From The DOE’s Brookhaven National Laboratory: “Structure of ‘Oil-Eating’ Enzyme Opens Door to Bioengineered Catalysts”

From The DOE’s Brookhaven National Laboratory

3.30.23
Karen McNulty Walsh
kmcnulty@bnl.gov
(631) 344-8350

Peter Genzer
genzer@bnl.gov
(631) 344-3174

Atomic level details reveal how enzyme selectively breaks hydrocarbon bonds suggesting bioengineering strategies for making useful chemicals.

Long-sought structure of oil-eating enzyme complex: A high-resolution cryo-EM map of the transmembrane two-protein complex (left) allows researchers to determine the locations of individual amino acids that make up the two proteins (right). AlkG (gray) serves and an electron carrier, transporting electrons from its single iron atom (red sphere) to the two iron atoms (red spheres) at the active site of the AlkB enzyme (colorful ribbon structure). The magenta structure below the active site is the substrate (see close-up views). Credit: BNL.

Scientists at the U.S. Department of Energy’s Brookhaven National Laboratory have produced the first atomic-level structure of an enzyme that selectively cuts carbon-hydrogen bonds—the first and most challenging step in turning simple hydrocarbons into more useful chemicals. As described in a paper just published in Nature Structural & Molecular Biology [below], the detailed atomic level “blueprint” suggests ways to engineer the enzyme to produce desired products.

“We want to create a diverse pool of biocatalysts where you can specifically select the desired substrate to produce wanted and unique products from abundant hydrocarbons,” said study co-lead Qun Liu, a Brookhaven Lab structural biologist. “The approach would give us a controllable way to convert cheap and abundant alkanes—simple carbon-hydrogen compounds that make up 20-50 percent of crude oil—into more valuable bioproducts or chemical precursors, including alcohols, aldehydes, carboxylates, and epoxides.”

The idea is particularly attractive because most industrial catalytic processes used for alkane conversions produce unwanted byproducts and heat-trapping carbon dioxide (CO2) gas. They also contain costly materials and require high temperatures and pressure. The biological enzyme, known as AlkB, operates under more ordinary conditions and with very high specificity. It uses inexpensive earth-abundant iron to initiate the chemistry while producing few unwanted byproducts.

“Nature has figured out how to do this kind of chemistry with an inexpensive abundant metal and at ambient temperature and pressures,” said John Shanklin, chair of Brookhaven Lab’s Biology Department and a senior author on the paper. “As a result, there’s been massive interest in this enzyme, but a complete lack of understanding of its architecture and how it works—which is necessary to re-engineer it for new purposes. With this structure, we have now overcome this obstacle.”

From rancid oil to sweet success

Research team: Brookhaven Lab scientists Jin Chai, Qun Liu, John Shanklin, and Sean McSweeney stand in front of the cryo-electron microscope (cryo-EM) used to decipher the long-sought structure of an enzyme that selectively cleaves hydrocarbon bonds. Credit: BNL.

AlkB was discovered 50 years ago in a machine shop where bacteria were digesting cooling oil making it smell rancid. Biochemists discovered the bacterial enzyme AlkB as the factor enabling the microbes’ unusual appetite. Scientists have been interested in harnessing AlkB’s hydrocarbon-chomping ability ever since.

Over the years, studies revealed that the enzyme sits partially embedded in the bacteria’s membranes, and that it operates in conjunction with two other proteins. Shanklin and Liu—and scientists elsewhere—tried solving the enzyme’s structure using x-ray crystallography. That method bounces high-intensity x-rays off a crystallized version of a protein to identify where the atoms are. But membrane proteins like AlkB are notoriously difficult to crystallize—especially when they are part of a multi-protein complex.

“We couldn’t get high enough resolution,” Liu said.

Then in early 2021, Brookhaven opened its new cryo-electron microscope (cryo-EM) facility, the Laboratory for BioMolecular Structure (LBMS). The scientists used a cryo-EM, which does not require a crystallized sample, to take pictures of a few million individual frozen protein molecules from many different angles. Computational tools then sorted through the images, identified and averaged the common features—and ultimately generated a high-resolution, three-dimensional map of the enzyme complex. Using this map, the scientists then pieced together the known atomic-level structures of the individual amino acids that make up the protein complex to fill in the details in three dimensions.

Identifying the right conditions to stabilize the transmembrane region of the enzyme and maintain the structural details was a challenge that required a good deal of trial and error. Shanklin credits Jin Chai, one of the researchers in his lab, “for his commitment and determination to solving this puzzle.”

Structure reveals how enzyme works

The detailed structure shows exactly how AlkB and one of the two associated proteins (AlkG) work together to cleave carbon-hydrogen bonds. In fact, the solved structure contained an unexpected bonus: a substrate alkane molecule that was trapped in the enzyme’s active site cavity.

Active site: These closeups of the AlkB active site show how nine histidine amino acids (denoted as “H” in the left image) form a cavity (gray shaded region, right). This cavity guides the substrate (magenta) to the active site (near the two iron, Fe, atoms) in a single orientation, where only the terminal carbon-hydrogen bond can be cleaved. Modifying the enzyme to change the shape of this cavity could allow the enzyme to attack different C-H bonds. Credit: BNL.

“Our structure shows how the amino acids that make up this enzyme form a cavity that orients the hydrocarbon substrate so that just one specific carbon-hydrogen bond can approach the active site,” Liu said. “It also shows how electrons move from the carrier protein (AlkG) to the di-iron center at the enzyme’s active site, allowing it to activate a molecule of oxygen to attack this bond.”

Shanklin suggests thinking of the enzyme as a bond-cutting machine like a circular saw: “How you hold the alkane with respect to the enzyme’s di-iron center determines how the activated oxygen interacts with the hydrocarbon. If you guide the end of the alkane against the activated oxygen, it’s going to initiate some chemistry on that last carbon.

“The engineering we want to do is to change the shape of the active site cavity so we can have the substrate (or a different substrate) approach the activated oxygen at different angles and in different C-H bond locations to perform different reactions.”

In nature, the scientists noted, a third protein not included in this structure (AlkT) provides the electrons to AlkG, the carrier protein. The carrier protein then transports the electrons to the two iron atoms that activate oxygen at AlkB’s active site. Replacing that electron donating protein with an electrode to supply electrons would be simpler and less costly than using the biological electron donor, they suggest.

DOE just funded the team’s proposal to develop such ‘Transformative Biohybrid Diiron Catalysts for C-H Bond Functionalization,’ based in part on this preliminary structural work.

“This structure and our knowledge of how the AlkG/AlkB complex works, puts us in a great position to bioengineer this enzyme to select which carbon-hydrogen bond gets activated in a variety of substrates and to control the electrons and oxygen to re-engineer its selectivity,” Liu said.

This work was supported by the DOE Office of Science (BES) and by Laboratory Directed Research and Development funds at Brookhaven Lab. LBMS is supported by the DOE Office of Science (BER). This research also used resources of Brookhaven Lab’s Center for Functional Nanomaterials (CFN), which is a U.S. Department of Energy Office of Science (BES) User Facility.

Nature Structural & Molecular Biology
See the science paper for instructive material with images.

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Brookhaven Campus. Credit: BNL.

One of ten national laboratories overseen and primarily funded by the The DOE Office of Science, The DOE’s Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world. Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.

Research at BNL specializes in nuclear and high energy physics, energy science and technology, environmental and bioscience, nanoscience and national security. The 5300 acre campus contains several large research facilities, including the Relativistic Heavy Ion Collider [below] and National Synchrotron Light Source II [below]. Seven Nobel prizes have been awarded for work conducted at Brookhaven lab.

BNL is staffed by approximately 2,750 scientists, engineers, technicians, and support personnel, and hosts 4,000 guest investigators every year. The laboratory has its own police station, fire department, and ZIP code (11973). In total, the lab spans a 5,265-acre (21 km^2) area that is mostly coterminous with the hamlet of Upton, New York. BNL is served by a rail spur operated as-needed by the New York and Atlantic Railway. Co-located with the laboratory is the Upton, New York, forecast office of the National Weather Service.

Major programs

Although originally conceived as a nuclear research facility, Brookhaven Lab’s mission has greatly expanded. Its foci are now:

Nuclear and high-energy physics
Physics and chemistry of materials
Environmental and climate research
Nanomaterials
Energy research
Nonproliferation
Structural biology
Accelerator physics

Operation

Brookhaven National Lab was originally owned by the Atomic Energy Commission and is now owned by that agency’s successor, the United States Department of Energy (DOE). DOE subcontracts the research and operation to universities and research organizations. It is currently operated by Brookhaven Science Associates LLC, which is an equal partnership of Stony Brook University and Battelle Memorial Institute. From 1947 to 1998, it was operated by Associated Universities, Inc. (AUI), but AUI lost its contract in the wake of two incidents: a 1994 fire at the facility’s high-beam flux reactor that exposed several workers to radiation and reports in 1997 of a tritium leak into the groundwater of the Long Island Central Pine Barrens on which the facility sits.

Foundations

Following World War II, the US Atomic Energy Commission was created to support government-sponsored peacetime research on atomic energy. The effort to build a nuclear reactor in the American northeast was fostered largely by physicists Isidor Isaac Rabi and Norman Foster Ramsey Jr., who during the war witnessed many of their colleagues at Columbia University leave for new remote research sites following the departure of the Manhattan Project from its campus. Their effort to house this reactor near New York City was rivalled by a similar effort at the Massachusetts Institute of Technology to have a facility near Boston, Massachusetts. Involvement was quickly solicited from representatives of northeastern universities to the south and west of New York City such that this city would be at their geographic center. In March 1946 a nonprofit corporation was established that consisted of representatives from nine major research universities — Columbia University, Cornell University, Harvard University, Johns Hopkins University, Massachusetts Institute of Technology, Princeton University, University of Pennsylvania, University of Rochester, and Yale University.

Out of 17 considered sites in the Boston-Washington corridor, Camp Upton on Long Island was eventually chosen as the most suitable in consideration of space, transportation, and availability. The camp had been a training center from the US Army during both World War I and World War II. After the latter war, Camp Upton was deemed no longer necessary and became available for reuse. A plan was conceived to convert the military camp into a research facility.

On March 21, 1947, the Camp Upton site was officially transferred from the U.S. War Department to the new U.S. Atomic Energy Commission (AEC), predecessor to the U.S. Department of Energy (DOE).

Research and facilities

Reactor history

In 1947 construction began on the first nuclear reactor at Brookhaven, the Brookhaven Graphite Research Reactor. This reactor, which opened in 1950, was the first reactor to be constructed in the United States after World War II. The High Flux Beam Reactor operated from 1965 to 1999. In 1959 Brookhaven built the first US reactor specifically tailored to medical research, the Brookhaven Medical Research Reactor, which operated until 2000.

Accelerator history

In 1952 Brookhaven began using its first particle accelerator, the Cosmotron. At the time the Cosmotron was the world’s highest energy accelerator, being the first to impart more than 1 GeV of energy to a particle.

BNL Cosmotron 1952-1966.

The Cosmotron was retired in 1966, after it was superseded in 1960 by the new Alternating Gradient Synchrotron (AGS).

BNL Alternating Gradient Synchrotron (AGS).

The AGS was used in research that resulted in 3 Nobel prizes, including the discovery of the muon neutrino, the charm quark, and CP violation.

In 1970 in BNL started the ISABELLE project to develop and build two proton intersecting storage rings.

The groundbreaking for the project was in October 1978. In 1981, with the tunnel for the accelerator already excavated, problems with the superconducting magnets needed for the ISABELLE accelerator brought the project to a halt, and the project was eventually cancelled in 1983.

The National Synchrotron Light Source operated from 1982 to 2014 and was involved with two Nobel Prize-winning discoveries. It has since been replaced by the National Synchrotron Light Source II. [below].

BNL National Synchrotron Light Source.

After ISABELLE’S cancellation, physicist at BNL proposed that the excavated tunnel and parts of the magnet assembly be used in another accelerator. In 1984 the first proposal for the accelerator now known as the Relativistic Heavy Ion Collider (RHIC)[below] was put forward. The construction got funded in 1991 and RHIC has been operational since 2000. One of the world’s only two operating heavy-ion colliders, RHIC is as of 2010 the second-highest-energy collider after the Large Hadron Collider (CH). RHIC is housed in a tunnel 2.4 miles (3.9 km) long and is visible from space.

On January 9, 2020, it was announced by Paul Dabbar, undersecretary of the US Department of Energy Office of Science, that the BNL eRHIC design has been selected over the conceptual design put forward by DOE’s Thomas Jefferson National Accelerator Facility [Jlab] as the future Electron–ion collider (EIC) in the United States.

Electron-Ion Collider (EIC) at DOE’s Brookhaven National Laboratory to be built inside the tunnel that currently houses the Relativistic Heavy Ion Collider [RHIC]. Credit: BNL.

In addition to the site selection, it was announced that the BNL EIC had acquired CD-0 from the Department of Energy. BNL’s eRHIC design proposes upgrading the existing Relativistic Heavy Ion Collider, which collides beams light to heavy ions including polarized protons, with a polarized electron facility, to be housed in the same tunnel.

Other discoveries

In 1958, Brookhaven scientists created one of the world’s first video games, Tennis for Two. In 1968 Brookhaven scientists patented Maglev, a transportation technology that utilizes magnetic levitation.

Major facilities

Relativistic Heavy Ion Collider (RHIC), which was designed to research quark–gluon plasma and the sources of proton spin. Until 2009 it was the world’s most powerful heavy ion collider. It is the only collider of spin-polarized protons.

Center for Functional Nanomaterials (CFN), used for the study of nanoscale materials.

BNL National Synchrotron Light Source II, Brookhaven’s newest user facility, opened in 2015 to replace the National Synchrotron Light Source (NSLS), which had operated for 30 years. NSLS was involved in the work that won the 2003 and 2009 Nobel Prize in Chemistry.

Alternating Gradient Synchrotron, a particle accelerator that was used in three of the lab’s Nobel prizes.
Accelerator Test Facility, generates, accelerates and monitors particle beams.
Tandem Van de Graaff, once the world’s largest electrostatic accelerator.

Computational Science resources, including access to a massively parallel Blue Gene series supercomputer that is among the fastest in the world for scientific research, run jointly by Brookhaven National Laboratory and Stony Brook University-SUNY.

Interdisciplinary Science Building, with unique laboratories for studying high-temperature superconductors and other materials important for addressing energy challenges.
NASA Space Radiation Laboratory, where scientists use beams of ions to simulate cosmic rays and assess the risks of space radiation to human space travelers and equipment.

Off-site contributions

It is a contributing partner to the ATLAS experiment, one of the four detectors located at the The European Organization for Nuclear Research [La Organización Europea para la Investigación Nuclear][Organization européenne pour la recherche nucléaire] [Europäische Organization für Kernforschung](CH)[CERN] Large Hadron Collider(LHC). Credit: CERN.

The European Organization for Nuclear Research [La Organización Europea para la Investigación Nuclear][Organization européenne pour la recherche nucléaire] [Europäische Organization für Kernforschung](CH)[CERN] map. Credit: CERN.

The European Organization for Nuclear Research [La Organización Europea para la Investigación Nuclear][ Organization européenne pour la recherche nucléaire] [Europäische Organization für Kernforschung] By now iconic image of (CH)[CERN] ATLAS. Credit: CERN.

It is currently operating at The European Organization for Nuclear Research [La Organización Europea para la Investigación Nuclear][Organization européenne pour la recherche nucléaire] [Europäische Organization für Kernforschung](CH) [CERN] near Geneva, Switzerland.

Brookhaven was also responsible for the design of the Spallation Neutron Source at DOE’s Oak Ridge National Laboratory, Tennessee.

DOE’s Oak Ridge National Laboratory Spallation Neutron Source annotated.

Brookhaven plays a role in a range of neutrino research projects around the world, including the Daya Bay Neutrino Experiment (CN) nuclear power plant, approximately 52 kilometers northeast of Hong Kong and 45 kilometers east of Shenzhen, China.

Daya Bay Neutrino Experiment (CN) nuclear power plant, approximately 52 kilometers northeast of Hong Kong and 45 kilometers east of Shenzhen, China .

DOE’s Fermi National Accelerator Laboratory DUNE LBNF from FNAL to Sanford Underground Research Facility, Lead, South Dakota.

BNL Center for Functional Nanomaterials. Credit: BNL.

DOE’s Brookhaven National Laboratory NSLS II. Interior. Credit: BNL.

DOE’s Brookhaven National Laboratory NSLS II. Credit: BNL.

DOE’s Brookhaven National Laboratory(US) RHIC Campus. Credit: BNL.

BNL RHIC’s newly enhanced STAR detector. The house-size STAR detector at the Relativistic Heavy Ion Collider (RHIC) acts like a giant 3D digital camera to track particles emerging from particle collisions at the center of the detector.

DOE’s Brookhaven National Laboratory(US)/RHIC Phenix detector. Credit: BNL..

Brookhaven sPhenix Assembly. Credit: BNL.

BNL RHIC Schematic view of the proposed sPHENIX detector. Credit: BNL.

BNL RHIC inner hadronic calorimeter being installed in the sPHENIX Detector. Credit: BNL.

From Massachusetts Institute of Technology (US) : “The power of two”

From Massachusetts Institute of Technology (US)

June 30, 2021
Saima Sidik | Department of Biology

Graduate student Ellen Zhong helped biologists and mathematicians reach across departmental lines to address a longstanding problem in electron microscopy.

Ellen Zhong, a graduate student from the Computational and Systems Biology Program, is using a computational pattern-recognition tool called a neural network to study the shapes of molecular machines.
Credit: Matthew Brown.

MIT’s Hockfield Court is bordered on the west by the ultramodern Stata Center, with its reflective, silver alcoves that jut off at odd angles, and on the east by Building 68, which is a simple, window-lined, cement rectangle. At first glance, Bonnie Berger’s mathematics lab in the Stata Center and Joey Davis’s biology lab in Building 68 are as different as the buildings that house them. And yet, a recent collaboration between these two labs shows how their disciplines complement each other. The partnership started when Ellen Zhong, a graduate student from the Computational and Systems Biology (CSB) Program, decided to use a computational pattern-recognition tool called a neural network to study the shapes of molecular machines. Three years later, Zhong’s project is letting scientists see patterns that run beneath the surface of their data, and deepening their understanding of the molecules that shape life.

Zhong’s work builds on a technique from the 1970s called cryo-electron microscopy (cryo-EM), which lets researchers take high-resolution images of frozen protein complexes. Over the past decade, better microscopes and cameras have led to a “resolution revolution” in cryo-EM that’s allowed scientists to see individual atoms within proteins. But, as good as these images are, they’re still only static snapshots. In reality, many of these molecular machines are constantly changing shape and composition as cells carry out their normal functions and adjust to new situations.

Along with former Berger lab member Tristan Belper, Zhong devised software called cryoDRGN. The tool uses neural nets to combine hundreds of thousands of cryo-EM images, and shows scientists the full range of three-dimensional conformations that protein complexes can take, letting them reconstruct the proteins’ motion as they carry out cellular functions. Understanding the range of shapes that protein complexes can take helps scientists develop drugs that block viruses from entering cells, study how pests kill crops, and even design custom proteins that can cure disease. Covid-19 vaccines, for example, work partly because they include a mutated version of the virus’s spike protein that’s stuck in its active conformation, so vaccinated people produce antibodies that block the virus from entering human cells. Scientists needed to understand the variety of shapes that spike proteins can take in order to figure out how to force spike into its active conformation.

Getting off the computer and into the lab

Zhong’s interest in computational biology goes back to 2011 when, as a chemical engineering undergrad at the University of Virginia (US), she worked with Professor Michael Shirts to simulate how proteins fold and unfold. After college, Zhong took her skills to a company called D. E. Shaw Research, where, as a scientific programmer, she took a computational approach to studying how proteins interact with small-molecule drugs.

“The research was very exciting,” Zhong says, “but all based on computer simulations. To really understand biological systems, you need to do experiments.”

This goal of combining computation with experimentation motivated Zhong to join MIT’s CSB PhD program, where students often work with multiple supervisors to blend computational work with bench work. Zhong “rotated” in both the Davis and Berger labs, then decided to combine the Davis lab’s goal of understanding how protein complexes form with the Berger lab’s expertise in machine learning and algorithms. Davis was interested in building up the computational side of his lab, so he welcomed the opportunity to co-supervise a student with Berger, who has a long history of collaborating with biologists.

Davis himself holds a dual bachelor’s degree in computer science and biological engineering, so he’s long believed in the power of combining complementary disciplines. “There are a lot of things you can learn about biology by looking in a microscope,” he says. “But as we start to ask more complicated questions about entire systems, we’re going to require computation to manage the high-dimensional data that come back.”

Reconstructing Molecules in Motion.

Before rotating in the Davis lab, Zhong had never performed bench work before — or even touched a pipette. She was fascinated to find how streamlined some very powerful molecular biology techniques can be. Still, Zhong realized that physical limitations mean that biology is much slower when it’s done at the bench instead of on a computer. “With computational research, you can automate experiments and run them super quickly, whereas in the wet lab, you only have two hands, so you can only do one experiment at a time,” she says.

Zhong says that synergizing the two different cultures of the Davis and Berger labs is helping her become a well-rounded, adaptable scientist. Working around experimentalists in the Davis lab has shown her how much labor goes into experimental results, and also helped her to understand the hurdles that scientists face at the bench. In the Berger lab, she enjoys having coworkers who understand the challenges of computer programming.

“The key challenge in collaborating across disciplines is understanding each other’s ‘languages,’” Berger says. “Students like Ellen are fortunate to be learning both biology and computing dialects simultaneously.”

Bringing in the community

Last spring revealed another reason for biologists to learn computational skills: these tools can be used anywhere there’s a computer and an internet connection. When the Covid-19 pandemic hit, Zhong’s colleagues in the Davis lab had to wind down their bench work for a few months, and many of them filled their time at home by using cryo-EM data that’s freely available online to help Zhong test her cryoDRGN software. The difficulty of understanding another discipline’s language quickly became apparent, and Zhong spent a lot of time teaching her colleagues to be programmers. Seeing the problems that nonprogrammers ran into when they used cryoDRGN was very informative, Zhong says, and helped her create a more user-friendly interface.

Although the paper announcing cryoDRGN was just published in February, the tool created a stir as soon as Zhong posted her code online, many months prior. The cryoDRGN team thinks this is because leveraging knowledge from two disciplines let them visualize the full range of structures that protein complexes can have, and that’s something researchers have wanted to do for a long time. For example, the cryoDRGN team recently collaborated with researchers from Harvard and Washington universities to study locomotion of the single-celled organism Chlamydomonas reinhardtii. The mechanisms they uncovered could shed light on human health conditions, like male infertility, that arise when cells lose the ability to move. The team is also using cryoDRGN to study the structure of the SARS-CoV-2 spike protein, which could help scientists design treatments and vaccines to fight coronaviruses.

Zhong, Berger, and Davis say they’re excited to continue using neural nets to improve cryo-EM analysis, and to extend their computational work to other aspects of biology. Davis cited mass spectrometry as “a ripe area to apply computation.” This technique can complement cryo-EM by showing researchers the identities of proteins, how many of them are bound together, and how cells have modified them.

“Collaborations between disciplines are the future,” Berger says. “Researchers focused on a single discipline can take it only so far with existing techniques. Shining a different lens on the problem is how advances can be made.”

Zhong says it’s not a bad way to spend a PhD, either. Asked what she’d say to incoming graduate students considering interdisciplinary projects, she says: “Definitely do it.”

See the full article here .

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USPS “Forever” postage stamps celebrating Innovation at MIT.

Massachusetts Institute of Technology (US) is a private land-grant research university in Cambridge, Massachusetts. The institute has an urban campus that extends more than a mile (1.6 km) alongside the Charles River. The institute also encompasses a number of major off-campus facilities such as the MIT Lincoln Laboratory, the Bates Center, and the Haystack Observatory, as well as affiliated laboratories such as the Broad and Whitehead Institutes.

Massachusettes Institute of Technology-Haystack Observatory(US) Westford, Massachusetts, USA, Altitude 131 m (430 ft).

Founded in 1861 in response to the increasing industrialization of the United States, Massachusetts Institute of Technology (US) adopted a European polytechnic university model and stressed laboratory instruction in applied science and engineering. It has since played a key role in the development of many aspects of modern science, engineering, mathematics, and technology, and is widely known for its innovation and academic strength. It is frequently regarded as one of the most prestigious universities in the world.

As of December 2020, 97 Nobel laureates, 26 Turing Award winners, and 8 Fields Medalists have been affiliated with MIT as alumni, faculty members, or researchers. In addition, 58 National Medal of Science recipients, 29 National Medals of Technology and Innovation recipients, 50 MacArthur Fellows, 80 Marshall Scholars, 3 Mitchell Scholars, 22 Schwarzman Scholars, 41 astronauts, and 16 Chief Scientists of the U.S. Air Force have been affiliated with Massachusetts Institute of Technology (US) . The university also has a strong entrepreneurial culture and MIT alumni have founded or co-founded many notable companies. Massachusetts Institute of Technology (US) is a member of the Association of American Universities (AAU).

Foundation and vision

In 1859, a proposal was submitted to the Massachusetts General Court to use newly filled lands in Back Bay, Boston for a “Conservatory of Art and Science”, but the proposal failed. A charter for the incorporation of the Massachusetts Institute of Technology, proposed by William Barton Rogers, was signed by John Albion Andrew, the governor of Massachusetts, on April 10, 1861.

Rogers, a professor from the University of Virginia (US), wanted to establish an institution to address rapid scientific and technological advances. He did not wish to found a professional school, but a combination with elements of both professional and liberal education, proposing that:

“The true and only practicable object of a polytechnic school is, as I conceive, the teaching, not of the minute details and manipulations of the arts, which can be done only in the workshop, but the inculcation of those scientific principles which form the basis and explanation of them, and along with this, a full and methodical review of all their leading processes and operations in connection with physical laws.”

The Rogers Plan reflected the German research university model, emphasizing an independent faculty engaged in research, as well as instruction oriented around seminars and laboratories.

Early developments

Two days after Massachusetts Institute of Technology (US) was chartered, the first battle of the Civil War broke out. After a long delay through the war years, MIT’s first classes were held in the Mercantile Building in Boston in 1865. The new institute was founded as part of the Morrill Land-Grant Colleges Act to fund institutions “to promote the liberal and practical education of the industrial classes” and was a land-grant school. In 1863 under the same act, the Commonwealth of Massachusetts founded the Massachusetts Agricultural College, which developed as the University of Massachusetts Amherst (US)). In 1866, the proceeds from land sales went toward new buildings in the Back Bay.

Massachusetts Institute of Technology (US) was informally called “Boston Tech”. The institute adopted the European polytechnic university model and emphasized laboratory instruction from an early date. Despite chronic financial problems, the institute saw growth in the last two decades of the 19th century under President Francis Amasa Walker. Programs in electrical, chemical, marine, and sanitary engineering were introduced, new buildings were built, and the size of the student body increased to more than one thousand.

The curriculum drifted to a vocational emphasis, with less focus on theoretical science. The fledgling school still suffered from chronic financial shortages which diverted the attention of the MIT leadership. During these “Boston Tech” years, Massachusetts Institute of Technology (US) faculty and alumni rebuffed Harvard University (US) president (and former MIT faculty) Charles W. Eliot’s repeated attempts to merge MIT with Harvard College’s Lawrence Scientific School. There would be at least six attempts to absorb MIT into Harvard. In its cramped Back Bay location, MIT could not afford to expand its overcrowded facilities, driving a desperate search for a new campus and funding. Eventually, the MIT Corporation approved a formal agreement to merge with Harvard, over the vehement objections of MIT faculty, students, and alumni. However, a 1917 decision by the Massachusetts Supreme Judicial Court effectively put an end to the merger scheme.

In 1916, the Massachusetts Institute of Technology (US) administration and the MIT charter crossed the Charles River on the ceremonial barge Bucentaur built for the occasion, to signify MIT’s move to a spacious new campus largely consisting of filled land on a one-mile-long (1.6 km) tract along the Cambridge side of the Charles River. The neoclassical “New Technology” campus was designed by William W. Bosworth and had been funded largely by anonymous donations from a mysterious “Mr. Smith”, starting in 1912. In January 1920, the donor was revealed to be the industrialist George Eastman of Rochester, New York, who had invented methods of film production and processing, and founded Eastman Kodak. Between 1912 and 1920, Eastman donated $20 million ($236.6 million in 2015 dollars) in cash and Kodak stock to MIT.

Curricular reforms

In the 1930s, President Karl Taylor Compton and Vice-President (effectively Provost) Vannevar Bush emphasized the importance of pure sciences like physics and chemistry and reduced the vocational practice required in shops and drafting studios. The Compton reforms “renewed confidence in the ability of the Institute to develop leadership in science as well as in engineering”. Unlike Ivy League schools, Massachusetts Institute of Technology (US) catered more to middle-class families, and depended more on tuition than on endowments or grants for its funding. The school was elected to the Association of American Universities (US)in 1934.

Still, as late as 1949, the Lewis Committee lamented in its report on the state of education at Massachusetts Institute of Technology (US) that “the Institute is widely conceived as basically a vocational school”, a “partly unjustified” perception the committee sought to change. The report comprehensively reviewed the undergraduate curriculum, recommended offering a broader education, and warned against letting engineering and government-sponsored research detract from the sciences and humanities. The School of Humanities, Arts, and Social Sciences and the MIT Sloan School of Management were formed in 1950 to compete with the powerful Schools of Science and Engineering. Previously marginalized faculties in the areas of economics, management, political science, and linguistics emerged into cohesive and assertive departments by attracting respected professors and launching competitive graduate programs. The School of Humanities, Arts, and Social Sciences continued to develop under the successive terms of the more humanistically oriented presidents Howard W. Johnson and Jerome Wiesner between 1966 and 1980.

Massachusetts Institute of Technology (US)‘s involvement in military science surged during World War II. In 1941, Vannevar Bush was appointed head of the federal Office of Scientific Research and Development and directed funding to only a select group of universities, including MIT. Engineers and scientists from across the country gathered at Massachusetts Institute of Technology (US)’s Radiation Laboratory, established in 1940 to assist the British military in developing microwave radar. The work done there significantly affected both the war and subsequent research in the area. Other defense projects included gyroscope-based and other complex control systems for gunsight, bombsight, and inertial navigation under Charles Stark Draper’s Instrumentation Laboratory; the development of a digital computer for flight simulations under Project Whirlwind; and high-speed and high-altitude photography under Harold Edgerton. By the end of the war, Massachusetts Institute of Technology (US) became the nation’s largest wartime R&D contractor (attracting some criticism of Bush), employing nearly 4000 in the Radiation Laboratory alone and receiving in excess of $100 million ($1.2 billion in 2015 dollars) before 1946. Work on defense projects continued even after then. Post-war government-sponsored research at MIT included SAGE and guidance systems for ballistic missiles and Project Apollo.

These activities affected Massachusetts Institute of Technology (US) profoundly. A 1949 report noted the lack of “any great slackening in the pace of life at the Institute” to match the return to peacetime, remembering the “academic tranquility of the prewar years”, though acknowledging the significant contributions of military research to the increased emphasis on graduate education and rapid growth of personnel and facilities. The faculty doubled and the graduate student body quintupled during the terms of Karl Taylor Compton, president of Massachusetts Institute of Technology (US) between 1930 and 1948; James Rhyne Killian, president from 1948 to 1957; and Julius Adams Stratton, chancellor from 1952 to 1957, whose institution-building strategies shaped the expanding university. By the 1950s, Massachusetts Institute of Technology (US) no longer simply benefited the industries with which it had worked for three decades, and it had developed closer working relationships with new patrons, philanthropic foundations and the federal government.

In late 1960s and early 1970s, student and faculty activists protested against the Vietnam War and Massachusetts Institute of Technology (US)’s defense research. In this period Massachusetts Institute of Technology (US)’s various departments were researching helicopters, smart bombs and counterinsurgency techniques for the war in Vietnam as well as guidance systems for nuclear missiles. The Union of Concerned Scientists was founded on March 4, 1969 during a meeting of faculty members and students seeking to shift the emphasis on military research toward environmental and social problems. Massachusetts Institute of Technology (US) ultimately divested itself from the Instrumentation Laboratory and moved all classified research off-campus to the MIT (US) Lincoln Laboratory facility in 1973 in response to the protests. The student body, faculty, and administration remained comparatively unpolarized during what was a tumultuous time for many other universities. Johnson was seen to be highly successful in leading his institution to “greater strength and unity” after these times of turmoil. However six Massachusetts Institute of Technology (US) students were sentenced to prison terms at this time and some former student leaders, such as Michael Albert and George Katsiaficas, are still indignant about MIT’s role in military research and its suppression of these protests. (Richard Leacock’s film, November Actions, records some of these tumultuous events.)

In the 1980s, there was more controversy at Massachusetts Institute of Technology (US) over its involvement in SDI (space weaponry) and CBW (chemical and biological warfare) research. More recently, Massachusetts Institute of Technology (US)’s research for the military has included work on robots, drones and ‘battle suits’.

Recent history

Massachusetts Institute of Technology (US) has kept pace with and helped to advance the digital age. In addition to developing the predecessors to modern computing and networking technologies, students, staff, and faculty members at Project MAC, the Artificial Intelligence Laboratory, and the Tech Model Railroad Club wrote some of the earliest interactive computer video games like Spacewar! and created much of modern hacker slang and culture. Several major computer-related organizations have originated at MIT since the 1980s: Richard Stallman’s GNU Project and the subsequent Free Software Foundation were founded in the mid-1980s at the AI Lab; the MIT Media Lab was founded in 1985 by Nicholas Negroponte and Jerome Wiesner to promote research into novel uses of computer technology; the World Wide Web Consortium standards organization was founded at the Laboratory for Computer Science in 1994 by Tim Berners-Lee; the MIT OpenCourseWare project has made course materials for over 2,000 Massachusetts Institute of Technology (US) classes available online free of charge since 2002; and the One Laptop per Child initiative to expand computer education and connectivity to children worldwide was launched in 2005.

Massachusetts Institute of Technology (US) was named a sea-grant college in 1976 to support its programs in oceanography and marine sciences and was named a space-grant college in 1989 to support its aeronautics and astronautics programs. Despite diminishing government financial support over the past quarter century, MIT launched several successful development campaigns to significantly expand the campus: new dormitories and athletics buildings on west campus; the Tang Center for Management Education; several buildings in the northeast corner of campus supporting research into biology, brain and cognitive sciences, genomics, biotechnology, and cancer research; and a number of new “backlot” buildings on Vassar Street including the Stata Center. Construction on campus in the 2000s included expansions of the Media Lab, the Sloan School’s eastern campus, and graduate residences in the northwest. In 2006, President Hockfield launched the MIT Energy Research Council to investigate the interdisciplinary challenges posed by increasing global energy consumption.

In 2001, inspired by the open source and open access movements, Massachusetts Institute of Technology (US) launched OpenCourseWare to make the lecture notes, problem sets, syllabi, exams, and lectures from the great majority of its courses available online for no charge, though without any formal accreditation for coursework completed. While the cost of supporting and hosting the project is high, OCW expanded in 2005 to include other universities as a part of the OpenCourseWare Consortium, which currently includes more than 250 academic institutions with content available in at least six languages. In 2011, Massachusetts Institute of Technology (US) announced it would offer formal certification (but not credits or degrees) to online participants completing coursework in its “MITx” program, for a modest fee. The “edX” online platform supporting MITx was initially developed in partnership with Harvard and its analogous “Harvardx” initiative. The courseware platform is open source, and other universities have already joined and added their own course content. In March 2009 the Massachusetts Institute of Technology (US) faculty adopted an open-access policy to make its scholarship publicly accessible online.

Massachusetts Institute of Technology (US) has its own police force. Three days after the Boston Marathon bombing of April 2013, MIT Police patrol officer Sean Collier was fatally shot by the suspects Dzhokhar and Tamerlan Tsarnaev, setting off a violent manhunt that shut down the campus and much of the Boston metropolitan area for a day. One week later, Collier’s memorial service was attended by more than 10,000 people, in a ceremony hosted by the Massachusetts Institute of Technology (US) community with thousands of police officers from the New England region and Canada. On November 25, 2013, Massachusetts Institute of Technology (US) announced the creation of the Collier Medal, to be awarded annually to “an individual or group that embodies the character and qualities that Officer Collier exhibited as a member of the Massachusetts Institute of Technology (US) community and in all aspects of his life”. The announcement further stated that “Future recipients of the award will include those whose contributions exceed the boundaries of their profession, those who have contributed to building bridges across the community, and those who consistently and selflessly perform acts of kindness”.

In September 2017, the school announced the creation of an artificial intelligence research lab called the MIT-IBM Watson AI Lab. IBM will spend $240 million over the next decade, and the lab will be staffed by MIT and IBM scientists. In October 2018 MIT announced that it would open a new Schwarzman College of Computing dedicated to the study of artificial intelligence, named after lead donor and The Blackstone Group CEO Stephen Schwarzman. The focus of the new college is to study not just AI, but interdisciplinary AI education, and how AI can be used in fields as diverse as history and biology. The cost of buildings and new faculty for the new college is expected to be $1 billion upon completion.

The Caltech/MIT Advanced aLIGO (US) was designed and constructed by a team of scientists from California Institute of Technology (US), Massachusetts Institute of Technology (US), and industrial contractors, and funded by the National Science Foundation (US) .

MIT/Caltech Advanced aLigo .

It was designed to open the field of gravitational-wave astronomy through the detection of gravitational waves predicted by general relativity. Gravitational waves were detected for the first time by the LIGO detector in 2015. For contributions to the LIGO detector and the observation of gravitational waves, two Caltech physicists, Kip Thorne and Barry Barish, and Massachusetts Institute of Technology (US) physicist Rainer Weiss won the Nobel Prize in physics in 2017. Weiss, who is also an Massachusetts Institute of Technology (US) graduate, designed the laser interferometric technique, which served as the essential blueprint for the LIGO.

The mission of Massachusetts Institute of Technology (US) is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the Massachusetts Institute of Technology (US) community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

From DOE’s Brookhaven National Laboratory: “Cell Membrane Proteins Imaged in 3-D”

From DOE’s Brookhaven National Laboratory

April 13, 2020 [From Year End Wrap-up]
Stephanie Kossman
skossman@bnl.gov
(631) 344-8671

Peter Genzer
genzer@bnl.gov
(631) 344-3174

Scientists used lanthanide-binding tags to image proteins at the level of a cell membrane, opening new doors for studies on health and medicine.

Ultrabright x-rays revealed the concentration of erbium (yellow) and zinc (red) in a single E.coli cell expressing a lanthanide-binding tag and incubated with erbium.

A team of scientists including researchers at the National Synchrotron Light Source II (NSLS-II) [below]—a U.S. Department of Energy (DOE) Office of Science User Facility at DOE’s Brookhaven National Laboratory—have demonstrated a new technique for imaging proteins in 3-D with nanoscale resolution. Their work, published in the Journal of the American Chemical Society, enables researchers to identify the precise location of proteins within individual cells, reaching the resolution of the cell membrane and the smallest subcellular organelles.

In the structural biology world, scientists use techniques like x-ray crystallography and cryo-electron microscopy to learn about the precise structure of proteins and infer their functions, but we don’t learn where they function in a cell,” said corresponding author and NSLS-II scientist Lisa Miller. “If you’re studying a particular disease, you need to know if a protein is functioning in the wrong place or not at all.”

The new technique developed by Miller and her colleagues is similar in style to traditional methods of fluorescence microscopy in biology, in which a molecule called green fluorescent protein (GFP) can be attached to other proteins to reveal their location. When GFP is exposed to UV or visible light, it fluoresces a bright green color, illuminating an otherwise “invisible” protein in the cell.

“Using GFP, we can see if a protein is in subcellular structures that are hundreds of nanometers in size, like the nucleus or the cytoplasm,” Miller said, “but structures like a cell membrane, which is only seven to 10 nanometers in size, are difficult to see with visible light tags like GFP. To see structures the size of 10 nanometers in a cell, you benefit greatly from the use of x-rays.”

To overcome this challenge, researchers at NSLS-II teamed up with scientists at the Massachusetts Institute of Technology (MIT) and Boston University (BU) who developed an x-ray-sensitive tag called a lanthanide-binding tag (LBT). LBTs are very small proteins that can bind tightly to elements in the lanthanide series, such as erbium and europium.

Part of the research team is shown at NSLS-II’s Hard X-ray Nanoprobe. Pictured from left to right are Xiaojing Huang, Randy Smith, Yong Chu, Hanfei Yan, Tiffany Victor, and Lisa Miller.

“Unlike GFP, which fluoresces when exposed to UV or visible light, lanthanides fluoresce in the presence of x-rays,” said lead author Tiffany Victor, a research associate at NSLS-II. “And since lanthanides do not occur naturally in the cell, when we see them with the x-ray microscope, we know the location of our protein of interest.”

The researchers at NSLS-II, MIT, and BU worked together to combine LBT technology with x-ray-fluorescence.

“Although LBTs have been used extensively over the last decade, they’ve never been used for x-ray fluorescence studies,” Miller said.

Beyond obtaining higher resolution images, x-ray fluorescence simultaneously provides chemical images on all trace elements in a cell, such as calcium, potassium, iron, copper, and zinc. In other studies, Miller’s team is researching how trace elements like copper are linked to neuron death in diseases like Alzheimer’s. Visualizing the location of these elements in relation to specific proteins will be key to new findings.

In addition to their compatibility with x-rays, LBTs are also beneficial for their relatively small size, compared to visible light tags.

“Imagine you had a tail attached to you that was the size of your whole body, or bigger,” Miller said. “There would be a lot of normal activities that you’d no longer be able to do. But if you only had to walk around with a tiny pig’s tail, you could still run, jump, and fit through doorways. GFP is like the big tail—it can be a real impediment to the function of a many proteins. But these little lanthanide-binding tags are almost invisible.”

To demonstrate the use of LBTs for imaging proteins in 3-D with nanoscale resolution, the researchers at MIT and BU tagged two proteins in a bacterial cell—one cytoplasmic protein and one membrane protein. Then, Miller’s team studied the sample at the Hard X-ray Nanoprobe (HXN) beamline at NSLS-II and the Bionanoprobe beamline at the Advanced Photon Source (APS)—a DOE Office of Science User Facility at DOE’s Argonne National Laboratory.

ANL Advanced Photon Source.

“HXN offers the world-leading x-ray focus size, which goes down to about 12 nanometers. This was critical for imaging the bacterial cell in 3-D with nanoscale resolution,” said Yong Chu, lead beamline scientist at HXN. “We also developed a new way of mounting the cells on a specialized sample holder in order to optimize the efficiency of the measurements.”

By coupling the unparalleled resolution of HXN with the capabilities of LBTs, the team was able to image both of the tagged proteins. Visualizing the cell membrane protein proved LBTs can be seen at a high resolution, while imaging the cytoplasmic protein showed LBTs could also be visualized within the cell.

“At high concentrations, lanthanides are toxic to cells,” Victor said, “so it was important for us to show that we could treat cells with a very low lanthanide concentration that was nontoxic and substantial enough to make it past the cell membrane and image the proteins we wanted to see.”

Now, with this new technique demonstrated successfully, scientists hope to be able to use LBTs to image other proteins within the cell at a resolution of 10 nanometers.

This study was supported by the U.S. Department of Energy and the National Science Foundation. Operations at NSLS-II and APS are supported by DOE’s Office of Science.

See the full article here .

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Brookhaven Campus.

BNL Center for Functional Nanomaterials.

BNL NSLS-II.

BNL NSLS II.

BNL RHIC Campus.

BNL/RHIC Star Detector.

BNL/RHIC Phenix.

One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world. Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.

From Scripps: “Pushing the Limits of Lower-Cost Electron Microscopes, with Incredible Results”

Scripps Research Institute

November 10, 2017
Bonnie Ward
Madeline McCurry-Schmidt

From Ebola virus’s deadly machinery to crucial human cell receptors, recent technical breakthroughs in cryo-electron microscopy (cryo-EM) have allowed scientists to obtain unprecedented insights into a variety of molecular structures directly involved in health and disease pathologies.

In fact, this technology—which gives researchers detailed three-dimensional views of biomolecules in near-native states—recently drew the eye of the Nobel Prize committee, which awarded the 2017 Prize in Chemistry to three founding members of the field of cryo-EM. The field has seen an explosive development over the past few years, both in terms of technical and methodological advances. Nowadays, scientists can reliably use this technique to visualize critical disease-relevant biomolecules, and the 3D structures of solved by cryo-EM are a cornerstone of scientific literature.

At The Scripps Research Institute (TSRI), Associate Professor Gabriel Lander, Ph.D., leads a team pushing the limits of cryo-EM technology to further improve and expand the utility of this technique. His lab’s most recent work, published in Nature Methods, demonstrates that TSRI researchers—and the scientific community as a whole—can visualize astonishing molecular details of biomolecules that were previously thought to be too small to be resolved. What’s more, they can accomplish this even on less expensive electron microscopes.

“This work has reshaped the way the EM field views these microscopes,” said Lander. “Hopefully research institutes and universities will realize that, without a massive investment, they can do a lot of this work themselves,” he said.

In their study, Lander and colleagues showed that resolutions of similar quality could be achieved using the 200-keV transmission electron microscope (TEM) versus the significantly more expensive 300-keV TEM.

“TSRI was one of the first institutes in the world to purchase this ‘mid-range’ electron microscope, and we have shown that it can be used to solve structures at resolutions that were previously only thought attainable using top-of-the-line ‘Titan Krios’-type microscopes,” said Lander.

The resolution of a structure is important because higher resolutions provide scientists with clear images of molecular interactions in minute detail that can be confidently applied towards drug development. “Cryo-EM lets us examine the machinery of cells at the atomic level,” said Mark Herzik, Ph.D., the study’s first co-author and a Helen Hay Whitney Foundation postdoctoral fellow in Lander’s lab. “This level of detail can aide researchers in designing drugs based on blocking certain cellular activities for therapeutic purposes,” he said, noting this approach is known as structure-based drug design.

Lander and his team’s desire to move forward with such research as quickly as possible led to their new discovery.

TSRI purchased a high-powered 300-keV TEM three years ago and researcher interest quickly grew—and so did the wait list to use the equipment.

“This is probably one of the best microscope suites in the world,” says Clint Potter, professor at TSRI and co-director of the National Resource for Automated Molecular Microscopy. Shown above is part of the new Titan Krios.(Photo by John Dole.)

“It took about three months to schedule a 24-hour time slot on the microscope,” said Lander.

This led TSRI to purchase a mid-level cryo-EM microscope (a 200-keV TEM) for the specific purpose of paring down cellular samples to the best candidates. TSRI bought the intermediate microscope last year, and Lander and his team soon got surprising results.

“We never expected to be able to resolve structures at this resolution on this microscope,” said Lander. “That really inspired us to try to push the resolution levels even higher. Through very careful sample preparation and microscope alignments, we ended up getting resolutions that were comparable to the higher-end model (300-keV TEM).”

Based on this discovery, TSRI researchers can now make greater use of cryo-EM. “We’ve essentially doubled the number of microscopes that can turn out high-resolution images 24-7,” said Lander. Together with improved data collection strategies, wait times also have vastly improved, going from three months to approximately one to two weeks for a microscope time slot, he said.

Along with improving access for TSRI researchers, Lander and his team hope their finding will boost cryo-EM research across the scientific community.

“Understanding disease, and how to develop therapeutics to effectively treat disease, is predicated on having very detailed structural information,” said study co-author Mengyu Wu, a graduate student in Lander’s lab. “Cryo-EM has become one of the most powerful methods for obtaining these critical insights.”

See the full article here .

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The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.