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Category Archives: Mind Building
Pressure on the NHS is unsustainable, medics warn
Chair of the BMA council, Professor Phil Banfield, is calling on the government to “take immediate action”.
New method precisely locates gene activity and proteins across tissues
A new method can illuminate the identities and activities of cells throughout an organ or a tumor at unprecedented resolution, according to a study co-led by researchers at Weill Cornell Medicine, NewYork-Presbyterian and the New York Genome Center.
The method, described Jan. 2 in a paper in Nature Biotechnology, records gene activity patterns and the presence of key proteins in cells across tissue samples, while retaining information about the cells’ precise locations. This enables the creation of complex, data-rich “maps” of organs, including diseased organs and tumors, which could be widely useful in basic and clinical research.
“This technology is exciting because it allows us to map the spatial organization of tissues, including cell types, cell activities and cell-to-cell interactions, as never before,” said study co-senior author Dr. Dan Landau, an associate professor of medicine in the Division of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a core faculty member at the New York Genome Center.
The other co-senior author was Dr. Marlon Stoeckius of 10x Genomics, a California-based biotechnology company that makes laboratory equipment for the profiling of cells within tissue samples. The three co-first authors were Dr. Nir Ben-Chetrit, Xiang Niu, and Ariel Swett, respectively a postdoctoral researcher, graduate student, and research technician in the Landau laboratory during the study.
The new method is part of a broad effort by scientists and engineers to develop better ways of “seeing” at micro scale how organs and tissues work. Researchers in recent years have made big advances particularly in techniques for profiling gene activity and other layers of information in individual cells or small groups of cells. However, these techniques typically require the dissolution of tissues and the separation of cells from their neighbors, so that information about profiled cells’ original locations within the tissues is lost. The new method captures that spatial information as well, and at high resolution.
The method, called Spatial PrOtein and Transcriptome Sequencing (SPOTS), is based in part on existing 10x Genomics technology. It uses glass slides that are suitable for imaging tissue samples with ordinary microscope-based pathology methods, but are also coated with thousands of special probe molecules. Each of the probe molecules contains a molecular “barcode” denoting its two-dimensional position on the slide. When a thinly sliced tissue sample is placed on the slide and its cells are made permeable, the probe molecules on the slide grab adjacent cells’ messenger RNAs (mRNAs), which are essentially the transcripts of active genes. The method includes the use of designer antibodies that bind to proteins of interest in the tissue — and also bind to the special probe molecules. With swift, automated techniques, researchers can identify the captured mRNAs and selected proteins, and map them precisely to their original locations across the tissue sample. The resulting maps can be considered alone, or compared to standard pathology imaging of the sample.
The team demonstrated SPOTS on tissue from a normal mouse spleen, revealing the complex functional architecture of this organ including clusters of different cell types, their functional states, and how those states varied with the cells’ locations.
Highlighting SPOTS’ potential in cancer research, the investigators also used it to map the cellular organization of a mouse breast tumor. The resulting map depicted immune cells called macrophages in two distinct states as denoted by protein markers — one state active and tumor-fighting, the other immune-suppressive and forming a barrier to protect the tumor.
“We could see that these two macrophage subsets are found in different areas of the tumor and interact with different cells — and that difference in microenvironment is likely driving their distinct activity states,” said Dr. Landau, who is also an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Such details of the tumor immune environment — details that often can’t be resolved due to immune cells’ sparseness within tumors — might help explain why some patients respond to immune-boosting therapy and some don’t, and thus could inform the design of future immunotherapies, he added.
This initial version of SPOTS has a spatial resolution such that each “pixel” of the resulting dataset sums gene activity information for at least several cells. However, the researchers hope soon to narrow this resolution to single cells, while adding other layers of key cellular information, Dr. Landau said.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Landau.
Self-assembling proteins can store cellular ‘memories’
As cells perform their everyday functions, they turn on a variety of genes and cellular pathways. MIT engineers have now coaxed cells to inscribe the history of these events in a long protein chain that can be imaged using a light microscope.
Cells programmed to produce these chains continuously add building blocks that encode particular cellular events. Later, the ordered protein chains can be labeled with fluorescent molecules and read under a microscope, allowing researchers to reconstruct the timing of the events.
This technique could help shed light on the steps that underlie processes such as memory formation, response to drug treatment, and gene expression.
“There are a lot of changes that happen at organ or body scale, over hours to weeks, which cannot be tracked over time,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, a professor of biological engineering and brain and cognitive sciences at MIT, a Howard Hughes Medical Institute investigator, and a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research.
If the technique could be extended to work over longer time periods, it could also be used to study processes such as aging and disease progression, the researchers say.
Boyden is the senior author of the study, which appears today in Nature Biotechnology. Changyang Linghu, a former J. Douglas Tan Postdoctoral Fellow at the McGovern Institute, who is now an assistant professor at the University of Michigan, is the lead author of the paper.
Cellular history
Biological systems such as organs contain many different kinds of cells, all of which have distinctive functions. One way to study these functions is to image proteins, RNA, or other molecules inside the cells, which provide hints to what the cells are doing. However, most methods for doing this offer only a glimpse of a single moment in time, or don’t work well with very large populations of cells.
“Biological systems are often composed of a large number of different types of cells. For example, the human brain has 86 billion cells,” Linghu says. “To understand those kinds of biological systems, we need to observe physiological events over time in these large cell populations.”
To achieve that, the research team came up with the idea of recording cellular events as a series of protein subunits that are continuously added to a chain. To create their chains, the researchers used engineered protein subunits, not normally found in living cells, that can self-assemble into long filaments.
The researchers designed a genetically encoded system in which one of these subunits is continuously produced inside cells, while the other is generated only when a specific event occurs. Each subunit also contains a very short peptide called an epitope tag — in this case, the researchers chose tags called HA and V5. Each of these tags can bind to a different fluorescent antibody, making it easy to visualize the tags later on and determine the sequence of the protein subunits.
For this study, the researchers made production of the V5-containing subunit contingent on the activation of a gene called c-fos, which is involved in encoding new memories. HA-tagged subunits make up most of the chain, but whenever the V5 tag shows up in the chain, that means that c-fos was activated during that time.
“We’re hoping to use this kind of protein self-assembly to record activity in every single cell,” Linghu says. “It’s not only a snapshot in time, but also records past history, just like how tree rings can permanently store information over time as the wood grows.”
Recording events
In this study, the researchers first used their system to record activation of c-fos in neurons growing in a lab dish. The c-fos gene was activated by chemically induced activation of the neurons, which caused the V5 subunit to be added to the protein chain.
To explore whether this approach could work in the brains of animals, the researchers programmed brain cells of mice to generate protein chains that would reveal when the animals were exposed to a particular drug. Later, the researchers were able to detect that exposure by preserving the tissue and analyzing it with a light microscope.
The researchers designed their system to be modular, so that different epitope tags can be swapped in, or different types of cellular events can be detected, including, in principle, cell division or activation of enzymes called protein kinases, which help control many cellular pathways.
The researchers also hope to extend the recording period that they can achieve. In this study, they recorded events for several days before imaging the tissue. There is a tradeoff between the amount of time that can be recorded and the time resolution, or frequency of event recording, because the length of the protein chain is limited by the size of the cell.
“The total amount of information it could store is fixed, but we could in principle slow down or increase the speed of the growth of the chain,” Linghu says. “If we want to record for a longer time, we could slow down the synthesis so that it will reach the size of the cell within, let’s say two weeks. In that way we could record longer, but with less time resolution.”
The researchers are also working on engineering the system so that it can record multiple types of events in the same chain, by increasing the number of different subunits that can be incorporated.
The research was funded by the Hock E. Tan and K. Lisa Yang Center for Autism Research, John Doerr, the National Institutes of Health, the National Science Foundation, the U.S. Army Research Office, and the Howard Hughes Medical Institute.
Good hydration linked to healthy aging
Adults who stay well-hydrated appear to be healthier, develop fewer chronic conditions, such as heart and lung disease, and live longer than those who may not get sufficient fluids, according to a National Institutes of Health study published in eBioMedicine.
Using health data gathered from 11,255 adults over a 30-year period, researchers analyzed links between serum sodium levels — which go up when fluid intake goes down — and various indicators of health. They found that adults with serum sodium levels at the higher end of a normal range were more likely to develop chronic conditions and show signs of advanced biological aging than those with serum sodium levels in the medium ranges. Adults with higher levels were also more likely to die at a younger age.
“The results suggest that proper hydration may slow down aging and prolong a disease-free life,” said Natalia Dmitrieva, Ph.D., a study author and researcher in the Laboratory of Cardiovascular Regenerative Medicine at the National Heart, Lung, and Blood Institute (NHLBI), part of NIH.
The study expands on research the scientists published in March 2022, which found links between higher ranges of normal serum sodium levels and increased risks for heart failure. Both findings came from the Atherosclerosis Risk in Communities (ARIC) study, which includes sub-studies involving thousands of Black and white adults from throughout the United States. The first ARIC sub-study started in 1987 and has helped researchers better understand risk factors for heart disease, while shaping clinical guidelines for its treatment and prevention.
For this latest analysis, researchers assessed information study participants shared during five medical visits — the first two when they were in their 50s, and the last when they were between ages 70-90. To allow for a fair comparison between how hydration correlated with health outcomes, researchers excluded adults who had high levels of serum sodium at baseline check-ins or with underlying conditions, like obesity, that could affect serum sodium levels.
They then evaluated how serum sodium levels correlated with biological aging, which was assessed through 15 health markers. This included factors, such as systolic blood pressure, cholesterol, and blood sugar, which provided insight about how well each person’s cardiovascular, respiratory, metabolic, renal, and immune system was functioning. They also adjusted for factors, like age, race, biological sex, smoking status, and hypertension.
They found that adults with higher levels of normal serum sodium — with normal ranges falling between 135-146 milliequivalents per liter (mEq/L) — were more likely to show signs of faster biological aging. This was based on indictors like metabolic and cardiovascular health, lung function, and inflammation. For example, adults with serum sodium levels above 142 mEq/L had a 10-15% associated increased odds of being biologically older than their chronological age compared to ranges between 137-142 mEq/L, while levels above 144 mEq/L correlated with a 50% increase. Likewise, levels of 144.5-146 mEq/L were associated with a 21% increased risk of premature death compared to ranges between 137-142 mEq/L.
Similarly, adults with serum sodium levels above 142 mEq/L had up to a 64% increased associated risk for developing chronic diseases like heart failure, stroke, atrial fibrillation and peripheral artery disease, as well as chronic lung disease, diabetes, and dementia. Conversely, adults with serum sodium levels between 138-140 mEq/L had the lowest risk of developing chronic disease.
The findings don’t prove a causal effect, the researchers noted. Randomized, controlled trials are necessary to determine if optimal hydration can promote healthy aging, prevent disease, and lead to a longer life. However, the associations can still inform clinical practice and guide personal health behavior.
“People whose serum sodium is 142 mEq/L or higher would benefit from evaluation of their fluid intake,” Dmitrieva said. She noted that most people can safely increase their fluid intake to meet recommended levels, which can be done with water as well as other fluids, like juices, or vegetables and fruits with a high water content. The National Academies of Medicine, for example, suggest that most women consume around 6-9 cups (1.5-2.2 liters) of fluids daily and for men, 8-12 cups (2-3 liters).
Others may need medical guidance due to underlying health conditions. “The goal is to ensure patients are taking in enough fluids, while assessing factors, like medications, that may lead to fluid loss,” said Manfred Boehm, M.D., a study author and director of the Laboratory of Cardiovascular Regenerative Medicine. “Doctors may also need to defer to a patient’s current treatment plan, such as limiting fluid intake for heart failure.”
The authors also cited research that finds about half of people worldwide don’t meet recommendations for daily total water intake, which often starts at 6 cups (1.5 liters).
“On the global level, this can have a big impact,” Dmitrieva said. “Decreased body water content is the most common factor that increases serum sodium, which is why the results suggest that staying well hydrated may slow down the aging process and prevent or delay chronic disease.”
This research was supported by the Division of Intramural Research at NHLBI. The ARIC study has been supported by research contracts from NHLBI, NIH, and the Department of Health and Human Services.
What It’s Like Being Me
I love asking people this question: What is it really like being you?
We can see how people speak and behave on the outside, but what do we know of their interior perspective?
What I love about this question is that it invites real intimacy and empathy. It’s an invitation into trust. I feel honored when someone does their best to answer honestly. It’s fascinating to discover how someone frames and experiences their interior world, at least to the extent they can articulate it.
I thought it would be interesting to answer this question too, if only to see what comes through when I try to answer it.
Centeredness
I love being me and really enjoy my life, which feels rich and rewarding. I feel like I figured out the big rocks and put them in place many years ago. I feel very aligned with the work I get to do and the people I regularly connect with, especially in Conscious Growth Club and the Transformational Leadership Council.
I don’t experience any meaningful doubt about the path I’m on, at least not at the macro level. I like to think carefully about the projects I commit to, but I can’t say that I ever seriously feel like making a significant change in my career path or lifestyle at this point. I’m always interested in upgrades and improvements, but the overall trajectory of my life feels like it’s already perfect for me.
So on the inside, I normally feel very centered and engaged with whatever I’m doing and experiencing. I enjoy a beautiful sense of harmony with my work and life balance. I don’t feel like work and life are separate. It feels more like the work and non-work parts of life are always dancing with each other.
Energy & Enthusiasm
One of the main emotions I experience is enthusiasm.
I love to feel positively stimulated with emotion, not all the time to the maximum, but as nice accents throughout each day. I like to feel amped up and engaged with life.
Partly this is a decision to move away from boredom and dullness. When I feel that the energy of a situation is a bit low for my tastes, I’ll often do something to shift it. For instance, I frequently like to play music and dance around while making meals. I love it when Rachelle does that with me too.
Every day I find something to feel enthusiastic about, usually many times each day. It could be a new business idea, but I’ll also generate enthusiasm for everyday experiences like greeting Rachelle when she gets up, doing a Zoom call, or watching a show together. I’ll even generate excitement about running errands.
My mind has a strong tendency to want to bounce away from boredom and towards feelings of engagement, playfulness, and fun. For me this aspect of my inner reality is solidly implanted.
Raising Vibes
I think this is something I learned from watching movies when I was younger. There are so many movie scenes where a high-energy character walks in, and the whole vibe of the scene changes. Or maybe it’s an unusual character who shifts the vibe of whatever scene they’re in. One example is Bill Murray’s character in Ghostbusters. Another is Val Kilmer’s character in Real Genius. Such characters were basically my heroes when I was younger. You’ve probably seen countless examples of these characters too.
When I interact with people socially, I often think about how I can stimulate them vibrationally… like what I could say or do to help connect them with more enthusiasm for their lives, experiences, and opportunities. Sometimes I feel that my role has been to shake people awake if they’ve been sleeping through life in zombie mode.
I sense that a great key to life is how we manage our energy, which includes thought energy, physical energy, and emotional energy. I think you can include spiritual energy too. I pay serious attention to the flow of energy through myself and through interactions with others. If the energy flow feels off somehow, I do my best to shift it in a more positive and constructive direction.
I think that for much of my life, I’ve felt a strong attraction to certain vibes and a strong repulsion towards others. As I’ve gotten older, I’ve gotten better and better at centering my life around the vibes I like and defending myself from vibes I dislike. I’m attracted to vibes like abundance, playfulness, curiosity, and creativity. I’m repulsed by neediness, close-mindedness, defeatism, and depression.
Thinking Algorithmically
Probably because I learned computer programming when I was a kid, I tend to think of life in terms of interesting problems to be solved and challenges to work through. I live in a world of puzzles to be figured out, and I love chipping away at these. These puzzles could include business challenges, creative challenges, personal challenges, and more.
I don’t worry if problems are solvable. I tend to regard everything as solvable and figureoutable. I generally assume that every problem has multiple solutions, so my mind starts churning on various solution pathways instead of fussing over whether it’s solvable. I’m much more concerned by which pathways seem the most elegant to me. I love to discover shortcuts.
Some problems in my life took me a long time to solve, but I eventually figured them out. It doesn’t bother me if some problems take years or even decades to solve. The time is going to pass anyway, and since I love working on interesting problems and challenges, I enjoy the experience of continuing to chip away at them.
I’m always looking to improve my toolset of problem-solving skills. Tackling interesting problems and challenges helps me improve those tools and upgrade my models of reality.
Belongingness
Imagine receiving thank you messages and expressions of appreciation from people around the world every day of your life. That’s been my reality for the past 18+ years, ever since I started blogging in 2004. That’s probably going to continue for the rest of my life, even if I stopped working.
Recently my book Personal Development for Smart People came out in China, so I’ve been getting a surge in appreciative emails from Chinese readers.
What does this do to my interior perspective? It gives me an unshakeable feeling of belongingness.
When I was younger, I often felt isolated and disconnected, like I was an alien in this world who didn’t belong here. I haven’t felt that way in decades though. Today I feel solidly at home here. I have zero doubt that this is where I belong – on this planet and in this field. I feel like I’m exactly where I’m supposed to be.
I feel at home whenever I travel too. Foreign locations don’t feel foreign to me. I’m so used to communicating with people from all over the world that it feels like the whole world is home.
Appreciation
I feel like I’m immersed in a reality that’s filled with experiences, people, and items to appreciate. I can’t seem to help feeling lots of appreciation each day. I appreciate my work. I appreciate my home. I appreciate Rachelle. I appreciate living in Las Vegas. I appreciate this community.
I also appreciate the little things in life. I spent time interacting with various objects and tech each day, and I learned how important it is to fill my life with items that evoke appreciation. This week I’ve been working with a bunch of hand tools to hang acoustic panels, and using them makes me smile sometimes because I carefully selected and purchased tools that I’d appreciate – such as a drill, tape measure, level, etc.
For me practicing appreciation was a huge key in shifting from scarcity to abundance, so this attitude of appreciation is indelibly woven into my mindset. Almost always when I touch something physically, there’s a part of me saying “thank you” internally for the experience. This happens when I put my hands on the steering wheel in my car, when I open up my laptop, when I pick up a knife in the kitchen, etc. I sense that we only have so many experiences in life, and I want even the most mundane ones to be infused with appreciation.
It would also be unusual for me to go through a day without saying thank you to someone for something. I love to express appreciation, and I sense that people could always use more of it. I would love to see more people expressing genuine gratitude for all the wonders we get to experience in this life instead of taking so much for granted.
When I die I want my last words to be: Thank you for this life.
Love
A big part of my interior perspective is that I enjoy being in love every day. I know a lot of people probably see me as a more mental creature due to seeing that side of me from my writing, but internally I feel a lot of love energy flowing through me each day.
I really, really, really enjoy and appreciate my relationship with Rachelle. Every day I get to spend with her is sheer delight.
Our relationship doesn’t feel effortful. It feels like a wonderful gift. I think that’s because we’re so ridiculously compatible. I recognize that what we have is very special, and on the inside that makes me feel very lucky.
I feel doubly fortunate that I get to see sides of Rachelle that she doesn’t often share with others. To people who don’t know her well, she may seem shy or introverted, but with me she shares so much playfulness, fun, love, warmth, and affection.
I’ve never had an issue with loneliness. I love solitary time too and don’t feel any significant resistance towards being alone. But I’ve spent most of my adult life in long-term relationships. I think one reason I’ve attracted partners pretty easily is that I just don’t feel needy in this area. I love being in a relationship, but I also love the experience of being on my own. I feel equally comfortable in both worlds.
I think this has been a key to new growth experiences. Don’t try to invite new experiences by resisting where you are. Try to love and appreciate your present reality as well as what you’d like to invite next. Send appreciation in all directions.
That was also a big part of shifting from scarcity to abundance. I wasted so much energy on the frustration of resisting scarcity when I was in my 20s. When I finally let go and surrendered to it – and actually welcomed it into my life as if I’d always be in scarcity till I died – that’s when the floodgates of abundance opened up. Learning to appreciate scarcity was a powerful lesson.
Freedom & Creativity
I also really enjoy my freedom. I haven’t had a job or a boss in 30+ years, so I’ve been on an independent entrepreneurial path since the early 1990s. It was rough during the first several years, but I eventually figured it out.
I don’t normally think of myself as an entrepreneur or business owner though. Those frames feel a bit too dull and mental to me. On the inside I don’t really fuss about my identity.
I love to create all sorts of things, so most days I’m thinking about what I’m creating. I could label myself as a creator, but that feels a bit off too. I’m not particularly concerned with how I’m labeled by myself or others. I’m much more in tune with whatever I’m engaging with in the moment. In terms of my identity, it feels more like water or wind – very flexible and adapting to wherever it goes.
The term “content creator” turns my stomach a bit, like it’s trying to smoosh something beautifully expansive into a small-minded box. It’s like putting a bird in a cage.
For me creativity and freedom are the Wonder Twins of my life. I see both as being essential for my long-term happiness and fulfillment. These are gifts from reality, but they must be claimed and defended.
Some people would say that they need freedom in order to create. I don’t think like that. It’s too limiting, and it points back to neediness, which is something I always want to bounce away from.
I regard freedom as something I can and must create. Freedom is a choice. But freedom without creativity is unsustainable, boring, and meaningless. I feel that I’ve invested a lot in creating freedom and freeing myself to create. On the inside it feels wonderful to be in a place where I can create, share, and express so much. This includes maintaining the freedom to keep creating without interference.
I don’t just think of creativity as doing creative work like writing articles, making courses, or doing workshops. I think of creativity as being the core essence of conscious living. That includes creating freedom, creating a life I love, and co-creating experiences with the right people.
Curiosity
On the inside I’m incredibly curious. I love to learn, grow, explore, and discover. I’m always finding something interesting to delve into. I love the process of discovering what the interior perspective of an experience is like. I’m very open to new experiences, especially experiences that can upgrade my thinking and understanding of life and reality.
Even when I’m not actively writing about it, I’m often doing some kind of personal growth experiment. Or I’m studying and exploring something new. Frequently I’m exploring multiple overlapping curiosities.
I’m currently doing a new dietary experiment involving testing a different macro balance (carbs, fat, protein). My goal is to aim for a caloric distribution of 70% carbs (or more), 20% fat (or less), and 10% protein (or less). This is similar to the 80/10/10 diet I did in January 2008 but with higher fat. It’s going very well so far.
I also recently researched acoustic panels, and this week I’ve been installing them in my home office. I also have some panels to install in my studio and a few in the living room. This will help to improve the audio quality on some recordings, and it will make my studio look nicer since I can finally remove the old sound blankets. I like the look of the panels too. Rachelle helped me pick the colors, and we spent a lot of time working on this together.
Last month I invested in some plumbing upgrades, hiring a plumber to install a new tankless water heater, water softener, and whole house water filtration system. I also did a plant medicine journey with some friends.
Last year around this time, I was exploring home theater systems and invested in a major upgrade there. That was one of my favorite explorations because it totally transformed the experience of watching movies and shows with Rachelle, especially action movies. That gave me even more to appreciate.
One of my biggest challenges is that I can get too curious and open too many new doors simultaneously. I love saying yes to new experiences and explorations, but I also have to practice saying no a lot to avoid overextending myself.
Order
On the inside, my mind feels very sharp and orderly. I’m usually very adept at focusing and directing my mind to advance the projects that I want to work on.
I have many dozens of projects mapped out with action steps (I currently use the Things app for this). Realistically it may take me years to complete all the projects I’ve already identified. Week by week I keep chipping away at them.
I also maintain a quarterly completion log, whereby I document what I’ve gotten done or experienced each calendar quarter. I’ve been doing this for about 5 years consistently, and it’s really helpful for progress visibility. I can see where I moved projects across the finish line. Sometimes I may feel like I didn’t get as much done as I would have liked, but when I review those quarterly logs, I’m usually impressed with how much I actually finished.
My life is typically a mix of pre-planned work plus spontaneous action. I’ve gotten pretty good at taking action both inspirationally and methodically. I love having the flexibility to choose which tasks and projects I’ll work on each day without prescheduling them. Most days my calendar is blank. But I also keep track of many competing priorities to weave in when the timing is right.
I like keeping my physical environment neat and tidy. When clutter piles up, it’s very temporary. I feel a strong desire to keep moving towards greater order. When items and tasks are in order, it frees my mind to think more clearly, to be more creative, and to take more action. I think one reason that I embrace order is that disorder is very distracting for me.
Optimism
I don’t get depressed. Simply never. My mind stays focused on the positive – on inspiring ideas, engaging people, action steps, interesting projects, creative explorations, etc.
I used to get depressed sometimes when I was younger, but I put a stop to that.
I decided a long time ago that depression is a stupid waste of life and that it was critical to defend against the slime pit of depression, self-doubt, and other downer modes of experience. Otherwise it becomes a trap where one can lose years of precious life. I regard depression as a nasty neural pattern – a mental and emotional virus – so I did what was necessary to ensure that my mind just doesn’t go there anymore. I felt that was one of the early personal development battles where I had to win a decisive victory. So this is a virus to which I’ve built a very strong immunity.
There were lots of pieces to this – cleaning up my diet (zero animal products); regular exercise that I enjoy; dropping misaligned people; committing to meaningful and fulfilling creative work; saying no to partial matches; and creating a life rich in intimacy, warmth, and affection.
I really appreciate my past self for putting so much effort into upgrading his mindset and heartset. That was a real challenge for him, but he did a fabulous job of solving those problems one by one. He gifted me with sustainably constructive thoughts and feelings. That’s a huge gift since I no longer feel like I have to fight with myself internally. My mind and emotions feel very harmonious.
Thoughtfulness
I like to be very thoughtful and deliberate in making decisions, especially important ones. I use many tools and processes to work through decisions methodically. For instance, when designing a new course, I follow a step-by-step design template that I’ve developed over the years. It’s one of the bonuses in the Amplify course.
To really know that I can complete a project, especially a big one, I have to reach a point of strong commitment. When I was younger, I left too many creative projects unfinished because I started them impulsively, and I hadn’t put the right level of thought into them up front. Then I’d struggle partway through with thoughts like, What’s the point of finishing this? Or something else would distract me, and I’d lose focus on the previous project.
Today I’m way better at finishing projects. I look at them carefully and analyze them from different angles, often spending weeks or months in the pre-commitment phase. Some projects don’t converge on commitment, but when I’m able to commit, I’m really good at following through all the way to the end.
What this does for my inner experience is that I have super strong creative trust. I know what it takes to complete a sizable creative project. I know how to get myself to the point of commitment, and I’m able to trust myself to follow through and finish. I also know how to recognize when the alignment isn’t there yet, and I shouldn’t commit myself.
It took time to discover the right process for me such that I could make wise decisions intelligently while also avoiding analysis paralysis. Having a process that converges really helps.
Relationships
Internally I think about almost all aspects of life through the lens of relationships. This includes people, tasks, projects, goals, possessions, food, activities, locations, and more.
Instead of thinking so objectively about different aspects of life, I usually favor subjective thinking. I imagine how different decisions will affect my inner experience. I think more about the dynamic flow of events than about the static nature of situations.
You could say that I think in terms of verbs more than nouns. Where is the energy flowing? How is it changing? How do I want to engage with these energy patterns?
When I’m considering a new creative project, I pay a lot of attention to how I’m going to relate to that project while I’m working on it. I don’t just think about the end goal or result. At least 80% of my thinking is focused on what the journey will be like (probably more like 90%+). I want to make that journey beautiful and engaging.
I’ve invested a lot of thought and energy into creating a beautiful and harmonious relationship with my work and life. This includes how I relate to the people who engage with my work.
What I love about this relationship model of thinking about life is that it helped me get really honest with myself. It encourages me to be more forthright about expressing how I really think and feel. Can I share that I’d love to see Vladimir Putin slowly fed feet-first into a wood chipper, while being given frequent espresso breaks along the way? That’s actually one of my intentions.
Defending Against Misalignments
Some of my energy flows into defensive activities, which is a part of my life that many people don’t see. I have standards for the people I want to engage with, and I’m not interested in lowering them to build a larger but misaligned audience.
That’s one reason I tell Trump supporters to begone. I have no interest in serving racist idiots and assholes. That isn’t political. It’s personal. I find such people utterly loathsome, and I want nothing to do with them. I don’t want to invest my energy in dealing with people who disgust me, so I choose not to deal with them. Moreover, I will continue to staunchly defend this community against them, especially Conscious Growth Club. Such idiocy has no place here.
I have to deal with occasional stalker-types as well, including people who clearly aren’t right in the head. That doesn’t get me down. I just see as it part of the experience of working in this field.
If I wanted to be a mental health professional who regularly engages with such people, I’d have chosen that as my career path. I realized a long time ago that I must carefully defend the path that resonates with me, and that requires being very firm in saying no to people and situations that I’m not willing to deal with. We don’t automatically get what we desire. We get what we’re willing to tolerate.
When people fall out of resonance with me, I prefer to just let them go. If someone violates my trust, I drop them from my life, and I really never let them back in because when I did so in the past, they always gave me cause to regret it. “Fool me once” is enough for me. There are so many interesting people to interact with in this life that it seems foolhardy to bother dealing with misaligned scraps. I now realize just how needy and desperate that is. That said, I very easily forgive people and have no interest in holding grudges, but when I close the door on someone, it’s really closed. From my own perspective, I see this as returning their energy back to the Simulator, where it can be recycled. This keeps my energy from getting stuck where it doesn’t want to be stuck.
I’m committed to flowing my energy where it wants to go and engaging with people who want to explore and engage with me in a mutually supportive way. That takes a certain degree of alignment and compatibility. It’s exquisitely joyful and rewarding to serve people who meet that standard. And it’s disappointing at the very least to attempt this with people who don’t.
Some people and experiences are like the perfect puzzle pieces that interlock with us in just the right ways. Even when our interactions are temporary, that kind of alignment is beautiful to behold. In order to invite more of this, I found it crucial to say a hard and definitive no to the misaligned. Otherwise partial matches and mismatches will block so much beauty, wonder, and delight from flowing through.
High-Trust Relationships & Audience Engagement
Years ago I went through the experience of building up lots of followers on social media and being very active on those services daily. It can feel fun and stimulating having so much attention, especially if you enjoy being in the limelight. I also found those interactions too random and chaotic, and I was glad to delete Twitter, Facebook, and Instagram and tighten up my social focus. Seeing what’s been happening on Twitter these days makes me even more grateful to have dumped it in 2014.
After that I went through a process of focusing more on audience alignment than on audience size. That shrunk my overall audience but also made me feel happier and more in tune with my work. It helped me go much deeper into explorations that inspire me and others – less blogging but more courses, workshops, and of course CGC itself. It’s like we become more courageous, more heart-centered, and more genuine when we’re surrounded by the right people.
I’ve gotten used to having an audience for my work since that’s been my daily reality for decades, all the way back to my computer games business. The people I serve are in my mind each day, and I interact with them every day in some way – through email, the CGC forums, Zoom calls, blogging, videos, in person, etc.
To me this doesn’t feel like a temporary situation. It feels permanent, at least as far as my lifespan is concerned. There are people in my audience in their 30s now who started reading my blog when they were teenagers. I know this because many of them have told me so. I expect that even decades from now, many of the same people who are engaging with my work today will still be engaging with it or with the community around this work.
That really makes me think about how to keep serving the people in this community for the long term. I know that the specific people in this community will fluctuate, but there’s clearly a core base of people that feel a sense of commitment and resonance, so I think we’ll be in each other’s lives for a long time to come.
I love engaging with people on the basis of mutual appreciation. I like having an audience that appreciates me and the work and I do, and I love engaging with people that I appreciate too. This is something I never take for granted. It’s something I always want to keep investing in.
High-trust relationships are very important to me. Trust empowers us to explore so much more together. That’s another reason that certain people have no place in this community. We can’t build high-trust relationships with people who serve as enablers of lying and deceit.
Caring
I think one reason I’ve enduring so long in this field is that I genuinely care about the people in this community. That’s an aspect of my interior perspective that I think a lot of people don’t see. Of all the items I’m sharing here, I’d say that the #1 insight I’d love people to know is that I really do care. I want to see the people in this community thrive and enjoy rich and fulfilling lives. Just writing this part makes me teary-eyed.
I work hard at figuring out how to help people grow and how to keep serving them year after year. For me this is a lifelong investment, and I want to keep getting better at it. Sharing ideas is just one piece to the puzzle. Another piece is having a stable community where people can invest in each other (Conscious Growth Club). And yet another piece is continuing to listen for where the latest needs, desires, and growth opportunities are.
The road ahead is going to bring so many fresh challenges and opportunities. I want to help the people in this community intelligently navigate those experiences. I love the challenge of playing that role and figuring out where I can be of service.
A big part of my motivation comes from the people I serve. I don’t write just to write. I always write for people. I create courses for people. I develop workshops for people. I coach people. And it’s not for people in general but specifically for the people in this community – past, present, and future.
Internally I often feel that it’s other people’s energies and intentions that summon me to do the work I do. Somehow they energetically invite me to help them. So I never feel like I’m writing or creating into an empty void. I always feel like I’m co-creating with the energy that invited me to the dance.
I also see an important connection between caring and defense. In order to feel safe expressing caring and building high-trust relationships, I think it’s critical to defend against the opposite. I don’t trust blindly. I test for trust, and when I see it, I keep investing. But when people abuse my trust, they get the sword and shield.
Support & Cooperation
Internally I feel very creatively supported, and I have a very cooperative relationship with life. Life has given me everything I need to do my best creative work. I wanted to be of service to people, and life said a big yes to that in response.
When I was younger, I tried to do a lot of work under pressure, especially financial pressure and time pressure. There was this sense of always trying to scramble to get enough done to make ends meet. That wasn’t a situation where I could do my best creative work.
Back then my mindset and heartset were more competitive than cooperative. I put too much attention on my individual success and accomplishments, even though that just created more stress and pressure for me. I tried to motivate myself with misaligned forms of motivation. I focused too much on end results, and I leaned too heavily on courage and discipline to try to push through difficulties. I wish I had known back then how much more effective it is to focus on the journey and on cultivating a beautiful relationship with it.
Today my life feels very much the opposite of stressful. It’s fun and engaging, but it’s also peaceful and relaxing when I want it to be. Life feels very spacious, welcoming, and encouraging.
I love that I get to spend so much time exploring the richness of life, relationships, creativity, and fresh possibilities. I feel very in tune with the journey I’m on, and I delight in how it’s unfolding each day.
This isn’t an exhaustive list, but hopefully you found some value in one or more of these insights that may be useful to you in your own life or work.
Happy New Year! 🥳 🎉
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Study discovers triple immunotherapy combination as possible treatment for pancreatic cancer
Researchers at The University of Texas MD Anderson Cancer Center have discovered a novel immunotherapy combination, targeting checkpoints in both T cells and myeloid suppressor cells, that successfully reprogrammed the tumor immune microenvironment (TIME) and significantly improved anti-tumor responses in preclinical models of pancreatic cancer.
In this study, published today in Nature Cancer, researchers used comprehensive immune profiling in mouse and human pancreatic cancers to systematically identify mechanisms of immunotherapy resistance and investigate potential therapeutic targets. They found that neutralizing several distinct immunosuppressive mechanisms of the TIME dramatically improved survival rates in laboratory models, pointing to a potential treatment option for this notoriously lethal and unresponsive cancer.
“This triple combination therapy led to an unprecedented curative response in our models,” said corresponding author Ronald DePinho, M.D., professor of Cancer Biology. “The prevailing view has been that pancreatic cancer is impervious to immunotherapy, but this preclinical study shows that it can be vulnerable to the right combination therapy. Moreover, the presence of these targets in human pancreatic cancer specimens raises the exciting possibility that such therapeutic combinations could one day help our patients.”
Pancreatic cancer is one of the leading causes of cancer death in the United States, partially because 80% of cases are diagnosed at an advanced stage. Pancreatic cancer is also considered to be “non-immunogenic,” meaning it is unresponsive to commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. This is due in part to the immunosuppressive conditions in the TIME, but the mechanisms behind this resistance are not fully understood.
The researchers used high-dimensional immune profiling and single-cell RNA sequencing to study how the TIME is affected by a variety of immunotherapies. They identified specific immune checkpoint proteins, 41BB and LAG, that were highly expressed in exhausted T cells.
In testing antibodies targeting these checkpoints, the researchers observed that models treated with a 41BB agonist and LAG3 antagonist in combination had slower tumor progression, higher levels of anti-tumor immunity indicators and significantly improved survival rates compared to treatment with either antibody alone or with other checkpoint inhibitors. Notably, these preclinical studies faithfully mirrored the human data in their lack of efficacy of anti-PD1 or anti-CTLA-4 therapy.
The researchers also confirmed these two therapeutic targets are present in human pancreatic cancer samples, with 81% and 93% of patients analyzed having T cells with 41BB and LAG3 expression, respectively.
Because this dual-therapy combination did not completely eliminate established tumors, the investigators also examined efforts to reprogram the TIME to further sensitize tumors to immunotherapy. At baseline, the TIME contained an abundance of myeloid-derived suppressor cells (MDSCs) expressing CXCR2, a protein associated with recruiting immunosuppressive cells. Inhibiting CXCR2 alone decreased MDSC migration and blocked tumor growth, but it was not curative. This prompted the investigators to consider a combination targeting 41BB, LAG3 and CXCR2.
It was this triple combination that resulted in complete tumor regression and improved overall survival in 90% of preclinical models. In a more stringent lab model that develops multiple spontaneously arising tumors with higher treatment resistance, the combination achieved complete tumor regression in over 20% of cases.
“These are encouraging results, especially considering the lack of effective immunotherapy options in pancreatic cancer,” DePinho said. “By targeting multiple synergistic mechanisms that get in the way of the immune response, we can give T cells a fighting chance to attack these tumors. Of course, we still need to see how this combination translates into a safe and effective regimen in the clinic, and we invite other researchers to build upon these results. We are optimistic that pancreatic cancers, and hopefully other non-immunogenic cancers, can ultimately be rendered vulnerable to combination immunotherapy.”
The authors point out that these particular immunotherapy agents currently are undergoing clinical trials as monotherapies, suggesting potential opportunities to rapidly translate this triple combination into clinical studies.
This work was supported by the National Institutes of Health/National Cancer Institute (P01 CA117969, RO1CA240526, RO1CA236864, R01CA231349, R01CA220236, P50CA221707), the Elsa U. Pardee Foundation, MD Anderson’s Advanced Scholar Program, the Eleanor Russo Fund for Pancreatic Research, Ralph A. Loveys Family Charitable Foundation, the Cultural & Charitable Club of Somerset Run, the New Jersey Health Foundation, the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, and MD Anderson’s Pancreatic Cancer Moon Shot®.
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