Look around you. Nearly everything you see is made up of molecules. Your hand, the wall, the paper page on which you might be reading these words. Heck, even the thoughts that are forming in your head as you scan this sentence are manifested by the release of neurotransmitters (molecules!) scampering across the synapses between your brain’s neurons (cells, which — spoiler alert! — are made up of clumps of molecules working in synchrony to carry out the busy business of life).
But what are they, actually? Molecules are formed by atoms — remember the periodic table? — that clasp each other tightly in ways dictated by the capricious orbits of their electrons and the relative numbers of their protons, neutrons and electrons. In doing so, they create magic. They blossom into more than the sum of their parts, becoming water, oxygen, even the genetic material that makes you, you.
But sometimes these tiny structures go awry. A change in the net electrical charge of the hemoglobin molecule that ferries oxygen from the lungs predisposes a person to a lifetime of sickle cell anemia; a missing building block in a molecule that controls the flow of salt and fluids across cellular membranes causes the buildup of thick, sticky mucus in the lungs of people with cystic fibrosis; a swap of a nucleic acid near a gene that controls how, when or how often a cell divides leads to an uncontrollably growing tumor.
And sometimes, a molecule made by a virus new to humans binds to other molecules on the surface of respiratory cells and, in the blink of an eye, launches a pandemic that is still raging across the world.
Understanding how molecules function in living organisms, and the health consequences of their failures, is the bedrock of what is still a relatively new field of science — molecular biology.
Recently, our ability to conduct such studies has catapulted forward with the development of new visualization technologies such as cryo-electron microscopy, the expanding computing capabilities available to biologists, and the development of new techniques to explore not just a molecule’s structure but also its neighborhood, identifying working groups and cliques that make a cell tick in a particular way in specific circumstances.
These advances are further illuminating the secret lives of molecules — peering behind the curtain, under the sheets and in the closets — in ways that are expected to revolutionize how medicine is practiced.
“We are at an extremely important point in scientific history,” said Ruth O’Hara, PhD, senior associate dean for research and Stanford Medicine’s Lowell W. and Josephine Q. Berry Professor.
“Molecular medicine is a vast domain that spans from basic science research aimed at understanding the molecular basis of diseases, to identifying potential therapeutic targets, to preclinical and clinical trials of new drugs. Mining complex molecular data and overlaying them on clinical outcomes is critical for precision health and medicine, and Stanford Medicine excels at it. This is a special place.”
Stanford has stood out among its peers since the medical school moved from San Francisco to Palo Alto in 1959 to cultivate the training of a rare breed of physician-scientists skilled not just in clinical care but also in the research techniques necessary to understand the causes of disease at the most basic biological level.
Some recent returns on this approach: Stanford researchers have cracked the code of vicious DNA circles that enable cancer cells to evade common treatments, plumbed the sticky consequences of too much mucus throughout the body (and how to combat it), and grappled with the need for an effective, nonaddictive painkilling molecule.
Taking the mystery out of molecules
To understand molecules, you have to know something about atoms, which were imagined as far back as the fifth century by Greek philosophers who believed the universe is made up of infinitesimally tiny particles.
They arrived at this conclusion by logicking their way to the idea that any substance, when divided in half, eventually reaches a state of being where it is impossible to divide it any further. (Think of striving to share a chocolate bar equally among hundreds of people in an office building.) They coined the remaining particles “atoms.”
Molecules, the philosophers surmised, are made up of two or more atoms tightly entwined, perhaps by a hook-and-eye-type fastener. (Today chemists call these relationships covalent bonds.) While embracing, the atoms assume new chemical and physical properties by virtue of their now shared electrons.
Hydrogen and oxygen, left to their own devices, are odorless, colorless gases. Together they become watery — quenching our thirst, keeping our iced tea cold and helping plants grow. Molecules are the smallest combination of atoms that maintain a material’s physical and chemical properties (when is that office chocolate bar no longer chocolate?).
Scientists have been fascinated with molecules for hundreds of years. Like Lego pieces, molecules combine in countless ways to build macromolecules like DNA, proteins and structural components of cells carrying out the machinations of life. But molecules existed long before life itself.
In 2019, planetary scientists reported the discovery of helium hydride in a distant nebula called NGC 7027. Formed a mere 100,000 years or so after the big bang, this first-ever molecule is nearly 14 billion years old. It arose when the intense heat and pressure of the earliest days of the universe smashed together one hydrogen atom and one helium atom to form the first molecule.
Researchers had speculated about the existence of helium hydride in nature since it was first observed in a laboratory in 1925. But observing it in the wild took the development of specialized infrared viewing technology nearly 100 years later, as well as a way to send that technology high into the stratosphere to evade atmospheric interference that would drown out the signal from the elusive molecule.
Molecular biologists faced a similar problem in the mid-1900s when geneticists studying the mechanisms of inheritance in plants, fruit flies and viruses that infect bacteria realized they’d come to the limits of what they could understand with their “if this, then what?” observation-based experiments.
They needed to see the stagehands behind the curtain: the molecules themselves. But to do so, they had to enlist the expertise of structural chemists, quantum physicists and crystallographers familiar with the techniques to study life at an atomic, or even subatomic, level.
X-ray crystallography — a technique in which molecules are coaxed to crystallize and are then bombarded with X-rays that ricochet off nuclei and barrel through electron orbits in a way that allows scientists to determine their structure — was the first technique to crack the three-dimensional structure of biological molecules such as cholesterol, penicillin and myoglobin.
Nuclear magnetic resonance spectroscopy, which zaps molecules in a magnetic field with radio waves, and electron microscopy, which uses beams of electrons to illuminate the structure of microorganisms, cells and molecules, have delivered behind-the-scenes glimpses at worlds only dreamed of by biologists 100 years ago. But each technique has its limits, and many questions remained unanswered.
One of the newest advances is a type of imaging platform called cryogenic electron microscopy, or cryo-EM. Developers of cryo-EM were awarded the 2017 Nobel Prize in Chemistry, and Stanford’s recent investment in five new cryo-EM machines establishes the university as a top center in the technology. Cryo-EM does more than just identify previously elusive molecules, however. It can also be used for the study of diseases and drug development — precisely what the early proponents of the medical school move had envisioned.
Redefining the medical school, refining molecular research
In the mid-1950s, Stanford University president Wallace Sterling and provost Frederick Terman were campaigning to shake up the medical school. At a time when the fashion was to streamline medical training to train more doctors more quickly, they wanted something that would set Stanford apart: a five-year program that encouraged budding physicians to spend an extra year researching a topic of their choosing.
“Our first principle was that Stanford was going to be a completely research-oriented medical school,” the late Avram Goldstein, MD, recalled in 2000 in a Stanford Medicine article commemorating the 40th anniversary of the move. Goldstein, then-chair of Stanford’s pharmacology department, recruited leading basic scientists and clinical researchers to Stanford. “It was a great challenge — and fun.”
The result, they hoped, would be hybrid physician-scientists well-equipped to merge the fields of clinical care and basic research — research that could lead to medical discoveries. But to do so, the trainees needed laboratories and mentors familiar with more than stethoscopes and scalpels.
In the migration south in 1959 the medical school integrated more closely with the university’s scientific departments and encouraged the crosstalk necessary to spark interdisciplinary collaborations.
It also allowed the school to recruit Arthur Kornberg, MD, and six of his colleagues from Washington University in St. Louis, including Paul Berg, PhD, to establish a new department of biochemistry — the study of the chemistry of life. Kornberg was a top researcher in the burgeoning field. With noted geneticist Joshua Lederberg, PhD, who joined Stanford from the University of Wisconsin to launch a department of genetics, the researchers transformed the medical school.
“I vividly recall our first class,” Berg said in an article about the early days of the biochemistry department. “Sixty students had enrolled, but the room, which seated 120, was jampacked.” Berg would go on to share the 1980 Nobel Prize in Chemistry for his research on the biochemistry of nucleic acids and recombinant DNA.
Stanford has since become a force in merging basic research — looking into and beyond the microscope at the most basic chemical reactions and building blocks of life — and translational medicine — the purposeful effort needed to shepherd findings born on a laboratory bench into the clinic to help patients.
What started as an aspirational new approach to medical training is still evolving in the form of Stanford’s recently launched Innovative Medicines Accelerator and its emerging Future of Life Sciences Initiative, which will enhance collaboration across the university and with the research and technology powerhouses in Silicon Valley and beyond.
The emphasis on raising up the next generation of stellar clinician researchers remains in the form of Stanford’s long-standing Medical Scientist Training Program, which allows students to simultaneously obtain a medical doctorate and a research doctorate in a six- to eight-year period of intense learning.
“Stanford School of Medicine reinvented itself more than six decades ago when it moved to the Palo Alto campus,” said Lloyd Minor, MD, dean of the School of Medicine. Since then, the school has been recognized with eight Nobel Prizes for transformative basic research that has had a direct impact on human health. These new initiatives build upon that strong foundation and extend beyond it to more effectively translate promising discoveries from the laboratory bench to the clinic while also promoting diversity, inclusion and health equity in the medical and research fields and in the communities they serve.”
Lederberg already had his Nobel Prize when he arrived at Stanford in 1959; Kornberg was awarded his in 1959, the year of the move, and Berg received his in 1980. In the subsequent years, Steven Chu, PhD; Andrew Fire, PhD, Brian Kobilka, MD; Roger Kornberg, PhD; Michael Levitt, PhD; and Thomas Südhof, MD, PhD, and would join the ranks of Stanford medical school faculty honored with the prestigious award. Each of these had his own research specialty, but they shared a common theme: the study of molecules.
It’s not always enough just to visualize molecules in never-before-seen detail, however. It’s also important to suss out what the little rascals are up to. Who do they hang out with, and when? What turns them on, or off? How can we distinguish the bad actors from the good? Sometimes it’s necessary to bring more brain power to bear than any one person or laboratory team can muster.
From molecules to medicine
The use of data science to understand basic biology is critical,” said Sylvia Plevritis, PhD, professor of biomedical data science and of radiology and chair of Stanford Medicine’s department of biomedical data science. “Without advances in data sciences, scientists can take months or years to analyze, by hand, the vast amounts of data generated by new biotechnology platforms.
With these advances, we can analyze data we’ve never worked with before and combine data from different platforms at different scales of resolution. And we can start to resolve patterns that can direct future areas of research.”
Stanford Medicine has been a leader in this area since 1982, when it launched a training program in medical information sciences — the first of its kind in the world. The program, which subsequently became the biomedical informatics program, emphasized the nexus among medicine, statistics and computer science and is now part of the Department of Biomedical Data Science, established in 2015.
Plevritis, who also heads Stanford’s Center for Cancer Systems Biology, uses computers to identify drivers in the matrix of signals that control cancer cell survival. Other researchers design algorithms to predict a tumor’s molecular architecture from fragments of DNA circulating in a patient’s blood, or to analyze countless cross sections of tissue from thousands of patients to quickly identify people with nascent cancers.
“We are on the cusp of a time when computers are going to have a massive impact on drug discovery,” said Nathanael Gray, PhD, the Krishnan-Shah Family Professor and professor of chemical and systems biology. “The challenge is figuring out how to design machine-friendly experiments, to enable the computer to understand patterns and relationships our brains can’t fundamentally comprehend.”
But understanding the molecular drivers of cancer or the cell structure in a suspicious growth doesn’t automatically translate to immediate changes in patient care. Sometimes, good ideas born on the lab bench or computer keyboard stumble and die in the face of the daunting amount of funding, expertise and time required to bring those ideas into the clinic.
“Most mere mortals can’t put all the pieces together to go from a basic science observation with a potential disease link to finding a small molecule, characterizing it, proving its safety in animal models, and getting money to fully develop it into a drug that can be tested in clinical trials,” said Gray, who also leads the small-molecule drug discovery program at the Innovative Medicines Accelerator.
The accelerator helps researchers advance basic science discoveries across translational medicine’s “valley of death” — the chasm that yawns between an idea in the lab and the first test of a new drug in people.
The goal is to reduce the time and cost of drug development and to deliver more effective medicines to patients by linking researchers to the technology, resources and expertise necessary to successfully bridge that gap.
A complementary program, SPARK, educates researchers and clinicians on how to work with partners in industry and academia to move projects from bench to bedside and trains students about the ins and outs of launching their own startup companies around promising drugs or discoveries.
“These programs exist to help people along that road. Old-school drug discovery was very phenotype- and organism-based because we didn’t know the molecular details behind diseases. The molecular biology revolution in the mid-1900s spurred the idea of target-based — or molecule-based — therapy, but that can have problems because it is very reductionist,” said Gray.
“Most modern drug discovery programs work from the top down, conducting population-based genetic studies of disease, as well as from the bottom up, thinking about molecular structure and atomic interactions. At Stanford, we have people with expertise at every step of the process.”
Programs like the Innovative Medicines Accelerator and SPARK will be critical components of the Life Sciences Initiative.
“Across the country, academic medical centers are focusing, from the very earliest stage of training, on molecular medicine,” said O’Hara, who is also the director of the Stanford Center for Clinical and Translational Research and Education, or Spectrum.
“Stanford is a preeminent basic science research institute, and this research occurs in clinical as well as across the basic science departments. We are optimally placed to translate promising discoveries into the clinical setting. The potential we’re seeing in fields like cancer immunotherapy, for example, is beyond exciting. I am a cautious person, but I believe we’re observing one of the most fundamental biomedical revolutions in real time.”
Big ideas lead to big change. But sometimes big changes rest on tiny but mighty foundations. Look around. What do you see?