The Hungry Brain

Gut brain Axis Feature Credited

 

Under normal, healthy conditions we eat whenever we are feeling hungry. In addition to the feeling of hunger, we also often have an appetite for a specific kind of food, and sometimes we simply crave the pleasure a certain food like chocolate or pizza may provide us. This pleasure is part of the hedonic aspect of food and eating. In fact, anhedonia or the absence of experiencing pleasure from previously pleasurable activities, such as eating enjoyable food, is a hallmark of depression. The hedonic feeling originates from the pleasure centre of the brain, which is the same one that lights up when addicts ‘get a fix’. Hedonic eating occurs independently of the gut-brain axis, which is why you will keep eating those crisps and chocolate, even when you know, you’re full. Hence, sayings like “These chips are addictive!” are much closer to the biological truth than many realise.  

But how do we know that we are hungry? Being aware of your surrounding and/or your internal feelings is the definition of consciousness. And a major hub for consciousness is a very primal brain structure, called the thalamus. This structure lies deep within the brain and constantly integrates sensory input from the outside world. It is connected to cognitive areas such as the cortex and the hippocampus, but also to distinct areas in the brainstem like the locus coeruleus, which is the main noradrenergic nucleus in the brain and regulates stress and panic responses. Directly below the thalamus and as such also closely connected to this ‘awareness hub’ lies the hypothalamus.

The hypothalamus is a very complex brain area with many different functions and nuclei. Some of them are involved in the control of our circadian rhythm and internal clock – the deciphering of which was awarded the 2017 Nobel Prize in Physiology or Medicine. But the main task of the hypothalamus is to connect the brain with the endocrine system (i.e. hormones) of the rest of the body. Hormones like ghrelin, leptin, or insulin are constantly signalling your brain whether you are hungry or not. They do so via several direct and indirect avenues, such as blood sugar levels, monitoring energy storage in adipose cells, or by secretion from the gastrointestinal mucosa.

There are also a number of mechanosensitive receptors that detect when your stomach walls distend, and you have eaten enough. However, similarly to the hormonal signals, the downstream effects of these receptors also take a little while to reach the brain and be (consciously) noticeable. Thus, the slower you eat, the less likely you will be to over-eat, because the satiety signals from hunger-hormones and stomach-wall-detectors will reach your consciousness only after about 20 to 30 minutes.

Leaving the gut and coming back to the brain, the hypothalamus receives endocrine and neuropeptidergic inputs related to energy metabolism and whether the body requires more food. Like most brain structures, the hypothalamus is made up of several sub-nuclei that differ in cell-type and downstream-function. One of these nuclei, the arcuate nucleus of the hypothalamus, is considered the main hub for feeding and appetite control. Within it there are a number of signalling avenues that converge and that – if altered or silenced – can induce for instance starvation. Major signalling molecules are the Neuropeptide Y, the main inhibitory neurotransmitter GABA, and the peptide hormone melanocortin. The neurons in the arcuate nucleus are stimulated by these and other signalling molecules in order to maintain energy homeostasis for the entire organism. There are two major subclasses of neurons in the arcuate nucleus that are essential for this homeostasis and that, once stimulated, cause very different responses: activation of the so-called POMC neurons decreases food intake, while the stimulation of AGRP neurons increases food intake. And this circuit even works the other way around: researchers found that by directly infusing nutrients into the stomach of mice, they were able to inhibit AGRP neurons and their promotion of food intake.

Given this intricate interplay between different signalling routes, molecules, and areas it is not surprising then that a disrupted balance between all of these players could be detrimental. Recent studies identified one key player that can either keep the balance or wreak havoc: the gut microbiome

 

Bacteria colonising intestinal villi make up the gut microbiome. Picture/Credit: ChrisChrisW/iStock.com

Bacteria colonising intestinal villi make up the gut microbiome. Picture/Credit: ChrisChrisW/iStock.com

 

The gut microbiome is the entirety of the microorganisms living in our gastrointestinal tract, and they can modulate the gut-brain axis. Most of the microorganisms living on and within us are harmless and in fact are very useful when it comes to digesting our food. However, sometimes this mutually beneficial symbiosis goes awry, and the microbes start ‘acting out’. For instance, they can alter satiety signals by modulating the ghrelin production and subsequently induce hunger before the stomach is empty, which could foster obesity. They can also block the absorption of vital nutrients by taking them up themselves and thereby inducing malnutrition. A new study which was published only last month revealed that Alzheimer patients display a different and less diverse microbiome composition than healthy control subjects. Another study from Sweden even demonstrated that the specific microbiome composition occurring in Alzheimer’s patients induces the development of disease-specific amyloid-beta plaques, thereby establishing a direct functional link between the gut microbiome and Alzheimer’s disease – at least in mice. Similarly, the composition and function of the microbiome might also directly affect movement impairments in Parkinson’s disease. In addition, there is also mounting evidence that neuropsychiatric diseases such as anxiety or autism are functionally linked to the microbiome

Moreover, even systemic diseases such as lung, kidney and bladder cancers have been recently linked to the gut microbiome. Albeit, in this case, not the disease development and progression seem to be directly related to our gut inhabitants. Instead, the researchers found that if the microbiome of the cancer patients was disrupted by a recent dose of antibiotics, they were less likely to respond well to the cancer treatment and their long-term survival was significantly diminished. It seems that the treatment with antibiotics disrupts specific components of the microbiome, which then negatively affects the function of the entire composition. 

While the cause or consequence mechanisms between these different afflictions and an altered microbiome have not been solved yet, it seems certain that it is involved in more than digestion. Hence, the already intricate gut-brain axis is further complicated by the gut microbiome, which not only affects when and what we eat, but can also determine our fate in health and disease.  

Immunotherapy: The Next Revolution in Cancer Treatment

Over the past 150 years, doctors have learned to treat cancer with surgery, radiation, chemotherapy and vaccines. Now there is a new weapon for treatment: immunotherapy. For some patients with previously incurable cancer, redirecting their immune system to recognise and kill cancer cells has resulted in long-term remission, with cancer disappearing for a year or two after treatment.

 

Lymphocytes attacking cancer cell. Credit: selvanegra/iStock.com

Lymphocytes attacking a cancer cell. Credit: selvanegra/iStock.com

 

Cancer immunotherapy has been used successfully to treat late stage cancers such as leukaemia and metastatic melanoma, and recently used to treat mid-stage lung cancer. Various forms of cancer immunotherapy have received regulatory approval in the US, or are in the approval process in the EU. These drugs free a patient’s immune system from cancer-induced suppression, while others engineer a patient’s own white blood cells to attack cancer. Another approach, still early in clinical development, uses antibodies to vaccinate patients against their own tumours, pushing their immune system to attack the cancer cells.

However, immunotherapy is not successful, or even an option, for all cancer patients. Two doctors used FDA approvals and US cancer statistics to estimate that 70 percent of American cancer deaths are caused by types of cancer for which there are no approved immunotherapy treatments. And patients that do receive immunotherapy can experience dramatic side effects: severe autoimmune reactions, cancer recurrence, and in some cases, death.

With such varied outcomes, opinions vary on the usefulness of immunotherapy. Recent editorials and conference reports describe “exciting times” for immunotherapy or caution to “beware the hype” about game-changing cancer treatment. Regardless of how immunotherapy could eventually influence cancer treatment, its development is a new revolution in cancer treatment, building on detailed biochemical knowledge of how cancer mutates and evades the immune response. Academic research into immunotherapy is also being quickly commercialised into personalised and targeted cancer treatments.

 

T-cells (red, yellow, and blue) attack a tumour in a mouse model of breast cancer following treatment with radiation and a PD-L1 immune checkpoint inhibitor, as seen by transparent tumour tomography. Credit: Steve Seung-Young Lee, National Cancer Institute\Univ. of Chicago Comprehensive Cancer Center

T-cells (red, yellow, and blue) attack a tumour in a mouse model of breast cancer following treatment with radiation and a PD-L1 immune checkpoint inhibitor, as seen by transparent tumour tomography. Credit: Steve Seung-Young Lee, National Cancer Institute\University of Chicago Comprehensive Cancer Center

Checkpoint inhibitors

Twenty years ago, James Allison, an immunologist at MD Anderson Cancer Center, was the first to develop an antibody in a class of immunotherapy called checkpoint inhibitors. These treatments release the immune system inhibition induced by a tumour. The drug he developed, Yervoy, received regulatory approval for the treatment of metastatic skin cancer in the US in 2011. By last year, Yervoy and two newer medications had reached 100,000 patients, and brought in $6 billion a year in sales.

In general, immunotherapy tweaks T-cells, white blood cells that recognise and kill invaders, to be more reactive to cancer cells. Tumours naturally suppress the immune response by secreting chemical messages that quiet T-cells. Cancer cells also bind to receptors on the surface of T-cells, generating internal messages that normally keep the immune system from attacking healthy cells.

One of those receptors is called CTLA-4. Allison and his colleagues blocked this receptor on T-cells with an antibody, and discovered that T-cells devoured cancer cells in mice. Since then, other checkpoint inhibitors have been developed and commercialised to block a T-cell receptor called PD-1 or its ligand PD-L1, present on some normal cells as well as cancer cells.

In the US, PD-1 and PD-LI inhibitors have been approved to treat some types of lung cancer, kidney cancer, and Hodgkin’s lymphoma. And the types of potentially treatable cancers are growing: Currently, more than 100 active or recruiting US clinical trials are testing checkpoint inhibitors to treat bladder cancer, liver cancer, and pancreatic cancer, among others.

 

CAR-T

Another type of cancer immunotherapy, called CAR-T, supercharges the ability of T-cells to target cancer cells circulating in the blood. In August, the first CAR-T treatment was approved in the US for children with aggressive leukaemia, and regulatory approval for a treatment for adults came in October.

To produce CAR T-cells, doctors send a patient’s blood to a lab where technicians isolate T-cells and engineer them to produce chimeric antigen receptors, or CARs. These CARs contain two fused parts: an antibody that protrudes from the surface of a T-cell to recognise a protein on cancerous B-cells (commonly CD-19) in the blood and a receptor inside the T-cell that sends messages to cellular machinery. When the antibody binds to a tumour cell, it activates the internal receptor, triggering the CAR T-cell to attack the attached cancer cell.

In clinical trials, some patients treated with CAR T-cells for aggressive leukaemia went into remission when other treatments had failed. But several high-profile trials had to be suspended because of autoimmune and neurological side effects, some leading to patient deaths.

To improve the safety of CAR-T treatment, researchers are now engineering “suicide switches” into the cells, genetically encoded cell surface receptors that trigger the cell to die when a small molecule drug binds them. If doctors see a patient experiencing side effects, they can prescribe the small molecule drug and induce cell death within 30 minutes.

Other safety strategies include improving the specificity of CAR T-cells for tumour cells because healthy cells also carry CD-19 receptors. To improve CAR-T tumour recognition, some researchers are adding a second CAR, so that the engineered cell has to recognise two antigens before mounting an attack.

 

As seen with pseudo-coloured scanning electron microscopy, two cell-killing T-cells (red) attack a squamous mouth cancer cell (white) after a patient received a vaccine containing antigens identified on the tumour. Credit: Rita Elena Serda, National Cancer Institute\Duncan Comprehensive Cancer Center at Baylor College of Medicine

As seen with pseudo-coloured scanning electron microscopy, two cell-killing T-cells (red) attack a squamous mouth cancer cell (white) after a patient received a vaccine containing antigens identified on the tumour. Credit: Rita Elena Serda, National Cancer Institute\Duncan Comprehensive Cancer Center at Baylor College of Medicine

Neoantigens

 A third type of immunotherapy aims to target mutated proteins that are a hallmark of cancer. Cancer cells display portions of these mutated proteins, called neoantigens, on their surface. Researchers are studying how to use tumour-specific neoantigens in vaccines to help the body mount an immune response targeted at the cancer.

Results from two recent small clinical trials for patients with advanced melanoma suggest that neoantigen vaccines can stop the cancer from growing, or in some cases, shrink the tumours with few reported side effects. But it’s too early in clinical development to know if the vaccines will extend the lives of cancer patients.

There are two steps to making a neoantigen vaccine: first, identify mutated proteins unique to most of a patient’s cancer cells and second, identify portions of those proteins that could most effectively stimulate an immune response.

To identify mutated proteins, researchers sequence the genome of cancer cells and compare it to the sequence in healthy cells. Next, they identify which mutations lead to the production of altered proteins. Finally, they use computer models or cellular tests to identify the portions of proteins that could be the most effective neoantigen.

This last step of predicting neoantigenicity is the most challenging part of developing a new neoantigen vaccine. Lab experiments to confirm the activity of multiple neoantigens are time consuming, and current computer models to predict antigenicity can be inaccurate due to low validation.

A few principles of cancer biology also make developing neoantigens for long-lasting treatment difficult. Some cancers may have too many mutations to test as potential neoantigens. Cancer cells also continue to mutate as tumours grow, and some cells may not display the neoantigens chosen for a vaccine. Finally, cancer cells may naturally stop displaying antigens on their surface, as part of their strategy for evading an immune response.

However, identifying neoantigens can still be useful as cancer biomarkers. Or if used in a vaccine, they may be most effective in combination with other drugs: a few patients in the small clinical trials whose cancer relapsed after the trials responded to treatment with a checkpoint inhibitor.

Cancer has been a common topic in Nobel Laureates’ lectures at many Lindau Meetings. Learn more about these lectures, as well as Nobel Prize winning research related to cancer, in the Mediatheque.

Digging for the Roots: Cancer Stem Cells

Weed is a phenomenon that has annoyed many gardeners. Fortunately, there is a pretty straightforward way to get rid of it: “You can keep cutting the leaves off the weed, but the weed will regrow. But if you cut the tap roots, the leaves will wither away.” This is the ever so perspicuous advice given to us by John Dick, Senior Scientist at the University of Toronto, and one could not be blamed for, at first glance, finding it to be of an apparently trivial nature.

But John Dick’s interests do not lie in gardening, and his advice is, in fact, not at all about getting rid of weed. Instead, it is a comment of far greater usefulness: about getting rid of cancer, a disease that we are, in most instances, to this day not able to cure. But what are cancers equivalents of a plant’s roots? They may well be a group of cells termed ‘cancer stem cells’, and great hopes have been set into treating cancer by targeting them. Since hope and hype often lie closely together, let us examine what this is all about…

1280px-Cancer_stem_cells_text_resized.svg

Schem showing the difference between conventional cancer therapy and cancer stem cell specific therapy Picture: Public Domain

The cancer stem cell hypothesis proposes that not all tumor cells have equal capacities. Rather, each tumor contains a small subset of cells with stem cell-like capacities that are responsible for initiating and sustaining tumor growth, while the bulk of the tumor cells lacks this ability. Importantly, they are also thought of as the culprits for cancer relapse, which can occur many years after the initial tumor has been treated. In fact, it is thought that common chemotherapies, targeting the fast-dividing cells, leave the relatively slow-dividing tumor stem cells unharmed and thus pave the way for an eventual relapse. Moreover, cancer stem cells also have been shown to exhibit a higher resistance to radiation treatment as well as a higher invasiveness correlating with a worse cancer prognosis. In short, if a cancer cell may be considered evil, a cancer stem cell is a lot worse!

A common misconception about the research field is that a tumor stem cell is actually a subtype of stem cell and that hence, cancer derives from stem cells. This is not the case. The term “tumor stem cell” only reflects the fact that this is a tumor cell with capacities similar to normal stem cells, such as the capability to maintain itself indefinitely. Tumor stem cells are mistaken for the “cell of origin” of a tumor. The actual cell of origin is different in each type of tumor, and does not have to be atumor stem cell. In some cases, for example with a type of brain tumors called gliomas, it is not even known yet.

Hirntumorstammzellen in einer Petrischale, so genannte

Brain tumor stem cells in a petri dish, so called “speroids”. Picture Minu D. Tizabi

But how did this research field come about ? In the Sixties, it was discovered that not all tumor cells have equal tumor-forming capabilities. 30 years down the road, in 1997, cancer researchers Dominique Bonnet and the above mentioned John Dick published a major report on their recently discovered leukemia stem cells in Nature Medicine, thereby starting off a whole new field in cancer research. The cancer stem cell theory was born, and the following years saw the discovery of such cells in many other cancers like breast, brain or prostate cancer. As with every theory in science, it initially had to face lots of doubt and criticism. A breakthrough was made in 2012, when three independent studies were published, all of which heavily supported the hierarchical organization of cells and hence, the cancer stem cell concept using scientifically powerful and conclusive techniques for tracing single tumor cells and their offspring in vivo. Ever since, there has been no more doubt about the general existence of cancer stem cells.

A lot of effort in tumor stem cell research has always been directed to finding a so-called marker, a molecule whose presence on a cell reliably identifies it as a cancer stem cell. To this date, no such reliable molecule has been identified – in one way or another, all proposed and utilized markers are disputed and controversial. In fact, it is unlikely that the marker problem is going to be solved at all, and it may be a better bet to try to define them according to their functional properties rather than their surface molecules, although arguably the latter would make therapeutic targeting easier. Unfortunately, a lot of literature in the field is purely based on assays in the petri dish, often conducted not even with primary cells directly derived from patients (which are more difficult to obtain) but with cells derived from long-grown cell lines instead, which are less representative of real tumors. On the other hand, first clinical trials with drugs designed to target cancer stem cells are now under way, so far yielding moderately positive results.

Doubts about the existence of cancer stem cells may have been washed away in 2012, but that has not made things much easier. Indeed, we only gradually begin to realize that things may be a lot more complicated and less clear-cut than they initially appeared to be.

A major new insight is the realization that different tumors of the same type may rely on entirely different tumor stem cell populations. As if that had not been complicated enough already, it has been discovered that even the very same tumor can harbor multiple different stem cell populations in its midst! And on another note, it may be possible that some cancers follow the cancer stem cell model while others do not. It is difficult to predict what the future will hold for the cancer stem cell field, but it is likely that the abovementioned insights will eventually transform our approach to the questions at hand.

First, cancer stem cells have appeared to be a huge trend, even hype within cancer research throughout the last one and a half decades, but the hope set into them stands on a solid experimental basis and is thus justified. Nevertheless, the field is – also due to the lack of standard conditions for important methods – currently struggling with many issues such as the challenge of developing a clear definition of what tumor stem cells actually are and how they can be identified. As with other potential cancer therapies, no one can tell if these efforts will pay off in terms of clinical results – but there is a good chance that they will and the research area might well be headed for a future Nobel prize. So let us all keep our eyes and ears open to future developments in this exciting field!


Slider image: Steve Garry (CC BY-ND 2.0)