Unit 6. Brain

Script 12. Diagnosing dementia.

Advance warning

How to detect Alzheimer's before symptoms appear-if you are a woman.

Alzheimer’s disease has no cure. There are, however, five drugs - known and approved - that can slow down the development of its symptoms. The earlier such drugs are administered, the better. Unfortunately, the disease is usually first noticed when people complain to their doctors of memory problems. That is normally too late for the drugs to do much good. A simple and reliable test for Alzheimer's that can be administered to everybody over the age of about 65, before memory-loss sets in, would therefore be useful.

Theo Luider, of the Erasmus University Medical Centre in Rotterdam, and his colleagues think they have found one - but it works only in women. They made their discovery, just reported in the Journal of Proteome Research, by tapping into a long-term, continuing study that started in 1995 with 1,077 non-demented and otherwise healthy people aged between 60 and 90. At the beginning of the project, and subsequently during the periods 1997-99 and 2002-04, participants were brought in for a battery of neurological and cognitive investigations, physical examinations, brain imaging and blood tests.

During the first ten years of the study, 43 of the volunteers developed Alzheimer's disease. When Dr. Luider compared blood samples from these people with samples from 43 of their fellow volunteers, matched for sex and age, who had remained Alzheimer's-free, he found something startling. Levels of a substance called pregnancy zone protein had been unusually high, even before their symptoms appeared, in some of those who went on to develop Alzheimer's disease.

Those "some", it turned out, were all women. On average, levels of pregnancy zone protein in those women who went on to develop Alzheimer's were almost 60% higher than those of women who did not. In men, levels of the protein were the same for both.

The reason for this curious result seems to be that the brain plaques associated with Alzheimer's disease are themselves turning out pregnancy zone protein. Certainly, when Dr Luider applied a chemical stain specific to that protein to the plaques of dead Alzheimer's patients he found the protein present in them.

Confusingly, though, it was there in the plaques of both sexes. Presumably, female cells (and therefore the plaques of female brains) make more of it than male cells do. But that remains to be proved. Whatever the reason, however, this result means that women, at least, may soon be able to tell whether and when they are at risk of Alzheimer's - and thus do something about it before they start losing their minds. (From The Economist, October 8, 2011)

Script 13.1 Growing model brains. Part I.

An embryonic idea

A group of stem-cell biologists have grown an organoid that resembles a brain.

Regenerative medicine, the science of producing tissues and organs from stem cells, is a rapidly developing field. This week, however, it took a leap forward that was big even by its own demanding standards. A team of researchers led by Madeline Lancaster of the Austrian Academy of Sciences, in Vienna, announced that they have grown things which, while not human brains, resemble brains in important ways.

Dr Lancaster’s organoids, as she calls them, are a far cry from the brains in jars beloved of the writers of horror movies. But they do contain several recognizably different types of nerve cell and have anatomical features which look like those of real brains. They might be used to study, in ways that would be unethical in a living human being or impossible even in a mouse, the crucial early stages of brain development, and how they can go wrong. They could be employed to test drugs in ways that mere cell cultures cannot be. And because they can be made, if needed, from the cells of living people, they might even illuminate the particular problems of individual patients.

To make an organoid, Dr Lancaster’s team start, as they describe in an article in Nature, with what is known as an embryoid body. Just as an organoid has some features of an organ without truly being one, so an embryoid body has some features of an embryo without actually being one. Embryoid bodies can be grown either from natural stem cells - themselves derived ultimately from real embryos - or from what are known as induced pluripotent cells, which are made from adult cells (usually skin cells) that have been treated with four crucial biochemical factors which cause them to forget their identity and behave like embryonic cells.

Embryos have three layers: endoderm, mesoderm and ectoderm. Each turns into an eclectic mixture of body parts in the complete organism. Nervous systems grow from the ectoderm (which also contributes dental enamel and the skin’s epidermis, among other things), so the team put ectodermal cells into droplets of gel and then floated the droplets in a nutrient broth in a gently rotating bioreactor (which allowed the cells to grow without being shaped by the constraint of a vessel such as a Petri dish) to see what would happen.

Though the result may not look much like a brain to a layman, to an expert the resemblance is remarkable. After ten days the organoid has developed neurons. After 30 days it has regions recognizably similar to some of those in a real brain. And though, because they lack the blood supply of a real brain, organoids never grow much bigger than 4 mm across, they live a long time. Some are now a year old and still going strong.

Real brains consist in large measure of layers of neurons called the cortex. This surrounds fluid-filled spaces known as ventricles. That is more or less the anatomy of an organoid. Many of them also contain areas which look like choroid plexuses. These are places that absorb nutrients from the bloodstream and dump waste into it. They also generate the cerebrospinal fluid that fills ventricles.

Signs of other structures turn up too. The various lobes of a real brain sport different mixtures of neurons. The team see signs of this in the organoids. They found evidence of retinas (the back of the eye is an outgrowth of the brain), of meninges (the membranes that surround the brain) and of hippocampal cells (the hippocampus is a part of the brain which is crucial for memory formation). The organoids, then, look as though they are making a fair fist of trying to become real brains.

Script 13.2 Growing model brains. Part II.

So the method clearly works. The next question was whether the team could do anything useful with it. And they could. They were able to realise one of the desiderata of stem-cell science and investigate the condition of a particular individual who has microcephaly.

Microcephaly, as its name suggests, is a developmental condition in which someone’s brain fails to grow as much as it should. The consequence is that his head is small and he suffers a range of debilitating symptoms. Microcephaly is hard to study in a laboratory because tinkering in mice with the genes that cause it in people does not replicate the severity of the condition. The team therefore wondered if they would have more luck by growing an organoid derived from their patient’s skin. And they did.

First, the organoid actually grew, proving the method works with induced cells as well as natural ones. Second, it showed that what seems to be going wrong in microcephaly is that the process of development is running too fast. Neurons differentiate more rapidly than they should. And once that has happened, the brain’s growth slows down.

This is no help to the patient. No one thinks microcephaly can be reversed. But if it were better understood, it might be prevented, as might a host of other neurological problems whose roots lie in the brain’s early development. Schizophrenia and autism, for example, are both suspected of being caused by mistakes in the migration of developing nerve cells through the early embryonic brain. Dr Lancaster hopes the group will be able to model these processes in the future.

Dr Lancaster’s organoids, then, would seem to have a bright future, helping scientists understand both how the brain works and what has gone wrong when it doesn’t. Small though they are, they could be the start of something very big indeed. (From The Economist, August 31, 2013)

Script 14.1 Genes and intelligence. Part I.

The 3% solution

A potent source of genetic variation in cognitive ability has just been discovered.

People are living longer, which is good. But old age often brings a decline in mental faculties and many researchers are looking for ways to slow or halt such decline. One group doing so is led by Dena Dubal of the University of California, San Francisco, and Lennart Mucke of the Gladstone Institutes, also in San Francisco. Dr Dubal and Dr Mucke have been studying the role in ageing of klotho, a protein encoded by a gene called KL. A particular version of this gene, KL-VS, promotes longevity. One way it does so is by reducing age-related heart disease. Dr Dubal and Dr Mucke wondered if it might have similar powers over age-related cognitive decline.

What they found was startling. KL-VS did not curb decline, but it did boost cognitive faculties regardless of a person’s age by the equivalent of about six IQ points. If this result, just published in Cell Reports, is confirmed, KL-VS will be the most important genetic agent of non-pathological variation in intelligence yet discovered.

Dr Dubal and Dr Mucke made their discovery when they looked at 220 volunteers aged 52 to 85, to study the effects of KL-VS on ageing. They assessed their volunteers’ faculties of memory, attention, visuo-spatial awareness and language. From these, they constructed a composite measure of cognition.

That measure suggested people with a VS version of the KL gene in their chromosomes had better cognition than those without one. When they analysed data collected by two other groups who work independently on KL-VS they discovered these researchers had found the same thing. That comparison brought the number of people examined to 718, a fifth of whom were possessors of KL-VS.

The six-point IQ gap is an extrapolation, since the cognitive tests did not measure general intelligence directly. But if it is correct, variation in the KL gene could account for as much as 3% of the variation of IQ in the general population (or, rather, in the population from which the researchers’ samples were drawn, namely white Americans). In comparison, the previous record holders, HMGA2 and NPTN, each account for only half a percent of that variation.

Script 14.2 Genes and intelligence. Part II.

This sort of result, it must be cautioned, has a tendency to come and go. The genome has so many genes in it that flukey correlations between one of them and some human trait are common. But there are two reasons to believe this is not a fluke. One is that these three independent studies have found it. The second is that Dr Dubal and Dr Mucke did not rest on their laurels, but did some experiments on mice to investigate KL-VS’s actions.

To do this they added the murine equivalent of KL-VS to the genomes of some mice. Doing this increases klotho levels in mice (an effect also seen in KL-VS-positive people). The genetically engineered animals did much better than regular mice at learning how to navigate mazes and other memory tests which psychologists like to inflict on their subjects. And analysis of their brain tissue revealed differences from regular mice in the structure of their synapses, the junctions between nerve cells that act as neural switches.

Signals cross synapses in chemical form. The most common messenger chemical, known as glutamate, is picked up by the receiving cell using molecules called NMDA receptors. It is known from previous work that glutamate stimulation of NMDA, or the lack of it, can strengthen or weaken synaptic connections. This is believed to be the basis of memory.

The team’s genetic engineering changed the nature of the NMDA receptors in the mice’s hippocampuses and frontal cortices—two regions of the brain particularly involved in memory formation—by doubling in them the number of a particular sort of molecular subunit, GluN2B. Previous research has found links between GluN2B levels and cognitive performance. Dr Dubal and Dr Mucke discovered that blocking GluN2B with a drug called ifenprodil abolished the genetically engineered mice’s advantage. That suggests klotho works its magic, at least in part, by increasing the number of GluN2B subunits in the NMDA receptors of the brain’s memory and learning circuits.

Dr Dubal and Dr Mucke hope, despite their failure to show any protective effect of KL-VS on age-related cognitive decline, that this knowledge may be put to use. A drug that elevates klotho levels, or mimics that protein’s function, might indeed enhance cognition, and there is no obvious reason why such a drug should be restricted to the elderly. If it could be developed everyone—except, maybe, those already in possession of a copy of KL-VS in their genes—might be able to take pills to make themselves a little brighter. (From The Economist, May 10, 2014)