In a new paper in Science, biochemist Dorothee Kern and her collaborators reveal the ancient origins of allosteric regulation for the first time.

One of the key features in the evolution of more complex organisms is the emergence of allosteric regulation. Allostery is a process by which a proteins activity can be modulated by binding an effector molecule distal to the active site.

Despite the enormous importance of allostery in biology, the question of how such a feature evolved is unexplored territory.

In an article published online on February 22 in Science, professor of biochemistry and Howard Hughes Medical Institute Investigator Dorothee Kern and her lab address what is arguably one of the most fundamental evolutionary drivers for biology allostery.

By tracing the evolutionary path of modern protein kinases from their ancient common ancestors about 1.5 billion years ago to the present, Kern and her colleagues discovered the ancient origins of allosteric regulation for the first time.

To study such a fundamental question, the researchers chose to resurrect the evolution of Aurora kinase together with its allosteric regulator, TPX2. These proteins control the cell cycle in humans and are therefore hot cancer targets.

In the paper, the scientists first calculated the amino acid sequences of these ancient proteins using the hugest sequence database available to date and bioinformatics. They then made these enzymes in the laboratory and characterized their biochemical properties.

They found that the oldest kinases (about 1.5 billion years old) already use autophosphorylation for their regulation. This makes sense from an evolutionary point of view since the process needs only its own catalytic machinery.

The more sophisticated allosteric regulation, via binding to a second protein, starts about 1 billion years ago with the occurrence of that partner, TPX2.

Strikingly, the scientists found that contrary to the common view, there is no coevolution reciprocal changes in both partners along the evolutionary trajectory but that rather the entire interphase of their interaction stays constant for 1 billion years. In other words, they found that co-conservation was an extremely strong evolutionary constraint.

But what happened to allosteric activation? This advanced regulation is gradually evolving over 1 billion years leading to the strongest allosteric activation in our human kinase. The researchers discovered that its mechanism is the evolution of a sophisticated allosteric network that spans the entire kinase from the site of the TPX2 binding to the other side of the protein.

Kerns findings have far-reaching implications for understanding the evolution of complexity from extremely primitive creatures to the human species, and for novel approaches to cancer therapy taking advantage of the newly discovered allosteric networks in our modern proteins.

Kerns coauthors were Adelajda Hadzipasic, Christopher Wilson, Vy Nguyen, Nadja Kern, Chansik Kim, Warintra Pitsawong, Janice Villali and Yuejiao Zheng, all from her lab.

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Ancient origins of allosteric activation in a Ser-Thr kinase - Brandeis University

Biochemistry

Finding the Root to Treat Aging through… – ScienceBlog.com

February 22, 2020 medical

Researchers at the University of Minnesota Medical School believe they discovered a new way in which diet influences aging-related diseases.

Our healthcare as we age is analogous to a tree, and the way we go about it now, when a branch gets diseased, we go to a doctor, and they trim the branch. Then, we go to another doctor, and they trim another branch, saidDoug Mashek, PhD, a professor in the Departments of Medicine and Biochemistry, Molecular Biology and Biophysics. Its the roots that we need to be focused onthe common roots of all of these diseases. Thats why we are excited because this pathway has been linked to almost all of them. Its the roots.

The root is part of a special dietone that Dr. Mashek and his team have studied over the last eight years with the help of multiple grants from the National Institutes of Health. Their research findings, recently published inMolecular Cell, focus on theMediterranean diet. The diet, originally touted by U-famedAmerican physiologist Ancel Keys, emerged during his Seven Countries Study when he helped link diet to cardiovascular disease for the first time.

Early studies suggested red wine was a major contributor to the health benefits of the Mediterranean diet because it contains a compound called resveratrol, which activated a certain pathway in cells known to increase lifespan and prevent aging-related diseases. However, work in Dr. Masheks lab suggests that it is the fat in olive oil, another component of the Mediterranean diet, that is actually activating this pathway.

We didnt start out by studying the Mediterranean diet; we first were focusing on fat, Dr. Mashek said. This fat is known to be protective against heart disease and many other aging-related diseases, so by identifying this pathway, it provides a new way of thinking about how consuming olive oil and the Mediterranean diet is actually linked to positive health benefits.

Yet, merely consuming olive oil is not enough to elicit all of the health benefits. Dr. Masheks studies suggest that when coupled with fasting, limiting caloric intake and exercising, the effects of consuming olive oil will be most pronounced.

We found that the way this fat works is it first has to get stored in microscopic things called lipid droplets, which is how our cells store fat. And then, when the fat is broken down during exercising or fasting, for example, is when the signaling and beneficial effects are realized, he said.

The next steps for their research are to translate it to humans with the goal of discovering new drugs or to further tailor dietary regimens that improve health, both short-term and long-term.

We want to understand the biology, and then translate it to humans, hopefully changing the paradigm of healthcare from you going to eight different doctors to treat your eight different disorders, Dr. Mashek said. These are all aging-related diseases, so lets treat aging.

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Finding the Root to Treat Aging through... - ScienceBlog.com

Biochemistry

A Newly Biochemical Compound Is Able to Break Down the Pollutant in The Atmosphere – Chemicals Market News

February 22, 2020 medical

Enzymes with flavin cofactor play an essential half in vegetation, fungi, microorganism, and animals: as oxygenases, they incorporate oxygen into natural compounds. For instance, this permits individuals to excrete international substances more successfully. Till now, scientists have been agreed that such flavin-dependent oxygenases use flavin C4a-peroxide as the oxidizing agent.

That is shaped by the C4a-atom of the flavin cofactor reacting with atmospheric oxygen (O2), earlier than one of many two oxygen atoms are transferred to the compound. A group headed by Dr. Robin Teufel from the Institute of Biology II on the University of Freiburg has found that O2 additionally reacts to flavin N5-peroxide with the N5-atom of the flavin cofactor. The researchers have printed their leads to the journal Nature Chemical Biology.

The newly-found flavin N5-peroxide has completely different reactive traits than the flavin C4a-peroxide. Some microorganism uses this to interrupt down secure chemical compounds, together with environmental pollution reminiscent of dibenzothiophene, an element of crude oil, or hexachlorobenzene, a plant safety agent. Utilizing X-ray structural evaluation and mechanistic research, the scientists had been in a position to clarify how the creation of this flavin N5-peroxide is managed at an enzymatic degree.

In future, Teufel and his crew need to examine how widespread this novel flavin biochemistry is in nature. In addition, they need to enhance understanding of the function, reactivity, and performance of the flavin N5-peroxide. With their work, theyre enabling additional research that can in the future permit the prediction of flavin enzyme performance or modification utilizing biotechnology. Robin Teufel and his workgroup are learning enzymatic reactions of the bacterial metabolism on the Institute of Biology II of the University of Freiburg.

Biochemistry

University of Windsor researchers test lemon grass extract in cancer treatment – Windsor Star

February 22, 2020 medical

University of Windsor biochemistry professor Siyaram Pandey speaks during a press conference at the school on Tuesday, February 18, 2020, regarding his research group and the ongoing project on the anti-cancer effects of dandelion root extract.Dan Janisse / Windsor Star

A University of Windsor research team whose dandelion root cancer cure-all fell short of human testing has its sights set on a clinical trial for another natural treatment.

Joined by students whove studied the cancer-fighting properties of lemon grass extract, biochemistry professor Dr. Siyaram Pandey announced on Tuesday an Indian food extract company has pledged $1 million to test a lemon grass supplement on humans in conjunction with chemotherapy treatments.

Before that can happen, Pandey said, his lab must determine the lemon grass product reduces cancer activity, has no toxicity, and has no negative interaction with chemotherapy drugs work the company, Synthite, has given $70,000 to.

Im not saying its going to cure everything, he said. But some patient in India who received the supplement in conjunction with chemotherapy outside the pending clinical trial ended up in remission after having low chances of such a successful outcome, he said.

Rodent tumours studied in Pandeys lab also saw a size reduction when given lemon grass extract at the same time as chemotherapy drugs.

Despite positive lab results and anecdotal cases for dandelion root extract as a cancer treatment, that projects funding body, Advanced Orthomolecular Research Canada, decided not to fund the research teams drug on drug interaction research.

I am a bit frustrated, because Im going uphill convincing the doctors. Doctors think it is a snake oil. This time I am really happy with oncologists so strongly supporting (us), Pandey said

If the lemon grass product does well as a supplement in the clinical trial, it is possible Pandey and his team could, in the future, shift focus onto lemon grass extract as a natural, non-toxic treatment to replace chemotherapy.

The group is also studying white tea, rosemary, long pepper and Lakshmi Taru for potential cancer treating properties.

Univeristy of Windsor science alumnus Lokanth Chawla pledged $100,000 to the teams cancer research on Tuesday. The 71-year-old presented a cheque for $50,000 and said he would give a second cheque in August.

Maybe after 20, 30 years you know how many people hes going to be helping? Chawla said. My mother died badly, with chemo and radiation. Thats the reason Im doing this.

The group began its work with dandelion root extract in 2010, funded in part by the family of Kevin Couvillion, who died that year at the age of 26 after a three-year battle with myeloid leukemia. The dandelion root research was named in his honour. Pandey and his changing team of students provide an update on their research each year on Couvillons birthday, Feb. 18.

More than 60 students have participated in Pandeys anti-cancer research since 2010, he said. Some of them have gone on to become doctors and pharmacists.

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University of Windsor researchers test lemon grass extract in cancer treatment - Windsor Star

Cell Biology

This Entrepreneur Is Changing the Face Of Cancer Treatment In India – Entrepreneur

February 22, 2020 medical

Dr. Manjiri Bakre is the founder of OncoStem Diagnostics, a Bengaluru-based start-up that has developed a test to help women with a certain kind of breast cancer be diagnosed and given the right kind of treatment.

February22, 20206 min read

You're reading Entrepreneur India, an international franchise of Entrepreneur Media.

Breast cancer is the most common cancer in women in India. Accounting for 25-32 per cent of all cancers in women, the mortality rate post-treatment is 60 per cent, compared to as much as 89 per cent in the United States. The numbers, to put it simply, are disappointing and an entrepreneur based in Bengaluru is trying to change that.

Dr. Manjiri Bakre, who has a postgraduate doctoral degree in cell biology, is the founder and chief executive officer of OncoStem Diagnostics, a start-up that has developed a test to help women with a certain kind of breast cancer be diagnosed and given the right kind of treatment.

One of her earliest encounters with breast cancer was when a friend during her PhD years was diagnosed with the same. Bakre says the friend felt the tumor herself, went to the doctor and since it was diagnosed early, got it removed. Thereafter, as did everyone, that friend went on her post doctoral fellowship, which was in Israel.

Thats when the cancer relapsed, and spread to multiple organs. It was so sudden; we really tried to help her by sending her for various therapies, even non-traditional ones but nothing helped, she says.

The sudden demise of this friend got Bakre thinking about why, despite early detection, so many patients like her are unable to survive.

If the tumor is five centimeters or ten centimeters large and has spread to nearby organs, then you understand that the patient has a limited lifespan but when the tumors are small and detected early, typically, such patients should be doing well.

While Bakre was thinking about those whys and working on a solution, a company in the US had come up with a similar test.

However, the biggest differences between patients there and in India is that the former are mostly postmenopausal women and because they have much better insurance schemes with regular, annual checkups, the tumors are also very small when first detected.

When the patient is elderly and diagnosed with a smaller tumor, the biology is different; our patients are younger and and we don't have great programmes of insurance, she says.

Compared to those in the west, Indian women are also more likely to have triple negative breast cancer, which is considered to be a more aggressive type.

Breast cancers are classified based on biomarkers that are proteins present on the tumor cells. If a patients tumor has three proteins: estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, they are called triple positive patients while their absence makes one a triple negative patient.

The hormone receptors are really key determinants of how the disease will progress; in the universe of breast cancer patients, if the patient's tumor has hormone receptors they do well, says Bakre.

OncoStems first and currently only test is for hormone receptorpositive patients. This test is only valid for early stage breast cancer patients, that is, for those at stage one and two.

With the tests, patients are certified into low recurrence or high recurrence categories and the treatments are done accordingly.

Majority of Indian patients are getting treated with chemotherapy, even in early stage hormone receptor positive cancer, which is supposed to be a less aggressive form of the disease. To really save the excessive chemotherapy, we decided to develop a test which would suit our population,

The idea was to cut down on chemotherapy,as the side effects are often enormous.

Another point where the company is different from others, according to her, is that theirs is a protein-based test while the others are gene-based. The company has a machine learning-based algorithm which gives the risk of cancer recurrence. Bakre claims the test is 95 per cent accurate.

The biomarker analysis process is patented while in her own terms, the ML-based algorithm is a trade secret.

Bakre incorporated the company in 2011 but it took six-seven years to develop the test and eventually go to market.

A major reason for such a long process was that they needed to do a five-year follow up. The patient base in India is huge but the system isnt organized enough to keep the follow ups going.

How the company managed to sustain over the period of time when they were developing the test and not making any revenue was through investor money. In the very early days, they received $1 million in seed funding from Artiman Ventures, an early stage Silicon Valley-based venture capital fund.

The biggest challenge, however, has been to work with hospitals, she says. Given that there are multiple layers to convince and explain the test to, it takes a lot of time and that's something investors are unable to understand. She feels a lack of clarity in terms of guidelines is also an issue that elongates processes.

On VC funding still not going much into the healthcare space, Bakre says, entrepreneurship is like bringing up a child; at every stage you have different issues, you cannot be like I have given you seed funding and thats enough, you have to think of the entrepreneur in the next stage.

Bakre feels that their kind of work requires a lot of patience from the side of the investors and a lot more than what many of the now well-known tech start-ups began with.

Our kind of work is not like you can buy a laptop and start working out of a coworking space, she jokes.

In 2017, the company raised $6 million in a Series A round led by Sequoia Capital.

Currently, the test is prescribed by 180 doctors across India and the company works with 15 hospitals, of which 12 are in India.

Bakre says the company is looking to touch the lives of about 1000 patients in the next one year and build from there. According to her, the way to reach the masses is through insurance schemes such as Pradhan Mantri Jan Arogya Yojana.

Because the majority of the chemotherapy costs for cancer patients are given by the government and so if 70 per cent don't need, it is saving about INR 750 crore per year, just on the cost of chemotherapy.

The test costs INR 60,000 to one patient and the strategy of working with government hospitals, and treating low-income patients is to provide discounts as the volumes go up.

If the numbers go up, our costs will come down, and then we can work on reducing the price of the test, says Bakre.

In terms of new offerings, OncoStem is now working on developing a test for triple negative patients as well as something for patients of ovarian cancer.

The ultimate goal, though, she says, is to work with pharmaceutical companies and help develop treatments for the patients being diagnosed.

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This Entrepreneur Is Changing the Face Of Cancer Treatment In India - Entrepreneur

Cell Biology

Researchers map the cellular diversity of entire salivary gland tumors – News-Medical.net

February 22, 2020 medical

What goes on inside and between individual cells during the very earliest stages of tumor development? Single cell sequencing technologies and a mouse model have enabled researchers to comprehensively map the cellular diversity of whole salivary gland tumors and trace the path of cancer stem cells.

Two research teams from the Max Delbrck Center for Molecular Medicine and their collaborators have produced a detailed cell atlas of an entire salivary gland tumor in a mouse model, mapping individual cells throughout the tumor and its surrounding tissue. The "single cell" approach, recently described in Nature Communications, has provided key insights about cellular composition changes through the earliest stages of cancer development.

A solid tumor is not, as many might assume, a lump of cells that are all the same. Rather it is mix of many different cell types, including a variety of stromal and immune cells besides the actual tumor cells.

"Conventional methods in molecular biology often consider a sample as a whole, which fails to recognize the complexity within it," said Dr. Samantha Praktiknjo, senior scientist and first author from MDC's Systems Biology of Gene Regulatory Elements Lab headed by Professor Nikolaus Rajewsky at the Berlin Institute for Medical Systems Biology (BIMSB). Developing a detailed understanding of the different cells within a tumor and how they interact could help identify more effective treatment strategies.

The team used single-cell RNA sequencing technologies developed in the Rajewsky lab and novel epitope profiling to produce the cell atlas, and identified the cells that were specific to the tumor by leveraging the reproducibility and the large sample size of their data.

The latter was possible by using a mouse model, developed in MDC's Signal Transduction in Development and Cancer Lab headed by Professor Walter Birchmeier, which harbors designed mutations that induce a salivary gland squamous cell carcinoma. This system provides a consistent supply of genetically similar tumors to sequence from the earliest stages of development, which is nearly impossible with human patients.

"In a patient, the tumor is already developed and you cannot go back and rewind time and look at how it started," said Dr. Benedikt Obermayer, a co-first author now at the Berlin Institute of Health (BIH). "Here, we have a model that is so controlled, we can watch it happen." And Dr. Qionghua Zhu, the third first author and a former postdoc at the Birchmeier Lab, added: "To fight cancer effectively, we need to find the driver mutations. This method gives us clues about the evolution trajectories of a tumor."

Sequencing technologies have advanced so that it is now possible to quickly and affordably sequence the RNA inside single cells, one at a time, as well as the proteins on the surfaces of cells in the tissues. While other methods grind up the tissue and identify what genes and molecules are present in the mix, the single cell approach precisely identifies how many of each type of cell is present, and which genes and molecules are associated with which cell.

For this study, the researchers sequenced more than 26,000 individual salivary gland cells from mice with tumors and healthy mice. They used computational models to analyze the huge amount of data and identify each individual cell and sort them into groups - such as stromal cells, immune cells, saliva producing cells, cancer cells - based on the hundreds of genes expressed and molecules present.

The single cell approach revealed something that surprised the researchers: "When I saw the data, I thought, where is the tumor?" Obermayer said. The population of cancer stem cells in the tumor was extremely small - less than one percent of all profiled cells in the tissue. Due to their low abundance, investigation of these cells still heavily depends on assumptions about surface markers and is often performed in cell culture-based systems. Here, the authors were able to identify the cancer stem cells directly from the solid tumor samples with their single cell approach.

Furthermore, the team was able to predict the progression of the different cell types through different stages of tumor development. Their model suggests that the cancer stem cells emerge from cancerous basal cells, then develop into another subtype before ultimately becoming a population of cells similar to luminal cells, a cell type present in normal, healthy salivary glands.

This progression supports the idea that when something goes awry in the basal cells of this solid tumor model, they are triggered to turn into cancer stem cells, which can then become a different type of cell. "What I found fascinating was clearly seeing the order of signals and events, transitioning from the progenitor to the progeny populations of the cancer stem cells," Praktiknjo said.

Further research is required to verify that individual cells are transforming through these stages, and explore the cellular and molecular interactions driving tumor growth. The team anticipates the approach they've demonstrated here can be applied to other cancer types as well.

To me the main conceptual insight is that we can apply ideas from single-cell based developmental biology to reconstruct molecular progression of tumorigenesis."

Professor Nikolaus Rajewsky, Head of MDC's Systems Biology of Gene Regulatory Elements Lab and scientific director of the BIMSB

Source:

Journal reference:

Praktiknjo, S.D., et al. (2020) Tracing tumorigenesis in a solid tumor model at single-cell resolution. Nature Communications. doi.org/10.1038/s41467-020-14777-0.

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Researchers map the cellular diversity of entire salivary gland tumors - News-Medical.net

Cell Biology

How the monkeyflower gets its spots – UC Berkeley

February 22, 2020 medical

The yellow monkeyflowers distinctive red spots serve as landing pads for bees and other pollinators, helping them access the sweet nectar inside. A new study reveals the genetic programming that creates these attractive patterns. (Image by PollyDot via PixaBay)

The intricate spotted patterns dappling the bright blooms of the monkeyflower plant may be a delight to humans, but they also serve a key function for the plant. These patterns act as bee landing pads, attracting nearby pollinators to the flower and signaling the best approach to access the sweet nectar inside.

They are like runway landing lights, helping the bees orient so they come in right side up instead of upside down, said Benjamin Blackman, assistant professor of plant and molecular biology at the University of California, Berkeley.

See the companion press release at UConn Today

In a new paper, Blackman and his group at UC Berkeley, in collaboration with Yaowu Yuan and his group at the University of Connecticut, reveal for the first time the genetic programming that helps the monkeyflower and likely other patterned flowers achieve their spotted glory. The study was published online today (Thursday, Feb. 20) in the journal Current Biology.

While we know a good deal about how hue is specified in flower petals whether it is red or orange or blue, for instance we dont know a lot about how those pigments are then painted into patterns on petals during development to give rise to these spots and stripes that are often critical for interacting with pollinators, Blackman said. Our lab, in collaboration with others, has developed the genetic tools to be able to identify the genes related to these patterns and perturb them so that we can confirm whats actually going on.

In the study, the research team used CRISPR-Cas9 gene editing to recreate the yellow monkeyflower patterns found in nature. On the left, a wild-type monkeyflower exhibits the typical spotted pattern. In the middle, a heterozygote with one normal RTO gene and one damaged RTO gene exhibits blotchier spots. And on the right, homozygote with two copies of the damaged RTO gene is all red, with no spots. (UC Berkeley photo by Srinidhi Holalu)

The positions of petals spots arent mapped out ahead of time, like submarines in a game of battleship, Blackman said. Instead, scientists have long theorized that they could come about through the workings of an activator-repressor system, following what is known as a reaction-diffusion model, in which an activator molecule stimulates a cell to produce the red-colored pigment that produces a spot. At the same time, a repressor molecule is expressed and sent to neighboring cells to instruct them not to produce the red pigment.

The results are small, dispersed bunches of red cells surrounded by cells that keep the background yellow color.

By tweaking the parameters how strongly a cell turns on an inhibitor, how strongly the inhibitor can inhibit the activator, how quickly it moves between cells it can lead to big spots, small spots, striped patterns, really interesting periodic patterns, Blackman said.

In the study, UC Berkeley postdoctoral researcher Srinidhi Holalu and research associate Erin Patterson identified two natural varieties of the yellow monkeyflower one type with the typical red spots in the throat of the flower and a second type with an all-red throat appearing in multiple natural populations in California and Oregon, including at the UC Davis McLaughlin Reserve. In parallel, UConn postdoctoral researcher Baoqing Ding worked with a very similar plant with fully red-throated flowers found when surveying a population of Lewiss monkeyflower that had induced DNA mutations.

When the scientists presented bees in the lab with the two types of monkeyflowers, they preferred the red tongue variety to the spotted variety, though the red tongue variety is less common in nature. (UC Berkeley video by Erin Patterson and Anna Greenlee)

In a previous study, the Yuan lab had found that a gene called NEGAN (nectar guide anthocyanin) acts as an activator in the monkeyflower petals, signaling the cells to produce the red pigment. Through detailed genomic analysis in both monkeyflower species, the two groups were able to pinpoint that a gene called RTO, short for red tongue, acts as the inhibitor.

The red-throated forms of the monkeyflower have defective RTO inhibitor genes, resulting in a characteristic all-red throat, rather than red spots. To confirm their findings, Holalu used the CRISPR-Cas9 gene editing system to knock out the RTO gene in spotted variants of the flower. The result was flowers with a flashy red throat. Further experiments revealed how the functional form of the RTO protein moves to neighboring cells and represses NEGAN to prevent the spread of pigmentation beyond the local spots. This study is the first reported use of CRISPR-Cas9 editing to research the biology of monkeyflowers.

The team also collaborated with Michael Blinov at the UConn School of Medicine to develop a mathematical model to explain how different self-organized patterns might arise from this genetic system.

This work is the simplest demonstration of the reaction-diffusion theory of how patterns arise in biological systems, said Yaowu Yuan, associate professor of ecology and evolutionary biology at UConn. We are closer to understanding how these patterns arise throughout nature.

Monkeyflower plants with the RTO gene knocked out by CRISPR-Cas9 gene editing produce one big patch where all flowers exhibit a fully red throat, in contrast to wild fields where red-tongued flowers appear in small dispersed spots (UC Berkeley photo by Srinidhi Holalu)

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How the monkeyflower gets its spots - UC Berkeley

Neuroscience

The Mind’s Reality Is Consistent with Neuroscience – Walter Bradley Center for Natural and Artificial Intelligence

February 21, 2020 medical

In a recent podcast, neurosurgeon Michael Egnor talked with Robert J. Marks about the mind and its relationship to the brain and about different theories as to how the mind works. They talked about eliminative theories (the mind doesnt really exist) and emergent theories (the mind arises from matter) earlier and then the conversation turned to dualism:

Heres a partial transcript:

17:49 | Dualist theories of the mind

Robert J. Marks (right): Well, there is materialism and panpsychism. What other theories of mind of the mind are on tap?

Michael Egnor: Well, there are a number of dualism theories of the mind. And dualism, generally considered, is the viewpoint that mental states are not the same thing as material states, as brain states. That is, what you consider material aspects of a human being, there is a remainder that is mental, that is not material. But there are a variety of ways of looking at dualism.

18:29 | Cartesian dualism

The classical dualism way of looking at things, at least in modern philosophy, is Cartesian dualism, which was proposed by Descartes back in the 17th century. he proposed that human beings are composites of matter extended in space and spirit, which he thought of as a thinking substance. So he thought that there were two separate substances that were joined to form a human being, basically the material body joined to the immaterial spirit.

Ren Descartes (15961650) was a creative mathematician of the first order, an important scientific thinker, and an original metaphysician

It is sometimes said that Descartes dualism placed the mind outside nature by rendering it as an immaterial substance. That is a retrospective judgment from a perspective in which immaterial substances are automatically deemed unnatural. For Descartes and his followers, mindbody interaction and its laws were included within the domain of natural philosophy or physics (in the general meaning of the latter term, as the theory of nature). Descartes spoke of regular relations between brain states and the resulting sensory experiences, which his followers, such as Regis, subsequently deemed laws of mindbody relation (see Hatfield 2000). In this way, Descartes and his followers posited the existence of psychophysical or psychophysiological laws, long before Gustav Fechner (180187) formulated a science of psychophysics in the nineteenth century.

There are certainly good things to say about the Cartesian understanding of the mind and body. But I think its fundamentally misguided from a philosophical and logical standpoint and that it has actually done quite a bit of harm philosophically because it was described in the 20th century by a philosopher named Gilbert Ryle as the ghost in the machine. And that is that Descartes understood human beings to be basically biological machines that were inhabited by a ghost which was the spirit or the mind. And materialists have simply said, well, theres no ghost. So well just understand human beings as biological machines. Thats a profound error but Descartes opened the door to that.

Note: Gilbert Ryle (19001976) used the phrase ghost in the machine in an influential 1949 book, The Concept of Mind. His own behaviorist theories are not now much regarded though they were influential in encouraging other materialist approaches, for example:

With his remarkable ability to turn a phrase, what Ryle even more famously did was to stigmatize mind as the Ghost in the Machine. Unfortunately, the phrase greatly advanced the enlightenment idea of Man a Machine. And it helped prepare the way for todays revolution in cognitive science based on the computational theory of mind, with the digital computer the model for intellectual operations.

20:00 | Hylomorphism

Michael Egnor (left): The perspective that Descartes cast aside was that of hylomorphism. Thats the view that all of nature consists of a composite of form and matter. Morphism means matter and hyle is the Greek word for form. Everything in nature is a composite of form, which Aristotle would call a principle of intelligibility, and matter, which is a principle of individuation. Its a rather profound metaphysical perspective and in that perspective, the soul or the mind is the form of the body. But its a different perspective from Descartes perspective and it doesnt see mind and body as being separate substances. It sees a human being as being a unitary thing, with different principles involved but not different substances.

Note: For more thoughts on hylomorphism (hylemorphism) see Michael Egnor, How can mind interact with matter? (Mind Matters News)

21:17 | Comparing theories of the mind

Robert J. Marks: One of the criteria that you mentioned for establishing a good model of the mind-brain problem is consistency with the results of neuroscience. How do these three different theories stack up, materialism, panpsychism, and dualism?

Michael Egnor: Well, panpsychism, I can see why some very intelligent people like Dr. Chalmers have made that inference [that everything is, in some sense, conscious], I dont think panpsychism is a particularly scientific viewpoint. Realistically, there is no particular reason to think that electrons or grains of sand have minds.

See also: Are electrons conscious? A classical philosopher can explain why the belief that everything is conscious is wrong (Michael Egnor)

Robert J. Marks: Im siting here thinking, how could you ever test something like that?

Michael Egnor: Well, you could ask an electron and people have tried but the electrons dont answer

Materialists have, of course, made the claim that neuroscience completely supports materialism. I had an internet debate with Dr. Steven Novella who is a neurologist at Yale a number of years ago and hes a materialist. And Dr. Novella said that every single bit of evidence in the history of neuroscience supports materialism. Which I think is not the case.

The problem with that is that neuroscientists generally work from a materialist perspective and they ask questions of the mind and the brain from a materialist perspective. And, goodness gracious, its no surprise that if thats they way you ask the questions, then materialism always seems like its the answer

I think dualism is a much, much better explanation for many aspects of neuroscience.

Robert J. Marks: That was my next question: Do you, speaking as an experienced neurosurgeon who has played around with the brains of many, many people, what do you believe? Do you believe that the mind is distinct from the brain, as a dualist does?

Michael Egnor: I think that, first of all, if you want to understand the mind and the brain, you need to start with a solid metaphysical foundation. And I think hylomorphism is a solid metaphysical foundation. I dont think Cartesian dualism is a good metaphysical foundation and I certainly dont think materialism is a good metaphysical foundation.

I think the best explanation of the relationship of the mind to the brain is Aristotelian hylomorphism which is the viewpoint that the soul is the form of the body and that certain powers of the soul, particularly the intellect and will, are not generated by matter but are immaterial thingswhat Thomas Aquinas would call the spirit. But other properties of the mind, like perception and memory and imagination are physical. They are directly related to brain matter and they are generated by brain matter. I think thats the best explanation philosophically for what we find in neuroscience.

Heres a brief introduction to hylomorphism:

Form and matter considered on their own are merely concepts in the mind; in things they are two distinct principles that make the one unified individual thing. The substantial form makes a thing what it is and the accidental forms (e.g. quantity and quality) modify it to have the types of quantity and qualities it has. So a substantial form makes a cat a cat, but an accidental form makes it a black cat.

What differentiates Seabiscuit from Secretariat is not horse-ness, since they are both horses; matter makes Seabiscuit this particular horse and Secretariat that particular horse.

Show Notes

See also the earlier parts of the discussion: Why eliminative materialism cannot be a good theory of the mind. Thinking that the mind is simply the brain, no more and no less, involves a hopeless contradiction. How can you have a proposition that the mind doesnt exist? That means propositions dont exist and that means, in turn, that you dont have a proposition.

and

Why the mind cannot just emerge from the brain. The mind cannot emerge from the brain if the two have no qualities in common. In his continuing discussion with Robert J. Marks, Michael Egnor argues that emergence of the mind from the brain is not possible because no properties of the mind have any overlap with the properties of brain. Thought and matter are not similar in any way. Matter has extension in space and mass; thoughts have no extension in space and no mass.

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The Mind's Reality Is Consistent with Neuroscience - Walter Bradley Center for Natural and Artificial Intelligence

Neuroscience

Ted W. Simon is being recognized by Continental Who’s Who – Yahoo Finance

February 21, 2020 medical

WINSTON, Ga., Feb. 21, 2020 /PRNewswire/ --Ted W. Simon is being recognized by Continental Who's Who as a Top Expert in the field of Education and Science as a Principal at Ted Simon, LLC.

An award-winning toxicologist and scientist, Dr. Simon has had a remarkable career on account of his expertise and dedication to toxicology and science. He served as the senior toxicologist in the waste management division of the Atlanta regional office of the Environmental Protection Agency for over ten years. Since 2006, Dr. Simon has worked in scientific consulting as the principal at Ted Simon, LL. He is knowledgeable about risk assessment, mathematical modeling, statistics, neuroscience, and environmental/ecological health issues. He has taught at university classes as an adjunct professor in Environmental Health Science at the University of Georgia. He has been an invited speaker at national and international events.

Dr. Simon received a Bachelor of Arts in biology from Middlebury College in 1971. After several years of working, he decided to continue his biological studies at George State University in Atlanta, and, in 1971 received his Ph.D. in neurobiology and behavior. His doctoral thesis titled "The Neural Basis of Light Evolved Walking in Crayfish" was recognized with an Honorable Mention for the Donald B. Lindsley Prize in Neuroscience. For several years after his Ph.D., he worked as a postdoctoral fellow at Emory University in cellular neuroscience.

Dr. Simon is a diplomate of the American Board of Toxicology (ABT) and a professional member of the Society of Toxicology (SOT) and the Society for Risk Analysis (SRA). Previously, he was a member of the Society for Neuroscience (SFN), concluding his membership in 1993.

Dr. Simon's awards include EPA's Science Achievement Award in 2002 for his work on "Risk Assessment Guidance for Superfund (RAGS): Volume III Probabilistic Risk Assessment". In 2017, Dr. Simon and his co-authors received an award for best paper of the year from the Risk Assessment Specialty Section of the Society of Toxicology for a work titled "How can carcinogenicity be predicted by high throughput "characteristics of carcinogens mechanistic data?". The full paper is available online.

Dr. Simon's publications include thirty peer-reviewed journals and one textbook: Environmental Risk Assessment: A Toxicological Approach, 2nd Edition. The textbook will be available in early 2020.

Outside of work, Dr. Simon enjoys photography, playing the violin, fishing, and spending time with his family. He and his wife Elizabeth have two children, Adam and Rebecca, and four grandchildren.

For more information, please visit http://www.tedsimon-toxicology.com

Contact: Katherine Green, 516-825-5634, pr@continentalwhoswho.com

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Ted W. Simon is being recognized by Continental Who's Who - Yahoo Finance

Neuroscience

Cognition in schizophrenia: a missing piece of the therapeutic puzzle – PLoS Blogs

February 21, 2020 medical

Note: This post was written by Jessica Brown, PhD student at the University of Manchester.

What kind of mental image springs to mind upon reading the word schizophrenia? Many envisage an individual locked in a dark institution, constantly plagued by non-existent voices and vivid hallucinations. Even as a final year BSc Biology student with a neuroscience research placement under my belt, I too was guilty of this reflex association. Upon skimming through project titles on FindaPhD.com, the word schizophrenia jumped out of the page. My excitement was sparked as I envisaged myself unravelling the intricacies of psychosis. As I examined the project title more closely, I admittedly experienced a minor surge of disappointment: the research was interested in targeting the cognitive deficits of schizophrenia. Cognitive deficits? I was unaware that cognition was significantly impaired in schizophrenia patients. And even if it was, did these symptoms really warrant extensive investigation? Surely, in the context of a disorder characterised by multimodal hallucinations and debilitating delusions, cognitive difficulties shouldnt be an urgent therapeutic priority.

The failure of current antipsychotics

A few hours of literature research and an interview with my PhD supervisor later, my appreciation of schizophrenia had been completely transformed.

Fortunately for our hypothetical institutionalised patient, modern antipsychotic drugs combating positive, psychotic symptoms have allowed many individuals to successfully function and flourish within their communities. So why, my supervisor pointed out to me, do so many schizophrenia patients still fail to achieve independent living, find employment and form relationships? Even more alarmingly, why are rates of symptomatic relapse so high? By the end of our conversation, I was convinced: the answer lies in the debilitating cognitive disturbances suffered by individuals, too often overlooked by research and crucially neglected by current drug therapies.

Cognitive impairment in schizophrenia: an unmet clinical need

Schizophrenia is a staggeringly heterogeneous disorder, with symptoms manifesting very differently in each patient. Amidst this variety, cognitive deficits are a consistent feature, persisting independently of circumstances such as medication, institutionalisation and advancement in cognition assessment tools. In particular, patients struggle in areas of verbal learning, processing speed and working memory.

Cognitive functioning in schizophrenia has been subjected to decades of research. However, the true impact of cognition upon disease outcomes has only recently come to light. A plethora of studies have drawn links between poor cognitive performance and impaired psychosocial functioning. One might argue that this is a rather obvious association. But why does it matter? Closer consideration reveals the enormous impact this has on daily life: if a schizophrenia patient is unable to perform hygiene-related tasks and keep up with their medications, they have little hope of finding employment or successfully integrating into community living.

As recently as January 2020, research has emphasised the detrimental effects of poor cognition. An Ecuadorian study conducted at the psychiatric Kennedy Hospital used the SCIP (Screening of Cognitive Deterioration in Psychiatry) tool alongside questionnaires assessing quality of life and sociodemographic status to reveal the inverse relationship between cognitive impairment and quality of life as perceived by the patient.

Even considering the impact of untreated cognitive symptoms upon quality of life, it is still reasonable to pose the question: so what? The sad reality is that for many patients, cognitive difficulties make antipsychotic drugs a futile intervention, leading to symptomatic remission and a substantial waste of resources. As if the significance of cognitive impairment had not been sufficiently demonstrated, a Swedish study following over 500 schizophrenia patients made the staggering finding that executive function independently predicted premature death.

Therapeutic intervention: a multi-pronged approach

In the face of such alarming data, it is unsurprising that the cognitive deficits of schizophrenia have become an urgent therapeutic target. But how can cognition be elevated? Amongst the most promising interventions are drugs targeting NMDA receptors located on neurons in the brain, these receptors mediate signalling crucial for learning and memory functions. One such medication is memantine, which has shown some promise in schizophrenia patients.

Unfortunately, using pharmacological treatments to improve cognition is far from straightforward. It is critical to remember that these patients still rely upon antipsychotics to manage positive symptoms, which often interfere with the activity of cognition-targeting drugs. Even without this complication, is it rational to expect a single-target approach to be effective in treating such a complex, multi-faceted disorder? This is where cognitive remediation therapy comes in. Using behavioural training, this technique is not only shown to improve performance across numerous cognitive domains, but also delay the relapse of symptoms.

Concluding thoughts

As scientists, I believe we are often drawn to the one size fits all approach: current medicine is geared toward identifying a magic bullet to target a single, disease-causing agent. The game plan is clear: find this drug, roll it out to patients and the problem will be solved.

Sadly, as research continues to search for successful schizophrenia treatment strategies, one thing is becoming painstakingly clear: one size does not fit all. A particular cocktail of drugs and behavioural therapies allowing one patient to thrive may be completely unsuccessful in another. Encouragingly, current efforts are directed toward identifying patients most likely to benefit from certain treatment strategies, using biological indicators or biomarkers.

In the world of science, it is all too easy to become immersed in the daily frustrations and unsolved mysteries of research and forget why one is even investigating a particular disorder. As a colleague in neuroscience R&D at Eli Lilly once said to me: in every meeting, there should always be a chair reserved for the most important person in the room. And that person is the patient.

There is an undeniably long way to go before schizophrenia patients will be able to make a complete recovery, with a low risk of relapse and a satisfactory quality of life. But recognising cognition as the wrongly neglected aspect of schizophrenia is certainly a step in the right direction.

References:

J, Avila, Villacrs L, Rosado D, and Loor E. Cognitive Deterioration and Quality of Life in Patients with Schizophrenia: A Single Institution Experience. Cureus 12, no. 1 (25 January 2020).

Molina, Juan, and Ming T. Tsuang. Neurocognition and Treatment Outcomes in Schizophrenia. In Schizophrenia Treatment Outcomes: An Evidence-Based Approach to Recovery, edited by Amresh Shrivastava and Avinash De Sousa, 3541. Cham: Springer International Publishing, 2020.

Schaefer, Jonathan, Evan Giangrande, Daniel R. Weinberger, and Dwight Dickinson. The Global Cognitive Impairment in Schizophrenia: Consistent over Decades and around the World. Schizophrenia Research 150, no. 1 (October 2013): 4250.

Evans, Jovier D., Robert K. Heaton, Jane S. Paulsen, Barton W. Palmer, Thomas Patterson, and Dilip V. Jeste. The Relationship of Neuropsychological Abilities to Specific Domains of Functional Capacity in Older Schizophrenia Patients. Biological Psychiatry 53, no. 5 (1 March 2003): 42230.

Semkovska, Maria, Marc-Andr Bdard, Lucie Godbout, Frdrique Limoge, and Emmanuel Stip. Assessment of Executive Dysfunction during Activities of Daily Living in Schizophrenia. Schizophrenia Research 69, no. 23 (1 August 2004): 289300.

Tsai, G. E. Ultimate Translation: Developing Therapeutics Targeting on N-Methyl-d-Aspartate Receptor. Advances in Pharmacology (San Diego, Calif.) 76 (2016): 257309.

Thomas, Michael L., Michael F. Green, Gerhard Hellemann, Catherine A. Sugar, Melissa Tarasenko, Monica E. Calkins, Tiffany A. Greenwood, et al. Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia. JAMA Psychiatry 74, no. 1 (1 January 2017): 3746.

Trapp, Wolfgang, Michael Landgrebe, Katharina Hoesl, Stefan Lautenbacher, Bernd Gallhofer, Wilfried Gnther, and Goeran Hajak. Cognitive Remediation Improves Cognition and Good Cognitive Performance Increases Time to RelapseResults of a 5 Year Catamnestic Study in Schizophrenia Patients. BMC Psychiatry 13 (9 July 2013): 184.

Helldin, Lars, Fredrik Hjrthag, Anna-Karin Olsson, and Philip D. Harvey. Cognitive Performance, Symptom Severity, and Survival among Patients with Schizophrenia Spectrum Disorder: A Prospective 15-Year Study. Schizophrenia Research 169, no. 13 (December 2015): 14146.

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Cognition in schizophrenia: a missing piece of the therapeutic puzzle - PLoS Blogs