Dr. Jon Lorsch

About Dr. Jon Lorsch

As NIGMS director, Jon oversees the Institute’s research, training and other programs. He’s committed to engaging the scientific community on a wide range of topics, including funding policies and trends, research evaluation, and workforce development and diversity.

Hypothesis Overdrive?

Historically, this blog has focused on “news you can use,” but in the spirit of two-way communication, for this post I thought I would try something that might generate more discussion. I’m sharing my thoughts on an issue I’ve been contemplating a lot: the hazards of overly hypothesis-driven science.

When I was a member of one study section, I often saw grant applications that began, “The overarching hypothesis of this application is….” Frequently, these applications were from junior investigators who, I suspect, had been counseled that what study sections want is hypothesis-driven science. In fact, one can even find this advice in articles about grantsmanship Exit icon.

Despite these beliefs about “what study sections want,” such applications often received unfavorable reviews because the panel felt that if the “overarching hypothesis” turned out to be wrong, the only thing that would be learned is that the hypothesis was wrong. Knowing how a biological system doesn’t work is certainly useful, but most basic research study sections expect that a grant will tell us more about how biological systems do work, regardless of the outcomes of the proposed experiments. Rather than praising these applications for being hypothesis-driven, the study section often criticized them for being overly hypothesis-driven.

Many people besides me have worried about an almost dogmatic emphasis on hypothesis-driven science as the gold standard for biomedical research (e.g., see Jewett, 2005; Beard and Kushmerick, 2009; Glass, 2014 Exit icon). But the issue here is even deeper than just grantsmanship, and I think it is also relevant to recent concerns over the reproducibility of scientific data and the correctness of conclusions drawn from those data Exit icon. It is too easy for us to become enamored with our hypotheses, a phenomenon that has been called confirmation bias. Data that support an exciting, novel hypothesis will likely appear in a “high-impact” journal and lead to recognition in the field. This creates an incentive to show that the hypothesis is correct and a disincentive to proving it wrong. Focusing on a single hypothesis also produces tunnel vision, making it harder to see other possible explanations for the data and sometimes leading us to ignore anomalies that might actually be the key to a genuine breakthrough.

In a 1964 paper Exit icon, John Platt codified an alternative approach to the standard conception of the scientific method, which he named strong inference. In strong inference, scientists always produce multiple hypotheses that will explain their data and then design experiments that will distinguish among these alternative hypotheses. The advantage, at least in principle, is that it forces us to consider different explanations for our results at every stage, minimizing confirmation bias and tunnel vision.

Another way of addressing the hazards of hypothesis-driven science is to shift toward a paradigm of question-driven science. In question-driven science, the focus is on answering questions: How does this system work? What does this protein do? Why does this mutation produce this phenotype? By putting questions ahead of hypotheses, getting the answer becomes the goal rather than “proving” a particular idea. A scientific approach that puts questions first and includes multiple models to explain our observations offers significant benefits for fundamental biomedical research.

In order to make progress, it may sometimes be necessary to start with experiments designed to give us information and leads—Who are the players? or What happens when we change this?—before we can develop any models or hypotheses at all. This kind of work is often maligned as “fishing expeditions” and criticized for not being hypothesis-driven, but history has shown us just how important it can be for producing clues that eventually lead to breakthroughs. For example, genetic screens for mutations affecting development in C. elegans set the stage for the discovery of microRNA-mediated regulation of gene expression.

Is it time to stop talking about hypothesis-driven science and to focus instead on question-driven science? Hypotheses and models are important intermediates in the scientific process, but should they be in the driver’s seat? Let me know what you think.

Call for Stunning Microscopy Images—Deadline March 10

A collage of images showing taste buds on the tongue, nerve fibers, microtubules and actin filaments, small intestine, and plague bacteria.

In a few months, stunning microscopy images from NIH grantees will be featured in an exhibit called Life: Magnified.

The exhibit, a joint project of the American Society for Cell Biology (ASCB), NIGMS and the Metropolitan Washington Airports Authority, will run from June through November of this year at Dulles International Airport. This is an exciting opportunity to educate the public about cutting-edge biomedical research.

If you have images you’d like us to consider for display, please see the submission Web site Exit icon for image requirements and instructions. Submissions are due by March 10. You can contact NIGMS’ Alisa Machalek or ASCB’s Thea Clarke with any questions. You don’t have to be an ASCB member or an NIGMS grantee to contribute images.

If you find yourself near the C Concourse at Dulles later this year, I encourage you to stop by the Gateway Gallery to check it out.

Funding Trends and Factors Affecting Success Rate

On January 17, the President signed into law the Consolidated Appropriations Act of 2014 Exit icon, funding the Federal Government for the remainder of the fiscal year and providing increased support for NIH relative to the post-sequester levels of 2013. The NIGMS Fiscal Year 2014 budget is $2.359 billion, which is about $66 million, or 2.9%, higher than it was in Fiscal Year 2013.

It’s too early to know what this will mean for the NIGMS grant application success rate—the number of competing R01 applications we fund divided by the total number of competing R01 applications we receive. A number of other, largely independent factors in addition to the budget can impact the success rate, as well. We hope that our latest analysis of NIGMS funding trends illuminates the interplay among some of these factors. Thanks to Tony Moore, Jim Deatherage and Ching-Yi Shieh for help with the data collection and analysis.

Figure 1 shows the percentage of R01 applications funded by NIGMS as a function of percentile scores for Fiscal Years 2009-2013. Fewer grants scoring above about the 12th percentile were funded last year than in the previous 4 years. In fact, the funding curves shifted more to the left each year in this period, except in 2012, which had a slightly better success rate than 2011. This was due in part to a dip in noncompeting R01 grants that had to be funded along with no increase in the number of competing applications relative to 2011. (For a 4-year R01, the second, third and fourth years are all noncompeting grants because they are funded without review by a study section. The funds required to pay the noncompeting awards are often referred to as “out-year commitments.”) Funding levels fell again in Fiscal Year 2013 due to the sequester cuts and increases in the numbers of competing applications and noncompeting grants (see below).

Figure 1. Percentage of competing R01 applications funded by NIGMS as a function of percentile scores for Fiscal Years 2009-2013. For Fiscal Year 2013, the success rate for R01 applications was 21%, and the midpoint of the funding curve was at approximately the 17th percentile. See more details about Figure 1 analysis.

Figure 2 presents a more granular view of the data for Fiscal Year 2013. The solid black bars correspond to the number of NIGMS competing R01 applications that scored at each percentile. The striped red bars show the number of these applications that we funded.

Figure 2. Number of competing R01 applications (solid black bars) assigned to NIGMS and number funded (striped red bars) in Fiscal Year 2013 as a function of percentile scores. See more details about Figure 2 analysis.

Figure 3 shows the success rate for Fiscal Years 2000-2013 (green line with triangles; right axis), the total number of NIGMS R01 applications each year (blue line with diamonds) and the number of funded competing R01 grants (red line with squares, left axis). Between Fiscal Years 2000 and 2003, the last year of the NIH budget doubling, the success rate was 37-38%. After the budget doubling ended, the success rate declined, falling to 26% in 2006. In 2007, the success rate jumped to 33%, largely due to a combination of a budget increase for NIH and a dip in the number of noncompeting grants NIGMS had to fund that year. (See below for more about changes in the number of noncompeting grants.) Over the next 6 years, the success rate for R01s dropped to 21%, the lowest level in two decades. Note that the Fiscal Year 2013 success rate for all research project grants (RPGs), which include R00s, R01s, R15s, R21s, R37s, P01s, DP1s, DP2s and U01s, was 19.9%. This is lower than the success rate for R01s alone, which was 21%.

Figure 3. Number of competing R01 applications assigned to NIGMS (blue line with diamonds, left axis) and number funded (red line with squares, left axis) for Fiscal Years 2000-2013. The success rate is shown in the green line with triangles (right axis).

One reason the success rate has fallen is that the number of applications increased between Fiscal Years 2002-2005 and then again between Fiscal Years 2010-2013. Similar trends are seen NIH-wide and are the result of a 50% increase in the number of investigators applying for grants along with a smaller increase in the average number of applications submitted per investigator.

Another factor that influences the success rate is the number of noncompeting awards. The more noncompeting awards we need to make in a given year, the fewer competing grants we can fund. The number of noncompeting RPGs cycles with a 4-year period, as shown in Figure 4.

Figure 4. Number of noncompeting (blue line with diamonds, left axis) and competing (red line with squares, right axis) RPGs funded by NIGMS for Fiscal Years 2000-2013. Note that the Y axes do not start at 0.

This cycle was apparently set in the early 1990s when the Institute shifted the duration of most competing RPGs from 5 to 4 years. The result was that the last group of 5-year awards and the first group of 4-year awards ended in the same year, creating a significant dip in noncompeting grants and a corresponding jump in competing grants that the Institute could fund. The bolus of grants awarded that year kept noncompeting commitments high for the next 3 years, until they all came up for renewal again. As you can see in Figure 4, the cycle has persisted to this day.

The cycle may lead you to wonder if you should try to time your application to correspond to a trough in noncompeting grants. You might get lucky and have all of the factors that drive success rate work in your favor. However, if other factors act to decrease the success rate, you might end up worse off. For example, even though 2011 was a trough year for noncompeting grants (Figure 4, blue line with diamonds), a jump in the number of applications (Figure 3, blue line with diamonds) worked in the opposite direction, and the success rate actually fell (Figure 3, green line with triangles).

Finally, the Institute’s budget is also a factor in determining the success rate. Figure 5 shows the NIGMS budget (red line with squares, left axis), the budget committed to competing and noncompeting RPGs (blue line with diamonds, left axis) and the ratio of the RPG budget to the total NIGMS budget (green line with triangles, right axis).

Figure 5. Total NIGMS budget (red line with squares, left axis) and budget committed to competing and noncompeting RPGs (blue line with diamonds, left axis) for Fiscal Years 2000-2013. The green line with triangles shows the ratio of the RPG budget to the total NIGMS budget (right axis). The jump in the NIGMS budget and corresponding drop in the RPG/NIGMS budget ratio occurred when large, primarily non-RPG programs were transferred to NIGMS along with their associated funds from the former National Center for Research Resources.

The Institute’s budget grew during the NIH budget doubling (1998-2003). It also jumped by nearly $400 million when the Institutional Development Award (IDeA) and Biotechnology Research Resources programs moved from the former National Center for Research Resources to NIGMS. A variety of pressures were responsible for the ~2% decline in the ratio of RPG funds to the NIGMS budget that occurred during Fiscal Years 2005-2011, including commitments to targeted initiatives and increased funding for training programs.

Because we don’t yet know the number of applications we will receive or the number of noncompeting grants that will end early due to retirements or other events, we can’t predict what our success rate will be in Fiscal Year 2014. We hope, however, that the steps we are taking to bolster our commitment to investigator-initiated RPGs will have a positive impact on the success rate.

Bolstering Our Commitment to Investigator-Initiated Research

As part of an ongoing examination of our grant portfolio to ensure that we invest taxpayer money as effectively and efficiently as possible, we recently analyzed changes over time in the distribution of investigator-initiated research compared to research funded through targeted funding opportunity announcements (FOAs).

Changes over time in NIGMS investments in investigator-initiated research (research grant funds not associated with targeted FOAs) (right axis) and research funded through targeted FOAs (left axis). The analysis does not include fellowship, career development and training awards; programs transferred to NIGMS from the former National Center for Research Resources; and some other programs. For more details about the analysis, which was performed by Jim Deatherage, chief of our Cell Biology Branch, see the NIGMS Funding Trends Web page.

The figure shows that in the early 1990s, 99% of NIGMS’ grant budget supported investigator-initiated research, compared to 80% today. During the budget doubling in Fiscal Years 1998-2003, the Institute’s investment in research funded through targeted FOAs increased dramatically, then continued to increase at a slower rate during Fiscal Years 2004-2009.

As I discussed in a previous post about our large-scale research initiatives and centers, there were many good reasons for using FOAs to target specific areas of research with some of the funds made available by the budget doubling. For example, FOAs allowed the Institute to experiment with catalyzing the development of such new and emerging fields as structural genomics, pharmacogenomics and systems biology.

Since the budget doubling ended, however, maintaining steady support for our targeted research portfolio has made it difficult to maintain steady support for investigator-initiated research project grants (RPGs). Partly as a result, the success rate for RPGs (the number of funded RPGs divided by the number of RPG applications) fell below 20% in Fiscal Year 2013. Although a number of factors have contributed to the declining success rate, a significant one is that targeted and investigator-initiated research grants compete directly with each other. To bolster the success rate, we need to decrease our commitment to targeted FOAs. Furthermore, because none of us knows where the next major advances will arise, the soundest investment strategy is to have a distributed portfolio in which researchers investigate a wide range of scientific questions. History strongly suggests that letting scientists “follow their noses”—which involves a combination of curiosity, expertise, creativity and serendipity—is the most productive route to findings that will eventually translate into medical and technological breakthroughs.

To rebalance our portfolio in order to renew and reinvigorate our commitment to investigator-initiated research, we will be reducing our use of targeted FOAs, generally reserving them for cases in which they are likely to have a major impact on a large segment of the biomedical research enterprise. These cases could include promoting the rapid development of accessible, cost-effective new technologies that enable major advances in understanding biological systems; more efficiently organizing the Nation’s basic biomedical research resources to provide scientists throughout the country access to high-end instrumentation and technical expertise; and, in some instances, using targeted FOAs with defined lifetimes to catalyze the rapid development of emerging research areas.

It is important to note that we are making a distinction between investigator-initiated research and targeted research, not between investigator-initiated research and team science. We strongly support team science, which can certainly be investigator-initiated, and we expect such collaborative efforts to increase as research probes more deeply into the complexities of living systems. Currently, team-based, investigator-initiated research can be funded through multi-PI R01s and can also occur through groups of individually funded PIs working together. In special cases, program project grants (P01s) may be appropriate, particularly for long-term, interdisciplinary collaborations that require dedicated core facilities. As we move forward with our strategic planning process, we will be exploring additional ways to support investigator-initiated team science. I invite you to send us ideas you have for how best to do this.

Principles for Initial Funding Decisions in Fiscal Year 2014

On October 16, Congress passed a continuing resolution to fund the Federal Government through January 15, 2014, at Fiscal Year 2013 levels. This short-term budget allows us to begin funding some of the grant applications approved by our Advisory Council in September. However, because the funds we have available are only for a fraction of the fiscal year and we don’t know what the budget for the rest of the year will be, we need to be conservative in our funding decisions until a longer-term budget is approved.

Led by NIGMS Acting Deputy Director Judith Greenberg, the directors of the NIGMS scientific divisions developed principles to help us decide which of the many outstanding applications we are considering should receive funding now and which should be deferred for later start dates, if sufficient funds become available after January 15.

The fundamental question the division directors addressed was which categories of investigators would face the most serious jeopardy from a delay in funding. Based on the group’s careful deliberations, we will give priority to highly rated applications from investigators who have little or no current support from any source. Within this category, we will generally give priority to competing renewal applications over new applications, although in each case, we will take into account the particular circumstances of the investigator and her/his laboratory. For instance, an application from an early stage investigator who has been a tenure-track faculty member for 4 years, has exhausted all start-up funds and has no additional sources of funding would be considered a high priority.

We recognize that a delay in funding presents challenges for every investigator, but we hope you understand that our top priority in these difficult fiscal times must be to ensure the health of the overall biomedical research enterprise in the United States. Keeping productive and promising labs open is an essential element of this goal.

Judith Greenberg Named Acting Deputy Director of NIGMS

Photo of Dr. Judith GreenbergI am pleased to tell you that Judith Greenberg has agreed to serve as acting deputy director of NIGMS while a search for a permanent deputy director takes place. A news announcement on her appointment is posted at http://www.nigms.nih.gov/News/Results/pages/
20131024a.aspx
.

As most of you know, Judith has served in numerous leadership roles at NIGMS and NIH, including two stints as NIGMS acting director.

In her new role, Judith will provide advice and expertise on all Institute activities. She will also continue to serve as director of the Division of Genetics and Developmental Biology, a position she has held since 1988.

Once the job announcement for a permanent deputy director is posted, I will be sure to alert you via this blog.

Opening the Shutters

I am pleased to report that NIGMS is back at work. The 16-day lapse in federal appropriations, which shuttered most of NIH and led to the furlough of 98 percent of NIGMS’ staff, ended early yesterday morning when the President signed a bill containing a short-term continuing resolution to fund the Federal Government through January 15. By the time I got to the Institute at 7:45 a.m. that day, many of our staff members were already here, eagerly diving into the piles of work that had accumulated in their absence. I’ve never seen people so glad to be back at their jobs! It was a testament to how dedicated our staff is to promoting the mission of NIGMS.

Although we are all very happy to have resumed operations, I cannot say we have resumed completely normal operations. We have some work to do to recover from the loss of all of the important events that were supposed to happen during the closure. For example, many of the study sections run by the NIH Center for Scientific Review had to be cancelled, presenting a challenge for all of the NIH institutes and centers, as well as for all of the applicants and their institutions. The NIH Office of Extramural Research and the Center for Scientific Review are rapidly developing plans for reviewing the applications that were going to be considered in these study sections. They are also updating relevant application submission deadlines. I strongly encourage everyone to keep informed about what is happening by reading Sally Rockey’s extramural research blog and by checking the NIH Guide for Grants and Contracts, where information about new deadlines and procedures will be posted.

An important piece of news that might have flown by under the radar during the shutdown was that five past and current NIGMS grantees won Nobel Prizes this year: Jim Rothman and Randy Schekman in physiology or medicine for their work on vesicle transport within cells (along with Thomas Südhof, also an NIH-funded investigator); and Martin Karplus, Michael Levitt and Arieh Warshel in chemistry for the development of multiscale molecular simulation methods. Congratulations to all of this year’s laureates! Their studies are shining examples of the importance of the fundamental, investigator-initiated biomedical research that is the essence of our mission.

Examining Our Large-Scale Research Initiatives and Centers, Including the PSI

There have been a lot of discussions lately at NIGMS about large-scale research initiatives and centers. In these conversations, we have drawn a distinction between initiatives and centers focused mainly on research and those focused mainly on resources. Examples of the latter include our human cell repository, synchrotron light sources, and databases, all of which serve the biomedical community in critical ways and, in most cases, require sustained support. In contrast, many of us feel that the primary purpose of research-focused initiatives and centers is to open untapped scientific areas, providing an initial, targeted investment that enables the research to develop sufficiently so that it can be sustained through other grant mechanisms, such as R01s and P01s.

Our discussions have led to the question of whether, when and how research initiatives and centers should be ended. Should all new research initiatives and centers have hard “sunset clauses” built into them, for example at 10 years, similar to what is done for projects funded by the NIH Common Fund? Or should it be possible for them to continue indefinitely as long as they are sufficiently productive?

An additional consideration is that many of our currently funded initiatives and centers were developed during the period in which the NIH budget was doubling (see figure). With a large infusion of new investment into biomedical research, it made sense to use a significant portion of the funds to open up new scientific territory through large-scale exploration in ways that were not previously possible.

Center Funding as a Proportion of the NIGMS Budget
Fiscal Years 1998-2012
Growth of NIGMS funding for centers (blue bars, left axis) for Fiscal Years 1998-2012. The total NIGMS budget each year during the same period is also shown (red line, right axis). The numbers on top of each blue bar represent the percentage of the total NIGMS budget committed to centers in that year. The data for 2012 do not include the funds for the Institutional Development Award (IDeA) program or the Biomedical Technology Research Centers program, which were transferred to NIGMS from the former National Center for Research Resources in that fiscal year.
View larger image
Growth of NIGMS funding for centers (blue bars, left axis) for Fiscal Years 1998-2012. The total NIGMS budget each year during the same period is also shown (red line, right axis). The numbers on top of each blue bar represent the percentage of the total NIGMS budget committed to centers in that year. The data for 2012 do not include the funds for the Institutional Development Award (IDeA) program or the Biomedical Technology Research Centers program, which were transferred to NIGMS from the former National Center for Research Resources in that fiscal year.

In the current budget environment, in order to start a new program or bolster support for existing priorities such as investigator-initiated research, other programs must be adjusted or ended.

These issues will be central as we begin a strategic planning process to ensure that we are using the most effective and efficient mechanisms to invest the taxpayers’ money in fundamental biomedical and behavioral research. We have already begun carefully examining our existing portfolio of research initiatives and centers and considering how to balance continued support for them with other priorities and opportunities.

At last week’s National Advisory General Medical Sciences Council meeting, Council members and staff discussed the future of one existing large-scale program, the Protein Structure Initiative (PSI). The Council heard the results of a midpoint evaluation of the PSI’s third 5-year phase, PSI:Biology. The evaluators found that PSI investigators have determined an impressive number of high-quality protein structures and that some of the program’s accomplishments, including methodological ones, could not have been readily achieved through R01-type investigator-initiated grants.

The evaluators concluded that the PSI will reach a point that no longer justifies set-aside funding and, as a result, strongly recommended that NIGMS begin planning the sunset of the PSI, being careful to identify resources developed by the initiative that should be retained for use by the biomedical community.

After numerous internal discussions and consultation with the Council, we have decided to follow this advice and begin planning to sunset the PSI in its current format after the completion of PSI:Biology in 2015. We are setting up two transition-planning committees, one made up of NIGMS staff and representatives from several other parts of NIH, and a second made up of scientists from the research community. These committees will work together to recommend the best methods for phasing out the program and identifying critical resources that should be retained. The committees will also suggest emerging challenges and opportunities in structural biology that may require new, smaller-scale targeted support.

The committees and NIGMS will need a great deal of input from the biomedical community as this transition-planning process moves forward. I hope that you will freely share your thoughts and suggestions with us, now and in the future.

Upcoming Advisory Council Meeting Includes Videocast and Public Comment Period Opportunities

The National Advisory General Medical Sciences Council will have its fall meeting on September 19-20. For the session open to the public on the second day, we will be trying something new: a videocast. If you’re interested in watching the presentations and subsequent discussions—and learning more about what happens during advisory council meetings—tune in at http://videocast.nih.gov. The videocast will also be archived for a limited time. If enough people watch the meeting live or later, making the experiment successful, we will continue to videocast the open session of future advisory council meetings.

Previously, the Feedback Loop posted a description of advisory council roles. Council members provide the second level of peer review of grant applications, assess the merits of appeals of study section reviews and provide ideas and guidance on scientific and training priorities.

We have just posted the open session agenda, which includes a presentation by Council member and Yale University chemistry professor and chair Scott Miller on recent discoveries at the chemistry-biology interface; a presentation by NIH Principal Deputy Director Larry Tabak on data reproducibility in biomedical research; and another new feature of the meeting: a period reserved for public comment.

Before I started at NIGMS, I was able to attend the open session of the May Council meeting, where I heard very exciting presentations about recent developments in cryo-electron microscopy and pharmacogenomics, plus lively discussions about training and workforce development issues. Although I have only been to this one meeting so far, based on what I heard at it, I recommend that you try to catch some of the September meeting—I think you’ll find it interesting and informative.

Looking Forward

Having been a fan of Jeremy Berg’s Feedback Loop posts, it’s a great pleasure to be writing one myself. I am very excited to be at NIGMS, and I am honored to have the chance to lead this extraordinary institute.

Over the past year, whenever I asked anyone familiar with NIGMS what the best thing about it was, they all said the same thing: the people who work there. My own observations have been completely consistent with these assessments. The staff at NIGMS is an exceptional group, deeply committed to ensuring that the biomedical and behavioral research enterprise thrives. No one embodies this commitment better than Judith Greenberg, who has done an outstanding job over the past 2 years steering the Institute through challenging times. I hope you will join me in thanking her for everything she has done.

A key part of Jeremy’s legacy at NIGMS was increasing communication between the Institute and the scientific community. I intend to stay on this course, using the Feedback Loop as well as other mechanisms to catalyze discussions. I encourage you to join in these conversations and to suggest specific questions that you’d like to see us address.

I also intend to push forward the data collection and analysis efforts begun by Jeremy, both to help inform our discussions with the scientific community and to guide our policy decisions.

Among my first orders of business are to conduct a thorough analysis of NIGMS’ grant portfolio and to begin developing a new strategic plan for the Institute. The overall goal of these synergistic undertakings is to ensure that we are investing the taxpayers’ money in the most efficient and effective way possible. Science and society both evolve rapidly, and the structures and strategies that worked well in the past are not necessarily optimal for the future. We will be thinking broadly, using data to inform our analyses, and we will be seeking your ideas and innovations.

This would also be a good time for the scientific community to engage in a parallel process of introspection, examining topics ranging from how the research enterprise is organized to how the impact of scientists’ work is assessed and recognized through peer review and other mechanisms. The process could happen both at a local level—within your own institutions—and at a national one, perhaps led by the relevant scientific and academic societies.

I will always be happy to hear your thoughts and suggestions, either through this blog or directly at jon.lorsch@nih.gov. I am looking forward to working with you!