Macro Roundup

“…The scientificchallenge has not just been to demonstrate convincingly that harsh environments cause nonrandom mutations. It has also beento find a plausible mechanism consistent with the rest of molecular biology that could make lucky mutations more likely. Waves of studies in bacteria and more complex organisms have sought those answers for decades. The latest and perhaps best answer — for explaining some kinds of mutations, anyway — has emerged from studies of yeast, as reported in June in PLOS Biology. A team led by Jonathan Houseley, a specialist in molecular biology and genetics at the Babraham Institute in Cambridge, proposed a mechanism that drives more mutation specifically in regions of the yeast genome where it could be most adaptive. “It’s a totally new way that the environment can have an impact on the genome to allow adaptation in response to need. It is one of the most directed processes we’ve seen yet,” said Philip Hastings, professor of molecular and human genetics at Baylor College of Medicine, who was not involved in the Houseley group’s experiments. Other scientists contacted for this story also praised the work, though most cautioned that much about the controversial idea was still speculative and needed more support….”

“We are actively working on that,” Houseley said, “but it’s still in the early days.”

Notwithstanding the doubters, Houseley and his team are persevering with their research to understand its relevance to cancer and other biomedical problems. “The emergence of chemotherapy-resistant cancers is commonplace and forms a major barrier to curing the disease,” Houseley said. He thinks that chemotherapy drugs and other stresses on tumors may encourage malignant cells to mutate further, including mutations for resistance to the drugs. If that resistance is facilitated by the kind of mechanism he explored in his work on yeast, it could very well present a new drug target. Cancer patients might be treated both with normal courses of chemotherapy and with agents that would inhibit the biochemical modifications that make resistance mutations possible.

“I think is beautiful and relevant to the adaptive mutation debate,” said Paul Sniegowski, a biologist at the University of Pennsylvania. “But in the end, it still represents a hypothesis.” To validate it more certainly, he added, “they’d have to test it in the way an evolutionary biologist would” — by creating a theoretical model and determining whether this adaptive mutability could evolve within a reasonable period, and then by challenging populations of organisms in the lab to evolve a mechanism like this.

Adaptive mutation theory, however, finds little acceptance among most biologists, and many of them view the original experiments by Cairns and the new ones by Houseley skeptically. They argue that even if higher mutation rates yield adaptations to environmental stress, proving that the higher mutation rates are themselves an adaptation to stress remains difficult to demonstrate convincingly. “The interpretation is intuitively attractive,” said John Roth, a geneticist and microbiologist at the University of California, Davis, “but I don’t think it’s right. I don’t believe any of these examples of stress-induced mutagenesis are correct. There may be some other non-obvious explanation for the phenomenon.”

Hastings at Baylor agreed, and praised the fact that Houseley’s mechanism explains why the extra mutations don’t happen throughout the genome. “You need to be transcribing a gene for it to happen,” he said.

The work of the Houseley team seems to bolster the case for that position. In the yeast mechanism “there’s not selection for a mechanism that actually says, ‘This is the gene I should mutate to solve the problem,’” said Patricia Foster, a biologist at Indiana University. “It shows that evolution can get speeded up.”

Experimental support for that specific idea eventually proved lacking, but some biologists were inspired to become proponents of a broader theory that has come to be known as adaptive mutation. They believe that even if cells can’t direct the precise mutation needed in a certain environment, they can adapt by elevating their mutation rate to promote genetic change.

Ever since 1943, when the microbiologist Salvador Luria and the biophysicist Max Delbrück showed with Nobel prize-winning experiments that mutations in E. coli occur randomly, observations like the bacterial SOS response have made some biologists wonder whether there might be important loopholes to that rule. For example, in a controversial paper published in Nature in 1988, John Cairns of Harvard and his team found that when they placed bacteria that could not digest the milk sugar lactose in an environment where that sugar was the sole food source, the cells soon evolved the ability to convert the lactose into energy. Cairns argued that this result showed that cells had mechanisms to make certain mutations preferentially when they would be beneficial.

The Adaptive Mutation Debate

“What we have defined is a mechanism that has arisen entirely through Darwinian selection of random mutations to give a process that stimulates nonrandom mutations at useful sites,” Houseley said. “It is not Lamarckian adaptation. It just achieves some of the same ends without the problems involved with Lamarckian adaptation.”

The key point is that these effects center on genes responding to the environment, and that they could give natural selection extra opportunities to fine-tune which levels of gene expression might be optimal against certain challenges. The results seem to present experimental evidence that a challenging environment could galvanize cells into controlling those genetic changes that would best improve their fitness. They may also seem reminiscent of the outmoded, pre-Darwinian ideas of the French naturalist Jean-Baptiste Lamarck, who believed that organisms evolved by passing their environmentally acquired characteristics along to their offspring. Houseley maintains, however, that this similarity is only superficial.

The cells seemed to be directing greater variation to the exact place in their genome where it would be useful. After more work, the researchers identified elements of the biological mechanism behind this phenomenon. It was already known that when cells replicate their DNA, the replication mechanism sometimes stalls. Usually the mechanism can restart and pick up where it left off. When it can’t, the cell can go back to the beginning of the replication process, but in doing so, it sometimes accidentally deletes a gene sequence or makes extra copies of it. That is what causes normal copy number variation. But Houseley and his team made the case that a combination of factors makes these copying errors especially likely to hit genes that are actively responding to environmental stresses, which means that they are more likely to show copy number variation.

But that change did not in itself mean much: If the environmental copper was causing mutations, then the change in CUP1 copy number variation might have been no more than a meaningless consequence of the higher mutation rate. To rule out that possibility, the researchers cleverly re-engineered the CUP1 gene so that it would respond to a harmless, nonmutagenic sugar, galactose, instead of copper. When these altered yeast cells were exposed to galactose, the variation in their number of copies of the gene changed, too.

Houseley therefore decided to test whether similar mechanisms might act on genes more directly activated by hazardous changes in the environment. In their 2017 paper, he and his team focused on CUP1, a gene that helps yeast resist the toxic effects of environmental copper. They found that when yeast was exposed to copper, the variation in the number of copies of CUP1 in the cells increased. On average, most cells had fewer copies of the gene, but the yeast cells that gained more copies — about 10 percent of the total population — became more resistant to copper and flourished. “The small number of cells that did the right thing,” Houseley said, “were at such an advantage that they were able to outcompete everything else.”

In 2015, Houseley and his colleagues described a mechanism by which yeast cells seemed to be driving extra copy number variation in genes associated with ribosomes, the parts of a cell that synthesize proteins. However, they did not prove that this increase was a purposefully adaptive response to a change or constraint in the cellular environment. Nevertheless, to them it seemed that the yeast was making more copies of the ribosomal genes when nutrients were abundant and the demand for making protein might be higher.

Jonathan Houseley leads a team that studies genome change at the Babraham Institute in Cambridge. Based on their studies of yeast, they recently proposed a mechanism that would increase the odds for adaptive mutations in genes that are actively responding to environmental challenges.

“Rather than asking very broad questions like ‘are mutations always random?’ I wanted to take a more mechanistic approach,” Houseley said. He and his colleagues directed their attention to a specific kind of mutation called copy number variation. DNA often contains multiple copies of extended sequences of base pairs or even whole genes. The exact number can vary among individuals because, when cells are duplicating their DNA before cell division, certain mistakes can insert or delete copies of gene sequences. In humans, for instance, 5 to 10 percent of the genome shows copy number variation from person to person — and some of these variations have been linked to cancer, diabetes, autism and a host of genetic disorders. Houseley suspected that in at least some cases, this variation in the number of gene copies might be a response to stresses or hazards in the environment.

Increasing Variety in the Genome

“It’s a totally new way that the environment can have an impact on the genome to allow adaptation in response to need. It is one of the most directed processes we’ve seen yet,” said Philip Hastings, professor of molecular and human genetics at Baylor College of Medicine, who was not involved in the Houseley group’s experiments. Other scientists contacted for this story also praised the work, though most cautioned that much about the controversial idea was still speculative and needed more support.

The latest and perhaps best answer — for explaining some kinds of mutations, anyway — has emerged from studies of yeast, as reported in June in PLOS Biology. A team led by Jonathan Houseley, a specialist in molecular biology and genetics at the Babraham Institute in Cambridge, proposed a mechanism that drives more mutation specifically in regions of the yeast genome where it could be most adaptive.

The scientific challenge has not just been to demonstrate convincingly that harsh environments cause nonrandom mutations. It has also been to find a plausible mechanism consistent with the rest of molecular biology that could make lucky mutations more likely. Waves of studies in bacteria and more complex organisms have sought those answers for decades.

The question that has tormented some evolutionary biologists ever since is whether nature favored this arrangement. Is the upsurge in mutations merely a secondary consequence of a repair process inherently prone to error? Or, as some researchers claim, is the increase in the mutation rate itself an evolved adaptation, one that helps bacteria evolve advantageous traits more quickly in stressful environments?

For the next two decades, Witkin sought to understand how and why these mutants had emerged. Her research led her to what is now known as the SOS response, a DNA repair mechanism that bacteria employ when their genomes are damaged, during which dozens of genes become active and the rate of mutation goes up. Those extra mutations are more often detrimental than beneficial, but they enable adaptations, such as the development of resistance to UV or antibiotics.

In 1944, a Columbia University doctoral student in genetics named Evelyn Witkin made a fortuitous mistake. During her first experiment in a laboratory at Cold Spring Harbor, in New York, she accidentally irradiated millions of E. coli with a lethal dose of ultraviolet light. When she returned the following day to check on the samples, they were all dead — except for one, in which four bacterial cells had survived and continued to grow. Somehow, those cells were resistant to UV radiation. To Witkin, it seemed like a remarkably lucky coincidence that any cells in the culture had emerged with precisely the mutation they needed to survive — so much so that she questioned whether it was a coincidence at all.

Beating the Odds for Lucky Mutations

Jordana Cepelewicz, "Beating the Odds for Lucky Mutations,"Quanta Magazine, August 16, 2017, https://www.quantamagazine.org/beating-the-odds-for-lucky-mutations-20170816/

more interesting part of Gates’s comments,

“…lagging performance of American students overall, the national averages mask a bigger story. When disaggregated by race, we see two Americas. One where white students perform along the lines of the best in the world—with achievement comparable to countries like Finland and Korea. And another America, where Black and Latino students perform comparably to the students in the lowest performing OECD countries, such as Chile and Greece…..”

Thank you.

Our role is to serve as a catalyst of good ideas, driven by the same guiding principle we started with: all students – but especially low-income students and students of color – must have equal access to a great public education that prepares them for adulthood. We will not stop until this has been achieved, and we look forward to continued partnership with you in this work in the years to come.

If there is one thing I have learned, it is that no matter how enthusiastic we might be about one approach or another, the decision to go from pilot to wide-scale usage is ultimately and always something that has to be decided by you and others the field.

I’m also hopeful this will attract other funders focused on particular approaches or who work in one state or community.

Giving schools and districts more flexibility is more likely to lead to solutions that fit the needs of local communities and are potentially replicable elsewhere.

Education is, without a doubt, one of the most challenging areas we invest in as a foundation. But I’m excited about the shift in our work and the focus on partnering with networks of schools.

Over the last 17 years, we have invested $1 billion in the cities represented in the room in support of school improvement and redesign efforts. We are proud of that work and have seen some good things come out of it that make me optimistic about the future.

We will continue to help high-performing charters expand to serve more students. But our emphasis will be on efforts that improve outcomes for special needs students – especially kids with mild-to-moderate learning and behavioral disabilities. This is a critical problem across the education sector, and we believe that charters have the flexibility to help the field solve this problem.

We anticipate that the final 15 percent of our funding in the next five years will go to the charter sector.

We are also interested in what role we can play to prepare students for the dramatic changes underway in the workforce. We have to make work-related experiences a consistent part of high schools in ways that build student engagement and relevant skills, and that put young people on a path to credentials with labor market value in our future economy.

Math is one area where we want to generate stronger evidence about what works. What would it take, for example, to get all kids to mastery of Algebra I? What kinds of intelligent tools do teachers and students need to get there? And how might we design these in partnership with the best math teachers in the country?

But the PreK-12 research, development and translation ecosystem is underfunded and fragmented, with less than 1 percent of total government spending in public education focused on R&D.

The conditions for developing and spreading new approaches in education, particularly technology-enabled ones, are better than ever. Broadband access in schools is reaching 90 percent. Students and teachers have access to more affordable and more powerful tools for learning. Educators are seeking each other out and sharing ideas in digital communities. And there are promising developments in neuroscience, cognitive psychology, and behavioral economics.

We expect that about 25 percent of our funding in the next five years will focus on big bets – innovations with the potential to change the trajectory of public education over the next 10 to 15 years.

In Washington DC, the school district has developed an innovative professional development program that is discipline-specific, curricula-aligned, and focused on improving teachers’ instructional skills at the school level. Teachers meet weekly with a coach who is an expert in the subjects they teach. They also meet in small groups with colleagues who teach the same subject to talk through lesson plans, what’s working, and how to adjust their instruction accordingly. While still early, 87 percent of teachers say the collaboration and feedback is improving their practice and knowledge.

Louisiana is a great example of where aligned curricula and professional development is helping teachers. 80 percent of districts have adopted fully aligned curricula in grades 3 through 8. And the state has created a marketplace of preferred professional development service providers to help schools implement these curricula effectively. Teachers report that they feel more equipped to help students meet the standards—for example, by closely reading texts for meaning.

Our goal is to work with the field to ensure that five years from now, teachers at every grade level in secondary schools have access to high-quality, aligned curriculum choices in English and math, as well as science curricula based on the Next Generation Science Standards. In a few places, we also will support pilots of scalable professional development supports anchored in high quality curriculum.

We also know that high-quality curricula can improve student learning more than many costlier solutions, and it has the greatest impact with students of novice and lower performing teachers. We also know it has the greatest impact when accompanied by professional learning and coaching.

We’ll also work with teacher and leader prep providers to ensure that these lessons and best practices are incorporated into local programs to further enrich and sustain this work.

We will work with partners to document these change efforts in schools and networks and ask them to share the lessons learned with others.

But we will leave it up to each network to decide what approaches they believe will work best to address their biggest challenges. They might decide, for example, to focus on student interventions in middle school… or adapting new and more rigorous curricula… or improving support for certain groups of students in the transition from high school to college.

There are two things these networks will share in common. A commitment to continuous improvement. And a focus on addressing common problems that are identified by using proven indicators predictive of students’ learning, progress, and postsecondary success.

Over the next several years, we will support about 30 of these networks, and will start initially with high needs schools and districts in 6 to 8 states. Each network will be backed by a team of education experts skilled in continuous improvement, coaching, and data collection and analysis.

We are seeing more examples of this popping up all the time. Like the CORE Districts in California – comprised of eight of the largest school districts in the state. And the LIFT Network in Tennessee, which includes educators from 12 rural and urban districts across the state.

We believe this kind of approach – where groups of schools have the flexibility to propose the set of approaches they want – will lead to more impactful and durable systemic change that is attractive enough to be widely adopted by other schools.

This network of schools is using data to identify strategies that educators can use to solve specific problems. From 2007 to 2015, the percentage of students on track to graduate from Chicago high schools rose from 61 to 85 percent. And four-year college enrollment rates in Chicago went from 36 to 44 percent.

Excited by insights like these, school leaders in Chicago partnered with the University of Chicago to create the Network for College Success.

In Chicago, researchers also found powerful insights in their data that are predictive of student progress and success. They determined, for example, that 9th graders who succeed on four key indicators – high attendance, course completion rates, credit accumulation, and grades – are more than four times as likely to graduate. And if their grades are a B+ or higher, they are much more likely to succeed in their first year of college.

So, it identified the teachers whose EL students were doing the best, talked to them and curated their materials, and applied those best practices across all Summit schools. In less than a year, the performance gap between English Learners and others decreased by 25 percent.

Summit Public Schools, which operates 11 charter schools in California and Washington, analyzed data and determined that English Learners entered school significantly behind and never caught up.

In Fresno, a new data system revealed that students weren’t aware of their college options. So, the district created individualized college information packets for every senior who met the state’s college requirements. The result was a 50 percent increase in the number of students applying to California public universities.

Many states, districts, and schools now have the data they need to track student progress and achievement, and some are using it to great effect.

We anticipate that about 60 percent of this will eventually support the development of new curricula and networks of schools that work together to identify local problems and solutions… and use data to drive continuous improvement.

Overall, we expect to invest close to $1.7 billion in U.S. public education over the next five years.

Finally, we will expand investments in innovative research to accelerate progress for underserved students.

There is some great learning coming from charters, but because there is other philanthropic money going to them, we will focus more of our work with charters on developing new tools and strategies for students with special needs.

Fourth, we will continue to support the development of high-quality charter schools.

Third, we are increasing our commitment to develop curricula and professional development aligned to state standards.

Second, we will focus on locally-driven solutions identified by networks of schools, and support their efforts to use data-driven continuous learning and evidence-based interventions to improve student achievement.

First, although we will no longer invest directly in new initiatives based on teacher evaluations and ratings, we will continue to gather data on the impact of these systems and encourage the use of these systems to improve instruction at the local level.

So, what does this mean for our work with you and others?

And last, schools are the unit of change in the effort to increase student achievement and they face common challenges – like inadequate curricular systems and insufficient support for students as they move between middle school, high school and college. And they need better strategies to develop students’ social and emotional skills. But solutions to these problems will only endure if they are aligned with the unique needs of each student and the district’s broader strategy for change.

Schools that track indicators of student progress — like test scores, attendance, suspensions, and grades and credit accumulation – improved high school graduation and college success rates.

Teachers need better curricula and professional development aligned with the Common Core. And we see that they benefit the most from professional development when they are working with colleagues to tackle the real problems confronting their students.

As we have reflected on our work and spoken with educators over the last few years, we have identified a few key insights that will shape our work and investments going forward.

As you know, we also backed the Common Core because we believed, and still believe, that all students – no matter where they go to school – should graduate with the skills and knowledge to succeed after high school. It’s exciting to see how the standards are being brought to life in schools and classrooms. But more needs to be done to fully realize their potential.

In addition, it became clear that teacher evaluation is one important piece of several critical elements to drive student achievement. School leadership, teacher professional development, climate, and curriculum also play critical roles in improving student achievement.

But districts and states have varied in how they have implemented these systems because they each operate in their local context.

This work has helped states across the country build comprehensive evaluation systems based on multiple measures. We’ve seen promising results in places like Cincinnati, Chicago, New York City, and Washington DC, where research shows these systems can help identify teachers who need to improve and those who are underperforming… and in places like Tennessee, where three out of four teachers say the evaluation process improves their teaching.

In 2007, we began investing in the Measures of Effective Teaching project. Over the last decade, it has contributed important knowledge to the field about how to gather feedback from students on their engagement and classroom learning experiences… and about observing teachers at their craft, assessing their performance fairly, and providing actionable feedback.

Understanding this, we saw an opportunity to move our work closer to the classroom – to systemically support schools across the country to improve the quality of teaching and raise academic standards.

Over time, we realized that what made the most successful schools successful – large or small – was their teachers, their relationships with students, and their high expectations of student achievement.

Results in other places – like Los Angeles and the Rio Grande Valley in Texas -were also encouraging. Yet, over time, we saw that the overall impact of this strategy was limited—the financial and political costs of closing existing schools and replacing them with new schools was too high.

In New York City, graduation rates of students attending small schools was more than 30 percentage points higher than the schools they replaced. And almost half of the students attending small schools enrolled in postsecondary education – a more than 20 percent difference from schools with similar demographics.

When we first got involved in U.S. education, we thought smaller schools were the way to increase high school graduation and college-readiness rates. In some places and in some ways, small schools worked.

Melinda and I made public education our top priority in the U.S. because we wanted to do something about the disparity in achievement and postsecondary success for students of color and low-income students. That inequity persists today, and we are just as determined now to eliminate it as we were when we started.

But like many of you, we want to see faster and lasting change in student achievement – and our commitment to that goal is steadfast. In fact, given the constraints and other demands on state and local budgets, it’s more important than ever that we continue to explore the best ideas for improving student achievement.

Fourth-grade reading and math scores in large city schools increased at almost double the rate of public schools nationally. And the 8th grade scores are even better.

There are some signs of progress. Over the past decade, in cities like Charlotte, Austin, and Fresno, high school graduation rates have gone up rapidly.

Without success in college or career preparation programs, students will have limited economic mobility and fewer opportunities throughout their lives. This threatens not only their economic future but the economic future and competitiveness of the United States.

And for all students in U.S. public schools, the percentage of high school graduates who enroll in postsecondary institutions has remained essentially flat.

When disaggregated by race, we see two Americas. One where white students perform along the lines of the best in the world—with achievement comparable to countries like Finland and Korea. And another America, where Black and Latino students perform comparably to the students in the lowest performing OECD countries, such as Chile and Greece.

While much has rightly been made of the OECD data that shows lagging performance of American students overall, the national averages mask a bigger story.

But first, I’d like to say a few words about the state of public education in the U.S. By and large, schools are still falling short on the key metrics of a quality education – math scores, English scores, international comparisons, and college completion.

Today, I’d like to share what we have learned over the last 17 years and how those insights will change what we focus on over the next five years.

And, taking their best ideas, we wanted to pilot potentially transformative solutions and understand what worked well and what didn’t.

We wanted to work with educators to better understand their needs and the needs of their students and communities.

Our #1 priority was – and still is – ensuring that all students get a great public education and graduate with the skills to succeed in the workplace.

When our foundation began working in education in 2000, we started with a few guiding principles.

Based on everything we have learned in the past 17 years, we are evolving our education strategy. I explained what’s changing in a speech today at the Council of the Great City Schools. Here’s the text of my speech:

Melinda and I got involved in U.S. education in 2000. A lot has changed since then, but our goal has not: We still want all children in America to get a great education. It’s key to realizing the vision of America as a country where all people have a chance to make the most of their talents.

Our Education Efforts Are Evolving

Bill Gates, “Our Education Efforts Are Evolving,”gatesnotes, October 19, 2017, https://www.gatesnotes.com/Education/Council-of-Great-City-Schools