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Scientists identify a plant molecule that sops up iron-rich heme

The peptide is used by legumes to control nitrogen-fixing bacteria; it may also offer leads for treating patients with too much heme in their blood

EP Staff



Written by Anne Trafton, MIT News Office

Symbiotic relationships between legumes and the bacteria that grow in their roots are critical for plant survival. Without those bacteria, the plants would have no source of nitrogen, an element that is essential for building proteins and other biomolecules, and they would be dependent on nitrogen fertilizer in the soil. 

To establish that symbiosis, some legume plants produce hundreds of peptides that help bacteria live within structures known as nodules within their roots. A new study from MIT reveals that one of these peptides has an unexpected function: It sops up all available heme, an iron-containing molecule. This sends the bacteria into an iron-starvation mode that ramps up their production of ammonia, the form of nitrogen that is usable for plants.

“This is the first of the 700 peptides in this system for which a really detailed molecular mechanism has been worked out,” says Graham Walker, the American Cancer Society Research Professor of Biology at MIT, a Howard Hughes Medical Institute Professor, and the senior author of the study.

This heme-sequestering peptide could have beneficial uses in treating a variety of human diseases, the researchers say. Removing free heme from the blood could help to treat diseases caused by bacteria or parasites that need heme to survive, such as P. gingivalis (periodontal disease) or toxoplasmosis, or diseases such as sickle cell disease or sepsis that release too much heme into the bloodstream.

“This study demonstrates that basic research in plant-microbe interactions also has potential to be translated to therapeutic applications,” says Siva Sankari, an MIT research scientist and the lead author of the study, which appears today in Nature Microbiology.

Other authors of the paper include Vignesh Babu, an MIT research scientist; Kevin Bian and Mary Andorfer, both MIT postdocs; Areej Alhhazmi, a former KACST-MIT Ibn Khaldun Fellowship for Saudi Arabian Women scholar; Kwan Yoon and Dante Avalos, MIT graduate students; Tyler Smith, an MIT instructor in biology; Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute investigator; Michael Yaffe, a David H. Koch Professor of Science and a member of MIT’s Koch Institute for Integrative Cancer Research; and Sebastian Lourido, the Latham Family Career Development Professor of Biology at MIT and a member of the Whitehead Institute for Biomedical Research.

Iron control

For nearly 40 years, Walker’s lab has been studying the symbiosis between legumes and rhizobia, a type of nitrogen-fixing bacteria. These bacteria convert nitrogen gas to ammonia, a critical step of the Earth’s nitrogen cycle that makes the element available to plants (and to animals that eat the plants).

Most of Walker’s work has focused on a clover-like plant called Medicago truncatula. Nitrogen-fixing bacteria elicit the formation of nodules on the roots of these plants and eventually end up inside the plant cells, where they convert to their symbiotic form called bacteroids.

Several years ago, plant biologists discovered that Medicago truncatula produces about 700 peptides that contribute to the formation of these bacteroids. These peptides are generated in waves that help the bacteria make the transition from living freely to becoming embedded into plant cells where they act as nitrogen-fixing machines.

Walker and his students picked one of these peptides, known as NCR247, to dig into more deeply. Initial studies revealed that when nitrogen-fixing bacteria were exposed to this peptide, 15 percent of their genes were affected. Many of the genes that became more active were involved in importing iron.

The researchers then found that when they fused NCR247 to a larger protein, the hybrid protein was unexpectedly reddish in color. This serendipitous observation led to the discovery that NCR247 binds heme, an organic ring-shaped iron-containing molecule that is an important component of hemoglobin, the protein that red blood cells use to carry oxygen.

Further studies revealed that when NCR247 is released into bacterial cells, it sequesters most of the heme in the cell, sending the cells into an iron-starvation mode that triggers them to begin importing more iron from the external environment.

“Usually bacteria fine-tune their iron metabolism, and they don’t take up more iron when there is already enough,” Sankari says. “What’s cool about this peptide is that it overrides that mechanism and indirectly regulates the iron content of the bacteria.”

Nitrogenase, the main enzyme that bacteria use to fix nitrogen, requires 24 to 32 atoms of iron per enzyme molecule, so the influx of extra iron likely helps those enzymes to become more active, the researchers say. This influx is timed to coincide with nitrogen fixation, they found.

“These peptides are produced in a wave in the nodules, and the production of this particular peptide is higher when the bacteria are preparing to fix nitrogen. If this peptide was secreted throughout the whole process, then the cell would have too much iron all the time, which is bad for the cell,” Sankari says.

Without the NCR247 peptide, Medicago truncatula and rhizobium cannot form an effective nitrogen-fixing symbiosis, the researchers showed.

“Many possible directions”

The peptide that the researchers studied in this work may have potential therapeutic uses. When heme is incorporated into hemoglobin, it performs a critical function in the body, but when it’s loose in the bloodstream, it can kill cells and promote inflammation. Free heme can accumulate in stored blood, so having a way to filter out the heme before the blood is transfused into a patient could be potentially useful.

A variety of human diseases lead to free heme circulating in the bloodstream, including sickle cell anemia, sepsis, and malaria. Additionally, some infectious parasites and bacteria depend on heme for their survival but cannot produce it, so they scavenge it from their environment. Treating such infections with a protein that takes up all available heme could help prevent the parasitic or bacterial cells from being able to grow and reproduce.

In this study, Lourido and members of his lab showed that treating the parasite Toxoplasma gondii with NCR427 prevented the parasite from forming plaques on human cells.

The researchers are now pursuing collaborations with other labs at MIT to explore some of these potential applications, with funding from a Professor Amar G. Bose Research Grant.

“There are many possible directions, but they’re all at a very early stage,” Walker says. “The number of potential clinical applications is very broad. You can place more than one bet in this game, which is an intriguing thing.”

Currently, the human protein hemopexin, which also binds to heme, is being explored as a possible treatment for sickle cell anemia. The NCR247 peptide could provide an easier to deploy alternative, the researchers say, because it is much smaller and could be easier to manufacture and deliver into the body.

The research was funded in part by the MIT Center for Environmental Health Sciences, the National Science Foundation, and the National Institutes of Health.

Science & Technology

A far-sighted approach to machine learning

New system can teach a group of cooperative or competitive AI agents to find an optimal long-term solution

EP Staff



Written by Adam Zewe, MIT News Office

Picture two teams squaring off on a football field. The players can cooperate to achieve an objective, and compete against other players with conflicting interests. That’s how the game works.

Creating artificial intelligence agents that can learn to compete and cooperate as effectively as humans remains a thorny problem. A key challenge is enabling AI agents to anticipate future behaviors of other agents when they are all learning simultaneously.

Because of the complexity of this problem, current approaches tend to be myopic; the agents can only guess the next few moves of their teammates or competitors, which leads to poor performance in the long run. 

Researchers from MIT, the MIT-IBM Watson AI Lab, and elsewhere have developed a new approach that gives AI agents a farsighted perspective. Their machine-learning framework enables cooperative or competitive AI agents to consider what other agents will do as time approaches infinity, not just over a few next steps. The agents then adapt their behaviors accordingly to influence other agents’ future behaviors and arrive at an optimal, long-term solution.

This framework could be used by a group of autonomous drones working together to find a lost hiker in a thick forest, or by self-driving cars that strive to keep passengers safe by anticipating future moves of other vehicles driving on a busy highway.

“When AI agents are cooperating or competing, what matters most is when their behaviors converge at some point in the future. There are a lot of transient behaviors along the way that don’t matter very much in the long run. Reaching this converged behavior is what we really care about, and we now have a mathematical way to enable that,” says Dong-Ki Kim, a graduate student in the MIT Laboratory for Information and Decision Systems (LIDS) and lead author of a paper describing this framework.

The senior author is Jonathan P. How, the Richard C. Maclaurin Professor of Aeronautics and Astronautics and a member of the MIT-IBM Watson AI Lab. Co-authors include others at the MIT-IBM Watson AI Lab, IBM Research, Mila-Quebec Artificial Intelligence Institute, and Oxford University. The research will be presented at the Conference on Neural Information Processing Systems.

More agents, more problems

The researchers focused on a problem known as multiagent reinforcement learning. Reinforcement learning is a form of machine learning in which an AI agent learns by trial and error. Researchers give the agent a reward for “good” behaviors that help it achieve a goal. The agent adapts its behavior to maximize that reward until it eventually becomes an expert at a task.

But when many cooperative or competing agents are simultaneously learning, things become increasingly complex. As agents consider more future steps of their fellow agents, and how their own behavior influences others, the problem soon requires far too much computational power to solve efficiently. This is why other approaches only focus on the short term.

“The AIs really want to think about the end of the game, but they don’t know when the game will end. They need to think about how to keep adapting their behavior into infinity so they can win at some far time in the future. Our paper essentially proposes a new objective that enables an AI to think about infinity,” says Kim.

But since it is impossible to plug infinity into an algorithm, the researchers designed their system so agents focus on a future point where their behavior will converge with that of other agents, known as equilibrium. An equilibrium point determines the long-term performance of agents, and multiple equilibria can exist in a multiagent scenario. Therefore, an effective agent actively influences the future behaviors of other agents in such a way that they reach a desirable equilibrium from the agent’s perspective. If all agents influence each other, they converge to a general concept that the researchers call an “active equilibrium.”

The machine-learning framework they developed, known as FURTHER (which stands for FUlly Reinforcing acTive influence witH averagE Reward), enables agents to learn how to adapt their behaviors as they interact with other agents to achieve this active equilibrium.

FURTHER does this using two machine-learning modules. The first, an inference module, enables an agent to guess the future behaviors of other agents and the learning algorithms they use, based solely on their prior actions.

This information is fed into the reinforcement learning module, which the agent uses to adapt its behavior and influence other agents in a way that maximizes its reward.

“The challenge was thinking about infinity. We had to use a lot of different mathematical tools to enable that, and make some assumptions to get it to work in practice,” Kim says.

Winning in the long run

They tested their approach against other multiagent reinforcement learning frameworks in several different scenarios, including a pair of robots fighting sumo-style and a battle pitting two 25-agent teams against one another. In both instances, the AI agents using FURTHER won the games more often.

Since their approach is decentralized, which means the agents learn to win the games independently, it is also more scalable than other methods that require a central computer to control the agents, Kim explains.

The researchers used games to test their approach, but FURTHER could be used to tackle any kind of multiagent problem. For instance, it could be applied by economists seeking to develop sound policy in situations where many interacting entitles have behaviors and interests that change over time.

Economics is one application Kim is particularly excited about studying. He also wants to dig deeper into the concept of an active equilibrium and continue enhancing the FURTHER framework.

This research is funded, in part, by the MIT-IBM Watson AI Lab.

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Flocks of assembler robots show potential for making larger structures

Researchers make progress toward groups of robots that could build almost anything, including buildings, vehicles, and even bigger robots

EP Staff



Written by David L. Chandler, MIT News Office

Researchers at MIT have made significant steps toward creating robots that could practically and economically assemble nearly anything, including things much larger than themselves, from vehicles to buildings to larger robots.

The new work, from MIT’s Center for Bits and Atoms (CBA), builds on years of research, including recent studies demonstrating that objects such as a deformable airplane wing and a functional racing car could be assembled from tiny identical lightweight pieces — and that robotic devices could be built to carry out some of this assembly work. Now, the team has shown that both the assembler bots and the components of the structure being built can all be made of the same subunits, and the robots can move independently in large numbers to accomplish large-scale assemblies quickly.

The new study shows that both the assembler bots and the components of the structure being built can all be made of the same subunits, and the robots can move independently in large numbers to accomplish large-scale assemblies quickly.
Credits:Courtesy of the researchers

The new work is reported in the journal Nature Communications Engineering, in a paper by CBA doctoral student Amira Abdel-Rahman, Professor and CBA Director Neil Gershenfeld, and three others.

A fully autonomous self-replicating robot assembly system capable of both assembling larger structures, including larger robots, and planning the best construction sequence is still years away, Gershenfeld says. But the new work makes important strides toward that goal, including working out the complex tasks of when to build more robots and how big to make them, as well as how to organize swarms of bots of different sizes to build a structure efficiently without crashing into each other.

As in previous experiments, the new system involves large, usable structures built from an array of tiny identical subunits called voxels (the volumetric equivalent of a 2-D pixel). But while earlier voxels were purely mechanical structural pieces, the team has now developed complex voxels that each can carry both power and data from one unit to the next. This could enable the building of structures that can not only bear loads but also carry out work, such as lifting, moving and manipulating materials — including the voxels themselves.

“When we’re building these structures, you have to build in intelligence,” Gershenfeld says. While earlier versions of assembler bots were connected by bundles of wires to their power source and control systems, “what emerged was the idea of structural electronics — of making voxels that transmit power and data as well as force.” Looking at the new system in operation, he points out, “There’s no wires. There’s just the structure.”

The robots themselves consist of a string of several voxels joined end-to-end. These can grab another voxel using attachment points on one end, then move inchworm-like to the desired position, where the voxel can be attached to the growing structure and released there.

Gershenfeld explains that while the earlier system demonstrated by members of his group could in principle build arbitrarily large structures, as the size of those structures reached a certain point in relation to the size of the assembler robot, the process would become increasingly inefficient because of the ever-longer paths each bot would have to travel to bring each piece to its destination. At that point, with the new system, the bots could decide it was time to build a larger version of themselves that could reach longer distances and reduce the travel time. An even bigger structure might require yet another such step, with the new larger robots creating yet larger ones, while parts of a structure that include lots of fine detail may require more of the smallest robots.

As these robotic devices work on assembling something, Abdel-Rahman says, they face choices at every step along the way: “It could build a structure, or it could build another robot of the same size, or it could build a bigger robot.” Part of the work the researchers have been focusing on is creating the algorithms for such decision-making.

“For example, if you want to build a cone or a half-sphere,” she says, “how do you start the path planning, and how do you divide this shape” into different areas that different bots can work on? The software they developed allows someone to input a shape and get an output that shows where to place the first block, and each one after that, based on the distances that need to be traversed.

There are thousands of papers published on route-planning for robots, Gershenfeld says. “But the step after that, of the robot having to make the decision to build another robot or a different kind of robot — that’s new. There’s really nothing prior on that.”

While the experimental system can carry out the assembly and includes the power and data links, in the current versions the connectors between the tiny subunits are not strong enough to bear the necessary loads. The team, including graduate student Miana Smith, is now focusing on developing stronger connectors. “These robots can walk and can place parts,” Gershenfeld says, “but we are almost — but not quite — at the point where one of these robots makes another one and it walks away. And that’s down to fine-tuning of things, like the force of actuators and the strength of joints. … But it’s far enough along that these are the parts that will lead to it.”

Ultimately, such systems might be used to construct a wide variety of large, high-value structures. For example, currently the way airplanes are built involves huge factories with gantries much larger than the components they build, and then “when you make a jumbo jet, you need jumbo jets to carry the parts of the jumbo jet to make it,” Gershenfeld says. With a system like this built up from tiny components assembled by tiny robots, “The final assembly of the airplane is the only assembly.”

Similarly, in producing a new car, “you can spend a year on tooling” before the first car gets actually built, he says. The new system would bypass that whole process. Such potential efficiencies are why Gershenfeld and his students have been working closely with car companies, aviation companies, and NASA. But even the relatively low-tech building construction industry could potentially also benefit.

While there has been increasing interest in 3-D-printed houses, today those require printing machinery as large or larger than the house being built. Again, the potential for such structures to instead be assembled by swarms of tiny robots could provide benefits. And the Defense Advanced Research Projects Agency is also interested in the work for the possibility of building structures for coastal protection against erosion and sea level rise.

The research team also included MIT-CBA student Benjamin Jenett and Christopher Cameron, who is now at the U.S. Army Research Laboratory. The work was supported by NASA, the U.S. Army Research Laboratory, and CBA consortia funding.

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Science & Technology

Study: Automation drives income inequality

New data suggest most of the growth in the wage gap since 1980 comes from automation displacing less-educated workers




Written by Peter Dizikes, MIT News

When you use self-checkout machines in supermarkets and drugstores, you are probably not — with all due respect — doing a better job of bagging your purchases than checkout clerks once did. Automation just makes bagging less expensive for large retail chains.

“If you introduce self-checkout kiosks, it’s not going to change productivity all that much,” says MIT economist Daron Acemoglu. However, in terms of lost wages for employees, he adds, “It’s going to have fairly large distributional effects, especially for low-skill service workers. It’s a labor-shifting device, rather than a productivity-increasing device.”

A newly published study co-authored by Acemoglu quantifies the extent to which automation has contributed to income inequality in the U.S., simply by replacing workers with technology — whether self-checkout machines, call-center systems, assembly-line technology, or other devices. Over the last four decades, the income gap between more- and less-educated workers has grown significantly; the study finds that automation accounts for more than half of that increase.

“This single one variable … explains 50 to 70 percent of the changes or variation between group inequality from 1980 to about 2016,” Acemoglu says.

The paper, “Tasks, Automation, and the Rise in U.S. Wage Inequality,” is being published in Econometrica. The authors are Acemoglu, who is an Institute Professor at MIT, and Pascual Restrepo PhD ’16, an assistant professor of economics at Boston University.

So much “so-so automation”

Since 1980 in the U.S., inflation-adjusted incomes of those with college and postgraduate degrees have risen substantially, while inflation-adjusted earnings of men without high school degrees has dropped by 15 percent.

How much of this change is due to automation? Growing income inequality could also stem from, among other things, the declining prevalence of labor unions, market concentration begetting a lack of competition for labor, or other types of technological change.

To conduct the study, Acemoglu and Restrepo used U.S. Bureau of Economic Analysis statistics on the extent to which human labor was used in 49 industries from 1987 to 2016, as well as data on machinery and software adopted in that time. The scholars also used data they had previously compiled about the adoption of robots in the U.S. from 1993 to 2014. In previous studies, Acemoglu and Restrepo have found that robots have by themselves replaced a substantial number of workers in the U.S., helped some firms dominate their industries, and contributed to inequality.

At the same time, the scholars used U.S. Census Bureau metrics, including its American Community Survey data, to track worker outcomes during this time for roughly 500 demographic subgroups, broken out by gender, education, age, race and ethnicity, and immigration status, while looking at employment, inflation-adjusted hourly wages, and more, from 1980 to 2016. By examining the links between changes in business practices alongside changes in labor market outcomes, the study can estimate what impact automation has had on workers.

Ultimately, Acemoglu and Restrepo conclude that the effects have been profound. Since 1980, for instance, they estimate that automation has reduced the wages of men without a high school degree by 8.8 percent and women without a high school degree by 2.3 percent, adjusted for inflation. 

A central conceptual point, Acemoglu says, is that automation should be regarded differently from other forms of innovation, with its own distinct effects in workplaces, and not just lumped in as part of a broader trend toward the implementation of technology in everyday life generally.

Consider again those self-checkout kiosks. Acemoglu calls these types of tools “so-so technology,” or “so-so automation,” because of the tradeoffs they contain: Such innovations are good for the corporate bottom line, bad for service-industry employees, and not hugely important in terms of overall productivity gains, the real marker of an innovation that may improve our overall quality of life.

“Technological change that creates or increases industry productivity, or productivity of one type of labor, creates [those] large productivity gains but does not have huge distributional effects,” Acemoglu says. “In contrast, automation creates very large distributional effects and may not have big productivity effects.”

A new perspective on the big picture

The results occupy a distinctive place in the literature on automation and jobs. Some popular accounts of technology have forecast a near-total wipeout of jobs in the future. Alternately, many scholars have developed a more nuanced picture, in which technology disproportionately benefits highly educated workers but also produces significant complementarities between high-tech tools and labor.

The current study differs at least by degree with this latter picture, presenting a more stark outlook in which automation reduces earnings power for workers and potentially reduces the extent to which policy solutions — more bargaining power for workers, less market concentration — could mitigate the detrimental effects of automation upon wages.

“These are controversial findings in the sense that they imply a much bigger effect for automation than anyone else has thought, and they also imply less explanatory power for other [factors],” Acemoglu says.

Still, he adds, in the effort to identify drivers of income inequality, the study “does not obviate other nontechnological theories completely. Moreover, the pace of automation is often influenced by various institutional factors, including labor’s bargaining power.”

Labor economists say the study is an important addition to the literature on automation, work, and inequality, and should be reckoned with in future discussions of these issues.

For their part, in the paper Acemoglu and Restrepo identify multiple directions for future research. That includes investigating the reaction over time by both business and labor to the increase in automation; the quantitative effects of technologies that do create jobs; and the industry competition between firms that quickly adopted automation and those that did not.

The research was supported in part by Google, the Hewlett Foundation, Microsoft, the National Science Foundation, Schmidt Sciences, the Sloan Foundation, and the Smith Richardson Foundation.

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