History of Changing the Treatment of Diseases With the Help of Biomedicine.
We live in a world of triumphant biomedicine. Its age began in the mid-20th century and continues to this day. Every five years, a new major discovery drives the science forward and brings us closer to victory over diseases that seemed incurable not so long ago. However, sometimes the biomedical approach demonstrates its downside, so our technological endeavors should focus on resolving this issue.
What is the biomedical approach, anyway? From its standpoint, a human is a biological object, a multitude of cells and chemical reactions between them, that needs to be explored down to its tiniest parts so that we can learn to cope with its "breakdowns" (i.e., diseases). Examining every detail of a big mechanism, detecting an error, fixing it, and reassembling the system - despite its imperfection, this approach has saved millions of lives.
What discoveries were made possible by this approach, and what diseases did it help to defeat? I will tell you about the most significant of them.
The industry of antibiotics and super antibiotics
The discovery of penicillin by Alexander Fleming, followed by its mass production during WWII, is often called the turning point of biomedicine. The unimaginable success of a simple substance that could help against many infectious diseases (including sepsis - this is why it became commonly used by the military) has proved the effectiveness of developing medications in a lab and reducing the human body to particular organs, tissues, and cells. Fungi of the Penicillium genus attacked only specific pathogens and did not affect the healthy tissue, giving researchers and medics the reasonable hope that similar "assassins" could be found for many other pathologies.
The fact that bacteria can become resilient to antibiotics was first mentioned several months after penicillin had been introduced, but the voices of concern were generally ignored. Scientists raised the alarm only when an MRSA strain was found in the UK in 1962, two years after methicillin had been discovered. By the 1970s, it became clear that almost all bacteria would eventually become resilient to antibiotics, and humanity might lose this race unless we changed our methods of applying available antibiotics and finding new ones.
Two major focuses of research can be distinguished in the 21st century: AI-assisted search for new antibiotics and detection/elimination of defense mechanisms that bacteria have developed during their accelerated evolution.
The biggest success of the former is the halicin antibiotic that was discovered using the machine learning method: the information on 6,000 various compounds was being "fed" to the AI until it found the molecule with the highest antimicrobial potential. Halicin proved its ability to cope with dozens of serious infections; the only bacterium it could not beat was the highly resistant Pseudomonas aeruginosa strain that causes severe lung infection. Without AI, scientists would have spent years trying to get such a powerful medication.
In 2020, Nature published a detailed article that described the methods of improving "old" antibiotics, to which bacteria have already become resistant. The new approach was exemplified by group A streptogramins. Streptogramin-resilient bacteria use virginiamycin acetyltransferases as a defense mechanism, i.e., they produce a special protein that can identify and deactivate antibiotics. To solve this problem, the scientists created seven different molecular modules for assembling various sets out of 62 group A streptogramin analogs.
Using cryo-EM and X-ray diffraction methods, the researchers prepared 3D images of substances of almost atomic-level resolution to define which parts of the molecule are responsible for antibiotic functions. After that, they made changes to these parts and tested new medications on dozens of pathogenic bacterial strains. The mouse model has proved that these «patched» antibiotics are ten times more effective than old streptogramins.
This is one of the most innovative methods of "editing" substances and it gives hope that the fight against antibiotic resistance will have a successful outcome. However, serious restrictions on antibiotics (e.g., making them prescription-only) may be required to solve the issue: biomedicine, educational programs, and legislative initiatives need to work side by side on that.
Stem cells: sensation-2000
I have already discussed in another article the impact that stem cell discovery made on biomedicine. Stem cells have a vast potential: regenerative medicine as a biomedical technology can deal with such life-threatening pathologies as strokes, cardiovascular diseases, diabetes, Parkinson's, Alzheimer's, ALS, osteoarthritis, severe burns, and numerous types of cancer.
Both embryonic (stem cells found in fetuses) and tissue (a limited number of which are present in a grown body) types were discovered in the early 1980s. The possibility to transform them into any other cell type fascinated the scientists. They were confident that if this transformation was ushered in the right direction, it would become possible to mold neurons, bone tissue, and internal organs from the stem cell clay and the much-awaited victory over hundreds of diseases would be at hand. At the turn of the century, it seemed that in academic circles, all they talked about is these miraculous cells.
However, as of now, stem cells are used mainly for research rather than for actual therapy. One of the major constraints is ethical - the application of the most promising embryonic cells lies within a deep gray legal and moral zone. Most probably, these issues will be solved by computer technologies; someday, perhaps, we will learn to synthesize building blocks for new organs in VR and culture them in vivo.
Immunotherapy as a cancer treatment type
Every person has their own, well-functioning (in most cases) system for eliminating harmful cells, particles, and pathogens - the immune system. As the immune system was discussed extensively during the COVID-19 pandemic, its functioning has become crystal clear to almost everyone: there are special cells in our body that can remember the pathogens and attack them on sight. What if we teach these cells to target not only viruses but, for example, malignant tumors?
Immunotherapy is the most progressive and the least invasive cancer treatment technology. It helps to effectively counter even later-stage oncology pathologies while having relatively few side effects.
For example, monoclonal antibodies - the artificial proteins stimulating major immune functions - have proved highly reliable. Like natural antibodies, they «cover» the surface of a cancer cell and provoke its destruction by the immune system.
Another immunotherapy therapy involves checkpoint inhibitors. The checkpoints are substances that dampen the immune response and prevent the organism from killing itself (like it does in the case of autoimmune diseases). Malignant cells exploit checkpoints and "disguise" themselves: the immune system does not realize it is facing a dangerous enemy and therefore does not attack the tumor. Inhibitors can help the immune system see through this cover, active itself, and take action against cancer cells.
Another cancer treatment type is adoptive cell transfer (ACT). In this case, the patient's immune cells are used for therapy, as they are extracted, multiplied in vitro, and returned to the organism.
All immunotherapy methods are owed to laboratory biomedicine; to put it simply, scientists dug their way down to the tiniest details of the intricate mechanisms of the human body and its pathologies, described these details and the processes they take part in, converted this information into digits, and armed themselves with the new knowledge. This is a far cry from therapy methods of the past that shared a holistic approach to the organism. However, when it comes to cancer diseases, this "pinpoint" work turned out to be extremely productive. With computer modeling technologies, we can push even further and try out other ways to activate the immune system - after all, we have just begun to understand and explore this sophisticated element of the human body.
Gene editing and CRISPR-Cas
Generally, the announcement of Nobel Prize laureates causes lengthy debates on whether the winners were worthy of it. However, the Nobel Prize in Chemistry 2020, given to Emmanuelle Charpentier (France) and Jennifer Doudna (US), caused no such controversy: CRISPR-Cas9 technology definitely deserves the award.
With the help of CRISPR-Cas9, scientists can make precise in vitro changes to the DNA of any living being - from bacteria to higher mammals, including people. Emmanuelle Charpentier and Jennifer Doudna have developed a way to cut, reassemble, and replace fragments of the DNA chain.
Biomedical reductionism has reached its pinnacle: the researchers are now "tweaking" the smallest part of the body and can rewrite its basic information. It is a highly reliable tool for treating various genetic disorders, applicable to many cases of cancer, Alzheimer's, diabetes, etc.; however, only some of these pathologies are congenital and other cases are caused by other reasons.
What is left to do is figure out what language the information in our DNA is written with and what each gene (including mutated ones) is responsible for. Almost every week, a new article is published in the scientific press that describes the genetic nature of various conditions, pathologies, and attributes - sometimes, dozens of "responsible" genes are involved. This means we can understand only particular words and utterances of the human genome language, yet we are still unable to translate the whole text, let alone write our own.
"Genetic drugs": Luxturna, Glybera, Kymriah, and others
In the late 2010s, the world saw an influx of "genetic drugs": highly expensive but effective medications against several, predominantly rare diseases. These drugs can deliver specific enzymes to specific cells so that they start synthesizing a necessary protein or activate a non-functioning mechanism in the body, thus eliminating the consequences of genetic mutations.
For instance, Luxturna does this trick to the human retina, giving patients with a rare disorder the chance to recover their eyesight or even see things for the first time. Another drug, Glybera, helps against lipoprotein lipase deficiency - a rare genetic pathology. Kymriah is the medication that treats acute lymphoblastic leukemia among patients under 25 and diffuses large B-cell lymphoma among grown-up patients by activating their immune system (so-called CAR T-cell therapy).
The price for these medications is exorbitant (up to 1 million USD), as the research and market introduction activities are both costly and labor-intensive when it comes to rare diseases. These breakthrough products, made possible by biomedicine, are the forerunners of human genome sequencing: once we have decoded the DNA "excerpts", we can detect pathologies and even mitigate them.
But to make sure the list of experimental drugs increases and their price drops down, we need to overhaul our approach to clinical trials. Most present-day studies suffer from a lack of participants, ethical and legal constraints, and the difficulty of switching from mouse models to human patients. In my opinion, the best solution is to completely reconsider the clinical trial procedures with the help of computer technologies.
Biological processes in silico
Even now, we have enough resources to make a complete "human model" in virtual reality. Thanks to the biomedical approach, we have reduced the organism to elements so minuscule that we can digitally recreate them and study biological processes in silico. Developing these models is a costly task that provides relative precision, but this is the most reliable path to take if we want to avoid many obstacles.
"Virtual patients" are already widely used in several disciplines of medical education, but we need to move forward and digitalize every element of the human body, every enzyme and amino acid, to recreate the whole bit by bit and pave the way to infinite opportunities for conducting research, testing medications, and observing various therapy scenarios.
Biomedical philosophy: the limits of reductionism
No approach is boundless. Biomedicine, with its treatment of the body as a sum of details and diseases as breakdowns in a complex mechanism, has helped us a lot and will continue to do so. However, some researchers believe this approach dehumanizes people, as it reduces them to a set of functions and chemical reactions while eliding the vital aspects of synergy.
We can examine the human body (or any other living being) down to atoms, describe their interactions, crack or even alter the genetic code - but this alone cannot save us from diseases, aging, or death. As far as I can see, biomedicine took reductionism to the extreme. Instead of stepping back to classical and traditional medicine, it needs to take a conceptual leap and start treating the organism as a complex system that cannot be narrowed down to its elements. Or at least, not always narrowed down to it - some pathologies can be coped with by manipulations with the DNA or the immune system, but many others cannot.
Biomedicine needs to evolve into ecobiomedicine, i.e., to consider external factors that affect our health and well-being. A disease is not just a malfunction; it is the effect of disrupted communication with the environment. For instance, the present-day biomedical approach tends to underemphasize psychological and environmental factors of disease development, always looking for a solution on the cellular level or among chemical reactions. However, it is not always productive, as many therapeutic methods offered by this approach solve the "internal" part of the problem only while leaving the "outer" part unchanged. That means it fights against symptoms instead of focusing on the root cause.
When we discuss "virtual patients" and in silico research methods, we often forget that the perfect goal is to imitate not only the organism but its environment, to create a second life for improving the real one.
Technologies are capable of such results: according to Forbes, the global medical robotics market alone will reach an incredible size of $20 billion by 2023. Meanwhile, the amount of global medical data doubles every 60-70 days - and the more data we have available (including information on external factors of health and disease rate), the more opportunities there are to overcome biomedical reductionism.
Another promising approach that offers an alternative to biomedicine is the narrative, or phenomenological, approach. Examining health and illnesses through the lens of life stories, with medical specialists adopting active listening skills, can be a lengthy and costly process but it seems to be highly effective.
Perhaps, artificial intelligence can partake in the analysis of patients' narratives and learn to detect emerging pathologies by life patterns, situations, environmental factors, and stress levels? I want to be optimistic and believe that eventually, we will combine the outstanding biomedical achievements and a greater perspective provided by modern psychology and philosophy. Health is not comprised of numbers and molecular interactions only - yet they can help us get a more profound and precise understanding of various pathologies.
About the author
Rustam Gilfanov is a venture partner of the LongeVC fund.