Rustam Gilfanov: The Impact of bioengineering on Humanity

Bioengineering is the science that reconciles the principles of biology and engineering. For some, even the name of this discipline is self-evident, yet there is an awe-inspiring story behind this simple definition. Bioengineering is the fusion of two seemingly incongruous worlds, the dream of 19th-century sci-fi writers coming true: we perceive living organisms as engineering systems and are learning to adjust and improve them.

This discipline has already contributed to our lives: thanks to it, we can use pacemakers and diagnose diseases via magnetic resonance imaging (MRI) and arthroscopy. Many things that we now consider commonplace were made possible by the tremendous efforts of bioengineering science.

It is bioengineering that gives us a chance to treat diseases that were previously considered incurable (including cancer), change our aging processes, and expand the horizons of regenerative medicine. What is now on the bleeding edge of bioengineering? What other breakthroughs and, I dare say, miracles can we expect? I will attempt to highlight the pivotal aspects and outline the development tendencies of the next few decades.

Cell self-recovery: the pathway to health

As stem cells divide, they can create new, specialized cells and update the body tissues by replacing sick cells with healthy ones. Scientists use several stem cell types for culturing, taken from embryos, umbilical cord blood, or bone marrow of an adult person.

Stem cells were first mentioned in the late 19th century. In 1909, Russian academician Alexander Maximow made this notion scientifically established and developed the stem cell theory. The first researchers to provide an experimental basis for this method were James Till and Ernest McCulloch (US). In the 1960s, they subjected mice to a lethal dose of radiation and transplanted to them marrow cells taken from another mouse — and their test subjects survived.

Bone marrow transplantation is commonly used in clinical practice, including the therapy against oncohematological and immune disorders. Another method of treating these diseases involves the transplantation of hematopoietic stem cells, taken from marrow or umbilical cord blood. Parents have the option to store the newborn's cord blood in biobanks.

In 1981, Martin Evans and Matt Kaufman proved the existence of embryonic stem cells (ECSs) capable of transforming into different tissue types (this ability is called) or even a whole organism. However, there are several ethical constraints to the research and usage of embryonic cells.

The next milestone was the invention of technology for reprogramming adult cells into pluripotent stem cells similar to embryonic ones. For this breakthrough achievement, Japanese scientist Shinya Yamanaka (who used skin cells in his research) won the Nobel Prize in 2012. This discovery gave an impetus to the development of the industry and helped initiate numerous studies.

As of now, we do not have enough clinical experience to answer the question of whether stem cells can effectively treat diseases unrelated to blood disorders. However, scientists acknowledge the vast potential of stem cell theory: this method is being tested for its efficiency against Parkinson's, Alzheimer's, and multiple sclerosis. These methods still need to get formal approval, yet several strategies of stem cell therapy for neurodegenerative disorders have already been developed.

It is interesting that this industry provokes huge attention and even controversy: call for any therapy for neurodegenerative disorders is so overwhelming that even the FDA tends to change the registration protocols in order to accelerate the process. And it’s just the beginning.

For instance, Japan officially approved using stem cells extracted from the bone marrow for treating spinal cord injuries in 2019. This technology was named Stemirac, and its efficiency has been proven by clinical trials involving 13 volunteers; however, the scientific community is concerned about the validity of the trials.

Stem cell therapy methods were legalized in regenerative medicine as well — but only if they involve growing tissues outside a human organism. In 2014, European Medicines Agency (EMA) recommended the first therapy product containing stem cells — Holoclar, developed by Chiesi.

Holoclar is used for treating a rare disorder — Limbal Stem Cell Deficiency (LSCD) due to burns to the eyes that may cause blindness. Limbal stem cells are located on the border between the cornea and the sclera (the white of the eye). They play an important role in the regeneration and recovery of the corneal epithelium and can be destroyed by burns. The therapy involves taking a biopsy from a small undamaged part of the cornea for growing the collecting cell culture in vitro and transplanting it to the damaged eye.

Thus, a patient has a lesser risk of tissue reduction compared to donor transplants. Besides, no surgical intervention is needed for the other eye; a small biopsy is enough.

There are failed experiments as well — for instance, the research on the regenerative potential of the heart. For more than 15 years, the team led by Piero Anversa had been studying the allegedly discovered heart stem cells (c-kit positive cells). It was assumed that these cells could help the heart muscle self-regenerate.

Human trials were approved for the method. That could have been a scientific revolution; however, several laboratories tried to replicate the pre-clinical trials and did not even get close to the results described by Anversa. Finally, in spring 2018, Harvard Medical School and Brigham and Women's Hospital, where Anversa had been working, had to retract 31 papers of his research team due to “discrepancies and/or fabrications of data and images”.

New neurons: curing Parkinson's

Parkinson's disease is a chronic neurological disorder caused by the destruction of neurons that synthesize dopamine; the patients may suffer from motor symptoms, mental disorders, and dementia. In the 2000s, Black Sabbath frontman Ozzy Osbourne was diagnosed with Parkinson's (still considered untreatable).

In 2020, Osbourne dared to undergo an experimental ESC therapy. His daughter Kelly called the results “mind-blowing”: He wants to get up. He wants to do things. He wants to be part of the world again. He’s walking better. He’s talking better. His symptoms are lessening.” By that moment, several attempts had been made to apply stem cell treatment against this neurodegenerative disorder; as of yet, none of these methods has been approved, of now.

Japan has demonstrated the greatest progress in that area of study by conducting the world's first transplantation of neurons grown from stem cells in 2018. Scientists at Kyoto University cultivated precursors to dopamine-producing neurons from skin cells and made the world's first transplantation of neurons. During the three-hour operation, neurosurgeon Takayuki Kikuchi's team successfully implanted 2.4 million of these cells into 12 brain sites of a patient in his 50s.

The surgery was a part of Kyoto University clinical trials, led by Jun Takahashi. The research has been going on: in 2021, Takahashi announced he was analyzing potential adverse effects.

Japanese pharmaceutical manufacturer Sumitomo Dainippon Pharma is already interested in the method and is ready to organize the production of this technology by 2023. The successful application of induced stem cells against Parkinson’s can provide numerous opportunities for treating other neurodegenerative disorders.

Training cells to produce insulin

Scientists have also learned how to use ECSs for synthesizing insulin-producing cells identical to healthy pancreatic cells. That gives hope that patients with type 1 diabetes will no longer need their daily injections.

Pancreatic beta cells produce insulin, the hormone regulating glucose levels in the blood. The immune system of patients with type 1 diabetes destroys these cells, causing insulin deficiency; to maintain its levels, patients have to take insulin shots every day.

Since the 1990s, medics have been practicing donor transplantation of islets of Langerhans, the clusters of insulin-producing beta cells. However, there were limitations on the donor material, as the recipient organism began to attack the "alien" cells. This response to the transplant had to be treated with immunosuppressants.

In 2014, researchers at Harvard University found a way to generate millions of beta cells from ECSs that can be transplanted to patients with diabetes. Later, other research teams managed to achieve similar results. The problem of immune response to these cells, however, remains unsolved.

Douglas Melton, who had taken part in the Harvard University research, founded his own startup Semma and continued to explore this technology. In 2019, Vertex, the US pharmaceutical company, acquired the startup for $1 billion. This March, Vertex announced its plans to enroll 17 patients for the first clinical trial of this method, i.e., for the first human tests on stem beta cell transplantation. The first results will become available in 2024.

Should we get ready for human cloning?

In 1995, the scientific team led by Ian Wilmut reported they had successfully cloned two sheep. For the first time in history, the researchers managed to clone a mature mammal — the famous Dolly sheep. They used the following mechanism: a nucleus was removed from a fertilized egg cell and was replaced by another one, composed of somatic (neither gametes nor stem cells) cells of an adult of the same species; the new egg cell was implanted into the uterus of a female sheep. Before that, this team had conducted experiments on sheep cloning, but they had used embryonic cells. The appearance of Dolly was not an immediate outcome of their endeavors: in total, the team had taken 277 attempts to do that. For pioneering the cloning of mammal species, Wilmut was knighted by Queen Elizabeth II.

When Dolly was 6.5 years old, she was euthanized due to viral lung disease. Despite concerns from the academic community, her illness was most probably caused not by her origin but by improper keeping conditions and bad heritage: the donor sheep had died of cancer as well.

Since the birth of Dolly, scientists have cloned other mammal species: mice, cats, dogs, pigs, cows, and even camels — 28 species in total. For many years, experiments on cloning monkeys had been a failure. Finally, the first successful cloning of a primate via the somatic cell nuclear transfer method was accomplished in China in 2017. Attempts were made to use cloning for saving endangered species; in 2001, scientists managed to clone a gaur, the rare bovine species. However, the cloned gaur died within 48 hours.

In 2008, Japanese researchers cloned dead mice that had been frozen for 16 years, using their brain nuclei. Before that, the "resurrection" of frozen extinct species (e.g., mammoths) had been considered impossible, as there were no "live" cells in the biological samples, and their DNA inevitably degraded. Although that experiment was a success, we do not have enough material to "revive" a mammoth, so that is not something we'll be able to see in the nearest future.

Several experiments on pig cloning were conducted. Pigs and humans have internal organs similar in structure and size, so those studies helped assess the probability of pig-to-human organ transplantation. In 2002, Scottish biotech company PPL Therapeutics reported having cloned five piglets with organs applicable for transplantations to human patients. Similar experiments were reported by other companies as well.

In theory, human cloning is also possible. Canadian company Clonaid even claimed it had created the first human clone, a girl named Eve. However, no one has seen the girl, and no proof of the experiment has been provided. Furthermore, such experiments are constrained by various ethical, religious, and legal norms. If a cloned person shares the same genome with the donor, how will this affect their personality, status, and rights? Meanwhile, treating a genetic copy of a human being as a source of "workable" organs for transplantation violates basic ethical principles.

What hinders bioengineering technologies?

Although bioengineering technologies can change the methods and effectiveness of treatment against numerous dangerous and previously incurable disorders, the research in this area faces many ethical and legal constraints.

In the 1980s, for example, several countries agreed to impose a 14-day limit for culturing embryos for research. This restriction was made less stringent in May 2021, as technologies become more complex and sophisticated. Now it is possible to extend the 14-day threshold, for individual cases and under strict supervision.

The extension of the “14-day rule” impacted the government guidelines in the US, where the position on embryonic stem cell usage had remained ambiguous for decades. Even in the 2000s, during George W. Bush presidency, federal funding on embryonic stem cell research was banned. The Obama administration lifted the ban in 2009, seeing the potential to defeat previously incurable ailments.

For a long time, Europe had been funding this type of research. In 2011, however, the European Court of Justice prohibited granting patents to methods involving embryonic stem cells. This ruling was the result of proceedings initiated by Greenpeace that sought to annul the patent on producing from embryonic stem cells, held by Oliver Brüstle. The reaction of the scientific community was ambiguous, with many researchers believing this decision would impede the development of several promising technologies. In 2014, the Court backtracked on its ruling,and stipulated that stem cells created from an unfertilized egg through pathogenesis are unable to develop into a human being and thus cannot be considered an embryo.

Creating embryos from human cells is a part of therapeutic cloning. Yet there is also reproductive cloning that involves creating a human being genetically identical to another person. In 1998, the Additional Protocol on the Prohibition of Cloning Human Beings to the Council of Europe Convention on Human Rights and Biomedicine was signed by 24 out of 43 Council member states.

Russia did not sign that protocol, yet it adopted a federal law banning human cloning in 2002; it is still in effect. In 2005, the UN urged its member states to introduce legislative acts that ban human cloning as a human dignity violation. In many countries, experiments on the reproductive cloning of people are considered a criminal offense.

Where will bioengineering take us?

Scientists see the great potential of stem cells as the tool for the self-recovery of the body. Exploring all the possibilities and the consequences of stem cell application may help discover theory methods for treating currently incurable diseases; especially after the ability to transform somatic human cells into pluripotent stem cells has been found.

In any case, human cloning and the usage of embryonic stem cells will be always limited by ethical or legal standards; however, these boundaries will probably shift as new scientific discoveries appear.

Modern digital technologies help study the potential outcome of innovative therapy methods, making it possible to model their application and adopt an individual approach, as well as to structure and process the resulting arrays of data.

​About author

Rustam Gilfanov is a famous IT entrepreneur, a founder of a large IT company, and a partner of the LongeVC Fund.

This article does not necessarily reflect the opinions of the editors or management of EconoTimes