg because I couldn’t feel a thing.

That’s the problem this Israeli team of biomedical engineers and medical doctors decided to tackle. They looked at the most recent research into neural prostheses which use sensors to connect severed nerves. But the existing solutions required external power sources. In other words, a battery.

For restoring the sense of touch in a finger, a battery was seen as impractical. So the research team at Tel Aviv University decided to develop a triboelectric nanogenerator, called a TENG. The TENG could be powered by the body’s own movements and nerves. Connecting it directly to a healthy nerve, therefore, would restore sensation.

The TENG is an implantable piezoelectric sensor powered by natural frictional forces. The sensor consists of two tiny plates, each 0.5 centimetres square. When frictional forces cause them to come into contact an electric charge is transmitted to the connected undamaged nerve. If implanted for an injured finger, the frictional tension can vary based on whether the person is using a firm or weak touch.

The TENG can be implanted anywhere in a body to restore tactile sensation. It is built from biocompatible materials so it is well tolerated. So far the team hasn’t used a human subject. But in test animals, they have used the TENG to restore normal walking despite motor nerve damage. In the near future, TENG sensors will be used in a clinical trial with human patients to restore feeling in their fingers.

States Dr. Ben M. Maoz at Tel Aviv University, “Restoring this ability can significantly improve people’s functioning and quality of life, and more importantly, protect them from danger. People lacking tactile sensation cannot feel if their finger is being crushed, burned or frozen.”

The research and invention are described in a journal article that appeared on June 17, 2021, in ACS Nano. The article is entitled, “Restoring Tactile Sensation Using a Triboelectric Nanogenerator.”

In the Asimov novel, the focus is on miniaturizing technology to send a submarine and human crew into the bloodstream and across the brain barrier to save the mind and life of an important scientist. That’s not the case here. No humans are being miniaturized.

Developed by Bionaut Labs with headquarters in Los Angeles, and research and development facilities in Israel and at the Max Planck Institute in Germany, a Bionaut is a remote-controlled microbot that comes in different designs to deliver biologics, nucleic acids, and small molecule therapies th the brain and central nervous system where traditional treatments have largely been unsuccessful or highly risky.

Bionauts are individually constructed with different form factors. No more than a millimeter in size, they come with a cargo compartment and contain moving parts that respond to a remote magnetic controller used to guide them to a targeted area in the brain or brain stem to deliver therapeutic payloads.

In a March 3, 2021 press release, Dr. Santosh Kesari, Chair of the Department of Translational Neurosciences and Director of Neuro-Oncology at St. John’s Cancer Institute, Santa Monica, California, is quoted stating, “The brain is uniquely designed to protect itself from external factors. This makes medical intervention in the central nervous system extremely challenging. The Bionaut technology opens the door to precise treatment for a wide variety of severe brain disorders.” 

For Brainstem glioma, a tumor that impacts children and young adults, today’s cure rates are low. But with the Bionaut in recent laboratory mouse tests with human glioma tumors, glioma treatment and elimination have been successful. Clinical human trials should follow in 2023.

What’s in Bionauts future? Delivery of new therapeutic capabilities such as antisense, siRNA, gene therapy, CRISPR-Cas9, and oncolytic viruses. With precision delivery, the Bionaut should make it possible to tackle Parkinson’s, Huntington’s Disease, Hydrocephalus Stroke, Focal Epilepsy, and more entering through the brain stem or through direct brain insertion.

As mentioned before, Bionauts come in a wide range of configurations, sizes, payloads, shapes, and topologies based on the desired task, disease and site location. The ability to construct different versions provides infinite flexibility and offers safer alternatives for treating specific brain and central nervous system diseases. The potential is to be able to deliver continuous therapeutics and disease monitoring using customized delivery to do a wide range of medical interventions including brain stimulation, microsurgery, and ablation.

The company was estalbished in 2016 by founders Aviad Maizels and Michael Shpigelmacher. They were motivated to find a means to do precision medicine using microbots, a burgeoning field of discovery and invention. Working with the Max Planck Institute, and with medical robot pioneers in Israel, Bionaut is an expression of two different evolutionary steps in medicine: using micro-robotics inside us to diagnose and treat diseases, and personalized medical therapies where drug delivery isn’t done through whole-body diffusion with all the potential consequences of side effects.

Both of these medical technology trends should lead to far better outcomes for patients and in the case of Bionaut, alleviate suffering from those with brain and central nervous system diseases, let’s hope, in the very near future.

COVID-19 may have made the world aware of mRNA vaccines with Pfizer-BionTech and Moderna’s contribution to battling the pandemic. But mRNA research goes back several decades. In a recent publicity event at the University of Pennsylvania, the two researchers behind the science were inoculated. Drew Weissman and Katalin Karikó partnered to harness the power of mRNA to create an entirely new type of delivery mechanism for fighting diseases such as:

• HIV (AIDS)
• Herpes
• Malaria
• Sickle-cell disease
• Influenza (the flu including H1N1, swine flu)
• Rabies
• Ebola
• Rhinovirus (the common cold)
• Dengue Fever
• Tacaribe
• TMEV
• Amapari
• Reovirus
• Adenovirus (respiratory infections)
• Murine Adenovirus (internal organ infections)
• Varicella-zoster (chicken pox)
• Zika

That’s quite a list going well beyond variants of coronavirus of which the latest, COVID-19, has infected more than 100 million and caused the death of over 2 million in one year.

mRNA plays a critical role in delivering instructions from DNA. Think of it as an envelope whose contents when opened carry a sequence of codes that instruct a cell to produce protein structures. It’s these proteins that have been the key to tackling COVID-19.

mRNA therapy was first attempted in 1990 using synthesized RNA. The initial tests failed because the body saw the introduced mRNA as an intruder causing a cytokine storm, a powerful immune response that ended up killing the recipients. Cytokine storms have been reported as being among the primary causes of COVID-19 deaths. So how can an mRNA therapy not cause such an overwhelming and deadly immune response?

It turns out that less of the cure was better than more. Encapsulating a synthetic mRNA-produced protein to mimic a protein on the surface of coronavirus and delivering it by injection turned out to be the way to arm the immune system to fight the disease. Packaging the mRNA required the development of a carrier, which is a substance that would protect the deliverable from being attacked before it finds its way to healthy cells. Lipid nanoparticles have proven to be just the right construct. They have protected mRNA content ensuring that it doesn’t degrade during transmission and is proving to be effective in transmission through injection.

In an article published in the MIT Technology Review this week, author Antonio Regalado describes the success of mRNA vaccine technology came out of a lucky break. He writes about Weissman and Karikó’s astonishment when the injected nanoparticles containing the mRNA homed in on dendritic cells, the perfect ones to put the immune system on alert. With efficacy approaching 95% for the two current mRNA vaccines, the researchers have created a potent tool for tackling a panoply of diseases such as those mentioned above. Why? Because mRNA is an information molecule. Switch out the protein and replace it with a protein to attack cancer or malaria, and you have a new instruction set that can cure what ails you.

That’s why mRNA vaccines are revolutionary. It’s not just hyperbole. This technology is the real deal.

June 11, 2020 – About a week ago I received an e-mail blast from Peter Diamandis, of X-Prize fame, in which he stated that the world is facing two pandemics: the first COVID-19, the second, aging. Aging has been with us as a species from the moment humans emerged from the tree of life. Calling it a pandemic seems facile. It’s like calling erectile dysfunction a disease in men rather than a sign of aging. But nonetheless, the biopharmaceutical industry and scientific community are tackling aging as if it were a disease.

In Peter’s e-mail he reviewed the technologies on the cutting edge that could add 20 to 30 healthy years to the lifespan of the average human. He describes 100 as the new 60 in the coming decades.

On this planet today live 7.8 billion humans of which 9% are over the age of 65. That’s approximately 720 million of us who have reached a point where the accumulations of our life’s journey has piled up leaving us with chronic health problems like heart and respiratory diseases, cancer, arthritis, dementia, and other conditions. These problems don’t start the day we turn 65. They are acquired over a lifetime and some believe they are symptoms of larger condition called aging. Peter argues that science and medicine is only now beginning to recognize the spectrum of conditions as being within the overall disease called aging.

Should we accept the natural limits of our species? And if we do, just what are these limits? Is it 90, 100, 110, or more? Many species on this planet outlive us. Bowhead whales can live for 200 years, and Greenland Sharks,  Sea Turtles, and some land tortoises can make it to 400 years or more. And then there are trees that can live thousands of years. What is innate in them that is not in us? Peter asks if this is a hardware or software problem, and if so, don’t we already have sufficient knowledge and the tools necessary to repair both?

On this blog site we write about some of these tools such as CRISPR, stem cells, gene drives, and more. Dr. David Sinclair of Harvard Medical School, in his book Lifespan, believes the technologies we have or are in the process of maturing will allow people born today to live to 120 in good health, and even make it to 150 or more. These tools include:

1. CRISPR & Gene Therapy
2. Stem Cell Therapy
3. Wnt Pathway Manipulation
4. Senolytic Medicines

CRISPR & Gene Therapy

Aging happens because our normal cell functions over a lifetime begin to destabilize. When cells no longer have the capacity to thrive they experience apoptosis, cell death. But in using gene therapy tools there is no reason for specific cells in our bodies to die. And with CRISPR-Cas9, we can go into our DNA and edit it inside the cell to provide a repair kit for almost any problem.