50 Lessons After 50:

The only consistent difference that I can identify between humans and other so-called intellectually evolved species, is that humans can dream collectively.  I say only, but that singular ability to dream collectively and work cooperatively to realize a dream has reshaped our planet, is reshaping our solar system as we speak, and may someday mean we can reshape our galaxy.  The building you are in, the chair you are sitting on, the screen you are looking at are all someone’s dream that has been realized.  And the process leading to the realization of a collective dream is extremely consistent.

Collective dreams begin as dreams of individuals who see the world as it is and think the world should be better and that they know how to make it better.  Of course, a dream alone is just a dream and, in the end, has no more value than the value the individual places on that dream.  What separates a collective dream from just another dream is that the individual that dreams it has a plan that plausibly might be successful at realizing the dream, and, he or she, is sufficiently galvanic to enlist other in sharing the dream.  I once thought that if I had a dream that I wanted to collectivize, I would need a fool-proof plan to convince people to join me in the endeavor.  I was wrong. I have learned from the people who have followed me that most of them thought my dream would fail but felt that the dream was plausible enough to give it a try.  To a person, the people who have been with me for decades tell me that their plan was to hang out for five years or so.

I have always been a big dreamer and have never understood why someone would bother with a little dream, and I have learned that big dreams sell, and they provide the space for others to feel that they have contributed and realized dreams of their own under the penumbra of a big dream. In fact, when I founded Ionis Pharmaceuticals, I embarked on the biggest dream possible in our industry, which was the creation, advancement and validation of a new platform for drug discovery.  We began with $5.2 million and over the next thirty years were able to raise somewhere around $10 billion to realize the dream and to see that dream continue to advance and grow in value.

But big dreams require big plans. They demand the willingness to admit failure and if you hit a wall that you cannot work around or climb over.  They also demand preserving over many disappointments, many outright failures and all sorts of mistakes made by leaders tying to realize that dream. Above all then realization takes stamina and commitment.  It also takes the ability to take failures, acknowledge them and refresh the dream and plan to convince those who dream with you to stay the course.

I suppose the question one could ask is ‘Is it worth it?”.  I can only speak for myself.  I can’t imagine my life any better than it has been because I took the risk to pursue a big collective dream.  I have also learned that anything worth saying has been said better by a poet.  And what I have learned has been said poetically by one of our modern poets, Bruce Springsteen.  It’s actually a title of one of his songs: Dream Baby Dream.

Arguably, the second greatest fear of modern humans is looking stupid, and many equate failure with looking stupid. Based on my experience, high achievers dislike looking stupid and certainly fear and loathe failure, but they know that it is inevitable. They know they will, on occasion, look stupid and actually do something or say something stupid but they soldier on and accept the risk of being embarrassed. They also know that the only way to avoid failing is to do only what is easy.

I think that the desire to do meaningful work is particularly true for people who gravitate toward medical science and business. Certainly, I have wanted to do meaningful work and the first line in culture statements I have created is “sick people depend on us”. I have found that a mission like “sick people depend on us” attracts and retains committed people who care about the work they do. That, in turn, supports demanding more from each individual and the organization in toto.

A mission-centered organization in which everyone is made to feel that they are contributing to the mission is an organization that has the potential to create a uniquely productive culture that is a true strategic asset.

To my mind, there are two ways to go through life: Demand that people earn your trust or trust people until they prove themselves untrustworthy. There is no doubt that the former approach is safer because there are untrustworthy people, but I find such an approach far too limiting and have chosen to assume that those whom I meet are trustworthy and say what they mean. Of course, I have experienced some real disappointments and even behaviors that I felt were betrayals. Nevertheless, for me the gains in simplicity of life and freedom to be myself have far outweighed the losses that the occasional untrustworthy person has caused.

From an organizational perspective, I think the argument for the assumption of trustworthiness is even more compelling. I believe that if we hire someone, we must believe that person is trustworthy. To treat employees as if they might be untrustworthy is costly because of all the controls and systems that must be installed and operated. More importantly, it means that the leadership of the organization cannot be fully transparent, and it creates secrets and the appearance of secrets that play into distrust and various, often inane conspiracy theories. I have also found that when employees are trusted, they become more trustworthy. Obviously, every organization must have some controls and processes to assure protection of the assets of the organization and compliance with laws and regulations, but they can be minimized by effective auditing of activities and behaviors and absolute intolerance of untrustworthy behavior that results in dismissal every time such behavior is discovered.

Interesting studies on fairness have shown the ontology of the two forms of fairness differ quite significantly. The recognition that an event or behavior is unfair to me is universal and is well developed at an early age. This sense of fairness seems unaffected by social mores or the type of environment in which children mature. In contrast, the recognition that an event or behavior is unfair to others develops much later and is influenced by the social mores and the environment in which children mature. Arguably, the most egregious example of this is slavery. Most children who had grown up as masters in an area in which slavery was the norm, developed a less robust and flawed ability to recognize unfairness to others. Sociopaths never develop this form of fairness or they simply don’t care.

In organizations I have led, I emphasized that the indivisible unit of value is the individual and that leaders and managers had no right to be deliberately unfair to an individual no matter how important the justification and that I believe deeply. It is also a slippery slope. If you can justify being unfair to an individual in one instance, it is likely that you will do it again. More importantly, the people you lead will see your behavior and the required trust will be lost. I believe that to be consistently fair, one must err on the side of generosity to all, but to be deliberately generous to one individual is, by definition, unfair to others in the organization.

What is a truly valuable asset for an individual in an organization or life? Respect; respect is earned by behavior that is equitable and effective. Trust; even if trust is given freely, it must be earned every day with behaviors that are fair and effective. The benefit of the doubt; especially in driven, highly productive organizations, the benefit of doubt is critical because it assures that people talk to each other before becoming angry at a behavior that may not seem proper. The benefit of the doubt is earned daily and is enhanced by friendships. Admiration; a leader who is admired can ask a great deal more of individuals and organizations than the average leader. Once again, this precious asset must be earned every day and can be lost because of a single misadventure. Love; anyone who has ever loved or been loved knows that love is fragile and can be lost in the blink of an eye. It must be earned anew every day.

As obvious as it is to say that everyone is fallible, many leaders and managers I have known over the years seemed to think that their subordinates expected them to be always right, and perfect. Most humans are much too smart to expect perfection from their supervisors. What they want to see out of their supervisors is a solid effort to deliver value, a strong effort to be fair, and a willingness to admit when they are wrong, made a mistake or misbehaved. It is amazing what simply saying you are sorry and will try to do better next time does.

When there is a significant failure, the organization needs its leaders to be at their best and the people in the organization need to know that they are getting the truth. The first step is to get the entire team or organization together and acknowledge the failure, discuss the implications for the organization and your plans to weather the difficulties. I have had to deal with many disappointments and failures in my career, as is common in the drug discovery and development industry, and some were organizationally existential.  Though the truth was often painful to tell, and the company hung in the balance more frequently than I care to think about, I told the truth and laid out a plan to move forward including the risks and the odds of success. I felt that I had asked people to invest in my dreams and always owed them the truth. Because I did that consistently through good days and bad, I earned trust and commitment and never lost a single person I needed to keep if we were to be successful.

Though we all learn from experience, to learn maximally from experience, I believe that one must take a systematic approach and I have throughout my adult life and institutionalized the process I use in the organizations I have led. After every significant event, I got the leadership team together and asked what just happened? What class event was it? There are limited classes of events in any business or organized activity and if one doesn’t classify events, one cannot extrapolate what is learned. I then ask what did I (we) do that made the outcome more favorable and what mistakes were made. Once again, it is essential to classify both successful actions and mistakes to extrapolate the learnings in a way that can be used to do a better job with the next similar event. I also imposed these rules. First, the fact that many of the factors were outside our control was irrelevant. We made the judgement that we should take the course that led to the event, so we are accountable. Second, the sole focus had to be internal: what did we do right; what did we do that didn’t work? It is very easy to blame factors outside your control or others for failures, but focusing on those items assures that you don’t learn from what you did right or wrong.

If you force yourself to classify mistakes you make, you will learn that there are only a few classes of mistakes and that you make the same type of mistakes repeatedly. My mistakes can all be classified as mistakes caused by intolerance, intemperance, impatience or being too optimistic. Because I know this about myself, I have gotten better over the years in reducing the number and impact of the mistakes I am prone to make and tried to surround myself with more cautious, more temperate individuals. Knowing the type of mistakes you make is important because that knowledge can be used as you build the team around you. You can construct a team with different strengths and weaknesses who complement your strengths and balance your proclivities with regard to the type of mistake you make. It is equally important to understand the classes of mistakes your team members are prone to make. 

Culture is a word that is widely used, but difficult to define. Operationally, I think of a culture as a surface like space-time. The analogy of space-time is apt because a culture is a surface created by behaviors over time in the organizational space.  A culture cannot invent behavior, but it can reinforce and disincent behaviors A strong culture is consistent and felt by all as it is the surface on which the individuals stand, and tasks are performed A string culture also selects individuals who are comfortable with the norms established by the culture, and it rejects those who are not in step with the values incorporated into the culture. 

The simplest way to think about a strong culture is that it is highly ordered. To be highly ordered, a culture must be clearly designed to support the key activities and behaviors thought to be necessary for success. It also must be coherent i.e. all HR and administrative approaches must be consistent with and reinforce the desired behaviors. Basic physics teaches that the natural state or lowest energy state of the universe is maximum disorder and to create and maintain an ordered system, energy must be expended. In an organization, energy tends to come from energetic, enthusiastic positive members of the team. Such people are of extraordinary value and a strong leader knows who they are and uses them to energize the organization. During challenging times, leaders must invest more energy into the organization, and it must be consistent with the desired culture. 

Although a good many leadership and management principles and practices apply broadly, the critical functions of an organization, that is those activities and functions that must be outstanding and productive for an organization to succeed, vary and require more customized approaches. For example, in a manufacturing organization, being the lowest cost producer is critical and management must focus on limiting costs across the board, from the nature of the facilities used, compensation practices, plant downtime, sales practices and so on. Additionally, safety, reproducibility and consistency are critical.  In contrast, in an organization that depends on innovation, cost per discovery matter, but far less than the number and quality of innovations.

Workforces also differ significantly depending on the key functions of an organization and those differences demand different approaches. Many of the modern approaches to management began during the industrial revolution and were geared to maximizing the productivity of assembly lines. Though those approaches have evolved to better motivate workers by enriching their daily activities, a manufacturing workforce differs dramatically from an organization committed to innovation. At the opposite end of the spectrum from manufacturing is the type of workforce involved in new drug discovery R&D. In such a workforce, essentially all employees are college graduates, and a remarkable proportion are people who have invested in earning PhDs, MDs and MD PhD degrees. They differ in knowledge, motivation and approach to work and life from a person who works on an assembly line and the leadership and management approaches that are successful respond to the unique nature of that workforce.

Most organizations have a well-defined hierarchy, but, from my perspective, the most significant value of a hierarchy is that it provides a means to make complex, difficult decisions crisply and assure that the actions that derive from the decision made are implemented effectively. Of course, another major benefit of a hierarchy is to assure that activities are choreographed to assure that steps are integrated effectively to drive progress toward defined goals, the third major benefit of a hierarchical organization. One of the most critical products of senior leadership is the choice of specific goals assigned to the organization.

Senior leaders are paid primarily for judgement. Judgement is the willingness and ability to make critical decisions with far less than needed information and be correct more often than not. Judgement is a product of courage, intellect, and what has been learned from prior experiences. 

Great organizations strive to make the BEST decisions and facilitate that by being certain that the person who must make the decision is fully informed. I believe strongly that committees ADVISE and leaders DECIDE. The relegation of decisions to a committee diffuses responsibility and may not take full advantage of the judgement of the senior leader. That an individual is accountable for the decision does not mean the decision is made in isolation or the process is autocratic. In strong organizations, leaders benefit from vigorous issue- centered, data driven discussions. In fact, for particularly complex and challenging decisions, I have often asked the most informed people to engage in a formal debate with one taking a “pro” stance while the other argues the “con”.

A consensus decision making process is a regression to the means in which the decision that makes the least number of people uncomfortable is inevitable. This, of course, leads to very cautious net actions which I believe is rarely a winning or even competitive outcome. In my organizations, I do not allow a leader to say, “the team “thinks”. I ask the leader to describe the various positions the team has considered, then the decision he/she recommends and why. I often ask the dissenting members of the team to discuss their position and the reasons for their position. This process often makes people uncomfortable, and some people simply cannot tolerate the exposure. Over time those people leave organizations I lead.

Management by objectives (MBO) is an approach that is widely used, but like all general HR practices, the value of an MBO approach is dependent on the integrity of leadership in the implementation of the system. There are also a number of variants that are vogue. Done well, an MBO system is a great tool that defines the key challenges and opportunities for an organization, aligns individuals and teams toward a common endpoint and an effective method of evaluation of the performance of an organization. In my experience, it is important to focus on setting specific measurable meaningful objectives and not allow a list of daytoday activities, to be substituted for real objectives that move the organization forward. I prefer simple systems that do not try to rank MBOs by some arbitrary percentage of value. To my mind, that substitutes numbers for judgement and implies a precision that I don’t think exists.  Because I want people to set challenging objectives, I prefer paying the full bonus if most of the critical objectives are achieved. Demanding 100% achievement of objectives seems to encourage setting of only relatively easy objectives. 

After significant positive events, I always conduct a post-mortem in which the focus is inward: What did we do well, what did we do poorly, are there changes in systems or approaches that need to be made, do we need to add new skills? I also classify the event and the mistakes we made to assure that the lessons learned can be applied when related issues are encountered. 

Most people spend as much time at work as they do with family and how they feel about work has a major impact on their happiness and that of their family. Of even more importance, in organizations that are very demanding, stress is a constant that has to be managed and friendships help. Knowing a person and liking that person makes communication franker and easier and supports giving each other the benefit of the doubt   when actions may seem inappropriate or simply when stress is high. 

Life and work should be fun and good organizations laugh even during hard times. Of course, this, like everything else, starts at the top. If senior leaders don’t have fun, are not capable of laughing at themselves and enjoying one another, the work environment suffers, and everyone loses the opportunity to enjoy life a bit more. 

I look for craftsmen-people who are driven to do an outstanding job, no matter the task or whether someone is watching I look also for people who know that their jobs are important, but they are simply another fallible human with a specific responsibility that has been entrusted to him/her. As CEO, it is easy to let the power and trappings of the position convince you that you are infallible or that the people who work for you need to feel you are infallible. CEOs who succumb to the temptation to be treated as though they are infallible are dangerous. 

In good organizations, every individual in every job is important and takes pride in their contribution to the achievements of the organization. Organizations who behave as though people are replaceable get exactly what they deserve: poor employee commitment and high turnover. At Ionis, I made it my business to know as many people personally as I could and as I walked the halls, I told people that I appreciated what they were doing, and we behaved as though everyone was vital and celebrated long service. For nearly two decades, the work we did at Ionis was dismissed by most, our options were of minimal value, and we faced several existential crises. Yet, our average turnover ranged from 3-6% with voluntary departures typically accounting for less than half the turnover. Meanwhile the average turnover in biotech was around 26% and most of that was voluntary. The commitment and stability of our workforce were critical to our survival. 

Organizations that are expected to deliver innovation consistently are comprised of individuals who, on average, differ in a number of important characteristics from those who gravitate to manufacturing, finance, marketing or sales and I am convinced that innovation in drug discovery differs in important ways from innovation in technology, fine chemicals or entertainment.

At least four elements make innovation in drug discovery and development different and more challenging than other types of industrial innovations. First, the timelines are dramatically extended in drug discovery and development compared to other innovative, industrial pursuits. It is well known that the average time for the development of a novel drug is about 16 years, but that tells half the story. The discovery process that leads to the first drug of a new mechanistic or chemical type is typically 20 plus years. Such timelines are vastly harder to comprehend than the two or three years to make a major technological advance or to script and film a movie.

The second major difference is the success rate and the timing of failures in the drug discovery and development industry. With traditional drug discovery platforms, the success rate is vanishingly small and varies depending on what is counted and who is counting. With newer more efficient platforms, the success rate is higher, but it is still true that most new product concepts fail, and they fail, not in the marketplace, but long before reaching the market. The combination of extraordinarily long timelines and the limited success rate drive pessimism and actually can mean that scientists can work a lifetime in the drug development industry and never experience the thrill of being involved with the development of an innovative new drug that is commercialized.

The third key difference is the type of risk encountered. Eventually, if a product concept is successful, the drug must be tested in humans and even if all the rules are followed and experts with broad experience lead the effort, adverse events can and do happen. The thought that one might leads to a great deal of caution and decisions that are often emotion laden.

The fourth key difference is the regulatory environment and the consequences of regulatory missteps. Because patients are at risk, the drug discovery and development industry is the most regulated industry and regulatory requirements and processes vary from country to country and within the FDA, division by division. Further, public companies also must comply with SEC and other financial regulations that demand public exposure long before all the facts are known.

Consistent primary innovators are often organizationally challenging, but if you want maximum innovation, you need to recruit and retain these unique people. Innovators see the world as it is and as it might be, and they are impatient to change the world. They usually are brighter and quicker than their colleagues and can be quite dismissive. If the organization has a plethora of rules and SOPs, they will break them. They are also frequently critical of management.

So, how do you live with them? First, you commit to creating an environment in such people can prosper. You create reward systems that recognize innovations. You establish as few rules as possible but enforce the rules that you think are important swiftly and emphatically. Sometimes, you need to sit down with an important innovator and be clear about what you will not tolerate. It ain’t easy, but it is fun to watch what an organization filled with such people can do.

Most compensation systems emphasize the number of employees supervised and that is appropriate, but innovators often are less interested in supervising employees and more interested in staying at the bench. At Ionis, we celebrated such people, and we established systems that rewarded innovators irrespective of the number of people supervised.

I believe that secrets and the appearance of secrets are cancers in organizations that lend themselves to distrust of leadership and various conspiracy theories. Transparency is even more important for an organization charged with innovation because scientists are trained to be skeptical and question existing notions and judgements irrespective of the seniority of the person making a judgement. Furthermore, the heart of the scientific method demands peer review and detailed interrogation of data and decisions made based on data.

At Ionis, we made about 90% of all decisions in meetings that were open to anyone in the company that were always well attended. Though there was anxiety at first about making decisions in public that included concerns that ranged from whether junior people might overinterpret negatives, whether senior leaders who “lost an argument” in public might lose authority over their subordinates to possible leaks of data to competitors or to the public, but I felt the benefits would outweigh the risks and that turned out to be true. The organization became comfortable with the process, enjoyed seeing how decisions were made, benefitted from seeing the fallibility of leaders and how hard we worked together to “get it right” and none of the fears ever materialized.

I think this is critical for any organization, but especially critical for an organization attempting to create a new platform for drug discovery and developing drugs for commercial approval. We basically had two committees that made most of the key decisions in public. Research management committee (RMC) dealt with all senior decisions concerning the technology and drug discovery programs and the Development management committee (DMC) dealt with decisions concerning drug being promoted to and advancing in development. The simplicity of the process to bring a topic to one of these committees, the extensive, often energetic and sometimes contentious debates led to better decisions and the rapidity with which decisions were made led to a very nimble organization. A great bonus of transparency was the opportunity to teach drug discovery and development to many in the company.

In scientific efforts, we begin with hypotheses to be tested. A hypothesis is not a whimsical “what if”. A hypothesis, no matter how novel, must have a solid rationale and a clear experimental plan, but many times there are a number of plausible hypotheses, so often when hypotheses are tested, scientists disprove them. In fact, that is part of the joy of science. In drug discovery and development, failure is vastly more frequent than success and, in many cases, a decade or more of work by scores to hundreds of scientists and hundreds of millions of dollars may have been invested. Though such events are common, they are crushing to companies and the many people who worked so hard to get the answers that turn out to be negative. Many of these failures are of such a magnitude that they alter the future of the company and have very negative effects on careers. Whether the failure has a modest impact on a small group or a major impact on a company, they are devastating. Failures can happen despite the successful performance at every critical step by the team in charge of the effort. On the other hand, failures can be due to poor performance by the team, or the poor performance may be a factor in the failure. Therefore, it is vital to differentiate the two types of disappointments. In fact, it is always important to measure the team performance independently of the outcome. I made it a practice of congratulating the team if it earned congratulations, then saying that we were fortunate that the outcome was positive or vice versa.

I strongly believe that great leaders ask from others only the type of effort they themselves are willing to invest and when disappointments occur, take the heat and protect the organization if performance merited. I also strongly believe that great leaders are direct and very clear when they are disappointed with effort or performance. If you want your accolades to matter, they must be earned, and the organization must be confident that you will let them know in equally clear terms when you are pleased and when you are disappointed. They also need to know that if you make a mistake, you will own it publicly and take full responsibility. 

The demand that senior leaders of scientific organizations practice science is atypical, but I know it is important to long term innovation because leaders stay current as science advances, and they also know how hard the day-to-day grind in the lab can be. 

I have had a number of outstanding scientists work for me who I had to learn to expect less from extemporaneously than others. They were people who needed to do scholarship and think before providing answers, but their answers were worth waiting forParticularly in a high intensity, verbal organization, it is important to listen in different ways to different types of intellects. Of course, that means that you have learn to listen and invest in getting to know the people who work for you. 

In a scientific organization, science must be the center. At Ionis, from day one, every Thursday morning, two scientists presented 30-minute talks about the science they were doing and were excited about – not a progress report on a specific program, but a celebration of the science conducted by the scientist. These also provide the opportunity for peer review and the opportunity to teach. I rarely missed one of those Thursday morning meetings. 

In addition to the Thursday morning “data clubs” we had semiannual reviews of each program and project. These typically lasted 3-4 hours and were attended by all senior leaders. Nor were they simply a summary of where the effort stood, but rather, they got into detail on the science. Additionally, in RMC and DMC, the science was subject to even more intense peer review. Science is not done till peer reviewed. 

The final stage in science is to submit a manuscript to a peer-reviewed scientific journal. This can be a time-consuming and frustrating process but has been shown to be of great value over the centuries of modern science. The other reasons to demand publications are that they enhance the reputation of individual scientists and the organization and enhance the opportunity for important collaborations.  

Especially in the drug discovery and development industry, it is almost always possible to posit multiple reasons why a proposed course of action will fail, but if the hypothesis is well founded, it is essential to have a bias to say yes to sensible hypotheses, good experiments and quality people. Some bureaucrats equate saying no to having power, but of course, a no leads nowhere and means no one has to accept risk. Saying yes simply to say yes is not what I am talking about. Rather, I mean to interrogate ideas thoroughly and even if you disagree, if the hypothesis is sound, find a way to say yes. It is shocking what a difference it makes for an organization to learn to look for reasons to encourage rather than discourage. And to learn to accept the risk of failure. 

In an organization that is focused on science and led by scientists, it is important to expect people in non-scientific positions to innovate in their area of expertise. It is even more important to make the non-scientists understand that by enabling the scientists to work more effectively, they contribute to innovation and to achieving the mission of helping sick people. It is especially important to work closely with HR and finance to be sure that they see their jobs as enabling and blocking scientific advances.

This adage is true for any endeavor, but for innovation-centered entities, always bet on the people who deliver more innovation per unit time, even if they may be difficult to live with. Give them the room, support and authority they need and build around them.

There are studies that have shown that the optimal size organization for innovation is typically around 500 people. Certainly, my experience is consistent with that. Size is a particular impediment to innovation in drug discovery and development because of the long timelines and the “need to know syndrome”. In any successful organization, real progress is driven by strong leaders and a handful of committed people who work with the leader. Nevertheless, there are always people who are not directly contributory, but do need to know what is going on. The larger the organization, the more people with a legitimate need to know. Each of those people will have opinions and most will have projects of their own that they think should be funded rather than the one moving forward. Over time, these ‘need to knowers” wear most innovators out and they always delay things.

To maximize innovation, keep organizations reasonably small.

In an organization paid to innovate, the cost of approaches that fail are infinite and the costs of those that really succeed, irrelevant. That is very different from tasks like manufacturing or accounting where being the low-cost provider matters most. Yet most organizations that have large, complex organizations try to have one HR system for all. Even if efforts to customize HR systems are made, it doesn’t usually work well and there always fractious issues like “those scientists in their ivory tower, don’t care about the business and don’t work like we do.”

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