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Mechanism-based cancer prevention is poised to further decrease the numbers of U.S. cancer deaths, says MIT professor emerita.

Anne Trafton | MIT News Office

June 25, 2018

Great progress has already been made in reducing the cancer death toll through prevention, according to a new article in the June 25 issue of Genes and Development by MIT Professor Emerita Nancy Hopkins and colleagues from the Broad Institute, Fox Chase Cancer Center, University of Texas M.D. Anderson Cancer Center, and Oxford University. The potential for further reduction is great for two reasons, these researchers say: If these approaches can be more widely applied, in principle about half of current U.S. cancer deaths could be prevented over the next two to three decades; and new discoveries about how cancer develops could help scientists develop even better prevention and screening methods. MIT News spoke with Hopkins, the Amgen Inc. Professor of Biology Emerita, about why this is an exciting time for cancer research.   

Q: What does your new article reveal about the impact of cancer prevention and early detection?

A: We’ve described how researchers are integrating the dramatic advances in understanding the molecular biology of cancer to explain long-known facts about how lifestyle choices and factors in the environment affect how cancers arise, and how they progress to become detectable tumors.

Prevention and early detection have already had a tremendous impact on reducing U.S. cancer death rates. In the cancer prevention community, it is well-known that about half of current U.S. cancer deaths could, in theory, be prevented over the next two to three decades simply by the full uptake of proven methods of cancer prevention. This important fact is not as well appreciated by the larger cancer research community. This is not a fault of the cancer researchers; it simply reflects the reality that after years of investment and growth, the field of cancer is very broad, with most people working in areas of specialty.

Given the difficulties in treating established cancers, preventing many cancers entirely would obviously produce a quantal leap in reducing U.S. cancer death rates. But in addition, we believe that recent progress in understanding the molecular mechanisms that underlie cancer, and new technologies associated with these advances, could also lead to novel approaches to preventing cancer, detecting it at earlier stages when treatment is often far more successful, or even intercepting the progression of incipient cancers before they develop into tumors.

Q: What interventions have had success preventing cancer, and what promising new approaches are on the horizon?

A: Spectacular examples of preventing cancers from arising in the first place (formally called “primary cancer prevention”) include (1) successful efforts that reduced smoking rates in the United States (from over 40 percent in the 1960s to about 15 percent today) and that have led to a decline in the incidence of lung cancer and a dozen or more other types of cancer caused by smoking; (2) vaccines for cancer-causing viruses, including hepatitis B virus (a cause of liver cancer) and papilloma viruses (the cause of cervical, head and neck, and several other cancers); (3) clean air and water acts and safer workplace laws in the United States that have prevented workers as well as the general population from exposure to high concentrations of certain industrial chemicals known to cause cancer; (4) the development of drugs to cure hepatitis C infection, which are expected to prevent the development of liver cancer in the future; (5) campaigns such as the one in Australia to prevent skin cancers (particularly melanoma) by behavioral changes related to sun exposure.

As for promising new approaches to primary cancer prevention, the fuller uptake of proven methods of prevention is obviously one way to ensure a dramatic decrease in U.S. cancer death rates in the next two to three decades. This would require a greater investment in public health measures. As our article outlines, we are only now coming to understand the mechanisms by which factors such as obesity, inflammation, and some lifestyle choices synergize with long-appreciated risk factors to promote cancer. Based on this improved understanding, prevention could also be aided by research into new drugs, for example to prevent nicotine addiction or to intercept cancer progression by targeting inflammation. Exciting, too, is the possibility that DNA sequencing of cancer genomes may help to identify additional external causes of cancers based on the “mutational signatures” they leave in our DNA after exposures. If so, these agents may prove to be removable or avoidable in future.

We also discuss a second type of intervention to prevent cancer. This is screening, sometimes referred to as “secondary cancer prevention,” which can detect precancers and cancers at an early enough stage to remove them completely or treat them much more successfully. Spectacular successes to date include the Pap test that has greatly reduced deaths from cervical cancer in the United States and elsewhere; newer molecular tests focused on HPV-virus detection have proven similarly effective and are now replacing traditional Pap tests which require expert pathologic interpretations, making screening more widely available. A second success is colonoscopy, which has been enormously successful at detecting precancerous polyps and early-stage colon cancers that can be removed through the endoscope, or detected earlier when they’re more likely to be responsive to treatment. Additionally, other less-invasive methods of colon cancer screening are readily available and highly effective. Also successful has been mammography in combination with follow-up treatment. Along with greatly improved treatment, it is credited with contributing to the declining death rate from breast cancer.

Q: What types of new screening methods do you believe could help to further improve early detection of cancer?

A: Many of the most successful screening methods are for cancers that develop on body surfaces and hence can be detected by visual inspection. Imaging can be hugely successful for cancers that lie deeper in the body — breast for example — but imaging that becomes more and more sensitive can identify many abnormalities that may not be cancer at all. This can lead to costly and invasive testing of what are sometimes referred to as “incidentalomas.” Much needed are novel methods of screening that may combine imagining with other markers to make it possible to distinguish true cancers from noncancerous aberrations occurring in internal organs.

The holy grail of cancer screening would be blood tests to detect early-stage cancers, and many efforts are now directed to this goal. This is an extremely exciting time for the emergence of powerful molecular diagnostics that can help pinpoint very early-stage tumors. Some of these rely on relatively noninvasive methods, such as measurement of DNA signatures found in the blood. Widespread availability and demonstrated effectiveness of such methods would greatly enhance the field of secondary prevention, but there remain substantial challenges and it is not yet known if this approach will succeed. Also very exciting are methods being developed by bioengineers here at MIT and in other places to try to amplify other signals arising from tumors that may be difficult to detect otherwise and include, for example, completely noninvasive urine-based tests.

After decades of effort, cancer is gradually coming under control thanks to prevention and early detection, improvements in “conventional” cancer treatment (imaging, surgery, radiation, chemotherapy, and some adjuvant therapies), and novel approaches to treatment based on immunotherapy and more personalized drugs. But it is likely that for now, the full implementation of proven methods of prevention offers the most reliable approach to large-scale reduction of U.S. cancer deaths. Meanwhile, research into novel mechanism-based approaches to preventing the initiation and progression of cancer may one day prevent the majority of cancers from occurring in the first place.

In a visit with the Department of Biology, Lydia Villa-Komaroff PhD '75 explains how “thinking fast makes changing slow.”

Raleigh McElvery | Department of Biology

June 26, 2018

The brain carries out many processes automatically and without our conscious recognition. This means that when we encounter certain information — like the name on a resume suggesting a specific gender or race — we make an immediate and unintentional judgement. At the Building 68 Department of Biology retreat on June 14, keynote speaker Lydia Villa-Komaroff PhD ’75 explained the physiological roots of this implicit bias and offered potential solutions.

Villa-Komaroff is a biologist and business woman advocating for diversity in STEM. When she received her PhD from the Department of Biology in 1975, she was one of the first Mexican American women to receive a doctorate in the sciences. She served as the chief operating officer and vice president of research for MIT’s Whitehead Institute for Biomedical Research for two years, and later founded her own one-woman consulting firm, Intersections, SBD. She is a board member, former CEO, and former chief science officer of the biotech company Cytonome/ST, LLC, and a member of the Biology Department Visiting Committee. She is also a co-founding member of the Society for the Advancement of Chicanos/Hispanics and Native Americans in Science (SACNAS).

According to Villa-Komaroff, it’s not that STEM fields are completely without diversity. Rather, there are fewer members of underrepresented groups in positions of academic power relative to their peer populations. Women and underrepresented minorities tend to hold instructor roles or assistant professorships, and are less likely to become full professors, deans, and presidents.

“There has been some progress,” she said, “since the proportion of women and underrepresented groups has climbed. Women have climbed at a faster rate than have individuals from underrepresented ethnic groups, but the rate of increase in both of those groups is still slow relative to the changing population. Clearly something is going on in our society, and it has been going on for a very long time, longer than any of us have been around. So what might that be?”

Data are amassing, and not only from sociologists and psychologists, but from neuroscientists as well, Villa-Komaroff pointed out. Research has shown that humans are wired to make quick decisions that serve us well must of the time, but these inclinations can also cause us to misjudge the abilities of the person before us.

Since the brain is constantly confronted with a deluge of information, over the course of time it developed two systems to sift through all the input. System 1 is automatic: It’s running all the time, requires very little energy, and is crucial to our survival — permitting us to recognize danger and possible threats in a split second. It also allows us to complete habitual tasks, like playing the violin or holding a pipette, with very little conscious effort.

System 2 begets what we generally consider to be “thinking.” It is deliberate and requires a lot of energy to run. Often without our conscious awareness, System 1 overtakes System 2 and our decisions are driven by our instincts. Villa-Komaroff said we need to fight this tendency to “trust our instincts” when it comes time to select colleagues or students. It’s not simply about activating your thinking, it’s about challenging it.

“I’m sorry to say that we — that is those of us in the hard sciences — have been the most resistant to thinking that this might be in the case,” she said. “I can’t tell you how many times my colleagues have said to me, ‘This is not a problem for us because we care only about merit, and that is what we are basing our decisions upon.’ It’s true we care about merit, but that is not the factor on which we often base our first initial decisions.”

In fact, it has been shown that science faculty presented with two applications for a lab manager position, identical except for the names “Jennifer” and “John,” will evaluate John as more competent, give him more money, and offer him more career mentorship. The kicker is that these implicit biases aren’t just limited to a particular segment of the population. Women often have biases against other women, and the same is true for members of underrepresented groups.

But hope is not lost, Villa-Komaroff said. We can do something to counter this tendency if we just teach ourselves to recognize our own biases and deliberately work to override them.

In one study, researchers noticed that the panels at the American Society for Microbiology General Meeting consisted primarily of males. The panel committees that selected them also happened to be predominantly all-male. The researchers presented these data to the selection committees, and gave them an explicit call to action: Do something about it. The next year, the number of female speakers increased, and the number of all-male session planning committees decreased.

In another study, researchers took 92 medicine, science, and engineering departments from the University of Wisconsin at Madison and divided them into a matching control and test group, where the test group was invited to enroll in a short, two-and-a-half hour workshop on implicit bias. Despite the fact that, on average, just 25 percent of the faculty from the test group departments attended the session, afterwards they reported more self-initiated efforts to promote gender equity and better conflict resolution. Most notably, over the next several years the percentage of hires from underrepresented groups rose from 8 percent to 11 percent, while the controls saw a decrease from 10 percent to 5 percent. 

As part of the Strategies and Tactics to Increase Diversity and Excellence (STRIDE) program at the University of Michigan, full professors must now attend workshops on implicit bias in the fall during peak faculty recruitment season. Between 2001 and 2007, the percentage of faculty searches resulting in a female hire rose from 15 percent to 32  in STEM disciplines. If nothing else, these kinds of interventions may kick in the second, deliberate decision-making system, and allow us to see past the name on the resume.

The Department of Biology will be modifying its laboratory classes to increase flexibility in the curriculum.

Raleigh McElvery

June 13, 2018

As part of an initiative to increase flexibility in the curriculum, the Department of Biology will be modifying its laboratory requirements over the next two years. These changes will make it easier for students to become acquainted with lab techniques during their first year at MIT, permitting them to join faculty-run labs as part of the Undergraduate Research Opportunities Program (UROP) soon after they arrive.

Effective fall of 2019, the 18-unit 7.02 (Introduction to Experimental Biology and Communication) will be replaced by two new classes: the six-unit 7.002 (Fundamentals of Experimental Molecular Biology) and the 12-unit 7.003 (not yet named).  7.02 will continue to be offered in the fall of 2018 and spring of 2019 while 7.002 is introduced concurrently.

“This modification to our curriculum should enable students to gain experience in laboratory techniques and approaches as early as their first year,” says Department Head Alan Grossman. “It will prepare them to join research labs as UROP students and to work with graduate students, postdocs, and faculty members in a collaborative research setting.”

7.02 has traditionally served as an introduction to experimental concepts and methods in molecular biology, biochemistry, and genetics. However, it requires the time commitment of roughly one-and-a-half full classes, making it difficult for first-year students to fit it into their schedule while still completing their General Institute Requirements. Students taking 7.02  also bring a wide range of lab experiences; some have completed related internships during high school, while others have little or no research experience.

“7.02 prepares students to pursue UROPs in the biological sciences,” says Dennis Kim, undergraduate officer and Ivan R. Cottrell Professor of Immunology. “However, the 18 units of 7.02 make the course difficult to take before sophomore year. 7.002 can be taken at an earlier time, even in the first year. This will give students an experimental laboratory experience at an earlier stage of their education, facilitating the pursuit of UROPs.”

7.002 will be fewer units, not have any pre-requisites, and allow first-year students to get acquainted with basic methods of molecular biology. 7.003, by contrast, will serve as a second subject in experimental biology, and likely require co-requisites like 7.03 (Genetics) and 7.05 (General Biochemistry).

7.002 will be offered for the first time during the fall of 2018, although students will still have the option to enroll in 7.02 at this time. Beginning in the fall of 2019, 7.003 will be offered as a follow-up to 7.002, and 7.02 will no longer be offered. 7.002 will fulfill six units towards completion of the Institute Lab Requirement.

“These revisions to our lab curriculum stem from our larger effort to give students more flexibility in selecting their classes,” Grossman says. “The structure of 7.002 should also make it easier for students to receive additional information and guidance from department faculty members about opportunities in curiosity-driven life science research.”

The development and launch of 7.002 is supported by the d’Arbeloff Fund.

Biophysicist will investigate the biology of RNA aggregation.

Merrill Meadow | Whitehead Institute

June 11, 2018

Biophysicist Ankur Jain will join the Whitehead Institute as its newest member this coming September. Jain will also be appointed an assistant professor in the MIT Department of Biology. In his research, he will use a combination of innovative approaches to investigate the biology of RNA aggregation.

While it is understood that protein aggregation is a key factor in certain neurological diseases, relatively little is known about RNA aggregation, its underlying biology, and the role it plays in disease. A class of neurological disorders called repeat expansion diseases, which includes amyotrophic lateral sclerosis (ALS) and fragile X syndrome, are marked by stretches of DNA nucleotide repeats in their cognate disease gene. The presence of repeats is associated with clumps of RNA aggregates and RNA binding proteins that undergo phase transition to form an “RNA gel” in the nucleus. At the Whitehead Institute, Jain will continue his investigation into the properties of these RNA aggregates in order to learn how they form, what properties they possess, and how they could be disrupted to restore normal cellular processes. Jain will use nuclear speckles — areas in the nucleus associated with pre-mRNA splicing — as a model for physiological RNA-protein granules.

His lab will also investigate the role of RNA-DNA interactions in chromatin organization — the complex, dynamic structure of DNA and proteins in the nucleus. There are instances of nucleotide repeats in our genome that occur even in the absence of repeat expansion disease genes. Repetitive DNA sequences at the end of our chromosomes interact with proteins to form our telomeres, structures critical for chromosome maintenance. Jain will study the RNA transcribed from the telomeric sequences in order to understand their structure and if they undergo phase separation similar to the one seen in repeat expansion diseases. In addition, Jain will build on his specialized expertise in quantitative light microscopy to drive development of new imaging-based technologies.

“Ankur brings an approach grounded in a combination of soft-matter physics and cell biology to help pioneer an important — potentially ground-breaking — way of investigating and understanding RNA aggregation and RNA-DNA interaction,” says David C. Page, Whitehead Institute director and member. “His insights are exciting, and the intellectual and scientific creativity he brings to his research is energizing.”

Jain is currently completing a postdoc with Ronald Vale at University of California at San Francisco. He earned a PhD in biophysics and computational biology from the University of Illinois at Urbana-Champaign in 2013, and a bachelor’s degree (with honors) in biotechnology and biochemical engineering from Indian Institute of Technology Kharagpur in 2007. He holds a National Institutes of Health Pathway to Independence Award (also known as a K99 Award), and has been a lead author on peer-reviewed studies in the journals Nature and Proceedings of the National Academy of Sciences.

“Understanding the biology of RNA aggregation and phase separation has the potential to crack open long-time mysteries in cell biology,” Jain explains. “I am grateful for the chance to pursue my investigations in the intellectually rich and scientifically fruitful environment that Whitehead Institute and MIT have to offer.”

Six faculty members are granted tenure in four departments.

Bendta Schroeder | School of Science

June 4, 2018

The School of Science has announced that six members of its faculty have been granted tenure by MIT.

This year’s newly tenured associate professors are:

Daniel Cziczo studies the interrelationship of atmospheric aerosol particles and cloud formation and its impact on the Earth’s climate system. Airborne particles can impact climate directly by absorbing or scattering solar and terrestrial radiation and indirectly by acting as the seeds on which cloud droplets and ice crystals form. Cziczo’s experiments include using small cloud chambers in the laboratory to mimic atmospheric conditions that lead to cloud formation and observing clouds in situ from remote mountaintop sites or through the use of research aircraft.

Cziczo earned a BS in aerospace engineering from the University of Illinois at Urbana-Champaign in 1992, and afterwards spent two years at the NASA Jet Propulsion Laboratory performing spacecraft navigation. Cziczo earned a PhD in geophysical sciences in 1999 from the University of Chicago under the direction of John Abbatt. Following research appointments at the Swiss Federal Institute of Technology and then the Pacific Northwest National Laboratory, where he directed the Atmospheric Measurement Laboratory, Cziczo joined the MIT faculty in the Department of Earth, Atmospheric and Planetary Sciences in 2011.

Matthew Evans focuses on gravitational wave detector instrument science, aiming to improve the sensitivity of existing detectors and designing future detectors. In addition to his work on the Advanced the Laser Interferometer Gravitational-Wave Observatory (LIGO) detectors, Evans explores the physical processes that set fundamental limits on the sensitivity of future gravitational wave detectors. Of particular interest are the quantum and thermal limitations which have the strongest impact on ground-based detectors like LIGO and also play a role in the related fields of ultra-stable frequency references and macroscopic quantum measurement.

Evans received a BS in physics from Harvey Mudd College in 1996 and a PhD from Caltech in 2002. After postdoctoral work on LIGO at Caltech, Evans moved to the European Gravitational Observatory to work on the Virgo project. In 2007, he took a research scientist position at MIT working on the Advanced LIGO project, where he helped design and build its interferometer. He joined the MIT faculty in the Department of Physics in 2013.

Anna Frebel studies the chemical and physical conditions of the early universe, and how the oldest, still-surviving stars can be used to obtain constraints on the nature of the very first stars and early supernova explosions, and associated stellar element nucleosynthesis. She is best known for her discoveries and subsequent spectroscopic analyses of 13 billion-year-old stars in the Milky Way and ancient faint stars in the least luminous dwarf galaxies, to uncover unique information about the physical and chemical conditions of the early Universe. With this work, she has been able to obtain a more comprehensive view of the formation of our Milky Way Galaxy with its extended stellar halo because the formation history of each galaxy is imprinted in the chemical signatures of its stars. To extract this information, Frebel is also involved in a large supercomputing project that simulates the formation and evolution of large galaxies like the Milky Way.

Frebel received her PhD from the Australian National University in 2007. After a W. J. McDonald Postdoctoral Fellowship at the University of Texas at Austin, she completed a Clay Postdoctoral Fellowship at the Harvard-Smithsonian Center for Astrophysics in 2009. Frebel joined the MIT faculty in the Department of Physics in 2012.

Aram Harrow works to understand the capabilities of the quantum computers and quantum communication devices and in the process creates connections to other areas of theoretical physics, mathematics, and computer science. As a graduate student, Harrow developed the idea of “coherent classical communication,” which along with his work on the resource inequality method, has greatly simplified the understanding of quantum information theory. Harrow has also produced foundational work on the role of representation theory in quantum algorithms and quantum information theory. In 2008, Harrow, Hassidim, and Lloyd developed a quantum algorithm for solving linear systems of equations that provides a rare example of an exponential quantum speedup for a practical problem. Recently Harrow has been investigating properties of entanglement, such as approximate “superselection” and “monogamy” principles with the goal of better understanding not only entanglement and its uses, but also the related areas of quantum communication, many-body physics, and convex optimization.

Harrow received his undergraduate degree in 2001 and his PhD in 2005 from MIT. After his PhD, he spent five years as a lecturer at the University of Bristol and then two years as a research assistant professor at the University of Washington. Harrow returned to MIT to join the faculty in the Department of Physics in 2013.

Adam Martin studies how cells and tissues change shape during embryonic development, giving rise to organs with distinct shapes and structure. He has developed a system to visualize and quantify the movement of molecules, cells, and tissues during tissue folding in the fruit fly early embryo, where cells and motor proteins within these cells can be readily imaged by confocal microscopy on the time scale of seconds. Tissue folding in the fruit fly involves conserved genes that also function to form the mammalian neural tube, which gives rise to the mammalian brain and spinal cord. Martin combines live imaging with genetic, cell biological, computational, and biophysical approaches to dissect the molecular and cellular mechanisms that sculpt tissues. In addition, the lab examines how tissues grow and are remodeled during development, investigating processes such as cell division and the epithelial-mesenchymal transition.

After Martin received a BS in biology from Cornell University in 2000, he completed his PhD in molecular and cell biology under the direction of David Drubin and Matthew Welch at the University of California at Berkeley in 2006. After a postdoctoral fellowship at Princeton University in the laboratory of Eric Weischaus, Martin joined the MIT faculty in the Department of Biology in 2011.

Kay Tye dissects the synaptic and cellular mechanisms in emotion and reward processing with the goal of understanding how they underpin addiction-related behaviors and frequently co-morbid disease states such as attention-deficit disorder, anxiety, and depression. Using an integrative approach including optogenetics, pharmacology, and both in vivo and ex vivo electrophysiology, she explores such problems as how neural circuits differently encode positive and negative cues from the environment; if and how perturbations in neural circuits mediating reward processing, fear, motivation, memory, and inhibitory control underlie the co-morbidity of substance abuse, attention-deficit disorder, anxiety, and depression; and how emotional states such as increased anxiety might increase the propensity for substance abuse by facilitating long-term changes associated with reward-related learning.

Tye received her BS in brain and cognitive sciences from MIT in 2003 and earned her PhD in 2008 at the University of California at San Francisco under the direction of Patricia Janak. After she completed her postdoctoral training with Karl Deisseroth at Stanford University in 2011, she returned to the MIT Department of Brain and Cognitive Sciences as a faculty member in 2012.

Chris Kaiser | School of Science

May 31, 2018

Alex Rich had a long and fertile career at MIT working on the relationship between the molecular structure and the function of biological information molecules DNA and RNA. Rich is perhaps best known for the elucidation of the three-dimensional structure of a transfer RNA molecule, and for the discovery of an alternative form of DNA that exists in certain biological contexts, known as Z-DNA.

Less well-recognized is Rich’s contribution to the discovery of nucleic acid hybridization. Hybridization is the process by which single-stranded RNA or DNA molecules can find each other in solution by the exact matching of complementary base sequences. The rate of hybridization is limited only by the rate of diffusion of molecules in solution. Because of its remarkable speed and specificity, hybridization remains today as one of two fundamental methods for reading out the identity of RNA or DNA molecules in different contexts — the direct determination of the base sequence, with the other being carrying out the matching by computer.

Rich grew up in a working-class neighborhood of Springfield, Massachusetts. In high school, he helped support his family by working in the U.S. Armory machining grooves in rifle barrels. As a young man, Rich was smart, resourceful, and ambitious and he received a fellowship to Harvard College and later attended Harvard Medical School. At Harvard, Rich had the opportunity to work with Professor of Biological Chemistry John Edsall, who sparked an interest the physical chemistry of biological macromolecules that eventually led him away from medicine to postgraduate research with the visionary chemist and ebullient polymath Linus Pauling at Caltech.

Pauling discovered the alpha helix as a basic element of protein structure and by doing this invented the method of model building as a way of predicting the large-scale structural features of complex macromolecules from the chemical bonding structures of their constituent parts. In Pauling, Rich found a powerful role model who showed by example how far you could travel by grasping a good idea or deep insight.

When Rich joined the lab, Pauling was working on a structure for DNA and then was, to put it bluntly, scooped by James Watson and Francis Crick. Watson and Crick’s structure for DNA, based on astute model building and the X-ray diffraction data of Rosalind Franklin, was published in 1953. The key feature of their structure was the exact pairing of the bases between two strands of DNA that twist around each other in a double helix. The base-pairing rules — adenine pairs with thymine and guanine pairs with cytosine — are imposed by the geometric constraints on the paired bases as they are held together by hydrogen bonds in the central core of the helix. The double helix can accommodate a string of bases of any sequence and thus carry genetic information encoded in linear sequences of four characters. Moreover, the exact base-pairing between strands means that each strand carries the same information as the other, but in complementary form, and immediately suggested how the genetic information can be duplicated for cell division.

Big Bang and the coding problem

The emerging picture that the base sequence of DNA carried instructions to synthesize linear strings of protein out of a set of 20 amino acids led to a deeper puzzle: how could information encoded in the sequence of one kind of macromolecule be translated into the sequence of an entirely different kind of molecule? Although its direct involvement had not yet been shown, RNA was strongly suspected to have a central role in this process. One of the clues to the involvement of RNA was that RNA was most abundant in animal or plant tissues undergoing rapid growth and therefore extensive new protein synthesis. DNA and RNA are similar molecules and both are polymers of four nucleotide bases, but they differ in that DNA contains a hydrogen atom at the 2’ position on the ribose ring, whereas RNA contains a hydroxyl group at this position. The absence of a hydroxyl group at this position makes DNA more chemically stable and therefore more suitable to carry the permanent copy of genetic information. Also, DNA carries the base thymine instead of the chemically similar base uracil in RNA.

The brilliant theoretical cosmological physicist George Gamow, who was an early proponent of the Big Bang theory, saw that there was something worthy of interest in RNA and what soon became known as the “coding problem.” Gamow helped to focus thinking about this problem by posing the question of how a code written in four bases could be translated into 20 different amino acids. The introduction of the principles of information theory, first proposed in Claude Shannon’s 1948 paper “A Mathematical Theory of Communication,” immediately suggested that at least three bases would be required to carry enough information to specify 20 different amino acids. Gamow organized interested scientists in a group that called themselves the RNA Tie Club — so named for members’ necktie clips that bore the abbreviation of an amino acid. Rich was a member, as were Watson and Crick; and these members would share with one another ideas and insights before publication. Since each member of the club was assigned a different amino acid, membership never exceeded 20.

Rich was captivated by the connection, as so beautifully illustrated by the DNA model, between chemical structure and biological function and he was determined to make his mark in this new field as a structural biologist. He wondered if RNA could form a double helical base-paired structure and what role might this structure have in translating a DNA code into amino acids. With the help of Watson, who was at Caltech at that time, Rich set about analyzing different kinds of natural RNA samples, but none showed the characteristic diffraction pattern in X-ray analysis that Franklin had seen for double helical DNA.

Rich took a job at the NIH. There and on a sabbatical to Cambridge, England, he had success with various structural and modelling studies, including a structure for collagen, but he kept coming back to the question of whether a double-stranded RNA helix could form. One of the most precise analytical tools for nucleic acids such as RNA available at the time was to measure the base composition — that is, the relative proportion of guanine, cytosine, adenine and uracil. For a fully double-stranded molecule, base pairing rules would dictate that the amount of guanine should equal cytosine and the amount of adenine should equal that of uracil. The natural RNA samples that Rich was studying had very different base compositions, but did not follow the rules expected for a double-stranded structure. Eventually, Rich decided to force the issue by synthesizing his own RNA molecule that could form a fully base–paired double strand.

Rich and his colleague David Davies used the enzyme polynucleotide phosphorylase, which could polymerize into chains whatever activated nucleotide precursors were provided, to prepare two RNA chains designed to be able to base pair with each other. In one reaction, they prepared a long strand of RNA with only adinines (oligo-A) and in a separate reaction a long strand of RNA made up entirely of uracil (oligo-U). Hoping to see some amount of base pairing, Rich mixed the two preparations together and was amazed to see the entire contents become converted into RNA with the properties of double-stranded molecules. X-ray analysis confirmed that the two chains had had coiled around each other into a double helix. This experiment showed that an RNA-based double helix was possible, but the speed with which the double-stranded molecules formed was entirely unexpected. Based on physical chemistry of polymers, Rich had expected that some additional factors, such as enzymes, would be needed to neatly coil long disordered chains around each other. The effect of seeing this dramatic reorganization of molecules happen so efficiently might be the equivalent of seeing two tangled fishing lines that were thrown together spontaneously wrap themselves into a neat braid.

Such spontaneous base pairing between different nucleic acid chains is known as hybridization and is the fundamental underlying chemical process by which the information in DNA is translated into protein. Rich went on to show that hybridization between a DNA strand (oligo-dT) and an RNA strand (oligo-A) could occur to form a hybrid of RNA based paired with DNA. This molecule provided a structural basis for copying information from the gene sequence in DNA into a complementary single-stranded messenger RNA molecule. Moreover, base pairing between triplet codons on the messenger RNA and the anticodon loop of a transfer RNA carrying a specific amino acid is the basis by which the nucleotide code is translated into amino acid sequence.

Hybridization has become an enduring method in molecular biology and biotechnology research. Shortly after Rich carried out his RNA hybridization reaction, it was shown that the two strands of DNA could be melted apart at high temperature and then could come back together in a sequence specific manner if held at a somewhat lower annealing temperature. Before methods for direct sequencing of DNA became available, hybridization was the only method by which specific DNA or RNA sequences could be identified in a complex mixture.

Hybridization has become an enduring method in molecular biology and biotechnology research. Shortly after Rich carried out his RNA hybridization reaction, it was shown that the two strands of DNA could be melted apart at high temperature and then could come back together in a sequence-specific manner if held at a somewhat lower annealing temperature. Before methods for the direct sequencing of DNA became available, hybridization was the only method by which specific DNA or RNA sequences could be identified in a complex mixture.

Hybridization was crucial for the discovery of splicing of messenger RNA made by MIT Institute Professor Phil Sharp and was the basis for Professor Susumu Tonegawa’s demonstration of DNA rearrangements that underlie the formation of functional genes for antibodies. Even now, with extremely powerful methods for DNA sequencing, hybridization is still often used to examine the structure of chromosomes and to conduct comprehensive studies of gene expression based on microarrays. Finally, sequence-specific hybridization is at the heart of natural processes that have been harnessed for RNA interference of gene expression and CRISPR-based genome editing.

Rich himself wrote and spoke extensively about the early years of molecular biology in ways that reveal two important characteristics as a scientist. The first is that his deep admiration for mentors such as Pauling and colleagues such as Crick and Watson was the basis of an intellectual network that sustained Rich his entire career. By his account, a new discovery in the lab was invariably followed by a letter or a phone call to those that he admired to get their reactions. All biologists, no matter how great, struggle with the problem that it is difficult — if not impossible — when setting out on a new problem to predict whether it will reveal insights fundamental to all living things or merely lead to odd details produced as a byproduct of the tinkering of evolution. Rich was adept at vetting new ideas through his constellation of brilliant friends to guide him toward the fundamental.

The second, related characteristic is Rich’s gift for seeing how new concepts may play out in time — well into the future. In the spirit of the RNA Tie Club, Rich freely shared his imaginative speculation about where he saw the field going, adding these forward-thinking ideas to his review articles and sprinkling their seeds in the discussion sections of his research papers. Among his more prescient ideas was the prediction that hybridization to messenger RNA of a complementary regulatory RNA could play a part in gene regulation; this prediction anticipated the discovery of microRNA-based regulation by about 40 years. He also hypothesized in the early 1960s that early life forms could have a genetic system without DNA that was made up of only RNA. This may be the first articulation of the now widely accepted idea of an RNA world. As I knew Rich in his later years, he remained engaged in and stimulated by new ideas. It was not difficult when chatting with him in his office or going on a walk-and-talk with him to feel connected to and stimulated by the sweep of brilliant ideas that have propelled molecular biology along from the very beginning.

Written by Chris Kaiser, Amgen Inc. Professor of Biology and the former head of the MIT Department of Biology

Published May 2, 2018