Clinical Neurology Lord Brain

[Juan Navarro]

Brainwas educated at Mill Hill School and New College, Oxford, where he began to read history, but disliked it. The First World War having begun in 1914, the following year he joined the Friends' Ambulance Unit as an alternative to volunteering for combat, and was sent to York, moving later to the King George Hospital in London, attached to the X-ray department. On the introduction of conscription in 1916, his work enabled him to be exempted as a conscientious objector.

After the war he returned to New College, and studied medicine, obtaining his BM BCh in 1922 and a DM in 1925; he specialised in neurology. Apart from his clinical practice, he was a member of a large number of government committees pertaining to physical and mental health, and was involved in the care of Winston Churchill on the latter's deathbed in 1965.

He was knighted in 1952,[3] made a baronet on 29 June 1954,[4] and on 26 January 1962, was created Baron Brain, of Eynsham in the County of Oxford.[5] In March 1964, he was elected a fellow of the Royal Society.[6]

In 1964, he gave the presidential address (Science and Behaviour) to the British Association meeting in Southampton.[7] In this address he discussed how humanity was approaching the anthropocene and he reiterated Alfred North Whitehead's warning that "A muddled state of mind is prevalent. The increased plasticity of the environment for mankind, resulting from the advances in scientific technology, is being construed in terms of habits of thought which find their justification in the theory of a fixed environment."[8]

He married Stella Langdon-Down and had two sons, Christopher (1926-2014) [9] and Michael Cottrell Brain (b. 1928) and one daughter, Janet Stella Brain (b. 1931). Janet went on to marry Dr. Leonard Arthur. Christopher Langdon Brain succeeded his father as the 2nd Baron Brain.[10] Upon the 2nd Baron's death in 2014, his brother, Michael, succeeded as 3rd Baron Brain.

Russell Brain (Fig 1) was born at Clovelly, Denmark Road, Reading, on 23 October 1895, the only son of Walter John Brain, solicitor, and his wife, Edith Alice. A quiet, reserved man of enormous intellect and integrity, he was revered as an eminent neurologist, philosopher, and author.

He moved to the King George Hospital, London, where in the X-ray department he met Stella, daughter of the physician Reginald Langdon Langdon-Down. They married in September 1920. He entered the London Hospital in October 1920, graduated BM BCh (Oxon) in 1922, proceeded DM in 1925, and was elected FRCP in 1931.

Brain joined the medical unit at the London Hospital.1 Under the influence of the Quaker Sir Henry Head and George Riddoch he took up neurology. He was appointed physician to Maida Vale Hospital for Nervous Diseases in 1925, assistant physician to the London Hospital in 1927, and physician to Moorfields Hospital. He was never on the staff of the National Hospital for Nervous Disease at Queen Square.

He made many outstanding contributions to clinical neurology.2 With the gifted if eccentric surgeon Dickson Wright and Marcia Wilkinson, he showed that the median nerve could be compressed at the wrist in the carpal tunnel; surgical relief of this would restore function.3 With D. W. C. Northfield and Marcia Wilkinson he demonstrated the importance of protrusion of the intervertebral disc in the cervical spine as a cause of root and cord compression with paralysis of the legs; this was named cervical spondylotic myelopathy,4 a common neurological disorder.

In an original concept he described the remote effects of cancer (i.e. not caused by secondary deposits) on the brain and peripheral nerves.5 The British Empire Cancer Campaign therefore established at the London Hospital a unit for the investigation of these carcinomatous neuropathies, which Brain directed until his death.

Having originally considered making a career in psychiatry, he never lost his interest in the enigmatic disorders of the mind, and particularly the problems of perception. Mind, Perception and Science (1951), the Riddell lectures on The Nature of Experience (1959), The cerebral basis of consciousness (1950), and his book, Speech Disorders (1961), were the outcome. From the time he was elected to the London Hospital, Brain earned his livelihood as a physician in consulting practice, in which he was very successful. His remarkable memory and flair for lucid yet succinct prose, resulted in Diseases of the Nervous System, first published in 1933 and, unusual for a one-author medical textbook, it reached a sixth edition in 1962 (under JN Walton, then Michael Donaghy, the 12th edition was published in 2012). It was almost compulsory reading for postgraduates in neurology and candidates for the MRCP.

He was a supremely astute clinician who, for example, predicted the nature of the inheritance in familial goiter in 1927. It was his clinical case reports, his interests in the brain-mind problem, the nature of consciousness, and the subtle aberrations of speech and perception which gave rise to his philosophical writings. In the seven years (1950-1957) when President of the Royal College of Physicians, he published thirty papers and two editions of his textbook, and sat on two Royal Commissions. At the same time in 1957, he published Tea with Walter de la Mare (cited as a Medical Classic in a 2008 issue of the BMJ). He achieved all this, supported by a clinical practice, an ease of writing, two secretaries, and the royalties from his successful textbooks. All his work was characterized by precision, great industry, and the refusal to waste a minute, so that he even dictated and read when traveling in the back of his car.

I remember Lord Brain as an impressive, shy, quiet, but kindly man of great learning. His lack of small talk was disconcerting, and his silences could be disturbing. Yet his well-prepared and self-rehearsed public speeches, addresses, and orations were disarmingly spontaneous, erudite, and witty.6 He once wrote:

He was knighted in 1952, created a baronet in 1954, and made Baron Brain of Eynsham in 1962. He was elected FRS in 19647 and an honorary Fellow of New College, Oxford in 1952. He received honorary degrees from many universities and was an honorary member of American and European neurological societies. He gave the Linacre lectures at Cambridge, the Riddell lectures at Durham, the Bryce lecture at Oxford, and the Osler oration in Canada. He was awarded the Osler medal for 1960 at Oxford.

He was succeeded to the baronetcy by his elder son, Christopher Langdon (b. 1926). His younger son, Michael, who attended Leighton Park School, became Professor of Haematology at McMaster University, Ontario.

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The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do not capture the earliest stages of disease development and offer limited opportunities for experimental intervention, so rarely yield complete mechanistic insights. The use of animal models relies on evolutionary conservation of pathways involved in disease and is limited by an inability to recreate human-specific processes. In vitro models that are derived from human pluripotent stem cells cultured in 3D have emerged as a new model system that could bridge the gap between patient studies and animal models. In this Review, we summarize how such organoid models can complement classical approaches to accelerate neurological research. We describe our current understanding of neurodevelopment and how this process differs between humans and other animals, making human-derived models of disease essential. We discuss different methodologies for producing organoids and how organoids can be and have been used to model neurological disorders, including microcephaly, Zika virus infection, Alzheimer disease and other neurodegenerative disorders, and neurodevelopmental diseases, such as Timothy syndrome, Angelman syndrome and tuberous sclerosis. We also discuss the current limitations of organoid models and outline how organoids can be used to revolutionize research into the human brain and neurological diseases.

Specific mutations can be introduced into organoids to study their effects on neurodevelopment; combined with high-throughput screening methods, this approach can determine the disease relevance of mutations in human tissue.

To study specific diseases, brain organoids can be generated from induced pluripotent stem cells from individual patients, thereby preserving the specific genetic background of the individual and generating an insightful model.

Through recapitulation of previously inaccessible periods of human brain development, brain organoids have enabled identification of novel mechanisms that underlie neurodevelopmental, neurodegenerative and infectious diseases.

Combining organoids, patient research and animal models enables us to take full advantage of each of these systems and will provide unprecedented insights into neurodevelopment and neurological diseases.

Neurological diseases are the leading cause of disability and the second leading cause of death worldwide1. Preventive strategies and interdisciplinary treatment regimens are improving outcomes of neurological conditions2, but advances in treatment require accurate understanding of disease aetiology and progression. This knowledge can be acquired by studying the disease in patients and by studying in vitro and animal disease models.

Studies in patients (left), such as sequencing, neuropathology or patient-derived xenograft models, provide a snapshot of disease at a given time point. Furthermore, these studies are usually not started until symptoms become apparent, meaning that the earliest pathogenic processes are not captured. Noninvasive and longitudinal studies to capture these early processes require large sample sizes and a lot of time. In animal studies (right), disease initiation can be controlled, so disease initiation, pathogenesis and progression can be studied throughout the disease course. Transfer of knowledge from animal studies to humans and vice versa relies on the assumption that disease mechanisms are conserved between humans and animal models, which is not always true. 3D human model systems such as organoids could be useful for bridging this gap, as they enable studies of early disease stages in human-derived tissue.

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