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Benefits of CLARITY?

Benefits of CLARITY?


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What are the benefits of CLARITY over this technique that was published more than a year earlier?

Of course the second technique needs a fancier microscope that is likely more expensive and requires more technical ability. But CLARITY requires an objective with a very long working distance. I'm no expert in optics, but I'm pretty sure this results in a significant decrease in numerical aperture and therefore resolution.

It seems as though the other method is simply better than CLARITY, and that a lab serious about doing whole brain imaging could afford to invest in a setup similar to the one described. Yet this technique received none of hype that was bestowed on CLARITY. Am I missing something?


To start with, CLARITY is a whole-brain imaging technique , there is no need for sectioning which destroys connections and can cause the brain slices to warp as they are being cut. The costs for setting up CLARITY are much lower because all that is needed is chemicals to get the prep ready for imaging whereas in the Nat Methods paper you have to set up an automated slicing and imaging system,not an easy task by any means. Therefore an investigator is more likely to use CLARITY due to its easy of setting up and low start up costs. Also, as with any brain slice technique , you lose patterns of connectivity among neurons that are more than the slice distance apart(i.e in the next slice) and you don't look at the "whole picture". Thus due to the complexity,high start-up costs and specialized machinery STP is a poorer method than CLARITY for whole-brain imaging.As for resolution, I agree with you on principle that CLARITY has worse resolution(I looked through the paper but couldn't find exact figures) although you have to consider this in terms of all the trade-offs.


The Importance of Clarity

You have had that wonderful, indefinable moment of creation, the initial idea, and in that single moment, you have sensed your idea&rsquos utility and power. But this is not enough. Building a team, devising a strategy, planning how to monetize your innovation &mdash sure, these will come later. For now, in the immediate aftermath of the arrival of inspiration, you must hold on to that idea and express it &mdash first to yourself, and then to the world at large.


Dreams help you learn

The wise often say that if you are undecided, &ldquosleep on it.&rdquo There is truth to this adage. After a good night&rsquos sleep, you may wake up with clarity or you may even have a dream that elicits an answer.

Dreams, according to a Harvard study published in Current Biology , also improve memory . In this study, 99 people were asked to play a virtual reality maze and remember the objects in the maze. Half had a 90-minute nap right after and half (the control group) did not.

Those who napped recalled more than the non-napping group, while those who dreamed of the maze, recalled the items ten times better. According to the researchers, dreaming reorganizes and consolidates memory.


Why CLARITY for Tissue Clearing?

CLARITY Tissue Clearing Process

CLARITY was born from the need to overcome the opacity of lipids in brain tissue, which caused light to scatter during microscopic visualization of neurons, thereby obscuring image quality. CLARITY allows a tissue sample to be rendered optically clear, retain its three-dimensional integrity and allows for tissue staining and re-interrogation multiple times. Though originally conceived to make brains transparent to light, CLARITY tissue clearing methods have now been used on multiple human, mouse and rat tumors, organs, bone and most other intact biological tissues, in addition to the brain.

CLARITY Tissue Clearing Genesis

Creating See-through Tissues

CLARITY Tissue Clearing Overview

In the CLARITY method, a tissue sample is first embedded in a hydrogel. This hydrogel provides a three-dimensional matrix that supports the tissue sample and retains the structural integrity and spatial orientation of the critical tissue components. The non-critical elements such as lipids are removed using detergent solutions. Light can then penetrate the tissue sample rendering it “see-through” or transparent.

Specific steps in the ClearLight CLARITY Tissue Clearing Process

Hydrogel Matrix

The first step in the tissue processing workflow is to place the fixed mouse, rat, or human tissue sample in a solution of hydrogel monomers and cross-linkers. For detailed explanations refer to Hydrogel-Tissue Chemistry.

Biomolecule Functionalization

The monomers and cross-linkers diffuse into the tissue’s cells and bind to biomolecules such as proteins and nucleic acids but not to light-scattering lipids.

Polymerization

The hydrogel is thermally treated and the monomers polymerize into stable mesh that locks proteins and biomolecules in place.

Lipid Clearing

A detergent is used to remove lipids and other unbound molecules from the tissue. The proteins, nucleic acids and other bound biomolecules remain embedded with the hydrogel mesh.

Immunostaining

If desired, antibody-based immunostaining or labeling for many nucleic acids (RNA/DNA) can be used in a multiplex panel to highlight specific structures in the tissue cleared sample. Learn more about immunohistochemistry (3D IHC).

Image Analysis

The tissue processing workflow moves from molecular labeling to imaging. The stained tissue is placed in a refractive index-matching mounting solution for imaging with a confocal or light sheet microscope or another imaging platform.

CLARITY Advantages

Benefits of using CLARITY in Tissue Processing Workflow

  • Compatible with previously frozen, fresh, formalin-fixed, and FFPE embedded tissue
  • Compatible with traditional pathology workflow methods
  • Non-destructive, fewer samples, allowing recapitulation of spatial heterogeneity without laborious sectioning and registering
  • No dehydration/rehydration steps involved as with FFPE samples, or other tissue clearing technologies
  • Compatible with standard nucleic acid and antibody interrogation techniques
  • Allows multiple interrogations of a single sample to increase 3D biomarker information
  • Samples can be stored for future biomarker analysis
  • Imaging compatibilities include: Confocal, Light Sheet, SPIM

Passive CLARITY vs Active CLARITY (CRYSTAL)

One of the disadvantages of the CLARITY method is the time it can take to fully clear a sample. To deal with this issue researchers have invented active CLARITY methods, most notably the CRYSTAL protocol that dramatically reduces the overall timeframes involved.

With CRYSTAL, detergent streams are directed at the tissue. These streams act like a pressure washer for the tissue sample, actively targeting particular areas instead of waiting for the passive diffusion.

To visualize this effect we can compare it to a situation we can all relate to. Imagine you are washing a dirty pan that has food stuck on the bottom. There are two basic approaches to cleaning the pan. You can let the pan soak for hours until the hardened food debris softens, or you can vigorously scrub and get the pan cleaned faster by putting in physical effort. Letting the pan soak is similar to passive CLARITY, while actively scrubbing the pan clean is like using CRYSTAL along with CLARITY.

While CRYSTAL technology is relatively new, we have a system currently in development that will help automate this process, and help make CLARITY practical for clinical settings, as well as research labs.

Services

Do you currently support tissue clearing for clinical applications?

We currently perform non-destructive tissue processing and future digital spatial image analysis in 3D to facilitate pre-clinical and clinical research studies. CLARITY combined with CRYSTAL will enable ClearLight to fully automate the process, to achieve competitive turnaround times associated with 2D thin section IHC methods.

I don’t see that you support the type of tissue I want cleared, stained, and assessed using your analysis software. What are the limitations on tissue types?

See Sample Requirements on the Services page. We may support situations not shown. Start a conversation with us using the Contact Us form, email, call (800) 251-8905 or chat with us online.

Does ClearLight sell reagents?

ClearLight provides CLARITY Tissue Clearing Kits to researchers who wish to perform lipid clearing of soft tissues on their own using the CLARITY method. Visit the online store to learn more about these products. Researchers can also engage lab services for CLARITY Tissue Clearing, 3D Immunohistochemistry and Tru3D Tissue Analysis. Visit Services to learn more.

Technology

What is the relationship between CRYSTAL and CLARITY?

Active or passive CLARITY tissue clearing is a very powerful and useful method, but lipid clearing and staining times take longer time than optimal for use in future clinical and diagnostic settings. CRYSTAL technology is a significant improvement to both the active and passive CLARITY tissue clearing methods by aiming detergent streams at specific areas of the tissue sample to be cleared. This can speed up the clearing process significantly, increasing the diagnostic relevance and usefulness of this technology in a clinical setting.

Did ClearLight invent the CLARITY method of tissue clearing?

No, the CLARITY method was originally developed at the Karl Deisseroth Lab at Stanford University Medical Center. Dr. Deisseroth is a founder and scientific advisor to ClearLight Biotechnologies. However, ClearLight is automating the method so that it can be utilized by researchers and eventually clinicians across the world.

Three-dimensional Imaging and Quantitative Analysis in CLARITY Processed Breast Cancer Tissues

Three-dimensional intact-tissue sequencing of single-cell transcriptional states

Why ClearLight for CLARITY?

ClearLight Scientists are Experts at CLARITY

Although CLARITY protocols have been published for several years, CLARITY tissue clearing can be difficult to get right. Many scientists and researchers who could benefit from using CLARITY do not have the experience or the time to master using these methods in the lab.

Instruments to automate the CLARITY tissue clearing process have fallen short of expectations. First, the cost of the machines is prohibitive, especially for researchers working off of grants. Second, many of these automated systems, in a working lab environment, fail to perform as designed. The quality of the clearing and staining work fails to deliver the full potential the CLARITY method has to offer.

In addition to the robust science behind CLARITY, there is an art to getting the best results using CLARITY tissue clearing. Our scientific team are experts in using CLARITY.

CLARITY started with our founder, Karl Deisseroth. CLARITY tissue clearing is foundational to ClearLight Biotechnologies. This is unlike other companies which sell reagents, tissue clearing kits, automated clearing instruments, etc.

ClearLight Biotechnologies is a contract research partner who can provide expert CLARITY tissue clearing, immunohistochemistry, and 3D imaging so researchers and scientists can see more biology.

ClearLight Biotechnologies has an exclusive, worldwide license agreement with Stanford University for development and commercialization of CLARITY for diagnostic and clinical applications.

CLARITY for Diagnostic and Clinical Applications

Imagine being able to peer inside the tumor microenvironment. Imaging fueling the power of your pre-clinical research. Imagine how this can empower better clinical diagnosis, prognosis, and predictive applications in the future. Imagine such capable instruments being deployed in every research and pathology laboratory around the world. Imagine immuno-oncology empowered with Tru3D imaging and tissue analysis and. This is the future we are working to make possible. We invite you to collaborate with us.


Mind & Body Articles & More

Daniela Kaufer is an associate professor at UC Berkeley who studies the biology of stress, examining at the molecular level how the brain responds to anxiety and traumatic events. Her recent findings reveal the difference between good stress and bad stress, as well as pointers for how to respond to stressful events in a healthy way. She was interviewed by health writer Peter Jaret for the Berkeley Wellness newsletter, where this Q&A originally appeared.

Peter Jaret: Most of us think of stress as a bad thing. Can stress be good for you?

Daniela Kaufer in the lab. © Peg Skorpinski, UC Berkeley

Daniela Kaufer: The prevailing idea in our culture is that stress is bad. People complain about being stressed out. But we’re learning that moderate amounts of stress have powerful benefits. The stress response is designed to help us react when something potentially threatening happens, to help us deal with it and learn from it. Our research shows that moderate, short-lived stress can improve alertness and performance and boost memory.

PJ: How do you measure the effects of stress?

DK: In our work, we study the effects of stress on rats, and we look specifically at the growth of stem cells in a part of the brain called the hippocampus. The hippocampus is involved in the stress response, and it’s also very important for learning and memory. We’ve found that when rats are exposed to moderate stress for a short time—being immobilized for a few hours, for instance—stem cell growth is stimulated, and those cells go on to form neurons, or brain cells. A couple of weeks later, tests show improvements in learning and memory. We’ve shown that the specific cells generated during stress have become activated. But when the animals are exposed to chronic or intense stress—being immobilized for days at a time, for example, or being immobilized and then exposed to the smell of a predator—stem cell growth is suppressed and fewer brain cells are generated.

PJ: What about people? Can manageable amounts of stress boost brain power?

DK: We think the same thing happens in people. Manageable stress increases alertness and performance. And by encouraging the growth of stem cells that become brain cells, stress improves memory. The increase in stem cells and neuron generation makes sense from an adaptive point of view. If an animal encounters a predator and manages to escape, it’s important to remember where and when that encounter happened, to avoid it in the future. If you’re walking down an alley and somebody threatens you, it’s important to remember exactly where you were in order to avoid that alley in the future. The brain is constantly responding to stress. Extreme or chronic stress can have a negative effect. But moderate and short-lived stress—like an upcoming exam or preparing to deliver a speech in public—improves cognitive performance and memory.

PJ: When does too much stress become harmful?

DK: Individuals vary widely in how they respond to stress. The same stressor may be manageable for one person and overwhelming for another, depending in part on perception. People who feel resilient and confident that they can manage stress are much less likely to be overwhelmed by it—and more likely to have a healthy response—than people who think of stress as bad. Another factor is control. Stress is much less likely to be harmful if people have some control over the situation. A tight deadline is stressful but manageable if you have the ability to meet it. If not, if you feel helpless, the stress is more likely to be harmful. Early life experiences also shape how people respond to stress. If you have a lot of stress in your early life, you may be more vulnerable to the harmful effects of stress. Research by Rachel Yehuda, a scientist at the Icahn School of Medicine at Mount Sinai and the James J. Peters Veterans Affairs Medical Center in New York, has shown that Holocaust survivors have increased levels of stress hormones. Her most recent research shows that even offspring of Holocaust survivors have higher stress hormone levels.

PJ: Your work focuses on the effects of stress on the brain. Does stress affect other systems of the body?

DK: Chronic stress can constrict blood vessels and increase the risk of cardiovascular disease. Research shows that too much stress can suppress the immune system. Ours and other research has shown that chronic stress also reduces fertility in animals. In female mice, for instance, stress lowers libido, reduces fertility, and increases the risk of miscarriage. We also know that extreme stress can lead to post traumatic stress disorder, which is an area I’m very interested in. As I’ve said, it’s important to remember threats. But it’s also important to be able to forget them as new experiences come along. Let’s say a man with a long white beard frightens you as a child. It’s healthy to begin to forget that memory as you come to see that men with long white beards aren’t inherently dangerous. The problem with post traumatic stress disorder is that people can’t forget. They can’t let traumatic memories go. The question is why. And we don’t have an answer yet.

More on Stress

Robert Sapolsky explores the psychology of stress.

Jeremy Adam Smith explains the relationship between stress and empathy.

PJ: Can you offer any helpful strategies to ensure that stress is beneficial rather than harmful?

DK: If you tend to have a positive attitude—a self-confident sense that you can get through a rough period—you’re more likely to have a healthy response than if you perceive stress as catastrophic. Another powerful factor is social support. If you have friends and family you can turn to during a stressful period, you’re more likely to handle the stress well. Social support buffers stress. That’s something most of us know intuitively. Now we’re beginning to understand it biologically. Researchers have identified a hormone called oxytocin that reduces the stress response. According to psychologist Kelly McGonigal, oxytocin is enhanced by social contact and support.

Another powerful buffer for stress is physical exercise. We see the evidence in animal studies. Rodents that are allowed to run are more likely to create new brain cells in response to stress than sedentary animals. I think the same thing may work for people. People who are active respond better when stress comes along than people who are inactive. Physical activity after a stressful experience also helps moderate the effects of stress.

PJ: What do you do when your own life gets stressful?

DK: I’m not the best role model. I’ll find myself writing grant proposals at one in the morning, totally stressed out. I know what I should do. Before I became a scientist, I trained as a yoga instructor. I know I should take a yoga break. But I guess it helps to know from my research that stress can be beneficial, so at least I have a positive attitude. And that plays a big role in helping people handle stress in a healthy way.

Greater Good wants to know: Do you think this article will influence your opinions or behavior?
About the Author

Peter Jaret

Peter Jaret is the author of several health-related books, including In Self-Defense: The Human Immune System, Nurse: A World of Care, and Impact: On the Frontlines of Public Health. A frequent contributor to National Geographic, The New York Times, Reader’s Digest, Health magazine, More, AARP Bulletin, and dozens of other periodicals, Jaret is the recipient of an American Medical Association award for journalism and two James Beard awards. He lives in Petaluma, California.


OPEN RESEARCH QUESTIONS

While many principles of model-based teaching and learning have been identified, research on model-based instruction in the college biology classroom is a growing field that still holds much room for progress and discovery. Important areas that require more research include best practices of instructional design and classroom implementation, as well as model-based learning of concepts and acquisition of science process skills.

Classroom Implementation and Instructional Design

Multiple kinds of models (Example Models section of the Modeling in the Classroom guide) are relevant in biology, including qualitative conceptual models of processes and pathways, quantitative models and simulations, three-dimensional models of molecular or anatomical structures, phylogenies representing hypotheses about evolutionary relationships, and more. Further research is necessary to build upon what is currently known from research on learning progressions (Schwarz et al., 2009) to identify which types of models and modeling skills should be included at different stages of undergraduate biology education. Research should also help educators define learning goals, design instruction and assessment, and optimize approaches for providing feedback to learners. Student-generated models, used as a type of assessment, can provide information about students’ conceptual understanding of a topic, but also about achievement of modeling skills and abilities—a core Vision and Change competency of undergraduate biology education.

What kinds of models should undergraduate biology students be able to create, interpret, and use at different stages in the curriculum?

What should the goals of model-based instruction be? Should modeling be used to help students develop deep conceptual understanding of biology, to teach specific modeling skills, or perhaps a combination of both?

How should instructors introduce and scaffold classroom activities to promote students’ fluency with models and modeling? Should instruction about different types of models (e.g., simulations, phylogenetic trees, conceptual models) be scaffolded in different ways?

When (e.g., for what kinds of models and what core concepts of biology) is it appropriate for students to build models, as opposed to using provided models?

How can modeling be effectively and efficiently integrated into assessment approaches?

How can we structure feedback on modeling such that it is meaningful and actionable for students?

Development of Knowledge and Skills

Under what conditions could model-based learning foster students’ development of science process skills (making hypotheses and predictions, articulating causal explanations, etc.)?

How can we teach students to evaluate models and to identify model limitations and constraints?

How can the integration of modeling in a biology curriculum support not only content understanding, but also development of systems thinking skills? How do we measure competence in systems thinking?


8 Science-Backed Ways Mindfulness Helps us Heal and Thrive

  1. Burnout: A review of 23 studies looking at the effects of Mindfulness-Based Stress Reduction (MBSR) on employee burnout found that 8 weeks of mindfulness training reduced stress, psychological distress, depression, anxiety, emotional exhaustion and occupational stress, and increased self-compassion, relaxation, sleep quality, and a feeling of personal accomplishment.
  2. Addiction: Mindfulness-based interventions may be helpful in decreasing craving and substance misuse according a review of several meta-analyses of 34 randomized controlled trials. Researchers suggest that mindfulness may be particularly effective in increasing a person’s awareness of stress, despair, anger, loneliness, and the cravings that can often trigger a relapse.
  3. Suicide: An examination of a handful of available studies on the impacts of mindfulness-based interventions on suicidal behavior found that mindfulness instruction may be particularly useful for helping individuals cope with stress and difficulties with problem-solving. It can also improve focused attention, and decrease suicidal thoughts all known risk factors for suicide attempts.
  4. Bias/harassment: A study of 72 college students revealed that mindfulness training can increase awareness of one’s underlying thoughts, and subsequently reduce negative attitudes and biases. In another study, students reported on their levels of mindfulness, self-esteem, and fear of being rejected in social situations. Those with low self-esteem were more afraid of rejection, however being more mindful decreased those effects.
  5. Team dynamics: A study of 311 employees working at three Chinese companies looked at how individual and team mindfulness affected work engagement. Both individual and team mindfulness were linked to better employee recovery from work-related stress, and higher engagement with work tasks. What’s more, being immersed in work also positively impacted employee performance.
  6. Worker and personal productivity : A review of 23 studies examining the benefits of mindfulness-based programs in the workplace found that following training, employees felt less stress, anxiety and psychological distress, and experienced greater overall well-being and sleep quality. Links between mindfulness training and other dimensions of work life, such as employee performance, leadership skill, and good decision-making were inconclusive.
  7. Focus/attention: Scientists at Ohio State University reviewed 56 studies of the long-term effects of mindfulness instruction on attentional control. Training approaches ranged from retreats and feasibility studies, to randomized controlled trials. Retreat and feasibility studies showed increased goal-directed focus and attention to bodily sensations following a mindfulness program. Results from randomized controlled trials with an active control group where participants received another form of instruction, were indecisive. (Not sure if this is satisfying in such a short form, but don’t want to give the impressions that RCTs align with the other findings).
  8. Creativity/innovation: Mindfulness and creativity are significantly related according to researchers who reanalyzed 33 published articles with 1,549 participants. They concluded that mindfulness-based interventions focusing on open-monitoring may boost creative abilities. Exactly why and how mindfulness contributes to the creative process remains a mystery.


Arrows in Biology: Lack of Clarity and Consistency Points to Confusion for Learners

In this article, we begin to unpack the phenomenon of representational competence by exploring how arrow symbols are used in introductory biology textbook figures. Out of 1214 figures in an introductory biology textbook, 632 (52%) of them contained arrows that were used to represent many different concepts or processes. Analysis of these figures revealed little correlation between arrow style and meaning. A more focused study of 86 figures containing 230 arrows from a second textbook showed the same pattern of inconsistency. Interviews with undergraduates confirmed that arrows in selected textbook figures were confusing and did not readily convey the information intended by the authors. We also present findings from an online survey in which subjects were asked to infer meaning of different styles of arrows in the absence of context. Few arrow styles had intrinsic meaning to participants, and illustrators did not always use those arrows for the meanings expected by students. Thus, certain styles of arrows triggered confusion and/or incorrect conceptual ideas. We argue that 1) illustrators need to be more clear and consistent when using arrow symbols, 2) instructors need to be cognizant of the level of clarity of representations used during instruction, and 3) instructors should help students learn how to interpret representations containing arrows.


Who Makes LipoFlavonoid?

The company is called Clairon Brands LLC, located at 27070 Miles Road Suite A Solon, Ohio, 44319. The contact phone number is : (844) 454-7632. This address (minus the “suite A”) is the same for other products including Absorbine Jr and something called “Anti-Monkey Butt Powder.”

Another company name is DSE Health Solutions located at 164 Northfield Drive, Edison NJ 08837. This address corresponds to Garden State Fulfillment as well as another supplement company called Numark Laboratories also called Numark Brands.

What Does This Mean? Numark Brands is the company behind LipoFlavonoid. Garden State Fulfillment is probably where the supplement is shipped from.


Benefits of CLARITY? - Biology

The Partnership Dilemma and the Moment of Clarity We see it all the time: A graduate of Yale or Stanford Law or wherever joins a highly regarded international law firm in New York City or Los Angeles. The lures are spectacular: Name brand clients known worldwide Powerful senior partners, a few of which may even be media figures back-up support staff to dream for -proofreaders, legal assistants, schedulers plus fellow lawyers equally brilliant and success-driven. For all-work-and-no-play achievers, such an achievement is like landing in Heaven. All that hard work has paid off.

  1. Am I cutting it? And just what is required to 'cut it.?' Am I up to this and can I keep it up for 30 years?
  2. Do some partners prefer working with certain associates? If so, what are these associates doing that I'm not?
  3. Which types of practice and which partners seem to hold the most power?
  4. Which partner might become my mentor? Will any partner ever take on this role with me? How do I get the process rolling?
  5. Which associates seem to be making the most headway?
  6. And if certain associates do seem to be making more headway, why is this happening? What are they doing that I'm not doing? Or, what am I doing wrong?
  7. How can I stand out from the other associates without causing some sort of backlash from them?
  8. Finally, how long will it take me to make partner? What are my chances? Who is likely to be my primary competition?

The Moment of Clarity
The attorney has begun to realize that the senior partners he or she works with every day are not gods, and that most of the work is routine and does not require a brilliant, break-through intellectual analysis. In short, the romance is gone. What is left is a future stretching into decades filled with 'more of the same.' The attorney realizes that he or she is just as competent as everyone else but has flaws. Perhaps these flaws have to do with social-interaction skills. Perhaps there is a lack of connection with certain partners that may prove to be harmful. Perhaps the attorney finds it impossible to bring in new business. Perhaps there is a relationship with another associate that causes daily, gnawing resentment. What the Moment of Clarity amounts to is a combination of summing up one's experience in the firm and a simultaneous dropping away of the veils of expectation, idealization, hope and promise. One's life and one's position in the firm is seen simply and starkly for what it is.

The Search for Legal Nirvana
What rests behind this Moment of Clarity is the contrast between what one's life has become and what an individual seeks, which is complete control over one's life. Such freedom, if there is indeed such a state, is instinctively sought, and this complete freedom is envisioned by most associates as earning a partnership in a big firm. Getting a partnership offer is the problem. There are no rules to follow, no G.P.A. to be achieved, not LSAT to pass. Instead, political skills, sheer determination and billable hours come into play. It may seem unfair that having run the gauntlet of high school grades, SAT, college grades, LSAT, law school G.P.A., law review, federal clerkship, and acceptance by a name-brand firm, the battle begins with new rules not cast in stone. These rules, as undefined as they are, seem to call upon one's ability to form bonds and deflect criticism. They seem to involve outworking everyone else. They seem to involve who can parlay enough family and other contacts into billable clients. And what does any of this have to do with being a good lawyer.

The problem with the associate's search for ways to make partner is that just running up the most billable hours is not enough. On the other hand, bringing in several million dollars of business and being able to keep at least nominal control of it would certainly guarantee a partnership -or, as a Plan B, the ability to move elsewhere with clients in tow. If one can achieve this, the associate's personality conflicts inside the firm, if any, become less important.

But What If A Lawyer Doesn't Want To Be A Rainmaker?
What then? Can one still make partner without bringing in clients? Yes. There are other ways. One can become an unrivaled expert in some narrow but revenue-producing corner of the law. Clients with specific types of problems will be drawn to the firm because it has a reputation for solving them. The associate with expertise in this field will get the bulk of this new work or have an important say in how this work is conducted. One can bill more hours than his or her competition (other associates in the same class). One can get visibility outside the firm by serving on commissions and boards. One can marry the managing partner's daughter or son. One can watch as other associates jump ship and hope that he or she will be the last one standing at the end of eight or so years.

Conclusion
Okay, so you've got big-time angst. You don't know what to do. Here's a solution. Let the situation play out. The worst that can happen is that you must leave big-firm life and try for happiness at a medium-sized firm. You might not make partner or find happiness there either, but you are more likely to keep your job and develop a life outside the firm. In such a scenario, the trajectory of your life is dictated for you by outside forces. Not a pleasant thought. On the other hand, everyone's life is dictated by outside forces, even those who stayed behind at your prior firm and made partner. For instance, they will die at a moment not likely to be of their own choosing. In the meanwhile there will be deaths in the family, divorces, possible disappointments with children and other unpleasantness. The key is to be content with a combination of what you have achieved and what is forced upon you. Partnerships are not at the center of such considerations. You only think they are if you allow the culture of the law firm to dominate your thinking. It is in the Moment of Clarity that you can gain a new perspective. Happiness won't likely be the result, but a sense of calm and acceptance will make the rest of your life that much better.