From computation to consciousness, explaining the brain remains the great challenge of science in the 21st century . Precisely, the brain is the organ for whose ailments a greater variety of medicines is used, at least in the Spanish national health system, which highlights the little knowledge we still have about its functioning and diseases.
We understand your tasks. The mission of the brain is the interrelation of the organism with its environment . To do this, this organ displays a repertoire of behaviors and properties from movement to memory through emotion, language or consciousness. How do you get it? It is the big question. To try to answer it, let’s break the big problem down into smaller questions.
How do billions of neurons work together to generate behavior? How do changes in the brain lead to disease? What makes the human brain different? These are some of the big questions that neuroscience has to answer, according to neuroscientist Cara Altimus and other authors who, in 2020, published in The Journal Of Neuroscience a summary of the advances in neuroscience in the last five decades and the foreseeable milestones for the next few years.
If we continue to break down the problem, we will be able to outline five of the great challenges that present and future neuroscience will have to explain in order to assert that the conquest of the human brain has been achieved.
Challenge 1: the fundamental components of the brain
We will never understand the human brain if we do not understand its structure and composition. In the last 150 years we have come a long way in describing the principles of its general organization thanks to Santiago Ramón y Cajal, who at the end of the 19th century already recognized that neurons are the main component of the nervous system. On the shoulders of this giant, numerous discoveries have been made in the following decades, although there are still many crucial details to be learned about the structure and fundamental components of the nervous system.
First of all, we need to understand in detail the molecules of the brain. A cell is a conglomeration of molecules (essentially proteins, nucleic acids and sugars) surrounded by a layer of lipids (fat) that surrounds it. To this day, we still do not know what is the complete set of proteins that neurons contain . As proteins are the main executors of the biochemical processes that define what a cell is capable of doing, we still do not know exactly what each of the neurons in the brain can do individually.
Second, there is much to be done in understanding the cellular composition and interconnection within the many groups and structures of neurons that exist in the brain. We know hundreds of brain regions that neuroscientists have been mapping for decades like intrepid sailors establishing a rough map of the continents, countries and regions, but we do not know who they are and what diversity there is among the inhabitants of each area. We know that not all neurons are the same. In fact, we know that there is a great diversity of neurons and that this contributes in a crucial way to the functioning of the brain, but we do not know how many types there are in total (the cell atlas) or why they are different.
One neuron can be distinguished from another in its exact molecular composition and in the pattern of connections with others. Neurons are connected by synapses, through which small packages of chemical signals, neurotransmitters, are sent that communicate an encrypted message. The same package does not mean the same in connections between different places in the brain. Therefore, finding out the exact layout of the connections of each and every one of the neurons of the nervous system (the connectome) is also a fundamental part of the challenge of understanding the material structure of the human brain.
Challenge 2: building the brain
Describing how an organism is built with billions of cells organized at multiple levels of detailed complexity is one of the great adventures of biology in general and, of course, of neuroscience as well. Explaining embryonic brain development is largely the answer to the “genes-environment” dilemma, because the two are intertwined in shaping the brain; Just as in the final morphology of a sculpture, the work of the sculptor (the effect of the environment) and the characteristics of the material used (the effect of the genes) are reflected.
We know that already at birth the human brain and that of other mammals has an important diversity of neurons. The question that immediately follows is: how is such diversity generated in embryonic development? We know that neurons, shortly after birth, travel within the brain in a process called neuronal migration in which they travel up to several millimeters in distance. Landed in their final position, the young neurons begin to extend processes to establish their connections with other neurons. Dendritic branches and axons again travel marathon distances to their corresponding targets to finally make multiple contacts (many are later eliminated). This is the process of synaptic pruning with which the connections between neurons are refined, leaving only those that work best.
The challenge remains to understand in full molecular detail the exact process of migration and establishment of synaptic connections of each of the types of neurons in the brain, and to understand how their anomalies give rise to neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities in which there are alterations in these processes.
Migration and the establishment of synaptic connections are very important processes, but they are not the totality of the phenomena involved in the construction of the brain. A fundamental process is the folding of the cerebral cortex , which has been of great importance in human evolution. Similarly, the very origin of neurons, especially in the adult brain, remains a matter of debate today. Until the 1980s, it was thought that all neurons in the adult human brain were formed before birth. However, recent research, such as that of the Spanish neuroscientist María Llorens-Martín, suggests that new neurons are indeed formed in the adult human brain . If so, the challenge for the future is to determine whether the generation of new neurons in the adult brain could have therapeutic potential in pathologies characterized by neurodegeneration or neuronal death.
Challenge 3: computing in the nervous system
If challenges 1 and 2 try to explain the structure and construction of the brain, this is about understanding the basic functioning of its fundamental components, which brings us to the fundamental question of computation and encoding of information in the nervous system.
Indeed, neurons are signal processors. They receive input messages (neurotransmitters that arrive from other neurons) that are integrated/processed to emit output messages (neurotransmitters that are released on other neurons) giving a specific response. Often, to explain computation, the brain-computer parallelism is used, which is useful, but has its limitations. We know that a silicon transistor in a computer can basically act as a switch or signal amplifier, like neurons. But we don’t know what other computational activities neurons carry out. We still don’t understand what the neural computing toolbox is.
On the other hand, we still do not fully understand the encoding of information in the nervous system. What is the meaning, what information do they contain, the nerve impulses that discharge the neurons? Just as the sensory neurons of the sense organs encode information from the environment (light, contrast, sound frequency, etc.) or the motor neurons encode instructions that move the muscles of the body, the information contained in the activity of the neurons in deep regions of the brain is more abstract and enigmatic.
Different types of neurons often show peculiar firing patterns that change dynamically depending on the context and the previous situation. There are neurons that discharge isolated action potentials, others that discharge bursts, some discharge more or less frequently. All this repertoire suggests a “neuronal language” that must be deciphered. The challenge is to understand exactly what the information content of each of these nerve impulses and discharge patterns is in each moment, situation and behavior.
Challenge 4: from neurons to behavior
Understanding the essential structure and function of the cells of the nervous system in isolation is not enough to explain the brain. Neurons do not act alone , they coordinate in the execution of behavior. When an animal moves, thousands or tens of thousands of neurons fire synchronously to generate the movement. The challenge, then, is knowing what they are and understanding how these neurons are coordinated.
Until recently, we could only analyze one or a few neurons while an animal exhibits a behavior and we could not know the exact identity of those neurons, but the landscape is changing rapidly, thanks to the emergence of new technologies such as optogenetics , which allows modulate the activity of neurons with unprecedented precision. With this technique, in the last 15 years the neural circuits involved in multiple behaviors have been dissected. In addition, recently, for the first time, it has been used in humans, allowing a person suffering from congenital blindness to recover their vision, restoring the ability of their retina to send visual signals to the brain.
By combining this ability to perturb neuronal activity with new technologies to monitor the activity of multiple neurons, we are beginning to establish the exact circuits that mediate particular behaviors. The next challenge is to go beyond vision and other sensory or motor functions to delve into the depths of the brain. It remains to explain the machinery responsible for the intimacies of the human mind, especially the aspects that most differentiate us from other animals.
To understand the human brain, we will need to discover the exact circuits that mediate human language and learning . With this information, it is probably possible to enhance these mechanisms and correct them in language dysfunctions, even designing brain-computer interfaces that allow people who have been completely immobilized by neurodegenerative diseases to communicate more effectively. In fact, people immobilized by amyotrophic lateral sclerosis have already been able to have basic communications using devices that read brain activity in sensorimotor areas and in the prefrontal cortex.
We will also have to clarify other peculiarities of human behavior such as the ability to mentally travel in time , one of the distinctive properties of human episodic memory. When we remember the first kiss, the birth of a child or graduation from university, the human being is capable of subjectively evoking the place and moment in which these events took place. This ability to mentally time travel is known to depend on a region of the brain called the medial temporal lobe that contains the hippocampus, an important structure in various aspects of memory in humans and other animals. However, as in other brain processes, many details remain to be clarified about the cellular and molecular actors involved. Understanding it well is a goal for the future that could have clinical consequences in the approach to diseases in which memory is impaired.
But perhaps the biggest challenge is to explain how human consciousness arises and what is called the hard problem of consciousness. How does the seemingly intangible substance of mind and consciousness emerge from concrete, tangible matter (nervous tissue)? The great debate is whether consciousness is the sum of its component parts or an emergent property. For some authors, explaining consciousness is a matter of explaining the mechanisms of all the mental phenomena involved (attentional processes, decision making, episodic memory, etc.). For other authors, explaining these parts of consciousness represents the “easy” problem. On this view, once the easy problems have been solved, consciousness will still not be explained because conscious experience is more than the sum of its parts and is therefore irreducible.
Challenge 5: beyond the neurons
So far we have only talked about neurons, but the nervous system is not only made up of neurons. The second major cellular component, and in fact just as abundant, are the Glia cells . They are found intermingled with neurons and, although they had traditionally been considered to perform a secondary function (structural and nutritional support and protection for neurons), recent research is revealing that they play important roles in the immune response to infections, in the maturation of neuronal circuits (in the process of synaptic pruning that contributes to the refinement of connections) and also by directly modulating synaptic transmission between neurons. Thus, these cells must also be considered as major players in the nervous system, but their exact role is even less well understood than that of neurons.
On the other hand, there are cells that even without being located in the brain, and even without being human cells, could have important influences on this organ. These are the bacteria that live in the intestine, the so-called intestinal microbiota, which, through the so-called gut-brain axis , could play an important role in the origin of different neurological diseases. Among all, its involvement in Parkinson’s disease is gaining momentum in recent years. It has been discovered that an alteration of the intestinal microbiota precedes the onset of motor symptoms in this disease, proposing that somehow the metabolites released by intestinal bacteria could influence the brain and initiate neurodegenerative processes. However, the exact connection is poorly understood and remains a challenge to be described.
Other challenges
Explaining the everyday life of the brain is a necessary step. We cannot forget about their diseases : understanding their origin and causes, understanding their risk factors and achieving effective and safe treatments and prevention programs are great pending challenges in most cases. It will also be important to understand what are the thresholds that separate the normal from the pathological and to recognize the diversity that exists within the normal category, to avoid overtreatment and underdiagnosis that cause so much harm today. For the benefits of research to reach humanity as a whole, it will be important to improve the inclusivity and representativeness of research subjects, including, in addition to Caucasian men, women and other groups. Methodologically, the reproducibility of research results must be improved so that the discipline advances on solid premises.
As devices for the intervention and monitoring of brain activity are democratized, regulations or neuro-rights will be necessary to prevent the abusive use of brain data, as proposed by the neuroscientist Rafael Yuste. Understanding the cerebral origin of socially reprehensible behaviors will have consequences on the legal conception of guilt or innocence in the face of criminal acts. It will be a challenge to integrate the findings of neuroscience into the regulatory framework both in criminal matters and in other domains of justice and law.
In other dimensions of society, it is anticipated that neuroscience will revolutionize the conception and exercise of economics. From so-called neuroeconomics to neuromarketing, understanding the brain will help fine-tune how companies sell their products and succeed commercially.
Will we understand the brain?
It is impossible to know a priori whether we will one day understand the human brain in its entirety. What we can say is that the attempt to explain it is warranted because human curiosity is unstoppable and because addressing the devastating diseases that afflict it is a pressing need.
A few weeks ago, on Twitter, a neuroscientist from Harvard University joked with a meme in which a well-known president appeared hanging a medal on another person whose face was also that of the president himself. The text read: “Me, speaking of the importance of the human brain.” A neuroscientist is, after all, a human brain talking about itself, about its own complexity. It is the paradox of neuro-narcissism, which teaches us to recognize both the importance and the very biases of our human brain. Will we understand the human brain? Surely more important than getting an answer in the affirmative will be the many interesting discoveries that are likely to be discovered along the way.
José Viosca Ros is a doctor in neuroscience and a biochemist. Scientific Director at Xpeer Medical Education. Author of The Brain, Amazing Minds, and Creating the World.
